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HK1064391B - Template-fixed peptidomimetics with antimicrobial activity - Google Patents

Template-fixed peptidomimetics with antimicrobial activity Download PDF

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Publication number
HK1064391B
HK1064391B HK04107145.5A HK04107145A HK1064391B HK 1064391 B HK1064391 B HK 1064391B HK 04107145 A HK04107145 A HK 04107145A HK 1064391 B HK1064391 B HK 1064391B
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HK
Hong Kong
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chr
lower alkyl
class
alkenyl
group
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HK04107145.5A
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Chinese (zh)
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HK1064391A1 (en
Inventor
D．奥伯克特
J．A．鲁宾逊
J．W．维布罗德
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波利弗尔有限公司
苏黎士大学
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Priority claimed from PCT/EP2002/001711 external-priority patent/WO2002070547A1/en
Publication of HK1064391A1 publication Critical patent/HK1064391A1/en
Publication of HK1064391B publication Critical patent/HK1064391B/en

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Description

Template-immobilized peptidomimetics with antimicrobial activity
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The present invention provides template-immobilized beta-hairpin peptidomimetics that incorporate 8-16 alpha-amino acid residues or some type of template-immobilized chain as defined later herein, which amino acid residues are Gly or Pro depending on their position in the chain. These template-immobilized beta-hairpin mimetics have broad-spectrum antimicrobial and anticancer activity. Furthermore, the present invention provides an efficient synthetic method by which these compounds can be prepared in a parallel procedural library-format (parallelibrary-format) if desired. These β -hairpin peptidomimetics show improved efficacy, bioavailability, half-life, on the other hand most importantly a significantly improved ratio between antimicrobial and anticancer activity, and on the other hand hemolyzed erythrocytes.
The increasing problem of microbial resistance to existing antibiotics has generated a great deal of interest in the development of new antimicrobial agents with novel modes of action (H.Breithaupt, nat. Biotechnol.1999, 17, 1165-. A new class of antibiotics is based on naturally occurring cationic peptides (T.Ganz, R.I.Lehrer, mol.medicine Today 1999, 5, 292-. These include disulfide-bridged β -hairpin and β -sheet peptides (e.g., protegrins [ V.N.. M.; O.V.Shamova, H.A.Korneva, R.I.Lehrer, FEBS Lett.1993, 327, 231. loop 236], tachyphylesins [ T.Nakamura, H.Furunaka, T.Miyata, F.Tokunaga, T.Muta, S.Iwana, M.Niwa, T.Takao, Y.Shimonishi, Y.J.biol.Chem.1988, 263, 16709. 16713] and defensens [ R.I.Lehrer, A.K.Lichtenin, T.Ganz, Imnu.Rev.128, 1993, 11, 105, α -helix peptides (e.g., amphipathic peptides, A.K.Lichtensin, T.Ganz., Imnu.Rev.128. 128. peptides, 11, 105. alpha-helix peptides (e.peptides, amphipathic peptides, E.S.H.S.I.Lehrer., FEBS Lett.1993, 327, 231. loop 236), T.S.I.I.I.S. peptide, S. 11, S. Biophynagensis, T.S.S.S. 31, T.S.S.S.S.S.S.S.A.S.S.S.A.S.S.S.S.S.S.S.S.S.S.S.S.S.A. A. A.S. 11, E.S.S. A. A.S. A.S.S. Biophynesis, S. 11, S.S., more complex mechanisms of action, including, for example, receptor-mediated signaling, are currently not excluded (M.Wu, E.Maier, R.Benz, R.E.Hancock, Biochemistry 1999, 38, 7235-.
The antimicrobial activity of a large number of these cationic peptides is often associated with their preferred secondary structures, which are observable in aqueous solutions or membranous environments (n.sitaram, r.nagaraj, biochim.biophysis.acta 1999, 1462, 29-54). Structural studies by Nuclear Magnetic Resonance (NMR) spectroscopy show that cationic peptides such as protegrin 1(a. aumelas, m. mangoni, c. roumesand, l. chiche, e.despaux, g.grassy, b.calas, a.chananieu, a.eur.j.biochem.1996, 237, 575-583; r.l.fahrner, t.dieckmann, s.s.l.harwig, r.i.lehrer, d.eisenberg, j.feigon, j.chem.biol.1996, 3, 543-and tachplesin I (k.kawano, t.yoneya, t.miyata, k.yoshiwa, f.tokuna aga, y.teua, s.ij, s.iwanj.1990, 15365. beta. disulfide bridges are well defined because of the two disulfide bridges. In protegrin analogs lacking one or two of these disulfide bonds, the stability of the β -hairpin configuration is reduced and antimicrobial activity is reduced (J.Chen, T.J.Falla, H.J.Liu, M.A.Hurst, C.A.Fujii, D.A.Mosca, J.R.Embreed.J.Loury, P.A.Radel, C.C.Chang, L.Gu, J.C.Fildes, Biopolymers2000, 55, 88-98; S.L.Harwing, A.Waring, H.J.Yang, Y.Cho, L.Tan, R.I.Lehrer, R.J.Eur.J.J.J.1996, 240, 352- -357, M.E.goniMan, A.aurlas, P.Aurentz, C.Charnakusen, Roche, Bubugs.J.J.J.J.J.J.J.J.J.J.J.J.1996, 240, 352-. Similar observations have been made in analogues of tachplesin I (h. tamamamura, r. ikoma, m. niwa, s. funakoshi, t. murakami, n. fujii, Chem, pharm. bull.1993, 41, 978-. These results show that the β -hairpin structure plays an important role in the antimicrobial activity and stability of these protegrin-like peptides. In the case of cationic peptides, preferably alpha-helical structures, the amphipathic structure of the helix appears to play a key role in determining antimicrobial activity (a.tossi, l.sandri, a.gianga roller, a.biopolymers 2000, 55, 4-30). Gramicidin S is a backbone-cyclic peptide with a well-defined β -hairpin structure (s.e. hill, r.karlsson, p.main, m.m.woolfson, e.j.dodson, Nature 1978, 275, 206-. However, the high hemolytic activity of these gramicidin S prevents its widespread use as an antibiotic. Recent structural studies by NMR show that high hemolytic activity is apparently related to the highly amphiphilic properties of the cyclic β -hairpin-like molecule, but that antimicrobial and hemolytic activity can be separated by modulating the conformation and amphiphilicity (l.h.kondejewski, m.jelokhani-Niaraki, s.w.farmer, b.lix, m.kay, b.d.sykes, r.e.cohanck, r.s.hodes, j.biol.chem.1999, 274, 13181-shot 13192; c.mcinnes l.h.kondejewski, r.s.hodges, b.d.sys, j.biol.chem.2000, 275, 14287-shot 14294).
Recently, a novel cyclic antimicrobial peptide RTD-1 from white blood cells of primates was reported (Y. -Q. Tang., J. Yuan, G. _ sapay, K. _ sapay, D. tran, C.J. Miller, A.J. Oellette, M.E.Selsted, Science 1999, 286, 498-. This peptide contains 3 disulfide bridges which act to make the cyclic peptide backbone a hairpin geometry. Cleavage of these 3 disulfide bonds results in a significant loss of antimicrobial activity. Analogs of protegrins (J.P.Tam, C.Wu, J. -L.Yang, Eur.J.Biochem.2000, 267, 3289-. In these cases, removal of all cystine restrictions does not always result in a substantial loss of antimicrobial activity, but does modulate the selectivity of membrane lysis (J.P.Tam, C.Wu, J. -L.Yang, Eur.J.biochem.2000, 267, 3289-.
One key issue in designing new cationic antimicrobial peptides is selectivity. Naturally occurring protegrins and tacchyplesins produce significant hemolytic activity on human erythrocytes. This is also the case for protegrin analogues such as IB367 (J.Chen, T.J.Falla, H.J.Liu, M.A.Hurst, C.A.Fujii, D.A.Mosca, J.R.Embree, D.J.Loury, P.A.Radel, C.C.Chang, L.Gu, J.C.Fi ddes, Biopolymers 2000, 55, 88-98; C.Chang, L.Gu, J.Chen, U.S. Pat: 5,916,872, 1999). This high hemolytic activity has mainly limited its use in vivo and presents serious drawbacks in clinical applications. Also, the antimicrobial activity of the analogs often decreases significantly with increasing salt concentration, such that under in vivo conditions (about 100-. Before intravenous use can be considered, routine toxicity, protein adhesion activity in serum, and protease stability become serious problems that must be properly solved.
Protegrin1 exhibited potent and similar antimicrobial activity against both gram positive and gram negative bacteria and fungi in both the low salt and high salt tests. This broad spectrum antimicrobial activity and the rapid mode of action and their ability to kill bacteria against other classes of antibiotics make them attractive targets for the development of clinically useful antibiotics. Antimicrobial activity against gram-positive bacteria is typically higher than antimicrobial activity against gram-negative bacteria. However, protegrin1 also exhibits high hemolytic activity to human erythrocytes and thus low selectivity for microbial cells. Oriented CD experiments (W.T.Heller, A.J.Waring, R.I.Lehrer, H.W.Huang, Biochemistry 1998, 37, 17331-17338) demonstrated that protegrin1 can be present in two different states upon interaction with membranes, and that these states are greatly influenced by lipid composition. The study of cyclic protegrin analogues (J. -P.Tam, C.Wu, J. -L.Yang, Eur.J.biochem.2000, 267, 3289-3300) demonstrated that, at least in a series of compounds studied, increasing conformational rigidity, leading to backbone cyclization and multiple disulfide bridges, can confer membrane deselection, which separates antimicrobial activity from hemolytic activity.
Protegrin 1 is an 18-residue linear peptide with an amidated carboxy terminus and two disulfide bridges. Tachplesin I contains 17 residues, also has an amidated carboxy terminus and contains two disulfide bridges. Recently described backbone-cyclic protegrin and tachplysin analogs typically contain 18 residues and up to 3 disulfide bridges (J.P.Tam, C.Wu, J.L.Yang, Eur.J.biochem.2000, 267, 3289-.
Cathelicidin, a 37-residue linear helix-type cationic peptide and analogs thereof, is currently being investigated as an inhalation therapeutic for Cystic Fibrosis (CF) lung disease (L.Saiman, S.Tabibi, T.D.Starner, P.san Gabriel, P.L.Winokur, H.P.Jia, P.B.McGray, Jr., B.F.tack, Antimicrob.Agents and Chemothers.2001, 45, 2838-2844; R.E.W.Hancock, R.Lehrer, trends Biotechnol.1998, 16, 82-88). More than 80% of CF patients suffer from chronic infection with Pseudomonas aeruginosa (C.A. Demko, P.J. Biard, P.B. Davies, J.Clin.epidemiol.1995, 48, 1041-.
Furthermore, evidence from the literature indicates that some cationic peptides exhibit interesting anticancer activity. Cerecropn B, a 35-residue α -helical cationic Peptide isolated from blood and lymph of Bombycis mori, a shorter analog from Cerecropn B has been studied as a potential anticancer compound (A.J. Moore, D.A. Devine, M.C. Bibby, Peptide Research 1994, 7, 265) -269).
In the compounds described below, a novel technique is introduced to stabilize the β -hairpin configuration of backbone-cyclic cationic peptidomimetics which exhibit antimicrobial and anticancer activity. This involves grafting cationic and hydrophobic hairpin sequences onto a template, whose function is to bring the peptide loop backbone into a hairpin geometry. The stiffness of the hairpin is also affected by the introduction of disulfide bridges. The template moiety may also serve as a point of attachment for other organic groups, which may modulate the antimicrobial and/or membrane lytic target selectivity of the molecule, and may be used to produce dimers in which the templates in each monomeric unit are linked by short spacers or linkers. Template-linked hairpin mimetics (D, Obrecht, M.Altorfer, J.A.Robinson, adv.Med.Chem.1999, 4, 1-68; J.A.Robinson, Syn.Lett.2000, 4, 429-441) are described in the literature, but these molecules have not previously been evaluated for the development of antimicrobial peptides. However, the ability to produce β -hairpin peptidomimetics using combinatorial and parallel synthetic methods is now established (L.Jiang, K.Moehle, B.Dhanapaal, D.Obrecht, J.A.Rob inson, Helv.Chim.acta.2000, 83, 3097-.
These methods enable the synthesis and screening of large hairpin mimetic libraries, which in turn greatly facilitates structure-activity studies, and thus the discovery of new molecules with potent antimicrobial and anticancer activity and low hemolytic activity towards human erythrocytes. Furthermore, this protocol enables the synthesis of β -hairpin peptidomimetics with novel selectivity against different types of pathogens, for example against various strains of Pseudomonas resistant to various drugs. The β -hairpin peptidomimetics obtained by this method can be used in other fields, for example as broad-spectrum antibiotics, as therapeutic agents for cystic fibrosis lung diseases and anticancer agents.
The beta-hairpin peptidomimetics of the invention and the pharmaceutically acceptable salts thereof are compounds of the general formula
And
wherein
Is one of the groups of the formula
Wherein
Is B is of the formula-NR20CH(R71) -or a residue of an L- α -amino acid of a residue of an enantiomer of one of the groups a1-a69 as defined herein after;
is one of the following groups
R1Is H; lower alkyl or aryl-lower alkyl;
R2is H; an alkyl group; an alkenyl group; - (CH)2)m(CHR61)sOR55；
-(CH2)m(CHR61)sSR56；-(CH2)m(CHR61)sNR33R34；
-(CH2)m(CHR61)sOCONR33R75；-(CH2)m(CHR61)sNR20CONR33R82；
-(CH2)o(CHR61)sCOOR57；-(CH2)o(CHR61)sCONR58R59；
-(CH2)o(CHR61)sPO(OR60)2；-(CH2)o(CHR61)sSO2R62Or
-(CH2)o(CHR61)sC6H4R8；
R3Is H; an alkyl group; an alkenyl group; - (CH)2)m(CHR61)sOR55；
-(CH2)m(CHR61)sSR56；-(CH2)m(CHR61)sNR33R34；
-(CH2)m(CHR61)sOCONR33R75；-(CH2)m(CHR61)sNR20CONR33R82；
-(CH2)o(CHR61)sCOOR57；-(CH2)o(CHR61)sCONR58R59；
-(CH2)o(CHR61)sPO(OR60)2；-(CH2)o(CHR61)sSO2R62Or
-(CH2)o(CHR61)sC6H4R8；
R4Is H; an alkyl group; an alkenyl group; - (CH)2)m(CHR61)sOR55；
-(CH2)m(CHR61)sSR56；-(CH2)m(CHR61)sNR33R34；
-(CH2)m(CHR61)sOCONR33R75；-(CH2)m(CHR61)sNR20CONR33R82；
-(CH2)p(CHR61)sCOOR57；-(CH2)p(CHR61)sCONR58R59；
-(CH2)p(CHR61)sPO(OR60)2；-(CH2)p(CHR61)sSO2R62Or
-(CH2)o(CHR61)sC6H4R8；
R5Is an alkyl group; an alkenyl group; - (CH)2)o(CHR61)sOR55；
-(CH2)o(CHR61)sSR56；-(CH2)o(CHR61)sNR33R34；
-(CH2)o(CHR61)sOCONR33R75；-(CH2)o(CHR61)sNR20CONR33R82；
-(CH2)o(CHR61)sCOOR57；-(CH2)o(CHR61)sCONR58R59；
-(CH2)o(CHR61)sPO(OR60)2；-(CH2)o(CHR61)sSO2R62Or
-(CH2)o(CHR61)sC6H4R8；
R6Is H; an alkyl group; an alkenyl group; - (CH) 2)o(CHR61)sOR55；
-(CH2)o(CHR61)sSR56；-(CH2)o(CHR61)sNR33R34；
-(CH2)o(CHR61)sOCONR33R75；-(CH2)o(CHR61)sNR20CONR33R82；
-(CH2)o(CHR61)sCOOR57；-(CH2)o(CHR61)sCONR58R59；
-(CH2)o(CHR61)sPO(OR60)2；-(CH2)o(CHR61)sSO2R62Or
-(CH2)o(CHR61)sC6H4R8；
R7Is an alkyl group; an alkenyl group; - (CH)2)q(CHR61)sOR55；
-(CH2)q(CHR61)sNR33R34；-(CH2)q(CHR61)sOCONR33R75；
-(CH2)q(CHR61)sNR20CONR33R82；-(CH2)r(CHR61)sCOOR57；
-(CH2)r(CHR61)sCONR58R59；-(CH2)r(CHR61)sPO(OR60)2；
-(CH2)r(CHR61)sSO2R62Or- (CH)2)r(CHR61)sC6H4R8；
R8Is H; cl; f; CF (compact flash)3；NO2(ii) a A lower alkyl group; a lower alkenyl group; an aryl group; aryl-lower alkyl; - (CH2)o(CHR61)sOR55；-(CH2)o(CHR61)sSR56；
-(CH2)o(CHR61)NR33R34；-(CH2)o(CHR61)sOCONR33R75；
-(CH2)o(CHR61)sNR20CONR33R82；-(CH2)o(CHR61)sCOOR57；
-(CH2)o(CHR61)sCONR58R59；-(CH2)o(CHR61)sPO(OR60)2；
-(CH2)o(CHR61)sSO2R62Or- (CH)2)o(CHR61)sCOR64；
R9Is an alkyl group; an alkenyl group; - (CH)2)o(CHR61)sOR55；
-(CH2)o(CHR61)sSR56；-(CH2)o(CHR61)sNR33R34；
-(CH2)o(CHR61)sOCONR33R75；-(CH2)o(CHR61)sNR20CONR33R82；
-(CH2)o(CHR61)sCOOR57；-(CH2)o(CHR61)sCONR58R59；
-(CH2)o(CHR61)sPO(OR60)2；-(CH2)o(CHR61)sSO2R62Or
-(CH2)o(CHR61)sC6H4R8；
R10Is an alkyl group; an alkenyl group; - (CH)2)o(CHR61)sOR55；
-(CH2)o(CHR61)sSR56；-(CH2)o(CHR61)sNR33R34；
-(CH2)o(CHR61)sOCONR33R75；-(CH2)o(CHR61)sNR20CONR33R82；
-(CH2)o(CHR61)sCOOR57；-(CH2)o(CHR61)sCONR58R59；
-(CH2)o(CHR61)sPO(OR60)2；-(CH2)o(CHR61)sSO2R62Or
-(CH2)o(CHR61)sC6H4R8；
R11Is H; an alkyl group; an alkenyl group; - (CH)2)m(CHR61)sOR55；
-(CH2)m(CHR61)sNR33R34；-(CH2)m(CHR61)sOCONR33R75；
-(CH2)m(CHR61)sNR20CONR33R82；-(CH2)o(CHR61)sCOOR57；
-(CH2)o(CHR61)sCONR58R59；-(CH2)o(CHR61)sPO(OR60)2；
-(CH2)o(CHR61)sSO2R62Or- (CH)2)o(CHR61)sC6H4R8；
R12Is H; an alkyl group; an alkenyl group; - (CH)2)m(CHR61)sOR55；
-(CH2)m(CHR61)sSR56；-(CH2)m(CHR61)sNR33R34；
-(CH2)m(CHR61)sOCONR33R75；-(CH2)m(CHR61)sNR20CONR33R82；
-(CH2)r(CHR61)sCOOR57；-(CH2)r(CHR61)sCONR58R59；
-(CH2)r(CHR61)sPO(OR60)2；-(CH2)r(CHR61)sSO2R62Or
-(CH2)r(CHR61)sC6H4R8；
R13Is an alkyl group; an alkenyl group; - (CH)2)q(CHR61)sOR55；
-(CH2)q(CHR61)sSR56；-(CH2)q(CHR61)sNR33R34；
-(CH2)q(CHR61)sOCONR33R75；-(CH2)q(CHR61)sNR20CONR33R82；
-(CH2)q(CHR61)sCOOR57；-(CH2)q(CHR61)sCONR58R59；
-(CH2)q(CHR61)sPO(OR60)2；-(CH2)q(CHR61)sSO2R62Or
-(CH2)q(CHR61)sC6H4R8；
R14Is H; an alkyl group; an alkenyl group; - (CH)2)m(CHR60)sOR55；
-(CH2)m(CHR61)sNR33R34；-(CH2)m(CHR61)sOCONR33R75；
-(CH2)m(CHR61)sNR20CONR33R82；-(CH2)q(CHR61)sCOOR57；
-(CH2)q(CHR61)sCONR58R59；-(CH2)q(CHR61)sPO(OR60)2；
-(CH2)q(CHR61)sSOR62Or- (CH)2)q(CHR61)sC6H4R8；
R15Is an alkyl group; an alkenyl group; - (CH)2)o(CHR61)sOR55；
-(CH2)o(CHR61)sSR56；-(CH2)o(CHR61)sNR33R34；
-(CH2)o(CHR61)sOCONR33R75；-(CH2)o(CHR61)sNR20CONR33R82；
-(CH2)o(CHR61)sCOOR57；-(CH2)o(CHR61)sCONR58R59；
-(CH2)o(CHR61)sPO(OR60)2；-(CH2)o(CHR61)sSO2R62Or
-(CH2)o(CHR61)sC6H4R8；
R16Is an alkyl group; an alkenyl group; - (CH)2)o(CHR61)sOR55；
-(CH2)o(CHR61)sSR56；-(CH2)o(CHR61)sNR33R34；
-(CH2)o(CHR61)sOCONR33R75；-(CH2)o(CHR61)sNR20CONR33R82；
-(CH2)o(CHR61)sCOOR57；-(CH2)o(CHR61)sCONR58R59；
-(CH2)o(CHR61)sPO(OR60)2；-(CH2)o(CHR61)sSO2R62Or
-(CH2)o(CHR61)sC6H4R8；
R17Is an alkyl group; an alkenyl group; - (CH)2)q(CHR61)sOR55；
-(CH2)q(CHR61)sSR56；-(CH2)q(CHR61)sNR33R34；
-(CH2)q(CHR61)sOCONR33R75；-(CH2)q(CHR61)sNR20CONR33R82；
-(CH2)q(CHR61)sCOOR57；-(CH2)q(CHR61)sCONR58R59；
-(CH2)q(CHR61)sPO(OR60)2；-(CH2)q(CHR61)sSO2R62Or
-(CH2)q(CHR61)sC6H4R8；
R18Is an alkyl group; an alkenyl group; - (CH)2)p(CHR61)sOR55；
-(CH2)p(CHR61)sSR56；-(CH2)p(CHR61)sNR33R34；
-(CH2)p(CHR61)sOCONR33R75；-(CH2)p(CHR61)sNR20CONR33R82；
-(CH2)p(CHR61)sCOOR57；-(CH2)p(CHR61)sCONR58R59；
-(CH2)p(CHR61)sPO(OR60)2；-(CH2)p(CHR61)sSO2R62Or
-(CH2)o(CHR61)sC6H4R8；
R19Is a lower alkyl group; - (CH)2)p(CHR61)sOR55；-(CH2)p(CHR61)sSR56；
-(CH2)p(CHR61)sNR33R34；-(CH2)p(CHR61)sOCONR33R75；
-(CH2)p(CHR61)sNR20CONR33R82；-(CH2)p(CHR61)sCOOR57；
-(CH2)p(CHR61)sCONR58R59；-(CH2)p(CHR61)sPO(OR60)2；
-(CH2)p(CHR61)sSO2R62Or- (CH)2)o(CHR61)sC6H4R8Or
R18And R19Together may form: - (CH)2)2-6-；-(CH2)2O(CH2)2-；
-(CH2)2S(CH2)2-or- (CH)2)2NR57(CH2)2-；
R20Is H; an alkyl group; alkenyl or aryl-lower alkyl;
R21is H; an alkyl group; an alkenyl group; - (CH)2)o(CHR61)sOR55；
-(CH2)o(CHR61)sSR56；-(CH2)o(CHR61)sNR33R34；
-(CH2)o(CHR61)sOCONR33R75；-(CH2)o(CHR61)sNR20CONR33R82；
-(CH2)o(CHR61)sCOOR57；-(CH2)o(CHR61)sCONR58R59；
-(CH2)o(CHR61)sPO(OR60)2；-(CH2)o(CHR61)sSO2R62Or
-(CH2)o(CHR61)sC6H4R8；
R22Is H; an alkyl group; an alkenyl group; - (CH)2)o(CHR61)sOR55；
-(CH2)o(CHR61)sSR56；-(CH2)o(CHR61)sNR33R34；
-(CH2)o(CHR61)sOCONR33R75；-(CH2)o(CHR61)sNR20CONR33R82；
-(CH2)o(CHR61)sCOOR57；-(CH2)o(CHR61)sCONR58R59；
-(CH2)o(CHR61)sPO(OR60)2；-(CH2)o(CHR61)sSO2R62Or
-(CH2)o(CHR61)sC6H4R8；
R23Is an alkyl group; an alkenyl group; - (CH)2)o(CHR61)sOR55；
-(CH2)o(CHR61)sSR56；-(CH2)o(CHR61)sNR33R34；
-(CH2)o(CHR61)sOCONR33R75；-(CH2)o(CHR61)sNR20CONR33R82；
-(CH2)o(CHR61)sCOOR57；-(CH2)o(CHR61)sCONR58R59；
-(CH2)o(CHR61)sPO(OR60)2；-(CH2)o(CHR61)sSO2R62Or
-(CH2)o(CHR61)sC6H4R8；
R24Is an alkyl group; an alkenyl group; - (CH)2)o(CHR61)sOR55；
-(CH2)o(CHR61)sSR56；-(CH2)o(CHR61)sNR33R34；
-(CH2)o(CHR61)sOCONR33R75；-(CH2)o(CHR61)sNR20CONR33R82；
-(CH2)o(CHR61)sCOOR57；-(CH2)o(CHR61)sCONR58R59；
-(CH2)o(CHR61)sPO(OR60)2；-(CH2)o(CHR61)sSO2R62Or
-(CH2)o(CHR61)sC6H4R8；
R25Is H; an alkyl group; an alkenyl group; - (CH)2)m(CHR61)sOR55；
-(CH2)m(CHR61)sSR56；-(CH2)m(CHR61)sNR33R34；
-(CH2)m(CHR61)sOCONR33R75；-(CH2)m(CHR61)sNR20CONR33R82；
-(CH2)o(CHR61)sCOOR57；-(CH2)o(CHR61)sCONR58R59；
-(CH2)o(CHR61)sPO(OR60)2；-(CH2)o(CHR61)sSO2R62Or
-(CH2)o(CHR61)sC6H4R8；
R26Is H; an alkyl group; an alkenyl group; - (CH)2)m(CHR61)sOR55；
-(CH2)m(CHR61)sSR56；-(CH2)m(CHR61)sNR33R34；
-(CH2)m(CHR61)sOCONR33R75；-(CH2)m(CHR61)sNR20CONR33R82；
-(CH2)o(CHR61)sCOOR57；-(CH2)o(CHR61)sCONR58R59；
-(CH2)o(CHR61)sPO(OR60)2；-(CH2)o(CHR61)sSO2R62Or
-(CH2)o(CHR61)sC6H4R8Or
R25And R26Together may form: - (CH)2)2-6-；-(CH2)rO(CH2)r-；
-(CH2)rS(CH2)r-or- (CH)2)rNR57(CH2)r-；
R27Is H; an alkyl group; an alkenyl group; - (CH)2)o(CHR61)sOR55；
-(CH2)o(CHR61)sSR56；-(CH2)o(CHR61)sNR33R34；
-(CH2)o(CHR61)sCOOR57；-(CH2)o(CHR61)sCONR58R59；
-(CH2)o(CHR61)sOCONR33R75；-(CH2)o(CHR61)sNR20CONR33R82；
-(CH2)o(CHR61)sPO(OR60)2；-(CH2)o(CHR61)sSO2R62Or
-(CH2)o(CHR61)sC6H4R8；
R28Is an alkyl group; an alkenyl group; - (CH)2)o(CHR61)s-OR55；
-(CH2)o(CHR61)sSR56；-(CH2)o(CHR61)sNR33R34；
-(CH2)o(CHR61)sOCONR33R75；-(CH2)o(CHR61)sNR20CONR33R82；
-(CH2)o(CHR61)sCOOR57；-(CH2)o(CHR61)sCONR58R59；
-(CH2)o(CHR61)sPO(OR60)2；-(CH2)o(CHR61)sSO2R62Or
-(CH2)o(CHR61)sC6H4R8；
R29Is an alkyl group; an alkenyl group; - (CH)2)o(CHR61)sOR55；
-(CH2)o(CHR61)sSR56；-(CH2)o(CHR61)sNR33R34；
-(CH2)o(CHR61)sOCONR33R75；-(CH2)o(CHR61)sNR20CONR33R82；
-(CH2)o(CHR61)sCOOR57；-(CH2)o(CHR61)sCONR58R59；
-(CH2)o(CHR61)sPO(OR60)2；-(CH2)o(CHR61)sSO2R62Or
-(CH2)o(CHR61)sC6H4R8；
R30Is H; an alkyl group; alkenyl or aryl-lower alkyl;
R31Is H; an alkyl group; an alkenyl group; - (CH)2)p(CHR61)sOR55；
-(CH2)p(CHR61)sNR33R34；-(CH2)p(CHR61)sOCONR33R75；
-(CH2)p(CHR61)sNR20CONR33R82；-(CH2)o(CHR61)sCOOR57；
-(CH2)o(CHR61)sCONR58R59；-(CH2)o(CHR61)sPO(OR60)2；
-(CH2)o(CHR61)sSO2R62Or- (CH)2)o(CHR61)sC6H4R8；
R32Is H; lower alkyl or aryl-lower alkyl;
R33is H; alkyl, alkenyl; - (CH)2)m(CHR61)sOR55；
-(CH2)m(CHR61)sNR34R63；-(CH2)m(CHR61)sOCONR75R82；
-(CH2)m(CHR61)sNR20CONR78R82；-(CH2)o(CHR61)sCOR64；
-(CH2)o(CHR61)s-CONR58R59，-(CH2)o(CHR61)sPO(OR60)2；
-(CH2)o(CHR61)sSO2R62Or- (CH)2)o(CHR61)sC6H4R8；
R34Is H; a lower alkyl group; aryl or aryl-lower alkyl;
R33and R34Together may form: - (CH)2)2-6-；-(CH2)2O(CH2)2-；
-(CH2)2S(CH2)2-or- (CH)2)2NR57(CH2)2-；
R35Is H; an alkyl group; an alkenyl group; - (CH)2)m(CHR61)sOR55；
-(CH2)m(CHR61)sNR33R34；-(CH2)m(CHR61)sOCONR33R75；
-(CH2)m(CHR61)sNR20CONR33R82；-(CH2)p(CHR61)sCOOR57；
-(CH2)p(CHR61)sCONR58R59；-(CH2)p(CHR61)sPO(OR60)2；
-(CH2)p(CHR61)sSO2R62Or- (CH)2)p(CHR61)sC6H4R8；
R36Is H, alkyl; an alkenyl group; - (CH)2)o(CHR61)sOR55；
-(CH2)p(CHR61)sNR33R34；-(CH2)p(CHR61)sOCONR33R75；
-(CH2)p(CHR61)sNR20CONR33R82；-(CH2)p(CHR61)sCOOR57；
-(CH2)p(CHR61)sCONR58R59；-(CH2)p(CHR61)sPO(OR60)2；
-(CH2)p(CHR61)sSO2R62Or- (CH)2)o(CHR61)sC6H4R8；
R37Is H; f; br; cl; NO2；CF3(ii) a A lower alkyl group;
-(CH2)p(CHR61)sOR55；-(CH2)p(CHR61)sNR33R34；
-(CH2)p(CHR61)sOCONR33R75；-(CH2)p(CHR61)sNR20CONR33R82；
-(CH2)o(CHR61)sCOOR57；-(CH2)o(CHR61)sCONR58R59；
-(CH2)o(CHR61)sPO(OR60)2；-(CH2)o(CHR61)sSO2R62or
-(CH2)o(CHR61)sC6H4R8；
R38Is H; f; br; cl; NO2；CF3(ii) a An alkyl group; an alkenyl group;
-(CH2)p(CHR61)sOR55；-(CH2)p(CHR61)sNR33R34；
-(CH2)p(CHR61)sOCONR33R75；-(CH2)p(CHR61)sNR20CONR33R82；
-(CH2)o(CHR61)sCOOR57；-(CH2)o(CHR61)sCONR58R59；
-(CH2)o(CHR61)sPO(OR60)2；-(CH2)o(CHR61)sSO2R62or
-(CH2)o(CHR61)sC6H4R8；
R39Is H; an alkyl group; chainAlkenyl or aryl-lower alkyl;
R40is H; an alkyl group; alkenyl or aryl-lower alkyl;
R41is H; f; br; cl; NO2；CF3(ii) a An alkyl group; an alkenyl group;
-(CH2)p(CHR61)sOR55；-(CH2)p(CHR61)sNR33R34；
-(CH2)p(CHR61)sOCONR33R75；-(CH2)p(CHR61)sNR20CONR33R82；
-(CH2)o(CHR61)sCOOR57；-(CH2)o(CHR61)sCONR58R59；
-(CH2)o(CHR61)sPO(OR60)2；-(CH2)o(CHR61)sSO2R62or
-(CH2)o(CHR61)sC6H4R8；
R42Is H; f; br; cl; NO2；CF3(ii) a An alkyl group; an alkenyl group;
-(CH2)p(CHR61)sOR55；-(CH2)p(CHR61)sNR33R34；
-(CH2)p(CHR61)sOCONR33R75；-(CH2)p(CHR61)sNR20CONR33R82；
-(CH2)o(CHR61)sCOOR57；-(CH2)o(CHR61)sCONR58R59；
-(CH2)o(CHR61)sPO(OR60)2；-(CH2)o(CHR61)sSO2R62or
-(CH2)o(CHR61)sC6H4R8；
R43Is H; an alkyl group; an alkenyl group; - (CH)2)m(CHR61)sOR55；
-(CH2)m(CHR61)sNR33R34；-(CH2)m(CHR61)sOCONR33R75；
-(CH2)m(CHR61)sNR20CONR33R82；-(CH2)o(CHR61)sCOOR57；
-(CH2)o(CHR61)sCONR58R59；-(CH2)o(CHR61)sPO(OR60)2；
-(CH2)o(CHR61)sSO2R62Or- (CH)2)o(CHR61)sC6H4R8；
R44Is an alkyl group; an alkenyl group; - (CH)2)r(CHR61)sOR55；
-(CH2)r(CHR61)sSR56；-(CH2)r(CHR61)sNR33R34；
-(CH2)r(CHR61)sOCONR33R75；-(CH2)r(CHR61)sNR20CONR33R82；
-(CH2)r(CHR61)sCOOR57；-(CH2)r(CHR61)sCONR58R59；
-(CH2)r(CHR61)sPO(OR60)2；-(CH2)r(CHR61)sSO2R62Or
-(CH2)r(CHR61)sC6H4R8；
R45Is H; an alkyl group; an alkenyl group; - (CH)2)o(CHR61)sOR55；
-(CH2)o(CHR61)sSR56；-(CH2)o(CHR61)sNR33R34；
-(CH2)o(CHR61)sOCONR33R75；-(CH2)o(CHR61)sNR20CONR33R82；
-(CH2)o(CHR61)sCOOR57；-(CH2)s(CHR61)sCONR58R59；
-(CH2)s(CHR61)sPO(OR60)2；-(CH2)s(CHR61)sSO2R62Or
-(CH2)s(CHR61)sC6H4R8；
R46Is H; an alkyl group; alkenyl or- (CH)2)o(CHR61)pC6H4R8；
R47Is H; an alkyl group; alkenyl or- (CH)2)o(CHR61)sOR55；
R48Is H; a lower alkyl group; lower alkenyl or aryl-lower alkyl;
R49is H; an alkyl group; an alkenyl group; - (CHR)61)sCOOR57；
(CHR61)sCONR58R59；(CHR61)sPO(OR60)2；-(CHR61)sSOR62Or- (CHR)61)sC6H4R8；
R50Is H; lower alkyl or aryl-lower alkyl;
R51is H; an alkyl group; an alkenyl group; - (CH)2)m(CHR61)sOR55；
-(CH2)m(CHR61)sSR56；-(CH2)m(CHR61)sNR33R34；
-(CH2)m(CHR61)sOCONR33R75；-(CH2)m(CHR61)sNR20CONR33R82；
-(CH2)o(CHR61)sCOOR57；-(CH2)o(CHR61)sCONR58R59；
-(CH2)o(CHR61)pPO(OR60)2；-(CH2)p(CHR61)sSO2R62Or
-(CH2)p(CHR61)sC6H4R8；
R52Is H; an alkyl group; an alkenyl group; - (CH)2)m(CHR61)sOR55；
-(CH2)m(CHR61)sSR56；-(CH2)m(CHR61)sNR33R34；
-(CH2)m(CHR61)sOCONR33R75；-(CH2)m(CHR61)sNR20CONR33R82；
-(CH2)o(CHR61)sCOOR57；-(CH2)o(CHR61)sCONR58R59；
-(CH2)o(CHR61)pPO(OR60)2；-(CH2)p(CHR61)sSO2R62Or
-(CH2)p(CHR61)sC6H4R8；
R53Is H; an alkyl group; an alkenyl group; - (CH) 2)m(CHR61)sOR55；
-(CH2)m(CHR61)sSR56；-(CH2)m(CHR61)sNR33R34；
-(CH2)m(CHR61)sOCONR33R75；-(CH2)m(CHR61)sNR20CONR33R82；
-(CH2)o(CHR61)sCOOR57；-(CH2)o(CHR61)sCONR58R59；
-(CH2)o(CHR61)pPO(OR60)2；-(CH2)p(CHR61)sSO2R62Or
-(CH2)p(CHR61)sC6H4R8；
R57Is H; an alkyl group; an alkenyl group; - (CH)2)m(CHR61)sOR55；
-(CH2)m(CHR61)sNR33R34；-(CH2)m(CHR61)sOCONR33R75；
-(CH2)m(CHR61)sNR20CONR33R82；-(CH2)o(CHR61)COOR57；
-(CH2)o(CHR61)sCONR58R59Or- (CH)2)o(CHR61)sC6H4R8；
R55Is H; a lower alkyl group; a lower alkenyl group; aryl-lower alkyl;
-(CH2)m(CHR61)sOR57；-(CH2)m(CHR61)sNR34R63；
-(CH2)m(CHR61)sOCONR75R82；-(CH2)m(CHR61)sNR20CONR78R82；
-(CH2)o(CHR61)s-COR64；-(CH2)o(CHR61)COOR57or
-(CH2)o(CHR61)sCONR58R59；
R56Is H; a lower alkyl group; a lower alkenyl group; aryl-lower alkyl;
-(CH2)m(CHR61)sOR57；-(CH2)m(CHR61)sNR34R63；
-(CH2)m(CHR61)sOCONR75R82；-(CH2)m(CHR61)sNR20CONR78R82；
-(CH2)o(CHR61)s-COR64or- (CH)2)o(CHR61)sCONR58R59；
R57Is H; a lower alkyl group; a lower alkenyl group; aryl-lower alkyl or heteroaryl-lower alkyl;
R58is H; a lower alkyl group; a lower alkenyl group; an aryl group; a heteroaryl group; aryl-lower alkyl or heteroaryl-lower alkyl;
R59is H; a lower alkyl group; a lower alkenyl group; an aryl group; a heteroaryl group; aryl-lower alkyl or heteroAryl-lower alkyl or
R58And R59Together may form: - (CH)2)2-6-；-(CH2)2O(CH2)2-；
-(CH2)2S(CH2)2-or- (CH)2)2NR57(CH2)2-；
R60Is H; a lower alkyl group; a lower alkenyl group; aryl or aryl-lower alkyl;
R61is an alkyl group; an alkenyl group; an aryl group; a heteroaryl group; aryl-lower alkyl; heteroaryl-lower alkyl; - (CH)2)mOR55；-(CH2)mNR33R34；-(CH2)mOCONR75R82；
-(CH2)mNR20CONR78R82；-(CH2)oCOOR37；-(CH2)oNR58R59Or
-(CH2)oPO(COR60)2；
R62Is a lower alkyl group; a lower alkenyl group; aryl, heteroaryl or aryl-lower alkyl;
R63is H; a lower alkyl group; a lower alkenyl group; aryl, heteroaryl; aryl-lower alkyl; heteroaryl-lower alkyl; -COR64；-COOR57；-CONR58R59；-SO2R62OR-PO (OR)60)2；
R34And R63Together may form: - (CH)2)2-6-；-(CH2)2O(CH2)2-；
-(CH2)2S(CH2)2-or- (CH)2)2NR57(CH2)2-；
R64Is H; a lower alkyl group; a lower alkenyl group; an aryl group; a heteroaryl group; aryl-lower alkyl; heteroaryl-lower alkyl; - (CH) 2)p(CHR61)sOR65；-(CH2)p(CHR61)sSR66Or- (CH)2)p(CHR61)sNR34R63；-(CH2)P(CHR61)sOCONR75R82；
-(CH2)P(CHR61)sNR20CONR78R82；
R65Is H; a lower alkyl group; a lower alkenyl group; aryl, aryl-lower alkyl; heteroaryl-lower alkyl; -COR57；-COOR57or-CONR58R59；
R66Is H; a lower alkyl group; a lower alkenyl group; an aryl group; aryl-lower alkyl; heteroaryl-lower alkyl or-CONR58R59；
m is 2 to 4; o is 0 to 4; p is 1 to 4; q is 0 to 2; r is 1 or 2; s is 0 or 1;
and
independently have any of the meanings defined above
With the exception that B is-NR20CH(R71) And A is other than (a1) or (a2) of A80, A81, A90, A91, A95 or A96, and other than (f) and (m), but wherein
R2Is- (CH)2)m(CHR61)sO-；-(CH2)m(CHR61)sS-；
-(CH2)m(CHR61)sNR34-or- (CH)2)o(CHR61)sCO-；
R3Is- (CH)2)m(CHR61)sO-；-(CH2)m(CHR61)sS-；
-(CH2)m(CHR61)sNR34-or- (CH)2)o(CHR61)sCO-；
R4Is- (CH)2)m(CHR61)sO-；-(CH2)m(CHR61)sS-；
-(CH2)m(CHR61)sNR34-or- (CH)2)p(CHR61)sCO-；
R5Is- (CH)2)o(CHR61)sO-；-(CH2)o(CHR61)sS-；
-(CH2)o(CHR61)sNR34-or- (CH)2)o(CHR61)sCO-；
R6Is- (CH)2)o(CHR61)sO-；-(CH2)o(CHR61)sS-；
-(CH2)o(CHR61)sNR34-or- (CH)2)o(CHR61)sCO-；
R7Is- (CH)2)q(CHR61)sO-；-(CH2)q(CHR61)sNR34-or
-(CH2)r(CHR61)sCO-；
R8Is- (CH)2)o(CHR61)sO-；-(CH2)o(CHR61)sS-；
-(CH2)o(CHR61)sNR34-or- (CH)2)o(CHR61)sCO-；
R9Is- (CH)2)o(CHR61)sO-；-(CH2)o(CHR61)sS-；
-(CH2)o(CHR61)sNR34-or- (CH)2)o(CHR61)sCO-；
R10Is- (CH)2)o(CHR61)sO-；-(CH2)o(CHR61)sS-；
-(CH2)o(CHR61)sNR34-or- (CH)2)o(CHR61)sCO-；
R11Is- (CH)2)m(CHR61)sO-；-(CH2)m(CHR61)sNR34-or
-(CH2)o(CHR61)sCO-；
R12Is- (CH)2)m(CHR61)sO-；-(CH2)m(CHR61)sNR34-or
-(CH2)r(CHR61)sCO-；
R13Is- (CH)2)q(CHR61)sO-；-(CH2)q(CHR61)sS-；
-(CH2)q(CHR61)sNR34-or- (CH)2)q(CHR61)sCO-；
R14Is- (CH)2)m(CHR61)sO-；-(CH2)m(CHR61)sNR34-or
-(CH2)q(CHR61)sCO-；
R15Is- (CH)2)o(CHR61)sO-；-(CH2)o(CHR61)sS-；
-(CH2)o(CHR61)sNR34-or- (CH)2)o(CHR61)sCO-；
R16Is- (CH)2)o(CHR61)sO-；-(CH2)o(CHR61)sS-；
-(CH2)o(CHR61)sNR34-or- (CH)2)o(CHR61)sCO-；
R17Is- (CH)2)q(CHR61)sO-；-(CH2)q(CHR61)sS-；
-(CH2)q(CHR61)sNR34-or- (CH)2)q(CHR61)sCO-；
R18Is-(CH2)p(CHR61)sO-；-(CH2)p(CHR61)sS-；
-(CH2)p(CHR61)sNR34-or- (CH)2)p(CHR61)sCO-；
R19Is- (CH)2)p(CHR61)s-；-(CH2)p(CHR61)sS-；
-(CH2)p(CHR61)sNR34-or- (CH)2)p(CHR61)sCO-；
R21Is- (CH)2)o(CHR61)sO-；-(CH2)o(CHR61)sS-；
-(CH2)o(CHR61)sNR34-or- (CH)2)o(CHR61)sCO-；
R22Is- (CH)2)o(CHR61)sO-；-(CH2)o(CHR61)sS-；
-(CH2)o(CHR61)sNR34-or- (CH)2)o(CHR61)sCO-；
R23Is- (CH)2)o(CHR61)sO-；-(CH2)o(CHR61)sS-；
-(CH2)o(CHR61)sNR34-or- (CH)2)o(CHR61)sCO-；
R24Is- (CH)2)o(CHR61)sO-；-(CH2)o(CHR61)sS-；
-(CH2)o(CHR61)sNR34-or- (CH)2)o(CHR61)sCO-；
R25Is- (CH)2)m(CHR61)sO-；-(CH2)m(CHR61)sS-；
-(CH2)m(CHR61)sNR34-or- (CH)2)o(CHR61)sCO-；
R26Is- (CH)2)m(CHR61)sO-；-(CH2)m(CHR61)sS-；
-(CH2)m(CHR61)sNR34-or- (CH)2)o(CHR61)sCO-；
R27Is- (CH)2)o(CHR61)sO-；-(CH2)o(CHR61)sS-；
-(CH2)o(CHR61)sNR34-or- (CH)2)o(CHR61)sCO-；
R28Is- (CH)2)m(CHR61)sO-；-(CH2)m(CHR61)sS-；
-(CH2)m(CHR61)sNR34-or- (CH)2)o(CHR61)sCO-；
R29Is- (CH)2)o(CHR61)sO-；-(CH2)o(CHR61)sS-；
-(CH2)o(CHR61)sNR34-or- (CH)2)o(CHR61)sCO-；
R31Is- (CH)2)p(CHR61)sO-；-(CH2)P(CHR61)sS-；
-(CH2)p(CHR61)sNR34-or- (CH)2)o(CHR61)sCO-；
R33Is- (CH)2)m(CHR61)sO-；-(CH2)m(CHR61)sNR34-or
-(CH2)o(CHR61)sCO-；
R37Is- (CH)2)p(CHR61)sO-；-(CH2)p(CHR61)sS-；
-(CH2)p(CHR61)sNR34-or- (CH)2)o(CHR61)sCO-；
R38Is- (CH)2)p(CHR61)sO-；-(CH2)p(CHR61)sS-；
-(CH2)p(CHR61)sNR34-or- (CH)2)o(CHR61)sCO-；
R41Is- (CH)2)p(CHR61)sO-；-(CH2)p(CHR61)sS-；
-(CH2)p(CHR61)sNR34-or-, (CH2)o(CHR61)sCO-；
R42Is- (CH)2)p(CHR61)sO-；-(CH2)p(CHR61)sS-；
-(CH2)p(CHR61)sNR34--Or- (CH)2)o(CHR61)sCO-；
R43Is- (CH)2)m(CHR61)sO；-(CH2)m(CHR61)sNR34-or
-(CH2)o(CHR61)sCO-；
R45Is- (CH)2)o(CHR61)sO-；-(CH2)o(CHR61)sS-；
-(CH2)o(CHR61)sNR34-or- (CH)2)s(CHR61)sCO-；
R47Is- (CH)2)o(CHR61)sO-；
R49Is- (CHR) 61)sO-；-(CHR61)sS-；-(CHR61)sNR34-or
-(CHR61)sCO-；
R51Is- (CH)2)m(CHR61)sO-；-(CH2)m(CHR61)sS-；
-(CH2)m(CHR61)sNR34-or- (CH)2)o(CHR61)sCO-；
R52Is- (CH)2)m(CHR61)sO-；-(CH2)m(CHR61)sS-；
-(CH2)m(CHR61)sNR34-or- (CH)2)o(CHR61)sCO-；
R53Is- (CH)2)m(CHR61)sO-；-(CH2)m(CHR61)sS-；
-(CH2)m(CHR61)sNR34-or- (CH)2)o(CHR61)sCO-；
R54Is- (CH)2)m(CHR61)sO-；-(CH2)m(CHR61)sNR34-or
-(CH2)o(CHR61)sCO-；
R55Is- (CH)2)m(CHR61)sO-；-(CH2)m(CHR61)sNR34-or
-(CH2)o(CHR61)sCO-；
R56Is- (CH)2)m(CHR61)sO-；-(CH2)m(CHR61)sNR34-or
-(CH2)o(CHR61)sCO-；
R64Is- (CH)2)p(CHR61)sO-；-(CH2)p(CHR61)sS-or
-(CH2)p(CHR61)sNR34-；
m, o, p, q, r and s are as defined above;
provided that if more than one substituent R is present2-R19、R21 to R29、R31、R33、R37、R38、R41 to R43、R45、R47、R49、R51To R56And R64Then only one of them has the just mentioned meaning and the other substituents have any of the previously mentioned meanings;
l is a direct bond or one of these linkers
L1：-(CH2)pCHR61[X(CH2)pCHR61]o-；
L2：-CO(CH2)pCHR61[X(CH2)pCHR61]oCO-；
L3：-CONR34(CH2)pCHR61[X(CH2)pCHR61]oNR34CO-；
L4：-O(CH2)pCHR61[X(CH2)pCHR61]oO-；
L5：-S(CH2)pCHR61[X(CH2)pCHR61]oS-；
L6：-NR34(CH2)pCHR61[X(CH2)pCHR61]oNR34-；
L7：-(CH2)oCHR61Y(CH2)oCHR61-；
L8：-CO(CH2)oCHR61Y(CH2)oCHR61CO-；
L9：-CONR34(CH2)oCHR61Y(CH2)oCHR61NR34CO-；
L10：-O(CH2)oCHR61Y(CH2)oCHR61O-；
L11：-S(CH2)oCHR61Y(CH2)oCHR61S-；
L12：-NR34(CH2)oCHR61Y(CH2)oCHR61NR34-；
L13：-CO(CH2)pCHR61[X(CH2)pCHR61]oNR34-；
L14：-CO(CH2)oCHR61Y(CH2)oCHR61NR34-；
L15-NR34(CH2)pCHR61[X(CH2)pCHR61]oCO-; and
L16-NR34(CH2)oCHR61Y(CH2)oCHR61CO-；
m, o, p, q, r and s are as defined above; x is O; s; NR (nitrogen to noise ratio)34；-NR32CONR34-or-OCOO-; and Y is-C6R67R68R69R70-；
R67Is H; cl; br; f; NO2；-NR34COR57(ii) a Lower alkyl or lower alkenyl;
R68is H; cl; br; f; NO2；-NR34COR57(ii) a Lower alkyl or lower alkenyl;
R69is H; cl; br;F；NO2；-NR34COR57(ii) a Lower alkyl or lower alkenyl; and
R70is H; cl; br; f; NO2；-NR34COR57(ii) a Lower alkyl or lower alkenyl;
provided that R is67、R68、R69And R70At least two of which are H; and
other preconditions are
-(CH2)m(CHR61)sO-may be bound to linker L1, L2, L3, L7, L8, or L9;
-(CH2)o(CHR61)so-may be bound to linker L1, L2, L3, L7, L8, or L9;
-(CH2)p(CHR61)so-may be bound to linker L1, L2, L3, L7, L8, or L9;
-(CH2)q(CHR61)so-may be bound to linker L1, L2, L3, L7, L8, or L9;
-(CHR61)so-may be bound to linker L1, L2, L3, L7, L8, or L9;
-(CH2)m(CHR61)ss-may be bound to linker L1, L2, L3, L7, L8 or L9 or may be bound to- (CH) 2)m(CHR61)sS-；-(CH2)o(CHR61)sS-；-(CH2)p(CHR61)sS-；-(CH2)q(CHR61)sS-or- (CHR)61)sS-disulfide bond formation;
-(CH2)o(CHR61)ss-may be bound to linker L1, L2, L3, L7, L8 or L9 or may be bound to- (CH)2)m(CHR61)sS-；-(CH2)o(CHR61)sS-；-(CH2)p(CHR61)sS-；-(CH2)q(CHR61)sS-or- (CHR)61)sS-disulfide bond formation;
-(CH2)p(CHR61)ss-may be bound to linker L1, L2, L3, L7, L8 or L9 or may be bound to- (CH)2)m(CHR61)sS-；-(CH2)o(CHR61)sS-；-(CH2)p(CHR61)sS-；
-(CH2)q(CHR61)sS-or- (CHR)61)sS-disulfide bond formation;
-(CH2)q(CHR61)ss-may be bound to linker L1, L2, L3, L7, L8 or L9 or may be bound to- (CH)2)m(CHR61)sS-；-(CH2)o(CHR61)sS-；-(CH2)p(CHR61)sS-；
-(CH2)q(CHR61)sS-or- (CHR)61)sS-disulfide bond formation;
-(CHR61)ss-may be bound to linker L1, L2, L3, L7, L8 or L9 or may be bound to- (CH)2)m(CHR61)sS-；-(CH2)o(CHR61)sS-；-(CH2)p(CHR61)sS-；
-(CH2)q(CHR61)sS-or- (CHR)61)sS-disulfide bond formation;
-(CH2)m(CHR61)sNR34-may bind to linker L1, L2, L3, L7, L8 or L9;
-(CH2)o(CHR61)sNR34-may bind to linker L1, L2, L3, L7, L8 or L9;
-(CH2)p(CHR61)sNR34-may bind to linker L1, L2, L3, L7, L8 or L9;
-(CH2)q(CHR61)sNR34-may bind to linker L1, L2, L3, L7, L8 or L9;
-(CHR61)sNR34-may bind to linker L1, L2, L3, L7, L8 or L9;
-(CH2)o(CHR61)sCO-may be bound to linker L4, L5, L6, L10, L11 or L12;
-(CH2)p(CHR61)sCO-may be bound to linker L4, L5, L6, L10, L11 or L12;
-(CH2)q(CHR61)sCO-may be bound to linker L4, L5, L6, L10, L11 or L12;
-(CH2)r(CHR61)sCO-may be bound to linker L4, L5, L6, L10, L11 or L12;
-(CHR61)sCO-may be bound to linker L4, L5, L6, L10, L11 or L12;
-(CH2)m(CHR61)so-can be conjugated to linker L13 or L14 and the resulting conjugate can be conjugated to- (CH) 2)m(CHR61)sCO-；-(CH2)o(CHR61)pCO-；-(CH2)q(CHR61)sCO-or- (CHR)61)sCO-binding;
-(CH2)o(CHR61)so-can be conjugated to linker L13 or L14 and the resulting conjugate can be conjugated to- (CH)2)o(CHR61)sCO-；-(CH2)o(CHR61)pCO-；-(CH2)q(CHR61)sCO-or- (CHR)61)sCO-binding;
-(CH2)p(CHR61)so-can be conjugated to linker L13 or L14 and the resulting conjugate can be conjugated to- (CH)2)o(CHR61)sCO-；-(CH2)o(CHR61)pCO-；-(CH2)q(CHR61)sCO-or- (CHR)61)sCO-binding;
-(CH2)q(CHR61)so-can be conjugated to linker L13 or L14 and the resulting conjugate can be conjugated to- (CH)2)o(CHR61)sCO-；-(CH2)o(CHR61)pCO-；-(CH2)q(CHR61)sCO-or- (CHR)61)sCO-binding;
-(CHR61)so-can be conjugated to linker L13 or L14 and the resulting conjugate can be conjugated to- (CH)2)o(CHR61)sCO-；-(CH2)o(CHR61)pCO-；-(CH2)q(CHR61)sCO-or- (CHR)61)sCO-binding;
-(CH2)m(CHR61)ss-can be conjugated to linker L13 or L14 and the resulting conjugate can be conjugated to- (CH)2)o(CHR61)sCO-；-(CH2)o(CHR61)pCO-；-(CH2)q(CHR61)sCO-or- (CHR)61)sCO-binding;
-(CH2)o(CHR61)ss-can be conjugated to linker L13 or L14 and the resulting conjugate can be conjugated to- (CH)2)o(CHR61)sCO-；-(CH2)o(CHR61)pCO-；-(CH2)q(CHR61)sCO-or- (CHR)61)sCO-binding;
-(CH2)p(CHR61)ss-can be conjugated to linker L13 or L14 and the resulting conjugate can be conjugated to- (CH)2)o(CHR61)sCO-；-(CH2)o(CHR61)pCO-；-(CH2)q(CHR61)sCO-or- (CHR)61)sCO-binding;
-(CH2)q(CHR61)ss-can be conjugated to linker L13 or L14 and the resulting conjugate can be conjugated to- (CH)2)o(CHR61)sCO-；-(CH2)o(CHR61)pCO-；-(CH2)q(CHR61)sCO-or- (CHR)61)sCO-binding;
-(CHR61)ss-can be conjugated to linker L13 or L14 and the resulting conjugate can be conjugated to- (CH)2)o(CHR61)sCO-；-(CH2)o(CHR61)pCO-；-(CH2)q(CHR61)sCO-or- (CHR)61)sCO-binding;
-(CH2)m(CHR61)sNR34-may be conjugated to linker L13 or L14 and the resulting conjugate may be conjugated to- (CH)2)o(CHR61)sCO-；-(CH2)o(CHR61)pCO-；-(CH2)q(CHR61)sCO-or- (CHR)61)sCO-binding;
-(CH2)o(CHR61)sNR34-may be conjugated to linker L13 or L14 and the resulting conjugate may be conjugated to- (CH)2)o(CHR61)sCO-；-(CH2)o(CHR61)pCO-；-(CH2)q(CHR61)sCO-or- (CHR)61)sCO-binding;
-(CH2)p(CHR61)sNR34-may be conjugated to linker L13 or L14 and the resulting conjugate may be conjugated to- (CH)2)o(CHR61)sCO-；-(CH2)o(CHR61)pCO-；-(CH2)q(CHR61)sCO-or- (CHR)61)sCO-binding;
-(CH2)q(CHR61)sNR34-may be conjugated to linker L13 or L14 and the resulting conjugate may be conjugated to- (CH)2)o(CHR61)sCO-；-(CH2)o(CHR61)pCO-；-(CH2)q(CHR61)sCO-or- (CHR)61)sCO-binding;
-(CHR61)sNR34-may be conjugated to linker L13 or L14 and the resulting conjugate may be conjugated to- (CH)2)o(CHR61)sCO-；-(CH2)o(CHR61)pCO-；-(CH2)q(CHR61)sCO-or- (CHR)61)sCO-binding;
-(CH2)o(CHR61)sCO-may be conjugated to L15 or L16 and the resulting conjugate may be conjugated to- (CH)2)m(CHR61)sX-、-(CH2)o(CHR61)sX-、-(CH2)p(CHR61)sX-、-(CH2)q(CHR61)sX-or- (CHR)61)sX-binding;
-(CH2)p(CHR61)sCO-may be conjugated to L15 or L16 and the resulting conjugate may be conjugated to- (CH)2)m(CHR61)sX-、-(CH2)o(CHR61)sX-、-(CH2)p(CHR61)sX-、-(CH2)q(CHR61)sX-or- (CHR)61)sX-binding;
-(CH2)q(CHR61)sCO-may be conjugated to L15 or L16 and the resulting conjugate may be conjugated to- (CH)2)m(CHR61)sX-、-(CH2)o(CHR61)sX-、-(CH2)p(CHR61)sX-、-(CH2)q(CHR61)sX-or- (CHR)61)sX-binding;
-(CH2)r(CHR61)sCO-may be conjugated to L15 or L16 and the resulting conjugate may be conjugated to- (CH)2)m(CHR61)sX-、-(CH2)o(CHR61)sX-、-(CH2)p(CHR61)sX-、-(CH2)q(CHR61)sX-or- (CHR)61)sX-binding;
-(CHR61)sCO-may be conjugated to L15 or L16 and the resulting conjugate may be conjugated to- (CH)2)m(CHR61)sX-、-(CH2)o(CHR61)sX-、-(CH2)p(CHR61)sX-、-(CH2)q(CHR61)sX-or- (CHR)61)sX-binding;
Z、Z1and Z2Independently is a chain of N alpha-amino acid residues, N being an integer from 8 to 16, the positions of said amino acid residues in said chain being counted starting from the N-terminal amino acid, whereby these amino acid residues, depending on their position in the chain, areGly or Pro, Z, Z1And Z2Either a chain of formula-A-CO-, or a chain of formula-B-CO-, or a chain of the type
C：-NR20CH(R72)CO-；
D：-NR20CH(R73)CO-；
E：-NR20CH(R74)CO-；
F：-NR20CH(R84) CO-; and
H：-NR20-CH(CO-)-(CH2)4-7-CH(CO-)-NR20-；
-NR20-CH(CO-)-(CH2)pSS(CH2)p-CH(CO-)-NR20-；
-NR20-CH(CO-)-(-(CH2)pNR20CO(CH2)p-CH(CO-)-NR20-; and
-NR20-CH(CO-)-(-(CH2)pNR20CONR20(CH2)p-CH(CO-)-NR20-；
R71is H; a lower alkyl group; a lower alkenyl group; - (CH)2)p(CHR61)sOR75；
-(CH2)p(CHR61)sSR75；-(CH2)p(CHR61)sNR33R34；
-(CH2)p(CHR61)sOCONR33R75；-(CH2)p(CHR61)sNR20CONR33R82；
-(CH2)o(CHR61)sCOOR75；-(CH2)pCONR58R59；
-(CH2)pPO(OR62)2；-(CH2)pSO2R62Or- (CH)2)o-C6R67R68R69R70R76；
R72Is H; a lower alkyl group; a lower alkenyl group; - (CH)2)p(CHR61)sOR85Or
-(CH2)p(CHR61)sSR85；
R73Is- (CH)2)oR77；-(CH2)rO(CH2)oR77；-(CH2)rS(CH2)oR77Or
-(CH2)rNR20(CH2)oR77；
R74Is- (CH)2)pNR78R79；-(CH2)pNR77R80；
-(CH2)pC(＝NR80)NR78R79；-(CH2)pC(＝NOR50)NR78R79；
-(CH2)pC(＝NNR78R79)NR78R79；-(CH2)pNR80C(＝NR80)NR78R79；
-(CH2)pN＝C(NR78R80)NR79R80；-(CH2)pC6H4NR78R79；
-(CH2)pC6H4NR77R80；-(CH2)pC6H4C(＝NR80)NR78R79；
-(CH2)pC6H4C(＝NOR50)NR78R79；
-(CH2)pC6H4C(＝NNR78R79)NR78R79；
-(CH2)pC6H4NR80C(＝NR80)NR78R79；
-(CH2)pC6H4N＝C(NR78R80)NR79R80；
-(CH2)rO(CH2)mNR78R79；-(CH2)rO(CH2)mNR77R80；
-(CH2)rO(CH2)pC(＝NR80)NR78R79；
-(CH2)rO(CH2)pC(＝NOR50)NR78R79；
-(CH2)rO(CH2)pC(＝NNR78R79)NR78R79；
-(CH2)rO(CH2)mNR80C(＝NR80)NR78R79；
-(CH2)rO(CH2)mN＝C(NR78R80)NR79R80；
-(CH2)rO(CH2)pC6H4CNR78R79；
-(CH2)rO(CH2)pC6H4C(＝NR80)NR78R79；
-(CH2)rO(CH2)pC6H4C(＝NOR50)NR78R79；
-(CH2)rO(CH2)pC6H4C(＝NNR78R79)NR78R79；
-(CH2)rO(CH2)pC6H4NR80C(＝NR80)NR78R79；
-(CH2)rS(CH2)mNR78R79；-(CH2)rS(CH2)mNR77R80；
-(CH2)rS(CH2)pC(＝NR80)NR78R79；
-(CH2)rS(CH2)pC(＝NOR50)NR78R79；
-(CH2)rS(CH2)pC(＝NNR78R79)NR78R79；
-(CH2)rS(CH2)mNR80C(＝NR80)NR78R79；
-(CH2)rS(CH2)mN＝C(NR78R80)NR79R80；
-(CH2)rS(CH2)pC6H4CNR78R79；
-(CH2)rS(CH2)pC6H4C(＝NR80)NR78R79；
-(CH2)rS(CH2)pC6H4C(＝NOR50)NR78R79；
-(CH2)rS(CH2)pC6H4C(＝NNR78R79)NR78R79；
-(CH2)rS(CH2)pC6H4NR80C(＝NR80)NR78R79；-(CH2)pNR80COR64；
-(CH2)pNR80COR77；-(CH2)pNR80CONR78R79Or
-(CH2)pC6H4NR80CONR78R79；
R75Is a lower alkyl group; lower alkenyl or aryl-lower alkyl;
R33and R75Together may form: - (CH)2)2-6-；-(CH2)2O(CH2)2-；
-(CH2)2S(CH2)2-or- (CH)2)2NR57(CH2)2-；
R75And R82Together may form: - (CH)2)2-6-；-(CH2)2O(CH2)2-；
-(CH2)2S(CH2)2-or- (CH)2)2NR57(CH2)2-；
R76Is H; a lower alkyl group; a lower alkenyl group; aryl-lower alkyl;
-(CH2)oOR72；-(CH2)oSR72；-(CH2)oNR33R34；-(CH2)oOCONR33R75；
-(CH2)oNR20CONR33R82；-(CH2)oCOOR75；
-(CH2)oCONR58R59；-(CH2)oPO(OR60)2；-(CH2)pSO2R62or
-(CH2)oCOR64；
R77is-C6R67R68R69R70R76Or a heteroaryl group of one of the formulae
R78Is H; a lower alkyl group; aryl or aryl-lower alkyl;
R78and R82Together may form: - (CH)2)2-6-；-(CH2)2O(CH2)2-；
-(CH2)2S(CH2)2-or- (CH)2)2NR57(CH2)2-；
R79Is H; a lower alkyl group; aryl or aryl-lower alkyl or
R78And R79Taken together, may be- (CH)2)2-7-；-(CH2)2O(CH2)2-or
-(CH2)2NR57(CH2)2-；
R80Is H or lower alkyl;
R81is H; lower alkyl or aryl-lower alkyl;
R82is H; a lower alkyl group; an aryl group; heteroaryl or aryl-lower alkyl;
R33and R72Together may form: - (CH)2)2-6-；-(CH2)2O(CH2)2-；
-(CH2)2S(CH2)2-or- (CH)2)2NR57(CH2)2-；
R83Is H; a lower alkyl group; aryl or-NR78R79；
R84Is- (CH)2)m(CHR61)sOH；-(CH2)pCONR78R79；
-(CH2)pNR80CONR78R79；-(CH2)pC6H4CONR78R79Or
-(CH2)pC6H4NR80CONR78R79；
R85Is lower alkyl or lower alkenyl;
with the proviso that Z, Z is present in said chain of n alpha-amino acid residues1And Z2In
-if n is 8, then the amino acid residues at positions 1-8 are:
-P1: class C or class D or class E or class F, or the residue is Pro;
-P2: class E or class D or class F;
-P3: class E or class C, or the residue is Pro;
-P4: e or formula-A-CO-;
-P5: e is of the formula or-B-CO-, or the residue is Gly;
-P6: class D, or the residue is Pro;
-P7: or class C or class D; and
-P8: class C or class D or class E or class F, or the residue is Pro; or P2 and P7, taken together, may form a group of the H class; and may also be the D-isomer at P4 and P5;
-if n is 9, then the amino acid residues at positions 1-9 are:
-P1: class C or class D or class E or class F, or the residue is Pro;
-P2: class E or class D or class F;
-P3: class C or class D or class E, or the residue is Pro;
-P4: class E or class D, or the residue is Pro;
-P5: e, or the residue is Gly or Pro;
-P6: class D or E, or the residue is Gly or Pro;
-P7: class E or class D or class C, or the residue is Pro;
-P8: class E or class D; and
-P9: class C or D or class E or class F, or the residue is Pro or
-P2 and P8, taken together, may form a group of the H type; and may also be the D-isomer at P4, P5 and P6;
-if n is 10, the amino acid residues at positions 1-10 are:
-P1: class C or class D or class E or class F, or the residue is Pro;
-P2: class E or class D, or the residue is Pro;
-P3: class C or class E;
-P4: class E or class D or class F, or the residue is Pro;
-P5: e or F or of the formula-A-CO-, or the residue is Gly;
-P6: e is of the formula or-B-CO-, or the residue is Gly;
-P7: class D or E, or the residue is Gly or Pro;
-P8: class D or class E;
-P9: class E or class D or class C, or the residue is Pro; and
-P10: class C or D or E or F or
-P3 and P8, taken together, may form a group of the H type; and may also be the D-isomer at P5 and P6;
-if n is 11, the amino acid residues at positions 1-11 are:
-P1: class C or class D or class E or class F, or the residue is Pro;
-P2: class E or class C or class D;
-P3: class D or E, or the residue is Pro;
-P4: class E or class C or class F;
-P5: class E or class F, or the residue is Gly or Pro;
-P6: class E or class F, or the residue is Gly or Pro;
-P7: class E or class F, or the residue is Gly or Pro;
-P8: class D or E or class F;
-P9: class D or E, or the residue is Pro;
-P10: class E or class C or class D; and
-P11: class C or D or class E or class F, or the residue is Pro or
-P4 and P8 and/or P2 and P10, taken together, may form a group of the H type; and may also be the D-isomer at P5, P6 and P7;
-if n is 12, then the amino acid residues at positions 1-12 are:
-P1: class C or class D or class E or class F, or the residue is Pro;
-P2: class E or class D;
-P3: class C or class D, or the residue is Pro;
-P4: class E or class F or class D;
-P5: class E or class D or class C, or the residue is Gly or Pro;
-P6: e or F or of the formula-A-CO-, or the residue is Gly;
-P7: class E or class F or of formula-B-CO-;
-P8: class D or class C, or the residue is Pro;
-P9: class E or class D or class F;
-P10: class D or class C, or the residue is Pro;
-P11: class E or class D; and
-P12: class C or D or class E or class F, or the residue is Pro or
-P4 and P9 and/or P2 and P11, taken together, may form a group of the H type; and may also be the D-isomer at P6 and P7;
-if n is 13, then the amino acid residues at positions 1-13 are:
-P1: class C or class D or class E or class F, or the residue is Pro;
-P2: class E or class F or class D;
-P3: class C or class D or class E, or the residue is Pro;
-P4: class E or class C or class F;
-P5: class E or class D, or the residue is Gly or Pro;
-P6: class E or class F, or the residue is Gly or Pro;
-P7: class E or class F, or the residue is Pro;
-P8: class D or E or class F, or the residue is Pro;
-P9: class D or E, or the residue is Pro;
-P10: class E or class C or class F;
-P11: class C or E, or the residue is Pro;
-P12: class E or class D or class C; and
-P13: class C or class D or class E or class F, or the residues are Pro or P4 and P10 and/or P2 and P12, taken together, may form a class H group; and may also be the D-isomer at P6, P7 and P8;
-if n is 14, then the amino acid residues at positions 1-14 are:
-P1: class C or class D or class E or class F, or the residue is Pro;
-P2: class E or class C or class D, or the residue is Pro;
-P3: class C or class D or class E;
-P4: class D or C or E, or the residue is Pro;
-P5: class E or class D;
-P6: class E or class F, or the residue is Gly or Pro;
-P7: e or F or of the formula-A-CO-, or the residue is Gly;
-P8: e or F or of the formula-B-CO-, or the residue is Gly;
-P9: class D or E, or the residue is Pro;
-P10: class C or class D or class E;
-P11: class E or class D or class F, or the residue is Pro;
-P12: class D or class E;
-P13: class E or class C or class D, or the residue is Pro; and
-P14: class C or D or class E or class F, or the residue is Pro or
-P5 and P10 and/or P3 and P12, taken together, may form a group of the H type; and may also be the D-isomer at P7 and P8;
-if n is 15, then the amino acid residues at positions 1-15 are:
p1: class C or class D or class E or class F, or the residue is Pro;
p2: class E or class F or class D;
p3: class C or class D or class E, or the residue is Pro;
p4: class E or class D or class F;
p5: class C or class D or class E, or the residue is Pro;
p6: class E or class D or class F;
p7: class C or E, or the residue is Pro;
p8: class E or class F, or the residue is Gly or Pro;
p9: class E or class F, or the residue is Gly or Pro;
p10: class E or class D;
p11: class C or class D or class E, or the residue is Pro;
p12: class E or class C or class F;
p13: class D or E, or the residue is Pro;
p14: class E or class C or class D; and
p15: class C or D or class E or class F, or the residue is Pro or
P6 and P10 and/or P4 and P12 and/or P2 and P14, taken together, may form a group of the H class; and may also be the D-isomer at P7, P8 and P9; and
-if n is 16, then the amino acid residues at positions 1-16 are:
-P1: class D, or class E, or class C or class F, or the residue is Pro;
-P2: class E or class F or class D;
-P3: class C or class D or class E, or the residue is Pro;
-P4: class E or class D or class F;
-P5: class D or C or E, or the residue is Pro;
-P6: class E or class D;
-P7: class E or class F, or the residue is Gly or Pro;
-P8: e or F or of the formula-A-CO-, or the residue is Gly;
-P9: e is of the formula or-B-CO-, or the residue is Gly;
-P10: class D or E, or the residue is Pro;
-P11: class E or class C or class D;
-P12: class D or C or E, or the residue is Pro;
-P13: class E or class C or class F;
-P14: class C or class D or class E, or the residue is Pro;
-P15: class E or class C or class D; and
-P16: class C or D or class E or class F, or the residue is Pro or
-P6 and P11 and/or P4 and P13 and/or P2 and P15, taken together, may form a group of the H type; and may also be the D-isomer at P8 and P9;
according to the invention, these β -hairpin peptidomimetics can be prepared by a method comprising:
(a) coupling a suitably functionalized solid support with a suitably N-protected derivative of an amino acid, wherein if N is an even number, the amino acid is in the desired end product n/2、n/2+1 orn/2Position-1, if n is an odd number, the amino acid is correspondingly inn/2+1/2Orn/2-1/2Any functional groups that may be present in the N-protected amino acid derivative are likewise suitably protected;
(b) removing the N-protecting group from the product thus obtained;
(c) coupling the product thus obtained with a suitably N-protected derivative of an amino acid which is suitably protected at a position in the desired end product close to the N-terminal amino acid residue, any functional groups which may be present in said N-protected amino acid derivative being likewise suitably protected;
(d) removing the N-protecting group from the product thus obtained;
(e) repeating steps (c) and (d), if necessary, until the N-terminal amino acid residue has been introduced;
(f) coupling the product thus obtained with a compound of the general formula;
wherein
As defined above, and X is an N-protecting group, or if
The above group (a1) or (a2), alternatively
(fa) coupling the product obtained in step (d) or (e) with a suitably N-protected derivative of an amino acid of formula III
HOOC-B-H III or HOOC-A-H IV
Wherein B and A are as defined above, any functional groups which may be present in the N-protected amino acid derivative are likewise suitably protected;
(fb) removing the N-protecting group from the product thus obtained; and
(fc) coupling of the product thus obtained with a suitable N-protected derivative of an amino acid having the above general formulae IV and III, respectively, any functional groups which may be present in said N-protected amino acid derivative being likewise suitably protected;
(g) removing the N-protecting group from the product obtained in step (f) or (fc);
(h) coupling the product thus obtained with a suitably N-protected derivative of an amino acid which is in the N-position in the desired end product, any functional groups which may be present in said N-protected amino acid derivative being likewise suitably protected;
(i) removing the N-protecting group from the product thus obtained;
(j) coupling the product thus obtained with a suitably N-protected derivative of an amino acid which is suitably protected at a position remote from the N-position in the desired end product, any functional groups which may be present in said N-protected amino acid derivative being likewise suitably protected;
(k) removing the N-protecting group from the product thus obtained;
(l) Repeating steps (j) and (k), if necessary, until all amino acid residues have been introduced;
(m) if desired, selectively deprotecting one or more of the protected functional groups present in the molecule and suitably replacing the reactive groups so released;
(o) detaching the product thus obtained from the solid support;
(p) cyclizing the product isolated from the solid support;
(q) if necessary, subjecting the mixture to a thermal treatment,
(qa) forming one or more interchain bonds between the side chains of suitable amino acid residues at opposite positions of the β -chain region; and/or
(qb) linking the two structural units of class Ia via a bridge-G1-L-G2-;
(r) removing any protecting groups present on the functional groups of any members of the chain of amino acid residues and, if desired, any protecting groups that may also be present in the molecule; and
(s) if desired, converting the product thus obtained into a pharmaceutically acceptable salt or converting the pharmaceutically acceptable or unacceptable salt thus obtained into the corresponding free compound of formula I or into a different pharmaceutically acceptable salt.
The peptidomimetics of the invention may also be enantiomers of the compounds of formulae Ia and Ib. These enantiomers were prepared by modification of the above method using all enantiomers of the chiral starting material.
The term "alkyl", as used in this specification, alone or in combination, represents a straight or branched chain saturated hydrocarbon group having up to 24, preferably up to 12, carbon atoms. Likewise, the term "alkenyl" represents a straight-chain or branched hydrocarbon radical having up to 24, preferably up to 12, carbon atoms and containing at least one, or depending on the chain length, up to 4, olefinic double bonds. The term "lower" represents residues and compounds having up to 6 carbon atoms. Thus, for example, the term "lower alkyl" represents a straight or branched chain saturated hydrocarbon group having up to 6 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, and the like. The term "aryl" represents an aromatic carbocyclic hydrocarbon radical containing 1 or 2 six-membered rings, such as phenyl or naphthyl, which may be substituted by up to 3 substituents, such as Br, Cl, F, CF3、NO2Lower alkyl or lower alkenyl. The term "heteroaryl" represents an aromatic heterocyclic residue containing 1 or 2 five-and/or six-membered rings, at least one of which contains up to 3 heteroatoms selected from O, S and N, and which rings are optionally substituted; representative examples of these optionally substituted heteroaryl groups incorporate R 77The definitions of (a) are given above in this text.
The structural element-A-CO-represents the amino acid building block which in combination with the structural element-B-CO-forms the templates (a1) and (a 2). Templates (a) - (p) constitute building blocks having N-and C-termini oriented in space in such a way that the distance between the two groups is 4.0-5.5A. Peptide chain Z, Z1Or Z2The C-terminus and N-terminus of templates (a) - (p) are linked via the respective N-and C-termini, such that the templates and the chain form a cyclic structure, for example as described in formula Ia. In the case where the distance between the N-and C-termini of the template is 4.0-5.5A, the template will be induced at peptide chain Z, Z1Or Z2To form the H-bond network necessary for the beta-hairpin configuration. The template and peptide chain thus form a β -hairpin mimetic. The β -hairpin mimetic can also be coupled through groups G1 and G2 and linker unit L to form a dimeric structure of formula Ib.
This beta-hairpin configuration is highly relevant for the antibiotic and anticancer activity of the beta-hairpin mimetics of the invention. The β -hairpin stable conformation properties of templates (a) - (p) play a key role not only for antibiotic and anticancer activity, but also for the synthetic methods defined herein above, since the introduction of the template in the middle of the linear protected peptide precursor significantly improves the cyclization yield.
The structural units A1-A69 belong to the class of amino acids whose N-terminus is the secondary amine-forming part of a ring. Only proline among the amino acids encoded by the gene falls into this class. The structural units A1-A69 are in configuration (D) and they are combined with the structural unit of the (L) -configuration-B-CO-. The preferred combination of templates (a1) is-DA1-CO-LB-CO-toDA69-CO-LB-CO-. Such that, for example,DPro-Lpro constitutes a prototype of template (a 1). Not preferred, but it may be that the template (a2) isLA1-CO-DB-CO-toLA69-CO-DA combination of B-CO-. Thus, for exampleLPro-DPro constitutes a prototype of the less preferred template (a 2).
It is understood that A has the structural unit of the (D) -configuration-A1-CO-to-A69-CO-carries the group R in the alpha-position to the N-terminus1。R1Are preferably H and lower alkyl, R1The most preferred values of (b) are H and methyl. As will occur to those skilled in the art, A1-A69 is shown in the (D) -configuration, where R is1Are H and methyl, corresponding to the (R) -configuration. According to Cahn, Ingold and Prelog-rules, with preference to R according to other values1This configuration can also be represented by (S).
Except that R1In addition, the structural units-A1-CO-to-A69-CO-may also carry a further substituent which is present as R2-R17And (4) showing. The further substituent may be H, and if it is not H,it is preferably smaller than the intermediate size aliphatic or aromatic group. R 2-R17Examples of preferred values of (b) are:
-R2: h; a lower alkyl group; a lower alkenyl group; (CH)2)mOR55(wherein R is55: lower alkyl or lower alkenyl); (CH)2)mSR56(wherein R is56: lower alkyl or lower alkenyl); (CH)2)mNR33R34(wherein R is33: lower alkyl or lower alkenyl; r34: h or lower alkyl; r33And R34Taken together to form: - (CH)2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-or- (CH)2)2NR57(CH2)2-；R57: h or lower alkyl); (CH)2)mOCONR33R75(wherein R is33: h or lower alkyl or lower alkenyl; r75: lower alkyl or R33And R75Together form:
-(CH2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-or- (CH)2)2NR57(CH2)2-; wherein R is57: h or lower alkyl); - (CH)2)mNR20CONR33R82(wherein R is20: h or lower alkyl; r33: h or lower alkyl or lower alkenyl; r82: h or lower alkyl or R33And R82Taken together to form: - (CH)2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-or- (CH)2)2NR57(CH2)2-; wherein R is57: h or lower alkyl); - (CH)2)oN(R20)COR64(wherein: R20: h or lower alkyl; r64: lower alkyl or lower alkenyl); - (CH)2)oCOOR57(wherein R is57: lower alkyl or lower alkenyl); - (CH)2)oCONR58R59(wherein R is58: lower alkyl or lower alkenyl; and R59: h or lower alkyl or R58And R59Taken together to form:
-(CH2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-or- (CH)2)2NR57(CH2)2-; wherein R is57: h or lower alkyl); - (CH)2)oPO(OR60)2(wherein R is60: lower alkyl or lower alkenyl); - (CH)2)oSO2R62(wherein R is62: lower alkyl or lower alkenyl) or- (CH)2)qC6H4R8(wherein R is 8：H；F；Cl；CF3(ii) a A lower alkyl group; lower alkenyl or lower alkoxy).
-R3: h; a lower alkyl group; a lower alkenyl group; - (CH)2)mOR55(wherein R is55: lower alkyl or lower alkenyl); - (CH)2)mSR56(wherein R is56: lower alkyl or lower alkenyl); - (CH)2)mNR33R34(wherein R is33: lower alkyl or lower alkenyl; r34: h or lower alkyl or R33And R34Taken together to form: - (CH)2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-or- (CH)2)2NR57(CH2)2-; wherein R is57: h or lower alkyl); - (CH)2)mOCONR33R75(wherein R is33: h or lower alkyl or lower alkenyl;R75: lower alkyl or R33And R75Taken together to form: - (CH)2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-or- (CH)2)2NR57(CH2)2-; wherein R is57: h or lower alkyl); - (CH)2)mNR20CONR33R82(wherein R is20: h or lower alkyl; r33: h or lower alkyl or lower alkenyl; r82: h or lower alkyl or R33And R33Taken together to form: - (CH)2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-or- (CH)2)2NR57(CH2)2-; wherein R is57: h or lower alkyl); - (CH)2)oN(R20)COR64(wherein: R20: h or lower alkyl; r64: lower alkyl or lower alkenyl); - (CH)2)oCOOR57(wherein R is57: lower alkyl or lower alkenyl); - (CH)2)oCONR58R59(wherein R is58: lower alkyl or lower alkenyl; and R59: h; lower alkyl or R58And R59Taken together to form: - (CH)2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-or- (CH)2)2NR57(CH2)2-; wherein R is57: h or lower alkyl); (CH)2)oPO(OR60)2(wherein R is60: lower alkyl or lower alkenyl); - (CH)2)oSO2R62(wherein R is 62: lower alkyl or lower alkenyl) or- (CH)2)qC6H4R8(wherein R is8：H；F；Cl；CF3(ii) a A lower alkyl group; lower alkenyl or lower alkylOxy) group.
-R4: h; a lower alkyl group; a lower alkenyl group; - (CH)2)mOR55(wherein R is55: lower alkyl or lower alkenyl); - (CH)2)mSR56(wherein R is56: lower alkyl or lower alkenyl); - (CH)2)mNR33R34(wherein R is33: lower alkyl or lower alkenyl; r34: h or lower alkyl or R33And R34Taken together to form: - (CH)2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-or- (CH)2)2NR57(CH2)2-; wherein R is57: h or lower alkyl); - (CH)2)mOCONR33R75(wherein R is33: h or lower alkyl or lower alkenyl; r75: lower alkyl or R33And R75Taken together to form: - (CH)2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-or- (CH)2)2NR57(CH2)2-; wherein R is57: h or lower alkyl); - (CH)2)mNR20CONR33R82(wherein R is20: h or lower alkyl; r33: h or lower alkyl or lower alkenyl; r82: h or lower alkyl or R33And R82Taken together to form: - (CH)2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-or- (CH)2)2NR57(CH2)2-; wherein R is57: h or lower alkyl); - (CH)2)mN(R20)COR64(wherein: R20: h or lower alkyl; r64: lower alkyl or lower alkenyl); - (CH)2)oCOOR57(wherein R is57: lower alkyl or lower alkenyl); - (CH)2)oCONR58R59(wherein R is58: lower alkyl or lower alkenyl; and R59: h or lower alkyl or R58And R59Together form: - (CH)2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-or- (CH)2)2NR57(CH2)2-; wherein R is57: h or lower alkyl); - (CH)2)oPO(OR60)2(wherein R is 60: lower alkyl or lower alkenyl); - (CH)2)oSO2R62(wherein R is62: lower alkyl or lower alkenyl) or- (CH)2)qC6H4R8(wherein R is8：H；F；Cl；CF3(ii) a A lower alkyl group; lower alkenyl or lower alkoxy).
-R6: a lower alkyl group; a lower alkenyl group; - (CH)2)oOR55(wherein R is55: lower alkyl or lower alkenyl); - (CH)2)oSR56(wherein R is56: lower alkyl or lower alkenyl); - (CH)2)oNR33R34(wherein R is33: lower alkyl or lower alkenyl; r34: h or lower alkyl or R33And R34Taken together to form: - (CH)2)2-4-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-or- (CH)2)2NR57(CH2)2-; wherein R is57: h or lower alkyl); - (CH)2)oOCONR33R75(wherein R is33: h or lower alkyl or lower alkenyl; r75: lower alkyl or R33And R75Taken together to form: - (CH)2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-or- (CH)2)2NR57(CH2)2-; wherein R is57: h or lower alkyl); (CH)2)oNR20CONR33R82(wherein R is20: h or lower alkyl; r33: h or lower alkyl or lower alkenyl; r82: h or lower alkyl or R33And R82Taken together to form: - (CH)2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-or- (CH)2)2NR57(CH2)2-; wherein R is57: h or lower alkyl); (CH)2)oN(R20)COR64(wherein: R20: h or lower alkyl; r64: an alkyl group; an alkenyl group; an aryl group; and aryl-lower alkyl; heteroaryl-lower alkyl); - (CH)2)oCOOR57(wherein R is57: lower alkyl or lower alkenyl); - (CH)2)oCONR58R59(wherein R is58: lower alkyl or lower alkenyl; and R59: h or lower alkyl or R 58And R59Taken together to form: - (CH)2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-or- (CH)2)2NR57(CH2)2-; wherein R is57: h or lower alkyl); - (CH)2)oPO(OR60)2(wherein R is60: lower alkyl or lower alkenyl); - (CH)2)oSO2R62(wherein R is62: lower alkyl or lower alkenyl) or- (CH)2)qC6H4R8(wherein R is8：H；F；Cl；CF3(ii) a A lower alkyl group; lower alkenyl or lower alkoxy).
-R6: h; a lower alkyl group; a lower alkenyl group; - (CH)2)oOR55(wherein R is55: lower alkyl or lower alkenyl); - (CH)2)oSR56(wherein R is56: lower alkyl or lower alkenyl); - (CH)2)oNR33R34(wherein R is33: lower alkyl or lower alkenyl; r34: h or lower alkyl or R33And R34Taken together to form: - (CH)2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-or- (CH)2)2NR57(CH2)2-; wherein R is57: h or lower alkyl); - (CH)2)oOCONR33R75(wherein R is33: h or lower alkyl or lower alkenyl; r75: lower alkyl or R33And R75Taken together to form: - (CH)2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-or- (CH)2)2NR57(CH2)2-; wherein R is57: h or lower alkyl); - (CH)2)oNR20CONR33R82(wherein R is20: h or lower alkyl; r33: h or lower alkyl or lower alkenyl; r82: h or lower alkyl or R33And R82Taken together to form: - (CH)2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-or- (CH)2)2NR57(CH2)2-; wherein R is57: h or lower alkyl); - (CH)2)oN(R20)COR64(wherein: R20: h or lower alkyl; r64: lower alkyl or lower alkenyl); - (CH)2)oCOOR57(wherein R is57: lower alkyl or lower alkenyl); - (CH)2)oCONR58R59(wherein R is58: lower alkyl or lower An alkenyl group; and R59: h or lower alkyl or R58And R59Taken together to form: - (CH)2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-or- (CH)2)2NR57(CH2)2-; wherein R is57: h or lower alkyl); - (CH)2)oPO(OR60)2(wherein R is60: lower alkyl or lower alkenyl); - (CH)2)oSO2R62(wherein R is62: lower alkyl or lower alkenyl) or- (CH)2)qC6H4R8(wherein R is8：H；F；Cl；CF3(ii) a A lower alkyl group; lower alkenyl or lower alkoxy).
-R7A lower alkyl group; a lower alkenyl group; - (CH)2)qOR55(wherein R is55: lower alkyl or lower alkenyl); - (CH)2)qSR56(wherein R is56: lower alkyl or lower alkenyl); - (CH)2)qNR33R34(wherein R is33: lower alkyl or lower alkenyl; r34: h or lower alkyl or R33And R34Taken together to form: - (CH)2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-or- (CH)2)2NR57(CH2)2-; wherein R is57: h or lower alkyl); - (CH)2)qOCONR33R75(wherein R is33: h or lower alkyl or lower alkenyl; r75: lower alkyl or R33And R75Taken together to form: - (CH)2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-or- (CH)2)2NR57(CH2)2-; wherein R is57: h or lower alkylRadical); (CH)2)qNR20CONR33R82(wherein R is20: h or lower alkyl; r33: h or lower alkyl or lower alkenyl; r82: h or lower alkyl or R33And R82Taken together to form: - (CH)2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-or- (CH)2)2NR57(CH2)2-; wherein R is57: h or lower alkyl); - (CH)2)qN(R20)COR64(wherein: R20: h or lower alkyl; r64: lower alkyl or lower alkenyl); - (CH)2)rCOOR57(wherein R is57: lower alkyl or lower alkenyl); - (CH) 2)qCONR58R59(wherein R is58: lower alkyl or lower alkenyl; and R59: h or lower alkyl or R58And R59Taken together to form: - (CH)2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-or- (CH)2)2NR57(CH2)2-; wherein R is57: h or lower alkyl); - (CH)2)rPO(OR60)2(wherein R is60: lower alkyl or lower alkenyl); (CH)2)rSO2R62(wherein R is62: lower alkyl or lower alkenyl) or- (CH)2)qC6H4R8(wherein R is8：H；F；Cl；CF3(ii) a A lower alkyl group; lower alkenyl or lower alkoxy).
-R8：H；F；Cl；CF3(ii) a A lower alkyl group; a lower alkenyl group; - (CH)2)oOR55(wherein R is55: lower alkyl or lower alkenyl); (CH)2)oSR56(wherein R is56: lower alkyl or lower alkenyl); - (CH)2)oNR33R34(wherein R is33: lower alkyl or lower alkenyl; r34: h or lower alkyl or R33And R34Taken together to form: - (CH)2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-or- (CH)2)2NR57(CH2)2-; wherein R is57: h or lower alkyl); - (CH)2)oOCONR33R75(wherein R is33: h or lower alkyl or lower alkenyl; r75: lower alkyl or R33And R75Taken together to form: - (CH)2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-or- (CH)2)2NR57(CH2)2-; wherein R is57: h or lower alkyl); - (CH)2)oNR20CONR33R82(wherein R is20: h or lower alkyl; r33: h or lower alkyl or lower alkenyl; r82: h or lower alkyl or R33And R82Taken together to form: - (CH)2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-or- (CH)2)2NR57(CH2)2-; wherein R is57: h or lower alkyl); - (CH)2)oN(R20)COR64(wherein: R20: h or lower alkyl; r64: lower alkyl or lower alkenyl); - (CH) 2)oCOOR57(wherein R is57: lower alkyl or lower alkenyl); - (CH)2)oCONR58R59(wherein R is58: lower alkyl or lower alkenyl; and R59: h or lower alkyl or R58And R59Taken together to form: - (CH)2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-or- (CH)2)2NR57(CH2)2-; wherein R is57: h or lower alkyl); - (CH)2)oPO(OR60)2(wherein R is60: lower alkyl or lower alkenyl); - (CH)2)oSO2R62(wherein R is62: lower alkyl or lower alkenyl) or- (CH)2)qC6H4R8(wherein R is8：H；F；Cl；CF3(ii) a A lower alkyl group; lower alkenyl or lower alkoxy).
-R9: a lower alkyl group; a lower alkenyl group; - (CH)2)oOR55(wherein R is55: lower alkyl or lower alkenyl); - (CH)2)oSR56(wherein R is56: lower alkyl or lower alkenyl); - (CH)2)oNR33R34(wherein R is33: lower alkyl or lower alkenyl; r34: h or lower alkyl or R33And R34Taken together to form: - (CH)2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-or- (CH)2)2NR57(CH2)2-; wherein R is57: h or lower alkyl); - (CH)2)oOCONR33R75(wherein R is33: h or lower alkyl or lower alkenyl; r75: lower alkyl or R33And R75Taken together to form: - (CH)2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-or- (CH)2)2NR57(CH2)2-; wherein R is57: h or lower alkyl); - (CH)2)mNR20CONR33R82(wherein R is20: h or lower alkyl; r33: h or lower alkyl or lowerAn alkenyl group; r82: h or lower alkyl or R33And R82Taken together to form: - (CH)2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-or- (CH)2)2NR57(CH2)2-; wherein R is57: h or lower alkyl); - (CH)2)oN(R20)COR64(wherein: R20: h or lower alkyl; r 64: lower alkyl or lower alkenyl); - (CH)2)oCOOR57(wherein R is57: lower alkyl or lower alkenyl); - (CH)2)oCONR58R59(wherein R is58: lower alkyl or lower alkenyl; and R59: h or lower alkyl or R58And R59Taken together to form: - (CH)2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-or- (CH)2)2NR57(CH2)2-; wherein R is57: h or lower alkyl); - (CH)2)oPO(OR60)2(wherein R is60: lower alkyl or lower alkenyl); - (CH)2)oSO2R62(wherein R is62: lower alkyl or lower alkenyl) or- (CH)2)qC6H4R8(wherein R is8：H；F；Cl；CF3(ii) a A lower alkyl group; lower alkenyl or lower alkoxy).
-R10: a lower alkyl group; a lower alkenyl group; - (CH)2)oOR55(wherein R is55: lower alkyl or lower alkenyl); - (CH)2)oSR56(wherein R is56: lower alkyl or lower alkenyl); - (CH)2)oNR33R34(wherein R is33: lower alkyl or lower alkenyl; r34: h or lower alkyl or R33And R34Taken together to form: - (C)H2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-or- (CH)2)2NR57(CH2)2-; wherein R is57: h or lower alkyl); - (CH)2)oOCONR33R75(wherein R is33: h or lower alkyl or lower alkenyl; r75: lower alkyl or R33And R75Taken together to form: - (CH)2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-or- (CH)2)2NR57(CH2)2-; wherein R is57: h or lower alkyl); - (CH)2)oNR20CONR33R82(wherein R is20: h or lower alkyl; r33: h or lower alkyl or lower alkenyl; r82: h or lower alkyl or R33And R82Taken together to form: - (CH)2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-or- (CH)2)2NR57(CH2)2-; wherein R is57: h or lower alkyl); - (CH) 2)oN(R20)COR64(wherein: R20: h or lower alkyl; r64: lower alkyl or lower alkenyl); - (CH)2)oCOOR57(wherein R is57: lower alkyl or lower alkenyl); - (CH)2)oCONR58R59(wherein R is58: lower alkyl or lower alkenyl; and R59: h; lower alkyl or R58And R59Taken together to form: - (CH)2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-or- (CH)2)2NR57(CH2)2-; wherein R is57: h or lower alkyl)；-(CH2)oPO(OR60)2(wherein R is60: lower alkyl or lower alkenyl); - (CH)2)oSO2R62(wherein R is62: lower alkyl or lower alkenyl) or- (CH)2)qC6H4R8(wherein R is8：H；F；Cl；CF3(ii) a A lower alkyl group; lower alkenyl or lower alkoxy).
-R11: h; a lower alkyl group; a lower alkenyl group; - (CH)2)mOR55(wherein R is55: lower alkyl or lower alkenyl); - (CH)2)mSR56(wherein R is56: lower alkyl or lower alkenyl); - (CH)2)mNR33R34(wherein R is33: lower alkyl or lower alkenyl; r34: h or lower alkyl or R33And R34Taken together to form: - (CH)2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-or- (CH)2)2NR57(CH2)2-; wherein R is57: h or lower alkyl); - (CH)2)mOCONR33R75(wherein R is33: h or lower alkyl or lower alkenyl; r75: lower alkyl or R33And R75Taken together to form: - (CH)2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-or- (CH)2)2NR57(CH2)2-; wherein R is57: h or lower alkyl); - (CH)2)mNR20CONR33R82(wherein R is20: h or lower alkyl; r33: h or lower alkyl or lower alkenyl; r82: h or lower alkyl or R33And R82Taken together to form: - (CH) 2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-or- (CH)2)2NR57(CH2)2-; wherein R is57: h or lower alkyl); - (CH)2)mN(R20)COR64(wherein: R20: h or lower alkyl; r64: lower alkyl or lower alkenyl); - (CH)2)oCOOR57(wherein R is57: lower alkyl or lower alkenyl); - (CH)2)oCONR58R59(wherein R is58: lower alkyl or lower alkenyl; and R59: h; lower alkyl or R58And R59Together form: - (CH)2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-or- (CH)2)2NR57(CH2)2-; wherein R is57: h or lower alkyl); - (CH)2)oPO(OR60)2(wherein R is60: lower alkyl or lower alkenyl); - (CH)2)oSO2R62(wherein R is62: lower alkyl or lower alkenyl) or- (CH)2)qC6H4R8(wherein R is8：H；F；Cl；CF3(ii) a A lower alkyl group; lower alkenyl or lower alkoxy).
-R12: h; a lower alkyl group; a lower alkenyl group; - (CH)2)mOR55(wherein R is55: lower alkyl or lower alkenyl); - (CH)2)mSR56(wherein R is56: lower alkyl or lower alkenyl); - (CH)2)mNR33R34(wherein R is33: lower alkyl or lower alkenyl; r34: h or lower alkyl or R33And R34Together form: - (CH)2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-or- (CH)2)2NR57(CH2)2-; wherein R is57: h or lower alkyl); - (CH)2)mOCONR33R75(wherein R is33: h or lower alkyl or lower alkenyl; r75: lower alkyl or R33And R75Taken together to form: - (CH)2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-or- (CH)2)2NR57(CH2)2-; wherein R is57: h or lower alkyl); - (CH)2)mNR20CONR33R82(wherein R is20: h or lower alkyl; r33: h or lower alkyl or lower alkenyl; r 82: h or lower alkyl or R33And R82Taken together to form: - (CH)2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-or- (CH)2)2NR57(CH2)2-; wherein R is57: h or lower alkyl); - (CH)2)mN(R20)COR64(wherein: R20: h or lower alkyl; r64: lower alkyl or lower alkenyl); - (CH)2)rCOOR57(wherein R is57: lower alkyl or lower alkenyl); - (CH)2)rCONR58R59(wherein R is58: lower alkyl or lower alkenyl; and R59: h or lower alkyl or R58And R59Taken together to form: - (CH)2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-or- (CH)2)2NR57(CH2)2-; wherein R is57: h or lower alkyl); - (CH)2)rPO(OR60)2(wherein R is60: lower alkyl or lower alkenyl); - (CH)2)oSO2R62(wherein R is62: lower alkyl or lower alkenyl) or- (CH)2)qC6H4R8(wherein R is8：H；F；Cl；CF3(ii) a A lower alkyl group; lower alkenyl or lower alkoxy).
-R13: a lower alkyl group; a lower alkenyl group; - (CH)2)qOR55(wherein R is55: lower alkyl or lower alkenyl); - (CH)2)qSR56(wherein R is56: lower alkyl or lower alkenyl); - (CH)2)qNR33R34(wherein R is33: lower alkyl or lower alkenyl; r34: h or lower alkyl or R33And R34Taken together to form: - (CH)2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-or- (CH)2)2NR57(CH2)2-; wherein R is57: h or lower alkyl); - (CH)2)qOCONR33R75(wherein R is33: h or lower alkyl or lower alkenyl; r75: lower alkyl or R33And R75Taken together to form: - (CH)2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-or- (CH)2)2NR57(CH2)2-; wherein R is57: h or lower alkyl); - (CH)2)qNR20CONR33R82(wherein R is20: h or lower alkyl; r 33: h or lower alkyl or lower alkenyl; r82: h or lower alkyl or R33And R82Taken together to form: - (CH)2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-or- (CH)2)2NR57(CH2)2-; wherein R is57: h or lower alkyl); - (CH)2)qN(R20)COR64(wherein: R20: h or lower alkyl; r64: lower alkyl or lower alkenyl); - (CH)2)rCOO57(wherein R is57: lower alkyl or lower alkenyl); - (CH)2)qCONR58R59(wherein R is58: lower alkyl or lower alkenyl; and R59: h or lower alkyl or R58And R59Taken together to form: - (CH)2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-or- (CH)2)2NR57(CH2)2-; wherein R is57: h or lower alkyl); - (CH)2)rPO(OR60)2(wherein R is60: lower alkyl or lower alkenyl); - (CH)2)rSO2R62(wherein R is62: lower alkyl or lower alkenyl) or- (CH)2)qC6H4R8(wherein R is8：H；F；Cl；CF3(ii) a A lower alkyl group; lower alkenyl or lower alkoxy).
-R14: h; a lower alkyl group; a lower alkenyl group; - (CH)2)mOR55(wherein R is55: lower alkyl or lower alkenyl); - (CH)2)mSR56(wherein R is56: lower alkyl or lower alkenyl); - (CH)2)mNR33R34(wherein R is33: lower alkyl or lower alkenyl; r34: h or lower alkyl or R33And R34Taken together to form: - (CH)2)2-6-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-or- (CH)2)2NR57(CH2)2-; wherein R is57: h or lower alkyl); - (CH)2)mOCONR33R75(wherein R is33: h or lower alkyl or lower alkeneA group; r75: lower alkyl or R33And R75Taken together to form: - (CH)2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-or- (CH)2)2NR57(CH2)2-; wherein R is57: h or lower alkyl); - (CH) 2)mNR20CONR33R82(wherein R is20: h or lower alkyl; r33: h or lower alkyl or lower alkenyl; r82: h or lower alkyl or R33And R82Taken together to form: - (CH)2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-or- (CH)2)2NR57(CH2)2-; wherein R is57: h or lower alkyl); - (CH)2)mN(R20)COR64(wherein: R20: h; a lower alkyl group; r64: lower alkyl or lower alkenyl); - (CH)2)oCOOR57(wherein R is57: lower alkyl or lower alkenyl); - (CH)2)oCONR58R59(wherein R is58: lower alkyl or lower alkenyl; and R59: h or lower alkyl or R58And R59Taken together to form: - (CH)2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-or- (CH)2)2NR57(CH2)2-; wherein R is57: h or lower alkyl); - (CH)2)oPO(OR60)2(wherein R is60: lower alkyl or lower alkenyl); - (CH)2)oSO2R62(wherein R is52: lower alkyl or lower alkenyl); - (CH)2)qC6H4R8(wherein R is8：H；F；Cl；CF3(ii) a A lower alkyl group; lower alkenyl orLower alkoxy).
-R15: a lower alkyl group; a lower alkenyl group; - (CH)2)oOR55(wherein R is55: lower alkyl or lower alkenyl); - (CH)2)oSR56(wherein R is56: lower alkyl or lower alkenyl); - (CH)2)oNR33R34(wherein R is33: lower alkyl or lower alkenyl; r34: h or lower alkyl or R33And R34Taken together to form: - (CH)2)2-6-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-or- (CH)2)2NR57(CH2)2-; wherein R is57: h or lower alkyl); - (CH)2)oOCONR33R75(wherein R is33: h or lower alkyl or lower alkenyl; r75: lower alkyl or R33And R75Taken together to form: - (CH) 2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-or- (CH)2)2NR57(CH2)2-; wherein R is57: h or lower alkyl); - (CH)2)oNR20CONR33R82(wherein R is20: h or lower alkyl; r33: h or lower alkyl or lower alkenyl; r82: h or lower alkyl or R33And R82Taken together to form: - (CH)2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-or- (CH)2)2NR57(CH2)2-; wherein R is57: h or lower alkyl); (CH)2)oN(R20)COR64(wherein: R20: h or lower alkyl; r64: lower alkyl or lower alkenyl); NR is particularly preferred20CO lower alkyl (R)20H or lower alkyl); - (CH)2)oCOOR57(wherein R is57: lower alkyl or lower alkenyl); - (CH)2)oCONR58R59(wherein R is58: lower alkyl or lower alkenyl; and R59: h; lower alkyl or R58And R59Taken together to form: - (CH)2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-or- (CH)2)2NR57(CH2)2-; wherein R is57: h or lower alkyl); - (CH)2)oPO(OR60)2(wherein R is60: lower alkyl or lower alkenyl); - (CH)2)oSO2R62(wherein R is62: lower alkyl or lower alkenyl) or- (CH)2)qC6H4R8(wherein R is8：H；F；Cl；CF3(ii) a A lower alkyl group; lower alkenyl or lower alkoxy).
-R16: a lower alkyl group; a lower alkenyl group; - (CH)2)oOR55(wherein R is55: lower alkyl or lower alkenyl); - (CH)2)oSR56(wherein R is56: lower alkyl or lower alkenyl); - (CH)2)oNR33R34(wherein R is33: lower alkyl or lower alkenyl; r34: h or lower alkyl or R33And R34Together form: - (CH)2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-or- (CH)2)2NR57(CH2)2-; wherein R is57: h or lower alkyl); - (CH) 2)oOCONR33R75(wherein R is33: h or lower alkyl or lower alkenyl; r75: lower alkyl or R33And R75Together form: - (CH)2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-or- (CH)2)2NR57(CH2)2-; wherein R is57: h or lower alkyl); - (CH)2)oNR20CONR33R82(wherein R is20: h or lower alkyl; r33: h or lower alkyl or lower alkenyl; r82: h or lower alkyl or R33And R82Taken together to form: - (CH)2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-or- (CH)2)2NR57(CH2)2-; wherein R is57: h or lower alkyl); - (CH)2)oN(R20)COR64(wherein: R20: h or lower alkyl; r64: lower alkyl or lower alkenyl); - (CH)2)oCOOR57(wherein R is57: lower alkyl or lower alkenyl); - (CH)2)oCONR58R59(wherein R is58: lower alkyl or lower alkenyl; and R59: h or lower alkyl or R58And R59Taken together to form: - (CH)2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-or- (CH)2)2NR57(CH2)2-; wherein R is57: h or lower alkyl); - (CH)2)oPO(OR60)2(wherein R is60: lower alkyl or lower alkenyl); - (CH)2)oSO2R62(wherein R is62: lower alkyl or lower alkenyl) or- (CH)2)qC6H4R8(wherein R is8：H；F；Cl；CF3(ii) a A lower alkyl group; lower alkenyl or lower alkoxy).
-R17: a lower alkyl group; a lower alkenyl group; - (CH)2)qOR55(wherein R is55: lower alkyl or lower alkenyl); - (CH)2)qSR56(wherein R is56: lower alkyl or lower alkenyl); - (CH)2)qNR33R34(wherein R is33: lower alkyl or lower alkenyl; r34: h or lower alkyl or R33And R34Taken together to form: - (CH) 2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-or- (CH)2)2NR57(CH2)2-; wherein R is57: h or lower alkyl); - (CH)2)qOCONR33R75(wherein R is33: h or lower alkyl or lower alkenyl; r75: lower alkyl or R33And R75Taken together to form: - (CH)2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-or- (CH)2)2NR57(CH2)2-; wherein R is57: h or lower alkyl); - (CH)2)qNR20CONR33R82(wherein R is20: h or lower alkyl; r33: h or lower alkyl or lower alkenyl; r82: h or lower alkyl or R33And R82Together form: - (CH)2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-or- (CH)2)2NR57(CH2)2-; wherein R is57: h or lower alkyl); - (CH)2)qN(R20)COR64(wherein: R20: h or lower alkyl; r64: lower alkyl or lower alkenyl); - (CH)2)rCOOR57(wherein R is57: lower alkyl or lower alkenyl); - (CH)2)qCONR58R59(wherein R is58: lower alkyl or lower alkenyl; and R59: h; lower alkyl or R58And R59Taken together to form: - (CH)2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-or- (CH)2)2NR57(CH2)2-; wherein R is57: h or lower alkyl); - (CH)2)rPO(OR60)2(wherein R is60: lower alkyl or lower alkenyl); - (CH)2)rSO2R62(wherein R is62: lower alkyl or lower alkenyl) or- (CH)2)qC6H4R8(wherein R is8：H；F；Cl；CF3(ii) a A lower alkyl group; lower alkenyl or lower alkoxy).
Among the structural units A1-A69, the following are preferred: r2A5, A8, A22, A25, R being H2A38, A42, A47 and A50 for H. Most preferred are building blocks of class A8':
wherein R is20Is H or lower alkyl; and R64Is an alkyl group; an alkenyl group; an aryl group; aryl-lower alkyl or heteroaryl-lower alkyl; in particular wherein R 64Is n-hexyl (A8' -1); n-heptyl (A8' -2); 4- (phenyl) benzyl (A8' -3); diphenylmethyl (A8' -4); 3-amino-propyl (A8' -5); 5-amino-pentyl (A8' -6); methyl (A8' -7); ethyl (A8' -8); isopropyl (A8' -9); isobutyl (A8' -10); n-propyl (A8' -11); cyclohexyl (A8' -12); cyclohexylmethyl (A8' -13); n-butyl (A8' -14); phenyl (A8' -15); benzyl (A8' -16); (3-indolyl) methyl (A8' -17); 2- (3-indolyl) ethyl (A8' -18); (4-phenyl) phenyl (A8' -19); and n-nonyl (A8' -20).
The structural unit A70 belongs to the open-chain alpha-substituted alpha-amino acid class, the structural units A71 and A72 to the corresponding beta-amino acid analogues, and the structural units A73-A104 to the cyclic analogues of A70. These amino acid derivatives have been shown to confine small peptides within a well-defined inverted or U-shaped configuration (C.M. Venkatachalam, Biopolymers, 1968, 6.1425-1434; W.Kabsch, C Sander, Biopplymers 1983, 22, 2577). These building blocks or templates are suitable for stabilizing the β -hairpin configuration in the Peptide loop (D.Obrecht, M.Altorfer, J.A.Robinson, "Novel Peptide mapping Blpcks and templates for Efficient Lead filing", adv.Med chem.1999, Vpl.4, 1-68; P.Balaram, "Non-standard amino acids in Peptide design and protein engineering", Current. Opin.Struct.Bipl.1992, 2, 851; M.Crisma, G.Valle, C.Toniolo, S.Prasad, R.B.Rao, HP.Balarn, ". β -Peptide mapping in Peptide library, S.Prasid, R.B.Rao, HP.Banstrum, P.beta.peptide mapping in Peptide library, strain, S.precursor, R.B.Rao, H.Bazart.J.J.27, J.J.J.Pat.35, J.249, J.J.J.Biocoding. J.31, J.J.Pat.32, J.J.J.Pat.35, J.Pat..
It has been shown that the two enantiomers of the structural elements-A70-CO-to A104-CO-combined with the structural elements-B-CO-of L-configuration can effectively stabilize and induce the β -hairpin configuration (D.Obrecht, M.Altorfer, J.A.Robinson, "Novel Peptide mimetic filing Blocks and Stretgies for effective Peptide binding", Adv.Med chem.1999, Vol.4, 1-68; D.Obrecht, C.Spiegler, P.Sch. nholzer, K.M muller, H.Heimgartner, F.Stierli, Helv.Chim.acta 1992, 75, 6-1696; D.Obrechhol, U.Dazel, J.Dal, C.Acmani, C.1995, Buv. Chim.C.Pat. C.3, C.D.H.H.D.H.D.C.D.H.Pat.7, C.7, C.C.D.7, C.C.C.D.E.D.D.H.D.D.D.E.C.3, C.E.C.D.D.E.C.D.D.7, C.E.C.D.E.C.D.3, C.E.C.C.D.D.D.D.E.D.C.D.D.D.D.D.D.D.D.D.D.D.E.E.C.C.C.D.D.C.D.E.C.C.C.D.D.D.D.D.D.C.C.D.D.D.D.E.C.C.D.C.C.E.C.D.E.C.C.C.D.C.D.35, H.D.D.D.C.C.D.D.D.D.C.D.D.C.C.D.D.D.D.D.C.C.C.C.D.D.D, 703-714).
Thus, for the purposes of the present invention, template (A1) may also consist of-A70-CO-to A104-CO-, where the structural element A70-A104, in combination with the structural element-B-CO-in the (L) -configuration, is either in the (D) -configuration or in the (L) -configuration.
R in A70-A10420Preferred values of (b) are H or lower alkyl, most preferably methyl. R in structural unit A70-A10418、R19And R21-R29Preferred values of (a) are as follows:
-R18: a lower alkyl group.
-R19: a lower alkyl group; a lower alkenyl group; - (CH)2)pOR55(wherein R is55: lower alkyl or lower alkenyl); - (CH)2)pSR56(wherein R is56: lower alkyl or lower alkenyl); - (CH)2)pNR33R34(wherein R is33: lower alkyl or lower alkenyl; r34: h or lower alkyl or R33And R34Taken together to form: - (CH)2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-or- (CH)2)2NR57(CH2)2-; wherein R is57: h or lower alkyl); - (CH)2)pOCONR33R75(wherein R is33: h or lower alkyl or lower alkenyl; r75: lower alkyl or R33And R75Taken together to form: - (CH)2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-or- (CH)2)2NR57(CH2)2-; wherein R is57: h or lower alkyl); - (CH)2)pNR20CONR33R82(wherein R is20: h or lower alkyl; r33: h or lower alkyl or lower alkenyl; r82: h or lower alkyl or R33And R82Taken together to form: - (CH)2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-or- (CH)2)2NR57(CH2)2-; wherein R is57: h or lower alkyl); - (CH)2)pN(R20)COR64(wherein: R20: h or lower alkyl; r64: lower alkyl or lower alkenyl); - (CH)2)pCOOR57(wherein R is57: lower alkyl or lower alkenyl); - (CH)2)pCONR58R59(wherein R is58: lower alkyl or lower alkenyl; and R59: h or lower alkyl or R58And R59Taken together to form: - (CH)2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-or- (CH)2)2NR57(CH2)2-; wherein R is 57: h or lower alkyl); - (CH)2)oPO(OR60)2(wherein R is60: lower alkyl or lower alkenyl); - (CH)2)pSO2R62(wherein R is62: lower alkyl or lower alkenyl) or- (CH)2)oC6H4R8(wherein R is8：H；F；Cl；CF3(ii) a A lower alkyl group; lower alkenyl or lower alkoxy).
-R21: h; a lower alkyl group; a lower alkenyl group; - (CH)2)oOR55(wherein R is55Lower alkyl or lower alkenyl); - (CH)2)oSR56(wherein R is56: lower alkyl or lower alkenyl); - (CH)2)oNR33R34(wherein R is33: lower alkyl or lower alkenyl; r34: h or lower alkyl or R33And R34Taken together to form: - (CH)2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-or- (CH)2)2NR57(CH2)2-; wherein R is57: h or lower alkyl); - (CH)2)oOCONR33R75(wherein R is33: h or lower alkyl or lower alkenyl; r75: lower alkyl or R33And R75Taken together to form: - (CH)2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-or- (CH)2)2NR57(CH2)2-; wherein R is57: h or lower alkyl); - (CH)2)oNR20CONR33R82(wherein R is20: h or lower alkyl; r33: h or lower alkyl or lower alkenyl; r82: h or lower alkyl or R33And R82Taken together to form: - (CH)2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-or- (CH)2)2NR57(CH2)2-; wherein R is57: h or lower alkyl); - (CH)2)oN(R20)COR64(wherein: R20: h or lower alkyl; r64: lower alkyl or lower alkenyl); - (CH)2)oCOOR57(wherein R is57: lower alkyl or lower alkenyl); - (CH)2)oCONR58R59(wherein R is58: lower alkyl or lower alkenyl; and R59: h; lower alkyl or R 58And R59Taken together to form: - (CH)2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-or- (CH)2)2NR57(CH2)2-; wherein R is57: h or lower alkyl); - (CH)2)oPO(OR60)2(wherein R is60: lower alkyl or lower chainAlkenyl); (CH)2)oSO2R62(wherein R is62: lower alkyl or lower alkenyl) or (CH)2)qC6H4R8(wherein R is8：H；F；Cl；CF3(ii) a A lower alkyl group; lower alkenyl or lower alkoxy).
-R22: a lower alkyl group; a lower alkenyl group; - (CH)2)oOR55(wherein R is55: lower alkyl or lower alkenyl); - (CH)2)oSR56(wherein R is56: lower alkyl or lower alkenyl); - (CH)2)oNR33R34(wherein R is33: lower alkyl or lower alkenyl; r34: h or lower alkyl or R33And R34Taken together to form: - (CH)2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-or- (CH)2)2NR57(CH2)2-; wherein R is57: h or lower alkyl); - (CH)2)oOCONR33R75(wherein R is33: h or lower alkyl or lower alkenyl; r75: lower alkyl or R33And R75Taken together to form: - (CH)2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-or- (CH)2)2NR57(CH2)2-; wherein R is57: h or lower alkyl); - (CH)2)oNR20CONR33R82(wherein R is20: h or lower alkyl; r33: h or lower alkyl or lower alkenyl; r82: h or lower alkyl or R33And R82Together form: - (CH)2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-or- (CH)2)2NR57(CH2)2-; wherein R is57: h or lower alkyl); - (CH)2)oN(R20)COR64(wherein: R20: h or lower alkyl; r64: lower alkyl or lower alkenyl); - (CH)2)oCOOR57(wherein R is57: lower alkyl or lower alkenyl); - (CH)2)oCONR58R59(wherein R is58: lower alkyl or lower alkenyl; and R 59: h; lower alkyl or R58And R59Taken together to form: - (CH)2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-or- (CH)2)2NR57(CH2)2-; wherein R is57: h or lower alkyl); - (CH)2)oPO(OR60)2(wherein R is60: lower alkyl or lower alkenyl); - (CH)2)oSO2R62(wherein R is62: lower alkyl or lower alkenyl) or- (CH)2)qC6H4R8(wherein R is8: h; f; cl; CF; a lower alkyl group; lower alkenyl or lower alkoxy).
-R23: h; a lower alkyl group; a lower alkenyl group; - (CH)2)oOR55(wherein R is55: lower alkyl or lower alkenyl); - (CH)2)oSR56(wherein R is56: lower alkyl or lower alkenyl); - (CH)2)oNR33R34(wherein R is33: lower alkyl or lower alkenyl; r34: h or lower alkyl or R33And R34Taken together to form: - (CH)2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-or- (CH)2)2NR57(CH2)2-; wherein R is57: h or lower alkyl); - (CH)2)oOCONR33R75(wherein R is33: h or lower alkyl or lower alkenyl; r75: lower alkyl or R33And R75Taken together to form: - (CH)2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-or- (CH)2)2NR57(CH2)2-; wherein R is57: h or lower alkyl); - (CH)2)oNR20CONR33R82(wherein R is20: h or lower alkyl; r33: h or lower alkyl or lower alkenyl; r82: h or lower alkyl or R33And R82Taken together to form: - (CH)2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-or- (CH)2)2NR57(CH2)2-; wherein R is57: h or lower alkyl); - (CH)2)oN(R20)COR64(wherein: R20: h or lower alkyl; r64: lower alkyl or lower alkenyl); NR is particularly preferred20CO lower alkyl (R) 20H or lower alkyl); - (CH)2)oCOOR57(wherein R is57: lower alkyl or lower alkenyl); - (CH)2)oCONR58R59(wherein R is58: lower alkyl or lower alkenyl; and R59: h; lower alkyl or R58And R59Together form: - (CH)2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-or- (CH)2)2NR57(CH2)2-; wherein R is57: h or lower alkyl); - (CH)2)oPO(OR60)2(wherein R is60: lower alkyl or lower alkenyl); - (CH)2)oSO2R62(wherein R is62: lower alkyl or lower alkenyl) or- (CH)2)qC6H4R8(wherein R is8：H；F；Cl；CF3(ii) a A lower alkyl group; lower alkenyl or lower alkoxy);
-R24: a lower alkyl group; a lower alkenyl group; - (CH)2)oOR55(wherein R is55: lower alkyl or lower alkenyl); - (CH)2)oSR56(wherein R is56: lower alkyl or lower alkenyl); - (CH)2)oNR33R34(wherein R is33: lower alkyl or lower alkenyl; r34: h or lower alkyl or R33And R34Taken together to form: - (CH)2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-or- (CH)2)2NR57(CH2)2-; wherein R is57: h or lower alkyl); - (CH)2)oOCONR33R75(wherein R is33: h or lower alkyl or lower alkenyl; r75: lower alkyl or R33And R75Taken together to form: - (CH)2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-or- (CH)2)2NR57(CH2)2-; wherein R is57: h or lower alkyl); - (CH)2)oNR20CONR33R82(wherein R is20: h or lower alkyl; r33: h or lower alkyl or lower alkenyl; r82: h or lower alkyl or R33And R82Taken together to form: - (CH)2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-or- (CH)2)2NR57(CH2)2-; wherein R is57: h or lower alkyl); - (CH) 2)oN(R20)COR64(wherein: R20: h or lower alkyl; r64: lower alkyl or lower alkenyl); NR is particularly preferred20CO lower alkyl (R)20H or lower alkyl); - (CH)2)oCOOR57(wherein R is57: lower alkyl or lower alkenyl); - (CH)2)oCONR58R59(wherein R is58: lower alkyl or lower alkenyl; and R59: h; lower alkyl or R58And R59Taken together to form: - (CH)2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-or- (CH)2)2NR57(CH2)2-; wherein R is57: h or lower alkyl); - (CH)2)oPO(OR60)2(wherein R is60: lower alkyl or lower alkenyl); - (CH)2)oSO2R62(wherein R is62: lower alkyl or lower alkenyl) or- (CH)2)qC6H4R8(wherein R is8：H；F；Cl；CF3(ii) a A lower alkyl group; lower alkenyl or lower alkoxy);
-R25: h; a lower alkyl group; a lower alkenyl group; - (CH)2)mOR55(wherein R is55: lower alkyl or lower alkenyl); - (CH)2)mNR33R34(wherein R is33: lower alkyl or lower alkenyl; r34: h or lower alkyl or R33And R34Taken together to form: - (CH)2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-or- (CH)2)2NR57(CH2)2-; wherein R is57: h or lower alkyl); - (CH)2)mOCONR33R75(wherein R is33: h or lower alkyl or lower alkenyl; r75: lower alkyl or R33And R75Taken together to form: - (CH)2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-or- (CH)2)2NR57(CH2)2-; wherein R is57: h or lower alkyl); - (CH)2)mNR20CONR33R82(wherein R is20: h or lower alkyl; r33: h or lower alkyl or lower alkenyl; r82: h or lower alkyl or R33And R82Taken together to form: - (CH) 2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-or- (CH)2)2NR57(CH2)2-; wherein R is57: h or lower alkyl); - (CH)2)mN(R20)COR64(wherein: R20: h or lower alkyl; r64: lower alkyl or lower alkenyl); - (CH)2)oCOOR57(wherein R is57: lower alkyl or lower alkenyl); - (CH)2)oCONR58R59(wherein R is58: lower alkyl or lower alkenyl; and R59: h; lower alkyl or R58And R59Taken together to form: - (CH)2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-or- (CH)2)2NR57(CH2)2-; wherein R is57: h or lower alkyl); - (CH)2)oPO(OR60)2(wherein R is60: lower alkyl or lower alkenyl); - (CH)2)oSO2R62(wherein R is62: lower alkyl or lower alkenyl) or- (CH)2)qC6H4R8(wherein R is8：H；F；Cl；CF3(ii) a A lower alkyl group; lower alkenyl or lower alkoxy).
-R26: h; a lower alkyl group; a lower alkenyl group; - (CH)2)mOR55(wherein R is55: lower alkyl or lower alkenyl); - (CH)2)mNR33R34(wherein R is33: lower alkyl or lower alkenyl; r34: h or lower alkyl or R33And R34Taken together to form: - (CH)2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-or- (CH)2)2NR57(CH2)2-; wherein R is57: h or lower alkyl); - (CH)2)mOCONR33R75(wherein R is33: h or lower alkyl or lower alkenyl; r75: lower alkyl or R33And R75Taken together to form: - (CH)2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-or- (CH)2)2NR57(CH2)2-; wherein R is57: h or lower alkyl); - (CH)2)mNR20CONR33R82(wherein R is20: h or lower alkyl; r33: h or lower alkyl or lower alkenyl; r82: h or lower alkyl or R33And R82Taken together to form: - (CH) 2)2-6-；-(CH2)2O(CH2)2-6-；-(CH2)2S(CH2)2-or- (CH)2)2NR57(CH2)2-6-; wherein R is57: h or lower alkyl); - (CH)2)mN(R20)COR64(wherein: R20: h or lower alkyl; r64: lower alkyl or lower alkenyl); - (CH)2)oCOOR57(wherein R is57: lower alkyl or lower alkenyl); - (CH)2)oCONR58R59(wherein R is58: lower alkyl or lower alkeneA group; and R59: h; lower alkyl or R58And R59Taken together to form: - (CH)2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-or- (CH)2)2NR57(CH2)2-; wherein R is57: h or lower alkyl); - (CH)2)oPO(OR60)2(wherein R is60: lower alkyl or lower alkenyl); - (CH)2)oSO2R62(wherein R is62: lower alkyl or lower alkenyl) or- (CH)2)qC6H4R8(wherein R is8：H；F；Cl；CF3(ii) a A lower alkyl group; lower alkenyl or lower alkoxy).
-in addition, R25And R26Taken together may be- (CH)2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-or- (CH)2)2NR57(CH2)2-; wherein R is57: h or lower alkyl).
-R27: h; a lower alkyl group; a lower alkenyl group; - (CH)2)oOR55(wherein R is55: lower alkyl or lower alkenyl); - (CH)2)oSR56(wherein R is56: lower alkyl or lower alkenyl); - (CH)2)oNR33R34(wherein R is33: lower alkyl or lower alkenyl; r34: h or lower alkyl or R33And R34Taken together to form: - (CH)2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-or- (CH)2)2NR57(CH2)2-; wherein R is57: h or lower alkyl); - (CH)2)oOCONR33R75(wherein R is33: h or lower alkyl or lower alkenyl; r75: lower alkyl or R33And R75Taken together to form: - (CH)2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-or- (CH)2)2NR57(CH2)2-; wherein R is57: h or lower alkyl); - (CH) 2)oNR20CONR33R82(wherein R is20: h or lower alkyl; r33: h or lower alkyl or lower alkenyl; r82: h or lower alkyl or R33And R82Taken together to form: - (CH)2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-or- (CH)2)2NR57(CH2)2-; wherein R is57: h or lower alkyl); - (CH)2)oN(R20)COR64(wherein: R20: h or lower alkyl; r64: lower alkyl or lower alkenyl); - (CH)2)oCOOR57(wherein R is57: lower alkyl or lower alkenyl); - (CH)2)oCONR58R59(wherein R is58: lower alkyl or lower alkenyl; and R59: h; lower alkyl or R58And R59Taken together to form: - (CH)2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-or- (CH)2)2NR57(CH2)2-; wherein R is57: h or lower alkyl); - (CH)2)oPO(OR60)2(wherein R is60: lower alkyl or lower alkenyl); - (CH)2)oSO2R62(wherein R is62: lower alkyl or lower alkenyl) or- (CH)2)qC6H4R8(wherein R is8：H；F；Cl；CF3(ii) a A lower alkyl group; lower alkenyl or lower alkoxy).
-R28: a lower alkyl group; a lower alkenyl group; - (CH)2)oOR55(wherein R is55: lower alkyl or lower alkenyl); - (CH)2)oS56(wherein R is56: lower alkyl or lower alkenyl); - (CH)2)oNR33R34(wherein R is33: lower alkyl or lower alkenyl; r34: h or lower alkyl or R33And R34Taken together to form: - (CH)2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-or- (CH)2)2NR57(CH2)2-; wherein R is57: h or lower alkyl); - (CH)2)oOCONR33R75(wherein R is33: h or lower alkyl or lower alkenyl; r75: lower alkyl or R33And R75Taken together to form: - (CH) 2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-or- (CH)2)2NR57(CH2)2-; wherein R is57: h or lower alkyl); - (CH)2)oNR20CONR33R82(wherein R is20: h or lower alkyl; r33: h or lower alkyl or lower alkenyl; r82: h or lower alkyl or R33And R82Taken together to form: - (CH)2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-or- (CH)2)2NR57(CH2)2-; wherein R is57: h or lower alkyl); - (CH)2)oN(R20)COR64(wherein: R20: h or lower alkyl; r64: lower alkyl or lower alkenyl); - (CH)2)oCOOR57(wherein R is57: lower alkyl or lower alkenyl); - (CH)2)oCONR58R59(wherein R is58: lower alkyl or lower alkenyl; and R59: h; lower alkyl or R58And R59Taken together to form: - (CH)2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-or- (CH)2)2NR57(CH2)2-; wherein R is57: h or lower alkyl); - (CH)2)oPO(OR60)2(wherein R is60: lower alkyl or lower alkenyl); - (CH)2)oSO2R62(wherein R is62: lower alkyl or lower alkenyl) or- (CH)2)qC6H4R8(wherein R is8：H；F；Cl；CF3(ii) a A lower alkyl group; lower alkenyl or lower alkoxy).
-R29: a lower alkyl group; a lower alkenyl group; - (CH)2)oOR55(wherein R is55: lower alkyl or lower alkenyl); - (CH)2)oSR56(wherein R is56: lower alkyl or lower alkenyl); - (CH)2)oNR33R34(wherein R is33: lower alkyl or lower alkenyl; r34: h or lower alkyl or R33And R34Taken together to form: - (CH)2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-or- (CH)2)2NR57(CH2)2-; wherein R is57: h or lower alkyl); - (CH)2)oOCONR33R75(wherein R is33: h or lower alkyl or lower alkenyl; r 75: lower alkyl or R33And R75Taken together to form: - (CH)2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-or- (CH)2)2NR57(CH2)2-; wherein R is57: h or lower alkyl); - (CH)2)oNR20CONR33R82(wherein R is20: h or lower alkyl; r33: h or lower alkyl or lower alkenyl; r82: h or lower alkyl or R33And R82Taken together to form: - (CH)2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-or- (CH)2)2NR57(CH2)2-; wherein R is57: h or lower alkyl); - (CH)2)oN(R20)COR64(wherein: R20: h or lower alkyl; r64: lower alkyl or lower alkenyl); particularly preferred is NR20CO lower-alkyl (R)20H or lower alkyl); - (CH)2)oCOOR57(wherein R is57: lower alkyl or lower alkenyl); - (CH)2)oCONR58R59(wherein R is58: lower alkyl or lower alkenyl; and R59: h; lower alkyl or R58And R59Taken together to form: - (CH)2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-or- (CH)2)2NR57(CH2)2-; wherein R is57: h or lower alkyl); - (CH)2)oPO(OR60)2(wherein R is60: lower alkyl or lower alkenyl); - (CH)2)oSO2R62(wherein R is62: lower alkyl or lower alkenyl) or- (CH)2)qC6H4R8(wherein R is8：H；F；Cl；CF3(ii) a A lower alkyl group; lower alkenyl or lower alkoxy).
For templates (b) - (p), e.g., (b1) and (c1), preferred values for the various symbols are as follows:
-R8：H；F；Cl；CF3(ii) a A lower alkyl group; a lower alkenyl group; - (CH)2)oOR55(wherein R is55: lower alkyl or lower alkenyl); - (CH)2)oSR56(wherein R is56: lower alkyl or lower alkenyl); - (CH)2)oNR33R34(wherein R is 33: lower alkyl or lower alkenyl; r34: h or lower alkyl or R33And R34Taken together to form: - (CH)2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-or- (CH)2)2NR57(CH2)2-; wherein R is57: h or lower alkyl); - (CH)2)oOCONR33R75(wherein R is33: h or lower alkyl or lower alkenyl; r75: lower alkyl or R33And R75Taken together to form: - (CH)2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-or- (CH)2)2NR57(CH2)2-; wherein R is57: h or lower alkyl); - (CH)2)oNR20CONR33R82(wherein R is20: h or lower alkyl; r33: h or lower alkyl or lower alkenyl; r82: h or lower alkyl or R33And R82Taken together to form: - (CH)2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-or- (CH)2)2NR57(CH2)2-; wherein R is57: h or lower alkyl); - (CH)2)oN(R20)COR64(wherein: R20: h or lower alkyl; r64: lower alkyl or lower alkenyl); - (CH)2)oCOOR57(wherein R is57: lower alkyl or lower alkenyl); - (CH)2)oCONR58R59(wherein R is58: lower alkyl or lower alkenyl; and R59: h or lower alkyl or R58And R59Taken together to form: - (CH)2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-or- (CH)2)2NR57(CH2)2-; wherein R is57: h or lower alkyl); - (CH)2)oPO(OR60)2(wherein R is60: lower alkyl or lower alkenyl); - (CH)2)oSO2R62(wherein R is62: lower alkyl or lower alkenyl) or- (CH)2)qC6H4R8(wherein R is8：H；F；Cl；CF3(ii) a A lower alkyl group; lower alkenyl or lower alkoxy).
-R20: h or lower alkyl.
-R30: H. a methyl group.
-R31: h; a lower alkyl group; a lower alkenyl group; - (CH)2)pOR55(wherein R is55: lower alkyl or lower alkenyl); - (CH) 2)pNR33R34(wherein R is33: lower alkyl or lower alkenyl; r34: h or lower alkyl or R33And R34Taken together to form: - (CH)2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-or- (CH)2)2NR57(CH2)2-; wherein R57: h or lower alkyl); - (CH)2)pOCONR33R75(wherein R is33: h or lower alkyl or lower alkenyl; r75: lower alkyl or R33And R75Taken together to form: - (CH)2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-or- (CH)2)2NR57(CH2)2-; wherein R is57: h or lower alkyl); - (CH)2)pNR20CONR33R82(wherein R is20: h or lower alkyl; r33: h or lower alkyl or lower alkenyl; r82: h or lower alkyl or R33And R82Taken together to form: - (CH)2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-or- (CH)2)2NR57(CH2)2-; wherein R is57: h or lower alkyl); - (CH)2)pN(R20)COR64(wherein: R20: h or lower alkyl; r64: lower alkyl or lower alkenyl); - (CH)2)oCOOR57(wherein R is57: lower alkyl or lower alkenyl); (-CH)2)oCONR58R59(wherein R is58: lower alkyl or lower alkenyl; and R59: h; lower alkyl or R58And R59Taken together to form: - (CH)2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-or- (CH)2)2NR57(CH2)2-; wherein R is57: h or lower alkyl); - (CH)2)oPO(OR60)2(wherein R is60: lower alkyl or lower alkenyl); - (CH)2)oSO2R62(wherein R is62: lower alkyl or lower alkenyl) or- (CH)2)rC6H4R8(wherein R is8：H；F；Cl；CF3(ii) a A lower alkyl group; lower alkenyl or lower alkoxy); most preferably is-CH2CONR58R59(R58: h or lower alkyl; r59: lower alkyl or lower alkenyl).
-R32: H. a methyl group.
-R33: a lower alkyl group; a lower alkenyl group; - (CH)2)mOR55(wherein R is55: lower alkyl or lower alkenyl); - (CH)2)mNR34R63(wherein R is34: lower alkyl or lower alkenyl; r63: h or lower alkyl or R34And R63Taken together to form: - (CH)2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-or- (CH)2)2NR57(CH2)2-; wherein R is57: h or lower alkyl); (CH)2)mOCONR75R82(wherein R is75: lower alkyl or lower alkenyl; r82: h or lower alkyl or R75And R82Taken together to form: - (CH)2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-or- (CH)2)2NR57(CH2)2-; wherein R is57: h or lower alkyl); - (CH)2)mNR20CONR78R82(wherein R is20: h or lower alkyl; r78: h or lower alkyl or lower alkenyl; r82: h or lower alkyl or R78And R82Together form: - (CH)2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-or- (CH)2)2NR57(CH2)2-; wherein R is57: h or lower alkyl); - (CH)2)mN(R20)COR64(wherein: R20: h or lower alkyl; r64: is low inLower alkyl or lower alkenyl); - (CH)2)oCOOR57(wherein R is57: lower alkyl or lower alkenyl); - (CH)2)oCONR58R59(wherein R is58: lower alkyl or lower alkenyl; and R59: h; lower alkyl or R58And R59Taken together to form: - (CH)2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-or- (CH)2)2NR57(CH2)2-; wherein R is57: h or lower alkyl).
-R34: h or lower alkyl.
-R35: h; a lower alkyl group; a lower alkenyl group; - (CH)2)mOR55(wherein R is55: lower alkyl or lower alkenyl); - (CH)2)mNR33R34(wherein R is33: lower alkyl or lower alkenyl; r34: h or lower alkyl or R 33And R34Taken together to form: - (CH)2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-or- (CH)2)2NR57(CH2)2-; wherein R is57: h or lower alkyl); - (CH)2)mOCONR33R75(wherein R is33: h or lower alkyl or lower alkenyl; r75: lower alkyl or R33And R75Taken together to form: - (CH)2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-or- (CH)2)2NR57(CH2)2-; wherein R is57: h or lower alkyl); - (CH)2)mNR20CONR33R82(wherein R is20: h or lower alkyl; r33: h or lower alkyl orA lower alkenyl group; r82: h or lower alkyl or R33And R82Taken together to form: - (CH)2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-or- (CH)2)2NR57(CH2)2-; wherein R is57: h or lower alkyl); - (CH)2)mN(R20)COR64(wherein: R20: h or lower alkyl; r64: lower alkyl or lower alkenyl); - (CH)2)oCOOR57(wherein R is57: lower alkyl or lower alkenyl); - (CH)2)oCONR59R59(wherein R is58: lower alkyl or lower alkenyl; and R59: h; lower alkyl or R58And R59Taken together to form: - (CH)2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-or- (CH)2)2NR57(CH2)2-; wherein R is57: h or lower alkyl).
-R36: a lower alkyl group; lower alkenyl or aryl-lower alkyl.
-R37: h; a lower alkyl group; a lower alkenyl group; - (CH)2)pOR55(wherein R is55: lower alkyl or lower alkenyl); - (CH)2)pNR33R34(wherein R is33: lower alkyl or lower alkenyl; r34: h or lower alkyl or R33And R34Taken together to form: - (CH)2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-or- (CH)2)2NR57(CH2)2-; wherein R is57: h or lower alkyl); - (CH)2)pOCONR33R75(wherein R is33: h or lower alkyl Alkyl or lower alkenyl; r75: lower alkyl or R33And R75Taken together to form: - (CH)2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-or- (CH)2)2NR57(CH2)2-; wherein R is57: h or lower alkyl); - (CH)2)pNR20CONR33R82(wherein R is20: h or lower alkyl; r33: h or lower alkyl or lower alkenyl; r82: h or lower alkyl or R33And R82Taken together to form: - (CH)2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-or- (CH)2)2NR57(CH2)2-; wherein R is57: h or lower alkyl); - (CH)2)pN(R20)COR64(wherein: R20: h or lower alkyl; r64: lower alkyl or lower alkenyl); - (CH)2)oCOOR57(wherein R is57: lower alkyl or lower alkenyl); - (CH)2)oCONR58R59(wherein R is58: lower alkyl or lower alkenyl; and R59: h; lower alkyl or R58And R59Taken together to form: - (CH)2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-or- (CH)2)2NR57(CH2)2-; wherein R is57: h or lower alkyl); - (CH)2)oPO(OR60)2(wherein R is60: lower alkyl or lower alkenyl); - (CH)2)oSO2R62(wherein R is62: lower alkyl or lower alkenyl) or- (CH)2)qC6H4R8(wherein R is8：H；F；Cl；CF3(ii) a A lower alkyl group; low gradeAlkenyl or lower alkoxy).
-R38: h; a lower alkyl group; a lower alkenyl group; - (CH)2)pOR55(wherein R is55: lower alkyl or lower alkenyl); - (CH)2)pNR33R34(wherein R is33: lower alkyl or lower alkenyl; r34: h or lower alkyl or R33And R34Taken together to form: - (CH)2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-or- (CH)2)2NR57(CH2)2-; wherein R is57: h or lower alkyl); - (CH)2)pOCONR33R75(wherein R is33: h or lower alkyl or lower alkenyl; r 75: lower alkyl or R33And R78Taken together to form: - (CH)2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-or- (CH)2)2NR57(CH2)2-; wherein R is57: h or lower alkyl); - (CH)2)pNR20CONR33R82(wherein R is20: h or lower alkyl; r33: h or lower alkyl or lower alkenyl; r82: h or lower alkyl or R33And R82Taken together to form: - (CH)2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-or- (CH)2)2NR57(CH2)2-; wherein R is57: h or lower alkyl); - (CH)2)pN(R20)COR64(wherein: R20: h or lower alkyl; r64: lower alkyl or lower alkenyl); - (CH)2)oCOOR57(wherein R is57: lower alkyl or lower alkenyl); - (CH)2)oCONR58R59(wherein R is58: lower alkyl or lower alkenyl; and R59: h; lower alkyl or R58And R59Taken together to form: - (CH)2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-or- (CH)2)2NR57(CH2)2-; wherein R is57: h or lower alkyl); - (CH)2)oPO(OR60)2(wherein R is60: lower alkyl or lower alkenyl); - (CH)2)oSO2R62(wherein R is62: lower alkyl or lower alkenyl) or- (CH)2)qC6H4R8(wherein R is8：H；F；Cl；CF3(ii) a A lower alkyl group; lower alkenyl or lower alkoxy).
-R39: h; a lower alkyl group; a lower alkenyl group; - (CH)2)mOR55(wherein R is55: lower alkyl or lower alkenyl); - (CH)2)mN(R20)COR64(wherein: R20: h or lower alkyl; r64: lower alkyl or lower alkenyl); - (CH)2)oCOOR57(wherein R is57: lower alkyl or lower alkenyl); - (CH)2)oCONR58R59(wherein R is58: lower alkyl or lower alkenyl; and R59: h; lower alkyl or R 58And R59Taken together to form: - (CH)2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-or- (CH)2)2NR57(CH2)2-; wherein R is57: h or lower alkyl).
-R40: a lower alkyl group; lower alkenyl or aryl-lower alkyl.
-R41: h; a lower alkyl group; lower alkenesA group; - (CH)2)pOR55(wherein R is55: lower alkyl or lower alkenyl); - (CH)2)pNR33R34(wherein R is33: lower alkyl or lower alkenyl; r34: h or lower alkyl or R33And R34Taken together to form: - (CH)2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-or- (CH)2)2NR57(CH2)2-; wherein R is57: h or lower alkyl); - (CH)2)pOCONR33R75(wherein R is33: h or lower alkyl or lower alkenyl; r75: lower alkyl or R33And R75Taken together to form: - (CH)2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-or- (CH)2)2NR57(CH2)2-; wherein R is57: h or lower alkyl); - (CH)2)pNR20CONR33R82(wherein R is20: h or lower alkyl; r33: h or lower alkyl or lower alkenyl; r82: h or lower alkyl or R33And R82Taken together to form: - (CH)2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-or- (CH)2)2NR57(CH2)2-; wherein R is57: h or lower alkyl); - (CH)2)pN(R20)COR64(wherein: R20: h or lower alkyl; r64: lower alkyl or lower alkenyl); - (CH)2)oCOOR57(wherein R is57: lower alkyl or lower alkenyl); - (CH)2)oCONR58R59(wherein R is58: lower alkyl or lower alkenyl; and R59: h; lower alkyl or R58And R59Taken together to form: - (CH)2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-or- (CH)2)2NR57(CH2)2-; wherein R is57: h or lower alkyl); - (CH)2)oPO(OR60)2(wherein R is60: lower alkyl or lower alkenyl); - (CH) 2)oSO2R62(wherein R is62: lower alkyl or lower alkenyl) or- (CH)2)qC6H4R8(wherein R is8：H；F；Cl；CF3(ii) a A lower alkyl group; lower alkenyl or lower alkoxy).
-R42: h; a lower alkyl group; a lower alkenyl group; - (CH)2)pOR55(wherein R is55: lower alkyl or lower alkenyl); - (CH)2)pNR33R34(wherein R is33: lower alkyl or lower alkenyl; r34: h or lower alkyl or R33And R34Taken together to form: - (CH)2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-or- (CH)2)2NR57(CH2)2-; wherein R is57: h or lower alkyl); - (CH)2)pOCONR33R75(wherein R is33: h or lower alkyl or lower alkenyl; r75: lower alkyl or R33And R75Taken together to form: - (CH)2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-or- (CH)2)2NR57(CH2)2-; wherein R is57: h or lower alkyl); - (CH)2)pNR20CONR33R82(wherein R is20: h or lower alkyl; r33: h or lowLower alkyl or lower alkenyl; r82: h or lower alkyl or R33And R82Taken together to form: - (CH)2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-or- (CH)2)2NR57(CH2)2-; wherein R is57: h or lower alkyl); - (CH)2)pN(R20)COR64(wherein: R20: h or lower alkyl; r64: lower alkyl or lower alkenyl); - (CH)2)oCOOR57(wherein R is57: lower alkyl or lower alkenyl); - (CH)2)oCONR58R59(wherein R is58: lower alkyl or lower alkenyl; and R59: h; lower alkyl or R58And R59Taken together to form: - (CH)2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-or- (CH)2)2NR57(CH2)2-; wherein R is57: h or lower alkyl); - (CH)2)oPO(OR60)2(wherein R is60: lower alkyl or lower alkenyl); - (CH) 2)oSO2R62(wherein R is62: lower alkyl or lower alkenyl) or- (CH)2)qC6H4R8(wherein R is8：H；F；Cl；CF3(ii) a A lower alkyl group; lower alkenyl or lower alkoxy).
-R43: h; a lower alkyl group; a lower alkenyl group; - (CH)2)mOR55(wherein R is55: lower alkyl or lower alkenyl); - (CH)2)mSR56(wherein R is56: lower alkyl or lower alkenyl); - (CH)2)mNR33R34(wherein R is33: lower alkyl or lower alkenyl; r34: h or lower alkyl or R33And R34Taken together to form: - (CH)2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-or- (CH)2)2NR57(CH2)2-; wherein R is57: h or lower alkyl); - (CH)2)mOCONR33R75(wherein R is33: h or lower alkyl or lower alkenyl; r75: lower alkyl or R33And R75Taken together to form: - (CH)2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-or- (CH)2)2NR57(CH2)2-; wherein R is57: h or lower alkyl); - (CH)2)mNR20CONR33R82(wherein R is20: h or lower alkyl; r33: h or lower alkyl or lower alkenyl; r82: h or lower alkyl or R33And R82Taken together to form: - (CH)2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-or- (CH)2)2NR57(CH2)2-; wherein R is57: h or lower alkyl); - (CH)2)mN(R20)COR64(wherein: R20: h or lower alkyl; r64: lower alkyl or lower alkenyl); - (CH)2)oCOOR57(wherein R is67: lower alkyl or lower alkenyl); - (CH)2)oCONR58R59(wherein R is58: lower alkyl or lower alkenyl; and R59: h; lower alkyl or R58And R59Taken together to form: - (CH)2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-or- (CH)2)2NR57(CH2)2-; wherein R is57: h or lower alkyl); - (CH) 2)oPO(OR60)2(wherein R is60: lower alkyl or lower alkenyl); - (CH)2)oSO2R62(wherein R is62: lower alkyl or lower alkenyl) or- (CH)2)qC6H4R8(wherein R is8：H；F；Cl；CF3(ii) a A lower alkyl group; lower alkenyl or lower alkoxy).
-R44: a lower alkyl group; a lower alkenyl group; - (CH)2)pOR55(wherein R is55: lower alkyl or lower alkenyl); - (CH)2)pSR56(wherein R is56: lower alkyl or lower alkenyl); - (CH)2)pNR33R34(wherein R is33: lower alkyl or lower alkenyl; r34: h or lower alkyl or R33And R34Taken together to form: - (CH)2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-or- (CH)2)2NR57(CH2)2-; wherein R is57: h or lower alkyl); - (CH)2)pOCONR33R75(wherein R is33: h or lower alkyl or lower alkenyl; r75: lower alkyl or R33And R78Taken together to form: - (CH)2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-or- (CH)2)2NR57(CH2)2-; wherein R is57: h or lower alkyl); - (CH)2)pNR20CONR33R82(wherein R is20: h or lower alkyl; r33: h or lower alkyl or lower alkenyl; r82: h or lower alkyl or R33And R82Taken together to form: - (CH)2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-or- (CH)2)2NR57(CH2)2-; wherein R is57: h or lower alkyl); - (CH)2)pN(R20)COR64(wherein: R20: h or lower alkyl; r64: lower alkyl or lower alkenyl); - (CH)2)pCOOR57(wherein R is57: lower alkyl or lower alkenyl); - (CH)2)pCONR58R59(wherein R is58: lower alkyl or lower alkenyl; and R59: h; lower alkyl or R58And R59Taken together to form: - (CH) 2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-or- (CH)2)2NR57(CH2)2-; wherein R is57: h or lower alkyl) or- (CH)2)oC6H4R8(wherein R is8：H；F；Cl；CF3(ii) a A lower alkyl group; lower alkenyl or lower alkoxy).
-R45: h; a lower alkyl group; a lower alkenyl group; - (CH)2)oOR55(wherein R is55: lower alkyl or lower alkenyl); - (CH)2)oSR56(wherein R is56: lower alkyl or lower alkenyl); - (CH)2)oNR33R34(wherein R is33: lower alkyl or lower alkenyl; r34: h or lower alkyl or R33And R34Taken together to form: - (CH)2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-or- (CH)2)2NR57(CH2)2-; wherein R is57: h or lower alkyl); - (CH)2)sOCONR33R75(wherein R is33: h or lower alkyl or lower alkenyl; r75: lower alkyl or R33And R75Taken together to form: - (CH)2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-or- (CH)2)2NR57(CH2)2-; wherein R is57: h or lower alkyl); - (CH)2)oNR20CONR33R82(wherein R is20: h or lower alkyl; r33: h or lower alkyl or lower alkenyl; r82: h or lower alkyl or R33And R82Taken together to form: - (CH)2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-or- (CH)2)2NR57(CH2)2-; wherein R is57: h or lower alkyl); - (CH)2)oN(R20)COR64(wherein: R20: h or lower alkyl; r64: lower alkyl or lower alkenyl); - (CH)2)oCOOR57(wherein R is57: lower alkyl or lower alkenyl); - (CH)2)oCONR58R59(wherein R is58: lower alkyl or lower alkenyl; and R59: h; lower alkyl or R58And R59Taken together to form: - (CH)2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-or- (CH)2)2NR57(CH2)2-; wherein R is57: h or lower alkyl) or- (CH) 2)sC6H4R8(wherein R is8：H；F；Cl；CF3(ii) a A lower alkyl group; lower alkenyl or lower alkoxy).
-R46: h; a lower alkyl group; a lower alkenyl group; - (CH)2)sOR55(wherein R is55: lower alkyl or lower alkenyl); - (CH)2)sSR56(wherein R is56: lower alkyl or lower alkenyl); - (CH)2)sNR33R34(wherein R is33: lower alkyl or lower alkenyl; r34: h or lower alkyl or R33And R34Taken together to form: - (CH)2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-or- (CH)2)2NR57(CH2)2-; wherein R is57: h or lower alkyl); - (CH)2)sOCONR33R75(wherein R is33: h or lower alkyl or lower alkenyl; r75: lower alkyl or R33And R75Taken together to form: - (CH)2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-or- (CH)2)2NR57(CH2)2-; wherein R is57: h or lower alkyl); - (CH)2)sNR20CONR33R82(wherein R is20: h or lower alkyl; r33: h or lower alkyl or lower alkenyl; r82: h or lower alkyl or R33And R82Together form: - (CH)2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-or- (CH)2)2NR57(CH2)2-; wherein R is57: h or lower alkyl); - (CH)2)sN(R20)COR64(wherein: R20: h or lower alkyl; r64: lower alkyl or lower alkenyl); - (CH)2)oCOOR57(wherein R is57: lower alkyl or lower alkenyl); - (CH)2)oCONR58R59(wherein R is58: lower alkyl or lower alkenyl; and R59: h; lower alkyl or R59And R59Is connected toTogether form: - (CH)2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-or- (CH)2)2NR57(CH2)2-; wherein R is57: h or lower alkyl) or- (CH)2)sC6H4R8(wherein R is8：H；F；Cl；CF3(ii) a A lower alkyl group; lower alkenyl or lower alkoxy).
-R47: h OR OR55(wherein R is55: lower alkyl or lower alkenyl).
-R48: h or lower alkyl.
-R49: h; a lower alkyl group; - (CH)2)oCOOR57(wherein R is57: lower alkyl or lower alkenyl); - (CH)2)oCONR58R59(wherein R is58: lower alkyl or lower alkenyl; and R59: h; lower alkyl or R58And R59Taken together to form: - (CH)2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-or- (CH)2)2NR57(CH2)2-; wherein R is57: h or lower alkyl) or (CH)2)sC6H4R8(wherein R is8：H；F；Cl；CF3(ii) a A lower alkyl group; lower alkenyl or lower alkoxy).
-R50: h; a methyl group.
-R51: h; a lower alkyl group; a lower alkenyl group; - (CH)2)mOR55(wherein R is55: lower alkyl or lower alkenyl); - (CH)2)mNR33R34(wherein R is33: lower alkyl or lower alkenyl; r34: h or lower alkyl or R33And R34Are connected togetherForming: - (CH)2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-or- (CH)2)2NR57(CH2)2-; wherein R is57: h or lower alkyl); (CH)2)mOCONR33R75(wherein R is33: h or lower alkyl or lower alkenyl; r75: lower alkyl or R33And R75Taken together to form: - (CH)2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-or- (CH)2)2NR57(CH2)2-; wherein R is57: h or lower alkyl); - (CH)2)mNR20CONR33R82(wherein R is20: h or lower alkyl; r33: h or lower alkyl or lower alkenyl; r82: h or lower alkyl or R33And R82Taken together to form: - (CH)2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-or- (CH)2)2NR57(CH2)2-; wherein R is57: h or lower alkyl); - (CH)2)mN(R20)COR64(wherein: R20: h or lower alkyl; r64: lower alkyl or lower alkenyl); - (CH) 2)pCOOR57(wherein R is57: lower alkyl or lower alkenyl); - (CH)2)pCONR58R59(wherein R is58: lower alkyl or lower alkenyl; and R59: h; lower alkyl or R58And R59Taken together to form: - (CH)2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-or- (CH)2)2NR57(CH2)2-; wherein R is57: h or lowAlkyl) or- (CH)2)rC6H4R8(wherein R is8：H；F；Cl；CF3(ii) a A lower alkyl group; lower alkenyl or lower alkoxy).
-R62: h; a lower alkyl group; a lower alkenyl group; - (CH)2)mOR55(wherein R is55: lower alkyl or lower alkenyl); - (CH)2)mNR33R34(wherein R is33: lower alkyl or lower alkenyl; r34: h or lower alkyl or R33And R34Taken together to form: - (CH)2)2-6；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-or- (CH)2)2NR57(CH2)2-; wherein R is57: h or lower alkyl); - (CH)2)mOCONR33R75(wherein R is33: h or lower alkyl or lower alkenyl; r75: lower alkyl or R33And R75Taken together to form: - (CH)2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-or- (CH)2)2NR57(CH2)2-; wherein R is57: h or lower alkyl); - (CH)2)mNR20CONR33R62(wherein R is20: h or lower alkyl; r33: h or lower alkyl or lower alkenyl; r82: h or lower alkyl or R33And R82Taken together to form: - (CH)2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-or- (CH)2)2NR57(CH2)2-；R57: h or lower alkyl); - (CH)2)mN(R20)COR64(wherein: R20: h or lower alkyl; r64: lower alkyl or lower chainAlkenyl); - (CH)2)pCOOR57(wherein R is57: lower alkyl or lower alkenyl); - (CH)2)pCONR58R59(wherein R is58: lower alkyl or lower alkenyl; and R59: h; lower alkyl or R 58And R59Taken together to form: - (CH)2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-or- (CH)2)2NR57(CH2)2-; wherein R is57: h or lower alkyl) or- (CH)2)rC6H4R8(wherein R is8：H；F；Cl；CF3(ii) a A lower alkyl group; lower alkenyl or lower alkoxy).
-R53: h; a lower alkyl group; a lower alkenyl group; - (CH)2)mOR55(wherein R is55: lower alkyl or lower alkenyl); - (CH)2)mNR33R34(wherein R is33: lower alkyl or lower alkenyl; r34: h or lower alkyl or R33And R34Taken together to form: - (CH)2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-or- (CH)2)2NR57(CH2)2-; wherein R is57: h or lower alkyl); - (CH)2)mOCONR33R75(wherein R is33: h or lower alkyl or lower alkenyl; r75: lower alkyl or R33And R75Taken together to form: - (CH)2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-or- (CH)2)2NR57(CH2)2-; wherein R is57: h or lower alkyl); - (CH)2)mNR20CONR33R82(wherein R is20: h or lower alkyl; r33: h or lower alkyl or lower alkenyl; r82: h or lower alkyl or R33And R82Taken together to form: - (CH)2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-or- (CH)2)2NR57(CH2)2-; wherein R is57: h or lower alkyl); - (CH)2)mN(R20)COR64(wherein: R20: h or lower alkyl; r64: lower alkyl or lower alkenyl); - (CH)2)pCOOR57(wherein R is57: lower alkyl or lower alkenyl); - (CH)2)pCONR58R59(wherein R is58: lower alkyl or lower alkenyl; and R59: h; lower alkyl or R58And R59Taken together to form: - (CH)2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-or- (CH)2)2NR57(CH2)2-; wherein R is57: h or lower alkyl) or- (CH)2)rC6H4R8(wherein R is8：H；F；Cl；CF3(ii) a A lower alkyl group; lower alkenyl or lower alkoxy).
-R54: a lower alkyl group; lower alkenyl or aryl-lower alkyl.
Among the structural elements A70-A104, preference is given to: r22A74 for H, R22A75, a76, a77, a78 and a79 which are H.
The structural units-B-CO-in templates (a1) and (a2) represent L-amino acid residues. Preferred values for B are: -NR20CH(R71) -and R2A5 radical R being H2Is the enantiomer of A8, a22, a25, a38, a42, a47, and a50 of H. Most preferably it is
Ala L-alanine
Arg L-arginine
Asn L-asparagine
Cys L-cysteine
Gln L-Glutamine
Gly glycine
His L-histidine
Ile L-isoleucine
Leu L-leucine
Lys L-lysine
Met L-methionine
Phe L-phenylalanine
Pro L-proline
Ser L-serine
Thr L-threonine
Trp L-Tryptophan
Tyr L-tyrosine
Val L-valine
Cit L-citrulline
Orn L-Ornithine
tBuA L-tert-butylalanine
Sar sarcosine
t-BuG L-tert-butylglycine
4AmPhe L-p-aminophenylalanine
3AmPhe L-m-aminophenylalanine
2AmPhe L-O-aminophenylalanine
Phe(mC(NH2) H) L-M-amidinophenylalanine
Phe(pC(NH2) (NH) L-Paramidinophenylalanine
Phe(mNHC(NH2) (NH) L-m-guanidinophenylalanine
Phe(pNHC(NH2) (NH) L-p-guanidinophenylalanine
Phg L-phenylglycine
Cha L-Cyclohexylalanine
C4al L-3-Cyclobutylalanine
C5al L-3-Cyclopentylalanine
Nle L-norleucine
2-Nal L-2-naphthylalanine
1-Nal L-1-naphthylalanine
4Cl-Phe L-4-chlorophenylalanine
3Cl-Phe L-3-chlorophenylalanine
2Cl-Phe L-2-chlorophenylalanine
3，4Cl2-Phe L-3, 4-dichlorophenylalanine
4F-Phe L-4-fluorophenylalanine
3F-Phe L-3-fluorophenylalanine
2F-Phe L-2-fluorophenylalanine
Tic L-1, 2, 3, 4-tetrahydroisoquinoline-3-carboxylic acid
Thi L-beta-2-thienylalanine
Tza L-2-Thiazolylalanine
Mso L-methionine sulfoxide
AcLys L-N-acetyl lysine
Dpr L-2, 3-diaminopropionic acid
A2Bu L-2, 4-diaminobutyric acid
Dbu (S) -2, 3-diaminobutyric acid
Abu gamma-aminobutyric acid (GABA)
Aha epsilon-aminocaproic acid
Aib alpha-aminoisobutyric acid
Y (Bzl) L-O-benzyltyrosine
Bip L-biphenylalanine
S (Bzl) L-O-benzylserine
T (Bzl) L-O-benzylthreonine
hHa L-homo-cyclohexylalanine
hCys L-homo-cysteine
hSer L-homo-serine
hArg L-homo-arginine
hPhe L-homo-phenylalanine
Bpa L-4-benzoylphenylalanine
Pip L-pipecolic acid
OctG L-octyl glycine
MePhe L-N-Methylphenylalanine
Menle L-N-Methylnorleucine
MeAla L-N-methylalanine
MeIle L-N-methylisoleucine
MeVal L-N-methylvaline
MeLeu L-N-methylleucine
Furthermore, the most preferred values of B also include groups of the type A8 "in the (L) -configuration:
wherein R is20Is H or lower alkyl and R64Is an alkyl group; an alkenyl group; an aryl group; aryl-lower alkyl or heteroaryl-lower alkyl; in particular wherein R64Is n-hexyl (A8' -21); n-heptyl (A8 "-22); 4- (phenyl) benzyl (A8 "-23); diphenylmethyl (A8 "-24); 3-amino-propyl (A8 "-25); 5-amino-pentyl (A8 "-26); methyl (A8' -27); ethyl (A8' -28); isopropyl (A8 "-29); isobutyl (A8 "-30); n-propyl (A8 "-31); cyclohexyl (A8 "-32); cyclohexylmethyl (A8 "-33); n-butyl (A8 "-34); phenyl (A8' -35); benzyl (A8' -36); (3-indolyl) methyl (A8 "-37); 2- (3-indolyl) ethyl (A8 "-38); (4-phenyl) phenyl (A8 "-39); and n-nonyl (A8 "-40).
As used hereinThe peptide chain Z, Z in the beta-hairpin mimetic1And Z2Are generally defined in terms of amino acid residues belonging to one of the following groups:
group-C-NR20GH(R72) CO-; "hydrophobic: small to medium size "
group-D-NR20CH(R73) CO-; "hydrophobic: large aromatic or heteroaromatic compounds "
group-E-NR20CH(R74) CO-; "polar-cationic", starvylamino "and" urea-derived "
group-F-NR20CH(R84) CO-; "polar-uncharged"
group-H-NR20-CH(CO-)-(CH2)4-7-CH(CO-)-NR20-；
-NR20-CH(CO-)-(CH2)pSS(CH2)p-CH(CO-)-NR20-；
-NR20-CH(CO-)-(-(CH2)pNR20CO(CH2)p-CH(CO-)-NR20-; and
-NR20-CH(CO-)-(-(CH2)pNR20CONR20(CH2)p-CH(CO-)-NR20-；
"interchain bond"
Moreover, chain Z, Z1And Z2The amino acid residue in (A) may also be of the formula-A-CO-or of the formula-B-CO-, wherein A and B are as defined above. Finally, Gly may also be chain Z, Z1And Z2And Pro may also be chain Z, Z1And Z2Provided that the position of the interchain bond (H) is excluded.
According to the substituent R72Group C includes amino acid residues having hydrophobic side chain groups of small to medium size. Hydrophobic residue means free at physiological pHAmino acid side chains that are electrically and repelled by aqueous solutions. And these side chains are typically free of hydrogen bond donor groups such as, but not limited to, primary and secondary amides, primary and secondary amines and their corresponding protonated salts, thiols, alcohols, phosphonates, phosphates, ureas, or thioureas. However, they may contain hydrogen bond acceptor groups such as ethers, thioethers, esters, tertiary amides, alkyl-or arylphosphonates and phosphates or tertiary amines. Small to medium size amino acids encoded by a gene include alanine, isoleucine, leucine, methionine and valine.
According to the substituent R73Group D includes amino acid residues having aromatic and heteroaromatic side chain groups. By aromatic amino acid residue is meant a hydrophobic amino acid having a side chain comprising at least one ring, said ring having a conjugated pi-electron system (aromatic group). In addition, they may contain hydrogen bond donor groups such as, but not limited to, primary and secondary amides, primary and secondary amines and their corresponding protonated salts, thiols, alcohols, phosphonates, phosphate esters, ureas or thioureas, and hydrogen bond acceptor groups such as, but not limited to, ethers, thioethers, esters, tertiary amides, alkyl-or arylphosphonates and phosphates or tertiary amines. Aromatic amino acids encoded by the gene include phenylalanine and tyrosine.
According to the substituent R77By heteroaromatic amino acid residue is meant, as is conventionally defined, a hydrophobic amino acid having a side chain containing at least one ring having a conjugated pi-system incorporating at least one heteroatom such as, but not limited to, O, S and N. In addition, these residues may contain hydrogen bond donor groups such as, but not limited to, primary and secondary amides, primary and secondary amines and their corresponding protonated salts, thiols, alcohols, phosphonates, phosphate esters, ureas, or thioureas, as well as hydrogen bond acceptor groups such as, but not limited to, ethers, thioethers, esters, tertiary amides, alkyl-or arylphosphonates, and phosphates or tertiary amines. The gene encodes heteroaromatic amino acids including tryptophan and histidine.
According to the substituent R74Group E includes amino acids containing side chains with polar-cationic, acylamino-and urea-derived residues. Polarity-Cationic refers to a basic side chain that is protonated at physiological pH. The polar-cationic amino acids encoded by the gene include arginine, lysine and histidine. Citrulline is an example of a urea-derived amino acid residue.
According to the substituent R84Group F includes amino acids containing side chains with polar-uncharged residues. Polar-uncharged residue refers to a hydrophilic side chain which is uncharged at physiological pH, but is not repelled by aqueous solutions. These side chains typically contain hydrogen bond donor groups such as, but not limited to, primary and secondary amides, primary and secondary amines, thiols, alcohols, phosphonates, phosphates, ureas, or thioureas. These groups can form a hydrogen bonding network with water molecules. In addition, they may also contain hydrogen bond acceptor groups such as, but not limited to, ethers, thioethers, esters, tertiary amides, alkyl-or arylphosphonates and phosphates or tertiary amines. The polar-uncharged amino acids encoded by the gene include asparagine, cysteine, glutamine, serine and threonine.
Group H includes side chains of preferably (L) -amino acids at relative positions of the beta-strand region where interchain bonds can be formed. The most widely known bond is the disulfide bond formed by cysteine and homocysteine located in opposite positions of the β -chain. Various methods are known for forming disulfide bonds, including those described in the following documents: synthesis 1979, 955-957, J.P.Tam et al; stewart et al, Solid Phase Peptide Synthesis, 2d Ed., Pierce chemical company, III., 1984; ahmed et al J.biol.chem.1975, 250, 8477-8482; and Pennington et al, Peptides, pages 164-. Most advantageously, disulfide bonds may be prepared using acetamidomethyl (Acm) -protecting groups for cysteine as described later in the relevant example (step 3) herein. A well-defined interchain linkage is that ornithine and lysine are linked to glutamic acid and aspartic acid residues, respectively, at opposite β -strand positions by formation of amide bonds. Preferred protecting groups for the side chain amino-groups of ornithine and lysine are allyloxycarbonyl (Alloc) and, for aspartic acid and glutamic acid, allyl esters, as described later in the relevant examples (step 4) herein. Finally, interchain linkages may also be established by linking the amino groups of lysine and ornithine at opposite β -strand positions to reagents such as N, N-carbonylimidazole to form cyclic ureas.
As previously mentioned, the interchain bonds are located as follows:
-if n is 8: positions P2 and P7 are linked together;
-if n is 9: positions P2 and P8 are linked together;
-if n ═ 10: positions P3 and P8 are linked together;
-if n ═ 11: positions P4 and P8; and/or P2 and P10 are linked together;
-if n ═ 12: positions P4 and P9; and/or P2 and P11 are linked together;
if n is 13: positions P4 and P10; and/or positions P2 and P12 are linked together;
-if n ═ 14: positions P5 and P10; and/or P3 and P12 are linked together; and
if n is 15: positions P6 and P10; and/or P4 and P12; and/or P2 and P14.
-if n ═ 16: positions P6 and P11; and/or P4 and P13; and/or P2 and P15 are linked together.
These interchain linkages are known to stabilize the β -hairpin configuration and thus constitute an important structural element of the appearance of β -hairpin mimetics.
Most preferred chain of amino acid residues Z, Z1And Z2Are those derived from natural alpha-amino acids. The following lists these amino acids as such or residues thereof suitable for the purposes of the present invention, the abbreviations of which correspond to the commonly employed convention:
three-letter code-one-letter code
Ala L-alanine A
Arg L-arginine R
Asn L-asparagine N
Asp L-aspartic acid D
Cys L-cysteine C
Glu L-glutamic acid E
Gln L-Glutamine Q
Gly glycine G
His L-histidine H
Ile L-isoleucine I
Leu L-leucine L
Lys L-lysine K
Met L-methionine M
Phe L-phenylalanine F
Pro L-proline P
DPro D-proline DP
Ser L-serine S
Thr L-threonine T
Trp L-Tryptophan W
Tyr L-tyrosine Y
Val L-valine V
Other α -amino acids suitable for use in the present invention by themselves or residues thereof include:
Cit L-citrulline
Orn L-Ornithine
tBuA L-tert-butylalanine
Sar sarcosine
Pen L-penicillamine
t-BuG L-tert-butylglycine
4AmPhe L-p-aminophenylalanine
3AmPhe L-m-aminophenylalanine
2AmPhe L-O-aminophenylalanine
Phe(mC(NH2) H) L-M-amidinophenylalanine
Phe(pC(NH2) (NH) L-Paramidinophenylalanine
Phe(mNHC(NH2) (NH) L-m-guanidinophenylalanine
Phe(pNHC(NH2) (NH) L-p-guanidinophenylalanine
Phg L-phenylglycine
Cha L-Cyclohexylalanine
C4al L-3-Cyclobutylalanine
C5al L-3-Cyclopentylalanine
Nle L-norleucine
2-Nal L-2-naphthylalanine
1-Nal L-1-naphthylalanine
4Cl-Phe L-4-chlorophenylalanine
3Cl-Phe L-3-chlorophenylalanine
2Cl-Phe L-2-chlorophenylalanine
3，4Cl2-Phe L-3, 4-dichlorophenylalanine
4F-Phe L-4-fluorophenylalanine
3F-Phe L-3-fluorophenylalanine
2F-Phe L-2-fluorophenylalanine
Tic 1, 2, 3, 4-tetrahydroisoquinoline-3-carboxylic acid
Thi L-beta-2-thienylalanine
Tza L-2-Thiazolylalanine
Mso L-methionine sulfoxide
AcLys N-acetyl lysine
Dpr 2, 3-diaminopropionic acid
A2Bu 2, 4-diaminobutyric acid
Dbu (S) -2, 3-diaminobutyric acid
Abu gamma-aminobutyric acid (GABA)
Aha epsilon-aminocaproic acid
Aib alpha-aminoisobutyric acid
Y (Bzl) L-O-benzyltyrosine
Bip L- (4-phenyl) phenylalanine
S (Bzl) L-O-benzylserine
T (Bzl) L-O-benzylthreonine
hHa L-homo-cyclohexylalanine
hCys L-homo-cysteine
hSer L-homo-serine
hArg L-homo-arginine
hPhe L-homo-phenylalanine
Bpa L-4-benzoylphenylalanine
4-AmPyrr1 (2S, 4S) -4-amino-pyrrolidine-L-carboxylic acid
4-AmPyrr2 (2S, 4R) -4-amino-pyrrolidine-L-carboxylic acid
4-Phepyrr1 (2S, 5R) -4-phenyl-pyrrolidine-L-carboxylic acid
4-Phepyrr2 (2S, 5S) -4-phenyl-pyrrolidine-L-carboxylic acid
5-Phepyrr1 (2S, 5R) -5-phenyl-pyrrolidine-L-carboxylic acid
5-Phepyrr2 (2S, 5S) -5-phenyl-pyrrolidine-L-carboxylic acid
Pro (4-OH)1 (4S) -L-hydroxyproline
Pro (4-OH)2 (4R) -L-hydroxyproline
Pip L-pipecolic acid
DPip D-pipecolic acid
OctG L-octyl glycine
MePhe L-N-Methylphenylalanine
Menle L-N-Methylnorleucine
MeAla L-N-methylalanine
MeIle L-N-methylisoleucine
MeVal L-N-methylvaline
MeLeu L-N-methylleucine
For group C, particularly preferred residues are:
ala L-alanine
Ile L-isoleucine
Leu L-leucine
Met L-methionine
Val L-valine
tBuA L-tert-butylalanine
t-BuG L-tert-butylglycine
Cha L-Cyclohexylalanine
C4al L-3-Cyclobutylalanine
C5al L-3-Cyclopentylalanine
Nle L-norleucine
hHa L-homo-cyclohexylalanine
OctG L-octyl glycine
MePhe L-N-Methylphenylalanine
Menle L-N-Methylnorleucine
MeAla L-N-methylalanine
MeIle L-N-methylisoleucine
MeVal L-N-methylvaline
MeLeu L-N-methylleucine
For group D, particularly preferred residues are:
his L-histidine
Phe L-phenylalanine
Trp L-Tryptophan
Tyr L-tyrosine
Phg L-phenylglycine
2-Nal L-2-naphthylalanine
1-Nal L-1-naphthylalanine
4Cl-Phe L-4-chlorophenylalanine
3Cl-Phe L-3-chlorophenylalanine
2Cl-Phe L-2-chlorophenylalanine
3，4Cl2-Phe L-3, 4-dichlorophenylalanine
4F-Phe L-4-fluorophenylalanine
3F-Phe L-3-fluorophenylalanine
2F-Phe L-2-fluorophenylalanine
Thi L-beta-2-thienylalanine
Tza L-2-Thiazolylalanine
Y (Bzl) L-O-benzyltyrosine
Bip L-biphenylalanine
S (Bzl) L-O-benzylserine
T (Bzl) L-O-benzylthreonine
hPhe L-homo-phenylalanine
Bpa L-4-benzoylphenylalanine
For group E, particularly preferred residues are:
arg L-arginine
Lys L-lysine
Orn L-Ornithine
Dpr L-2, 3-diaminopropionic acid
A2Bu L-2, 4-diaminobutyric acid
Dbu (S) -2, 3-diaminobutyric acid
Phe(pNH2) L-p-aminophenylalanine
Phe(mNH2) L-m-aminophenylalanine
Phe(oNH2) L-O-aminophenylalanine
hArg L-homo-arginine
Phe(mC(NH2) H) L-M-amidinophenylalanine
Phe(pC(NH2) (NH) L-Paramidinophenylalanine
Phe(mNHC(NH2) (NH) L-m-guanidinophenylalanine
Phe(pNHC(NH2) (NH) L-p-guanidinophenylalanine
Cit L-citrulline
For group F, particularly preferred residues are:
asn L-asparagine
Cys L-cysteine
Glu L-Glutamine
Ser L-serine
Thr L-threonine
Cit L-citrulline
Pen L-penicillamine
AcLys L-N epsilon-acetyl lysine
hCys L-homo-cysteine
hSer L-homo-serine
In dimeric structure Ib, preferred substituents for forming groups G1 and G2 are as follows, with the proviso that R33Is lower alkyl or lower alkenyl; r34Is H or lower alkyl; and R is61Is H:
R2：-(CH2)mO-；-(CH2)mNR33R34-；-(CH2)oCO-
R5：-(CH2)oO-；-(CH2)oNR33R34-；-(CH2)oCO-
R6：-(CH2)oO-；-(CH2)oNR33R34-；-(CH2)oCO-
R8：-(CH2)oO-；-(CH2)oNR33R34-；-(CH2)oCO-
R9：-(CH2)oO-；-(CH2)oNR33R34-；-(CH2)oCO-
R10：-(CH2)oO-；-(CH2)oNR33R34-；-(CH2)oCO-
R11：-(CH2)mO-；-(CH2)mNR33R34-；-(CH2)oCO-
R14：-(CH2)mO-；-(CH2)mNR33R34-；-(CH2)oCO-
R15：-(CH2)mO-；-(CH2)mNR33R34-；-(CH2)oCO-
R16：-(CH2)mO-；-(CH2)mNR33R34-；-(CH2)oCO-
R18：-(CH2)pO-；-(CH2)pNR33R34-；-(CH2)pCO-
R19：-(CH2)pO-；-(CH2)pNR33R34-；-(CH2)pCO-
R21：-(CH2)oO-；-(CH2)oNR33R34-；-(CH2)oCO-
R23：-(CH2)oO-；-(CH2)oNR33R34-；-(CH2)oCO-
R24：-(CH2)oO-；-(CH2)oNR33R34-；-(CH2)oCO-
R25：-(CH2)mO-；-(CH2)mNR33R34-；-(CH2)oCO-
R26：-(CH2)mO-；-(CH2)mNR33R34-；-(CH2)oCO-
R28：-(CH2)oO-；-(CH2)oNR33R34-；-(CH2)oCO-
R29：-(CH2)oO-；-(CH2)oNR33R34-；-(CH2)oCO-
R31：-(CH2)pO-；-(CH2)pNR33R34-；-(CH2)pCO-
R37：-(CH2)pO-；-(CH2)pNR33R34-；-(CH2)oCO-
R38：-(CH2)pO-；-(CH2)pNR33R34-；-(CH2)oCO-
R41：-(CH2)pO-；-(CH2)pNR33R34；-(CH2)oCO-
R42：-(CH2)pO-；-(CH2)pNR33R34-；-(CH2)oCO-
R45：-(CH2)oO-；-(CH2)oNR33R34-；-(CH2)sCO-
R47：-(CH2)oO-
R49：-(CH2)sO-；-(CH2)sCO-
R51：-(CH2)mO-；-(CH2)mNR33R34-；-(CH2)oCO-
R52：-(CH2)mO-；-(CH2)mNR33R34-；-(CH2)oCO-
R53：-(CH2)mO-；-(CH2)mNR33R34；-(CH2)oCO-
and with the further proviso that preferred linker molecules L are defined below, R34Is H or lower alkyl; x is O; s; NR (nitrogen to noise ratio)34；-NR34CONR34or-OCOO-; and Y is C 6R67R68R69R70：
L1：-(CH2)p[X(CH2)p]o-
L2：-CO(CH2)p[X(CH2)p]oCO-
L3：-CONR34(CH2)p[X(CH2)p]oNR34CO-
L4：-O(CH2)p[X(CH2)p]oO-
L6：-NR34(CH2)p[X(CH2)p]oNR34-
L7：-(CH2)oY(CH2)o-
L8：-CO(CH2)oY(CH2)oCO-
L9：-CONR34(CH2)oY(CH2)oNR34CO-
L10：-O(CH2)oY(CH2)oO-
L11：-S(CH2)oY(CH2)oS-
L12：-NR34(CH2)oY(CH2)oNR34-
L13：-CO(CH2)p[X(CH2)p]oNR34-
L14：-CO(CH2)oY(CH2)oNR34-
L15 -NR34(CH2)p[X(CH2)p]oCO-
L16-NR34(CH2)oY(CH2)oCO-
Provided that
-(CH2)mO-may be bound to linker L1, L2, L3, L7, L8, or L9;
-(CH2)oo-can be connected with a jointL1, L2, L3, L7, L8 or L9;
-(CH2)po-may be bound to linker L1, L2, L3, L7, L8, or L9;
-(CH2)so-may be bound to linker L1, L2, L3, L7, L8, or L9;
-(CH2)mNR34-may bind to linker L1, L2, L3, L7, L8 or L9;
-(CH2)oNR34-may bind to linker L1, L2, L3, L7, L8 or L9;
-(CH2)pNR34-may bind to linker L1, L2, L3, L7, L8 or L9;
-(CH2)oCO-may be bound to linker L4, L5, L6, L1O, L11 or L12;
-(CH2)pCO-may be bound to linker L4, L5, L6, L10, L11 or L12;
-(CH2)sCO-may be bound to linker L4, L5, L6, L1O, L11 or L12;
-(CH2)mo-can be conjugated to linker L13 or L14 and the resulting conjugate can be conjugated to- (CH)2)oCO-；-(CH2)pCO-or- (CH)2)sCO-binding;
-(CH2)oo-can be conjugated to linker L13 or L14 and the resulting conjugate can be conjugated to- (CH)2)oCO-；-(CH2)pCO-or- (CH)2)sCO-binding;
-(CH2)po-can be conjugated to linker L13 or L14 and the resulting conjugate can be conjugated to- (CH)2)oCO-；-(CH2)pCO-or- (CH)2)sCO-binding;
-(CH2)so-canTo linker L13 or L14 and the resulting conjugate may be conjugated to- (CH)2)oCO-；-(CH2)pCO-or- (CH)2)sCO-binding;
-(CH2)mNR34-may be conjugated to linker L13 or L14 and the resulting conjugate may be conjugated to- (CH)2)oCO-；-(CH2)pCO-or- (CH)2)sCO-binding;
-(CH2)oNR34-may be conjugated to linker L13 or L14 and the resulting conjugate may be conjugated to- (CH) 2)oCO-；-(CH2)pCO-or- (CH)2)sCO-binding;
-(CH2)pNR34-may be conjugated to linker L13 or L14 and the resulting conjugate may be conjugated to- (CH)2)oCO-；-(CH2)pCO-or- (CH)2)sCO-binding;
-(CH2)oCO-may be conjugated to linker L15 or L16 and the resulting conjugate may be conjugated to- (CH)2)mX-；-(CH2)oX-；-(CH2)pX-or- (CH)2)qX-binding;
-(CH2)pCO-may be conjugated to linker L15 or L16 and the resulting conjugate may be conjugated to- (CH)2)mX-；-(CH2)oX-；-(CH2)pX-or- (CH)2)qX-binding;
-(CH2)sCO-may be conjugated to linker L15 or L16 and the resulting conjugate may be conjugated to- (CH)2)mX-；-(CH2)oX-；-(CH2)pX-or- (CH)2)qX-binding;
in general, peptide chain Z, Z within the beta-hairpin mimetics of the invention1Or Z2Comprising 8 to 16 amino acid residues (n-8-16). Each amino acid residue is inChain Z, Z1Or Z2Position P in1-PnThe definition is as follows: p1Representative chain Z, Z1Or Z2The first amino acid in (a), which is coupled with its N-terminus to the C-terminus of template (B) - (P) or to a group-B-CO-in template (a1), or to a group-A-CO-in template a2, and PnRepresentative chain Z, Z1Or Z2The last amino acid in (a), which is coupled with its C-terminus to the N-terminus of template (B) - (p) or to a group-A-CO-in template (a1) or to a group-B-CO-in template (a 2). Position P1-PnEach of which preferably contains an amino acid residue belonging to one or both of the above C-F classes, as follows:
-if n is 8, the amino acid residues in positions 1-8 are preferably:
-P1: class C or class D or class E;
-P2: class E or class D;
-P3: class E;
-P4: class E or formula-A1-A69-CO-;
-P5: e or formula-B-CO-;
-P6: class D;
-P7: class E or class D and
-P8: class C or class D or class E;
-it may also be the D-isomer at P4 and P5;
-if n is 9, the amino acid residues in positions 1-9 are preferably:
-P1: class C or class D or class E;
-P2: class E or class D;
-P3: class C;
-P4: class E, or the residue is Pro;
-P5: class E, or the residue is Pro;
-P6: class D or E, or the residue is Pro;
-P7: class E or class D;
-P8: class E or class D and
-P9: class C or class D or class E;
-it may also be the D-isomer at P4, P5 and P6;
-if n is 10, the amino acid residues in positions 1-10 are preferably:
-P1: class C or class D or class E;
-P2: class E or class D;
-P3: class C;
-P4: class E or class D;
-P5: class E or formula-A1-A69-CO-;
-P6: e or formula-B-CO-;
-P7: class D or class E;
-P8: class D;
-P9: class E or class D and
-P10: class C or class D or class E;
-it may also be the D-isomer at P5 and P6;
-if n is 11, the amino acid residues in positions 1-11 are preferably:
-P1: class C or class D or class E;
-P2: class E or class D;
-P3: class D;
-P4: class E or class C;
-P5: class E, or the residue is Pro;
-P6: class E, or the residue is Pro;
-P7: class E, or the residue is Pro;
-P8: class D or class E;
-P9: class D;
-P10: class E or class D and
-P11: class C or class D or class E;
-it may also be the D-isomer at P5, P6 and P7;
-if n is 12, the amino acid residues in positions 1-12 are preferably:
-P1: class C or E or class D or class F;
-P2: class E or class D;
-P3: class C or class D;
-P4: class E;
-P5: class E or class C;
-P6: class E or class F or of formula-A1-A69-CO-;
-P7: e or formula-B-CO-;
-P8: class D;
-P9: class E or class D;
-P10: class D;
-P11: class E or class D and
-P12: class C or E or class D or class F;
-it may also be the D-isomer at P6 and P7;
-if n is 13, the amino acid residues in positions 1-13 are preferably:
-P1: class C or class D or class E;
-P2: class E or class D;
-P3: class C or class D;
-P4: class E or class C;
-P5: class E or class D;
-P6: class E or class F, or the residue is Pro;
-P7: class E, or the residue is Pro;
-P8: class D, or the residue is Pro;
-P9: class D;
-P10: class E or class C;
-P11: class C or class D;
-P12: class E or class D and
-P13: class C or class D or class E;
-it may also be the D-isomer at P6, P7 and P8;
-if n is 14, the amino acid residues in positions 1-14 are preferably:
-P1: class C or class D or class E;
-P2: class E or class D;
-P3: class C or class D;
-P4: class D;
-P5: class E;
-P6: class E;
-P7: class E or class F or of formula-A1-A69-CO-;
-P8: e or formula-B-CO-;
-P9: class D;
-P10: class C;
-P11: class E or class D;
-P12: class D or class C;
-P13: class E or class D and
-P14: class C or class D or class E;
-it may also be the D-isomer at P7 and P8;
-if n is 15, the amino acid residues in positions 1-15 are preferably:
-P1: class C and class D or class E;
-P2: class E or class D;
-P3: class C and class D;
-P4: class E or class C;
-P5: class C;
-P6: class E or class D;
-P7: class C, or the residue is Pro;
-P8: class E or class F, or the residue is Pro;
-P9: class E or class F, or the residue is Pro;
-P10: class E;
-P11: class C;
-P12: class E or class C;
-P13: class D or class C;
-P14: class E or class D and
-P15: class C and class D or class E;
-it may also be the D-isomer at P7, P8 and P9; and
-if n is 16, the amino acid residues in positions 1-16 are preferably:
-P1: class D or class E;
-P2: class E or class D;
-P3: class C or class D;
-P4: class E or class D;
-P5: class D;
-P6: class E;
-P7: class E or class F;
-P8: class E or class F or of formula-A1-A69-CO-;
-P9: e or formula-B-CO-;
-P10: class D;
-P11: class E;
-P12: class D;
-P13: class E or class C;
-P14: class C or class D;
-P15: class E or class D and
-P16: class C or class D or class E;
d-isomers are also possible at P8 and P9.
If n is 12, the amino acid residues in positions 1-12 are most preferably:
-P1: leu; arg; lys; tyr; trp; val; gln or 4-AmPhe;
-P2: arg; trp or Gln;
-P3: leu; val; ile or Phe;
-P4: lys; arg; gln or Orn;
-P5: lys or Arg;
-P6: arg; y (Bzl) orDY(Bzl)；
-P7：Arg；
-P8: trp; bip; 1-Nal; y (Bzl) or Val;
-P9: lys; arg or n; tyr; trp or Gln;
-P10: tyr; t (Bzl) or Y (Bzl);
-P11: arg or Tyr; and
-P12: val; arg; 1-Nal or 4-AmPhe.
Particularly preferred β -peptide mimetics of the invention include those described in examples 106, 137, 161, 197, 206, 222, 230, 250, 256, 267, 277, 281, 283, 284, 285, 286, 289, 294, 295, 296, 297 and 298.
The method of the invention can advantageously be carried out as a parallel batch (array) synthesis, resulting in a library of template-immobilized β -hairpin peptidomimetics having the general formula I above. These parallel syntheses can yield a batch (typically 24-192, usually 96) of compounds of formula I in high yield and specified purity, minimizing the formation of dimeric and multimeric by-products. Thus, proper selection of the functionalized solid support (i.e., solid support plus linker molecule), template, and cyclization sites plays an important role.
The functionalized solid support is conveniently obtained from polystyrene cross-linked with preferably 1-5% divinylbenzene; coated with polyethylene glycol spacer (Tentagel)R) The polystyrene of (4); and polyacrylamide resins (see also Obrecht, d.; villgordo, j. -M, "Solid-Supported binding and Parallel Synthesis of Small Molecular Weight compound libraries", tetrahedral organic chemistry Series (Tetrahedron organic chemistry Series), volume 17, Pergamon, Elsevier Science, 1998).
The solid support is functionalized by a linker, i.e. a bifunctional spacer molecule comprising at one end an anchoring group for attachment to the solid support and at the other end a selectively cleavable functional group for subsequent chemical conversion and cleavage steps. For the purposes of the present invention, the linker must be designed to ultimately release the carboxyl group under mildly acidic conditions that do not affect the protecting groups present on any of the functional groups in the various amino acid side chains. Linkers suitable for use in the present invention form acid labile esters with the carboxyl group of amino acids, typically acid labile benzyl, benzhydryl and trityl esters; examples of such linker structures include 2-methoxy-4-hydroxymethylphenoxy (Sasrin) RLinker), 4- (2, 4-dimethoxyphenyl-hydroxymethyl) -phenoxy (Rink linker), 4- (4-hydroxymethyl-3-methoxyphenoxy) butanoic acid (HMPB linker), trityl and 2-chlorotritylAnd (4) a base.
Preferably the support is obtained from polystyrene cross-linked with most preferably 1-5% divinylbenzene and functionalized by a 2-chlorotrityl linker.
When carried out as a parallel batch synthesis, the process of the invention may advantageously be carried out as described below, but if it is desired to synthesize a single compound having formula Ia or Ib above, it will be immediately apparent to the skilled person how the process steps must be modified.
A number of reaction vessels (generally 24-192, usually 96) equal to the total number of compounds to be synthesized by the parallel method are loaded with 25-1000mg, preferably 100mg, of a suitably functionalized solid support, preferably 1-3% cross-linked polystyrene or tentagel resin.
The solvent used must be capable of swelling the resin and includes, but is not limited to, Dichloromethane (DCM), Dimethylformamide (DMF), N-methylpyrrolidone (NMP), dioxane, toluene, Tetrahydrofuran (THF), ethanol (EtOH), Trifluoroethanol (TFE), isopropanol, and the like. Solvent mixtures comprising a polar solvent as at least one component (e.g., 20% TFE/DCM, 35% THF/NMP) are beneficial for ensuring high reactivity and solvation of resin-bonded peptide chains (Fields, G.B., Fields, C.G., J.Am.chem.Soc.1991, 113, 4202-4207).
Significant progress has been made in the synthesis of protected peptide chain fragments with the development of various linkers capable of releasing a C-terminal carboxylic acid group under mild acidic conditions that do not affect the acid labile group protecting the functional group in the side chain. 2-methoxy-4-hydroxybenzyl alcohol-derived linker (Sasrin)RLinker, Mergler et al, Tetrahedron Lett.1988, 294005-4008) can be cleaved with dilute trifluoroacetic acid (0.5-1% TFA in DCM) and stabilized against Fmoc deprotection conditions during peptide synthesis, other protecting groups based on Boc/tBu being suitable for this protection scheme. Other linkers suitable for use in the method of the invention include the superacid labile 4- (2, 4-dimethoxyphenyl-hydroxymethyl) -phenoxy linker (Rink linker, Rink, H.tetrahedron Lett.1987, 28, 3787-one 3790) where the removal of the peptide requires 10%DCM for acetic acid or DCM for 0.2% trifluoroacetic acid; 4- (4-hydroxymethyl-3-methoxyphenoxy) butanoic acid-derived linker (HMPB-linker, Fl rsheimer)&Riniker, Peptides 1991, 1990131), which is also cleaved with 1% TFA/DCM to give a peptide chain fragment containing the acid labile side chain protecting group used; and, a 2-chlorotrityl chloride linker (Barlos et al, tetrahedron Lett.1989, 30, 3943-.
Protecting groups applicable to amino acids, correspondingly to their residues, are, for example
For amino groups (e.g. also present in the side chain of lysine)
Cbz benzyloxycarbonyl
Boc tert-butyloxycarbonyl
Fmoc 9-fluorenylmethoxycarbonyl
Alloc allyloxycarbonyl radical
Teoc trimethylsilyl ethoxycarbonyl
Tc Trichloroethoxycarbonyl
Nps o-nitrophenylsulfonyl;
trt triphenylmethyl or trityl
For carboxyl groups (e.g. also present in the side chains of aspartic and glutamic acid), conversion into esters with an alcohol component
tBu tert-butyl
Bn benzyl group
Me methyl group
Ph phenyl
Pac benzoyl methyl
Allyl radical
Tse Trimethylsilylethyl group
Tce trichloroethyl;
for guanidino (e.g. present in the side chain of arginine)
Pmc 2, 2, 5, 7, 8-pentamethylbenzodihydropyran-6-sulfonyl group
Ts tosyl (i.e., p-toluenesulfonyl)
Cbz benzyloxycarbonyl
Pbf pentamethyl dihydrobenzofuran-5-sulfonyl
For hydroxyl groups (e.g.in the side chains of threonine and serine)
tBu tert-butyl
Bn benzyl group
Trt trityl radical
And for thiol groups (e.g. present in the side chain of cysteine)
Acm Acylaminomethyl group
tBu tert-butyl
Bn benzyl group
Trt trityl radical
Mtr 4-methoxytrityl.
9-fluorenylmethoxycarbonyl- (Fmoc) -protected amino acid derivatives are preferably used as building blocks to construct template-immobilized β -hairpin loop mimetics of the formulae Ia and Ib. For deprotection, i.e. cleavage of the Fmoc group, 20% piperidine in DCM or 2% DBU/2% piperidine in DMF can be used.
The amount of reactants, i.e., amino acid derivatives, is typically 1-20 equivalents based on the milliequivalents per gram (meq/g) loading of functionalized solid support originally weighed into the reaction tube (typically 0.1-2.85meq/g polystyrene resin). Additional equivalents of reactants may be used if necessary to drive the reaction to completion within a reasonable time. The reaction tube, as well as the clamp member and manifold, are reinserted into the reservoir member and the device is secured together. Gas begins to flow through the manifold to provide a controlled environment, such as nitrogen, argon, air, and the like. The gas stream may also be heated or cooled prior to flowing through the manifold. The heating or cooling of the reaction well is achieved by heating the reaction part or external cooling with isopropanol/dry ice and the like to obtain the desired synthesis reaction. Stirring is achieved by shaking or magnetic stirring (within the reaction tube). Preferred workstations, but not limited to, are the Labsource's Combi-chem workstation and the MultiSynTech's-Syro synthesizer.
Amide bond formation requires activation of the alpha-carboxyl group for the acylation step. When this activation is carried out by means of a conventional carbodiimide such as dicyclohexylcarbodiimide (DCC, Sheehan & Hess, J.Am.chem.Soc.1955, 77, 1067-. In a variation of the carbodiimide process, 1-hydroxybenzotriazole (HOBt, K _ nig & Geiger, chem. Ber 1970, 103, 788-. HOBt prevents dehydration, inhibits racemization of activated amino acids and acts as a catalyst to promote slow coupling reactions. Certain phosphonium reagents have been used as direct coupling reagents, such as benzotriazol-1-yl-oxy-tris- (dimethylamino) -phosphonium hexafluorophosphate (BOP) (Castro et al, Tetrahedron Lett.1975, 14, 1219-; these phosphonium reagents are also suitable for forming HOBt esters in situ with protected amino acid derivatives. More recently, diphenoxyphosphoryl azide (DPPA) or O- (7-aza-benzotriazol-1-yl) -N, N, N, N ' -tetramethyluronium tetrafluoroborate (TATU) or O- (7-aza-benzotriazol-1-yl) -N, N, N ', N ' -tetramethyluronium Hexafluorophosphate (HATU)/7-aza-1-hydroxybenzotriazole (HOAt, Carpino et al, Tetrahedron Lett.1994, 35, 2279-.
Since close to quantitative coupling reactions is critical, it is desirable to have experimental data on reaction completion. Ninhydrin tests (Kaiser et al, anal. biochemistry 1970, 34, 595) can be easily and quickly performed after each coupling step, where a positive colorimetric response to an aliquot of the resin-bound peptide qualitatively indicates the presence of a primary amine. Fmoc chemistry enables spectrophotometric detection of Fmoc chromophores when they are released by bases (Meienhofer et al, int.J. peptide Protein Res.1979, 13, 35-42).
The resin bound intermediates within each reaction tube are washed free of excess retained reagents, solvents, and byproducts by repeated exposure to cleaning solvents using one of two methods:
1) filling the reaction well with a solvent (preferably 5ml), dipping and stirring the reaction tube and the holder part and manifold for 5 to 300 minutes, preferably 15 minutes, and then discharging by gravity and then by air pressure applied through the inlet of the manifold (while closing the outlet) to discharge the solvent;
2) the manifold is removed from the holder assembly and an aliquot (preferably 5ml) of the solvent is dispensed from the top of the reaction tube and discharged by gravity through a filter into a receiving container such as a test tube or vial.
Both washing steps are repeated up to about 50 times (preferably about 10 times), and the efficiency of reagent, solvent, and byproduct removal is monitored by methods such as TLC, GC, or visual inspection of the wash filtrate.
The above steps of reacting the resin bound compound with the reagent in the reaction well and subsequently removing excess reagent, by-products and solvent are repeated for each successive conversion until the final resin bound fully protected linear peptide is obtained.
Before the detachment of the totally protected linear peptide from the solid support, one or several protected functional groups present in the molecule can be optionally deprotected and the reactive groups thus released suitably substituted, if desired. For this purpose, the functional group in question must initially be protected by a protecting group which can be selectively removed without affecting the residual protecting groups present. Alloc (allyloxycarbonyl) is an example of such a protecting group for an amino group, which can be formed, for example, by Pd.cndot.and CH2Cl2The phenylsilane in (a) is selectively removed, with no effect on the remaining protecting groups present in the molecule, such as Fmoc. The reactive groups thus released may then be treated with a reagent suitable for introducing the desired substituents. For example, an amino group can be acylated by an acylating agent, corresponding to the introduction of an acyl substituent.
All protected linear peptides were detached from the solid support by dipping the reaction tube and the clamp parts and manifold into a reaction well containing a cleaving reagent solution (preferably 3-5 ml). Gas flow, temperature control, agitation, and reaction monitoring are performed as described above and the disengagement reaction is performed as desired. The reaction tubes, as well as the clamp member and manifold, are disconnected from the reservoir member and raised above the solution level but below the upper lip of the reaction well, and then air pressure is applied through the manifold inlet (while closing the outlet) to effectively drain the final product solution into the reservoir well. The resin remaining in the reaction tube is then washed 2-5 times with 3-5ml of a suitable solvent as described above to extract (wash out) as much of the liberated product as possible. The product solutions thus obtained were combined, taking care to avoid intermixing. The individual solutions/extracts are then processed as necessary to isolate the final compound. Typical treatments include, but are not limited to, evaporation, concentration, liquid/liquid extraction, acidification, basification, neutralization or other solution reactions.
The solution containing all the protected linear peptide derivatives that have been cleaved from the solid support and neutralized with a base is evaporated and subsequently cyclized in solution with a solvent such as DCM, DMF, dioxane, THF. Various coupling reagents mentioned earlier can be used for the cyclization. The duration of the cyclization is about 6 to 48 hours, preferably about 24 hours. The progress of the reaction is followed, for example, by RP-HPLC (reverse phase high performance liquid chromatography). The solvent is then removed by evaporation, the entire protected cyclic peptide derivative is dissolved in a water-immiscible solvent such as DCM, and the solution is then extracted with water or a mixture of water-miscible solvents to remove any excess coupling reagent.
Before removing the protecting group from the fully protected cyclic peptide, interchain bonds may be formed between the side chains of suitable amino acid residues at the relative positions of the β -chain regions, if desired; and/or two structural units of the formula Ia are linked via a bridge-G1-L-G2-to give a dimeric structure of the formula Ib.
The interchain bonds and their formation are discussed above, in conjunction with an explanation of the class H group, which may be, for example, a disulfide bond formed by: through the formation of amide bonds by cysteine and homocysteine at opposite beta-chain positions, or by ornithine linked by glutamic and aspartic acid residues and correspondingly lysine at opposite beta-chain positions. The formation of these interchain bonds can be carried out by methods well known in the art.
The interchain bonds and their formation are discussed above, in conjunction with an explanation of the class H group, which may be, for example, a disulfide bridge formed by: through the formation of amide bonds by cysteine and homocysteine at opposite beta-chain positions, or by ornithine linked by glutamic and aspartic acid residues and correspondingly lysine at opposite beta-chain positions. The formation of these interchain bonds can be carried out by methods well known in the art.
To construct the bridge-G1-L-G2-to obtain a dimeric structure, methods known in the art may also be used. Thus, for example, a linker carrying a linker containing a suitably protected alcohol group (e.g. protected as a t-butyldiphenylsilyl group), thiol group (e.g. protected as a t-butyldiphenylsilyl group) may be prepared using methods well known to those skilled in the artProtected as acetamidomethyl) or amino (NR)34(ii) a E.g. protected as allyloxycarbonyl) group G1 or G2 and reacting with a suitable activating linker (L) precursor; for example:
for L1, the corresponding structural element is Br (Cl, I) (CH)2)pCHR61[X(CH2)pCHR61]oOH: the resulting alcohol may be prepared by methods well known to those skilled in the art (e.g., P (Ph)3，CBr4) Conversion to the corresponding bromide (chloride or iodide) and binding of a second β -hairpin mimetic bearing a group G1 or G2 containing an alcohol, thiol or amine group. The dimeric all side chain protected molecule can be all deprotected and purified by preparative HPLC chromatography as described in step 1 herein after.
For L2, the corresponding building block is ClOC (CH)2)pCHR61[X(CH2)pCHR61]oCOO allyl: the resulting ester can be converted to the corresponding acid by methods well known to those skilled in the art and conjugated to a second β -hairpin mimetic carrying a group G1 or G2 containing an alcohol, thiol or amine group. The dimeric all side chain protected molecule can be all deprotected and purified by preparative HPLC chromatography as described in step 1 herein after.
For L3, the corresponding structural element is
O＝C＝N(CH2)pCHR61[X(CH2)pCHR61]oNR34And (3) Alloc: the resulting Alloc-protected amine can be deprotected and converted to the corresponding isocyanate by methods well known to those skilled in the art (e.g. triphosgene) and bound to a second β -hairpin mimetic carrying a group G1 or G2 containing an alcohol, thiol or amine group. The dimeric all side chain protected molecule can be all deprotected and purified by preparative HPLC chromatography as described in step 1 herein after.
-just L7For example, the corresponding structural unit is Br (Cl, I) (CH)2)oCHR61Y(CH2)oCHR61OH: the resulting alcohol may be prepared by methods well known to those skilled in the art (e.g., P (Ph)3，CBr4) Conversion to the corresponding bromide (chloride or iodide) and binding of a second β -hairpin mimetic bearing a group G1 or G2 containing an alcohol, thiol or amine group. The dimeric all side chain protected molecule can be deprotected and purified by preparative HPLC chromatography as described in step 1 herein after.
For L8, the corresponding building block is ClOC (CH)2)oCHR61Y(CH2)oCHR61COO allyl: the resulting ester can be converted to the corresponding acid by methods well known to those skilled in the art and conjugated to a second β -hairpin mimetic carrying a group G1 or G2 containing an alcohol, thiol or amine group. The dimeric all side chain protected molecule can be deprotected and purified by preparative HPLC chromatography as described in step 1 herein after.
For L9, the corresponding structural element is O ═ C ═ N (CH)2)oCHR61Y(CH2)oCHR61NR34And (3) Alloc: the resulting Alloc-protected amine can be deprotected and converted to the corresponding isocyanate by methods well known to those skilled in the art (e.g. triphosgene) and bound to a second β -hairpin mimetic carrying a group G1 or G2 containing an alcohol, thiol or amine group. The dimeric all side chain protected molecule can be deprotected and purified by preparative HPLC chromatography as described in step 1 herein after.
For L13, the corresponding building block is ClOC (CH)2)pCHR61[X(CH2)pCHR61]oNR34And (3) Alloc: the resulting Alloc-protected amine can be deprotected by methods readily available to those skilled in the art and conjugated to a second β -hairpin mimetic carrying a carboxylic acid group-containing group G1 or G2. The dimeric all side chain protected molecule may be deprotected and passed through steps as described later hereinPreparative HPLC chromatographic purification as described in step 1.
For L14, the corresponding building block is ClOC (CH)2)oCHR61Y(CH2)oCHR61NR34And (3) Alloc: the resulting Alloc-protected amine can be deprotected by conventional methods and conjugated to a second β -hairpin mimetic carrying a carboxylic acid group-containing group G1 or G2. The dimeric all side chain protected molecule can be deprotected and purified by preparative HPLC chromatography as described in step 1 herein after.
In addition, a fully side-chain protected β -hairpin peptidomimetic carrying a group G1 or G2 containing a suitably protected thiol group (e.g., protected as an acetamidomethyl group) can be selectively deprotected using methods well known to those skilled in the art and reacted with a second β -hairpin peptidomimetic carrying a thiol group-containing group G1 or G2 to form a disulfide bond via oxidation (air or iodine). The dimeric molecule may then be fully deprotected and purified by preparative HPLC chromatography as described in step 1 herein after.
Finally, all side chain protected β -hairpin peptidomimetics carrying a group G1 or G2 containing a suitably protected carboxylic acid group (e.g. an allyl ester) can be selectively deprotected and reacted with a suitable activating linker (L) precursor using methods well known in the art; for example:
for L4, the corresponding structural element is HO (CH)2)pCHR61[X(CH2)pCHR61]oOAlloc: the resulting Alloc-protected alcohol can be deprotected by methods well known to those skilled in the art and bound to a second β -hairpin mimetic carrying a carboxylic acid group-containing group G1 or G2. The dimeric all side chain protected molecule can be deprotected and purified by preparative HPLC chromatography as described in step 1 herein after.
For L5, the corresponding structural element is HS (CH)2)pCHR61[X(CH2)pCHR61]oSAlloc: obtained byThe Alloc-protected thiol can be deprotected by methods known in the art and conjugated to a second β -hairpin mimetic carrying a carboxylic acid group-containing group G1 or G2. The dimeric all side chain protected molecule can be deprotected and purified by preparative HPLC chromatography as described in step 1 herein after.
For L6, the corresponding structural element is HNR34(CH2)pCHR61[X(CH2)pCHR61]oNR34And (3) Alloc: the resulting Alloc-protected amine can be deprotected by methods familiar to those skilled in the art and conjugated to a second β -hairpin mimetic carrying a carboxylic acid group-containing group G1 or G2. The dimeric all side chain protected molecule can be deprotected and purified by preparative HPLC chromatography as described in step 1 herein after.
For L10, the corresponding structural element is HO (CH)2)oCHR61Y(CH2)oCHR61OAlloc: the resulting Alloc-protected alcohol can be deprotected by methods well known to those skilled in the art and bound to a second β -hairpin mimetic carrying a carboxylic acid group-containing group G1 or G2. The dimeric all side chain protected molecule can be deprotected and purified by preparative HPLC chromatography as described in step l herein after.
For L11, the corresponding structural element is HS (CH) 2)oCHR61Y(CH2)oCHR61SAlloc: the resulting Alloc-protected thiol can be deprotected by methods well known in the art and conjugated to a second β -hairpin mimetic carrying a carboxylic acid group-containing group G1 or G2. The dimeric all side chain protected molecule can be deprotected and purified by preparative HPLC chromatography as described in step 1 herein after.
For L12, the corresponding structural element is HNR34(CH2)oCHR61Y(CH2)oCHR61NR34And (3) Alloc: the resulting Alloc-protected amines can be prepared by methods known to those skilled in the artThis deprotects and binds to a second β -hairpin mimetic carrying a carboxylic acid group-containing group G1 or G2. The dimeric all side chain protected molecule can be deprotected and purified by preparative HPLC chromatography as described in step 1 herein after.
For L15, the corresponding structural element is HNR34(CH2)pCHR61[X(CH2)pCHR61]oCOO allyl: the allyl esters obtained can be deprotected by conventional methods and carry in combination an alcohol-, thiol-or amino group (NR)34) A second beta-hairpin mimetic of group G1 or G2. The dimeric all side chain protected molecule can be deprotected and purified by preparative HPLC chromatography as described in step 1 herein after.
For L16, the corresponding structural element is HNR34(CH2)oCHR61Y(CH2)oGHR61COO allyl: the allyl esters obtained can be deprotected by methods known to the skilled worker and combine compounds carrying alcohol-, thiol-or amino groups (NR) 34) A second beta-hairpin mimetic of group G1 or G2. The dimeric all side chain protected molecule can be deprotected and purified by preparative HPLC chromatography as described in step 1 herein after.
Finally, the totally protected peptide derivatives of class Ia or Ib were treated with 95% TFA, 2.5% H2O, 2.5% TIS or another scavenger for cleavage of the protecting group. The cleavage reaction time is usually 30 minutes to 12 hours, preferably 2 hours. Most of the TFA was then evaporated and the product precipitated with ether/hexane (1: 1) or other suitable solvent. After careful removal of the solvent, the cyclic peptide derivative obtained as the final product can be isolated. Depending on its purity, the peptide derivative can be used directly for biological analysis, or it must be further purified, for example by preparative HPLC.
As previously mentioned, if desired, the whole of the protected product thus obtained may then be converted into a pharmaceutically acceptable salt or the pharmaceutically acceptable or unacceptable salt thus obtained may be converted into the corresponding free compounds of formulae Ia and Ib or into a different pharmaceutically acceptable salt. Any of these operations can be performed by methods well known in the art.
The starting materials for the process of the invention, the preformed starting materials therefor, and the preparation of these starting materials and preformed starting materials will now be discussed in detail.
The class A building blocks can be synthesized according to literature methods described below. The corresponding amino acids have been described as unprotected or as Boc-or Fmoc-protected racemates, (D) -or (L) -isomers. It is clear that unprotected amino acid building blocks can be readily converted to the corresponding Fmoc-protected amino acid building blocks required for the present invention by standard protecting group treatment. Articles describing conventional methods for alpha-amino acid synthesis include: duthaler, tetrahedron (report) 1994, 349, 1540 and 1650; M.M.Williams, "Synthesis of aqueous active α -amino acids", Tetrahedron Organic Chemistry Series, Vol.7, J.E.Baldwin, P.D.Magnus (Eds.), Pergamon Press, Oxford 1989. expression using effective method for the Synthesis of aqueous active α -amino acids for expression in catalysis (M.A.Verhovskaya, I.A.Yakov, Russian Chemistry Rev.1991, 60, 1163. 1179; R.M.Williams, "Synthesis of aqueous active α -amino acids", Mg.279.7. expression of expression in expression J.279. expression of expression in expression, P.J.279, expression of expression in expression. Hydrolytics in volts hydrosis of amides and nitriles by minor suspensions or nitriles, cleavage of N-acyl groups by isocyanates, and ester hydrolytics by lipids or enzymes in a well tolerated host enzyme with free specific to the drive (L) -aromatic microorganisms in aqueous phases, e.g.: R.Duthalter, Tetrahedron port, 349, 1650; R.M.Williams, "Synthesis of aqueous alpha-amides", Tetrahedron Organic Chemistry, balance, J.S.P.1989. P.S.A. A.P.A. A.B.A.A.B.A.A.B.S.A.A.A.B.B.A.B.B.A.B.B.A.B.B.A.B.B.B.A.B.A.B.A.B.B.S.A.B.B.B.S.A.B.B.B.S.B.B.S.B.B.B.S.A.B.B.S.B.S.B.S.B.B.S.S.S.S.A.B.B.S.B.S.B.B.S.B.B.S.S.S.B.S.S.S.S.S.S.S.S.S.B.S.S.S.S.S.S..
A1: see D.Ben-Ishai, Tetrahedron 1977, 33, 881-; sato, A.P.Kozikowski, tetrahedron Lett.1989, 30, 4073-; baldwin, c.n.farting, a.t.russell, c.j.schofield, a.c.spirey, Tetrahedron lett.1996, 37, 3761-; baldwin, r.m.adl ington, n.g.robinson, j.chem.soc.chem.commun.1987, 153-; p.wipf, y.uto, Tetrahedron lett.1999, 40, 5165-; baldwin, R.M.Adl ington, A.O' Neil, A.C.Spirey, J.B.Sweeney, J.chem.Soc.chem.Commun.1989, 1852-1＝H，R2＝H)；T.Hiyama，Bull.Chem.Soc.Jpn.1974，47，2909-29l0；T.Wakamiya，K.Shimbo，T.Shiba，K.Nakajima，M.Neya，K.Okawa，Bull.Chem.Soc.Jpn.1982，55，3878-3881；I.Shima，N.Shimazaki，K.Imai，K.Hemmi，M.Hashimoto，Chem.Pharm.Bull.1990，38，564-566；H.Han，J.Yoon，K.D.Janda，J.Org.Chem.1998，63，2045-2048(R1＝H，R2＝Me)；J.Legters，G.H.Willems，L.Thij s，B.Zwannenburg，Recl.Trav.Chim.Pays-Bas 1992，111，59-68(R1＝H，R2＝hexyl)；J.Legters，L.Thijs，B.Zwannenburg，Recl.Trav.Chim.Pays-Bas 1992，111，16-21；G.A.Molander，P.J.Stengel，J.Org.Chem.1995，21，6660-6661(R1＝H，R2＝Ph)；I.Funaki，L.Thijs，B.Zwannenburg，Tetrahedron 1996，52，9909-9924(R1＝H，R2＝Bn)；A.S.Pepito，D.C.Dittmer，J.Org.Chem.1997，62，7920-7925；(R1＝H，R2＝CH2OH)；M.Egli，A.S.Dreiding，Helv.Chim.Acta1986，6g，1442-1460(R2＝CH(OH)CH2OH)；M.Carduccu，S.Fioravanti，M.A.Loreto，L.Pellacani，P.A.Tardella，Tetrahedron Lett.1996，37，3777-3778；F.J.Lakner，L.P.Hager，Tetrahedron：Asymmetry 1997，21，3547-3550(R1＝Me，R2＝H，Me)；G.A.Molander，P.J.Stengel，Tetrahedron 1997，26，8887-8912；M.A.Loreto，F.Pompei，P.A.Tardella，D.Tofani，Tetrahedron 1997，53，15853-15858(R1＝Me，R2＝CH2SiMe3)；H.Shao，J.K.Rueter，M.Goodman，J.Org.Chem.1998，63，5240-5244(R1＝Me，R2＝Me)。
A2: see a.rao, m.k.gurj _ r, v.vivarr, Tetrahedron: asymmetry 1992, 3, 859-862; R.L.Johnson, G.Rayakumar, K.L.Yu, R.K.Misra, J.Med.chem.1986, 29, 2104-2107 (R.L.Johnson, G.Rayakumar, K.L.Yu, R.K.Misra, J.Med.chem.1986)1＝H，R2＝H)；J.E.Baldwin，R.M.Adlington，R.H.Jones，C.J.Schofield，C.Zarcostas，J.Chem.Soc.Chem.Commun.1985，194-196；J.E.Baldwin，R.M.Adlington，R.H.Jones，C.J.Schofield，C.Zarcostas，Tetrahedron 1986，42，4879-4888(R1＝H，R2＝CH2OH，CH2CHO，CH2CH2COOH，CH2CH2OH)；A.P.Kozikowski，W.Tueckmantel，I.J.Reynolds，J.T.Wroblewski，J.Med.Chem.1990，33，1561-1571；A.P.Kozikowski，W.Tueckmantel，Y.Liao，H.Manev，S.Ikonomovic J.T.Wroblenski，J.Med.Chem.1993，36，2706-2708(R1＝H，R2＝CH2OH，CHCONH2，CONHCH2COOH，COOtBu)；D.Seebach，T.Vett iger，H.-M.Müller，D.Plattner，W.Petter，Liebigs Ann.Chem.1990，687-695(R1＝ArylCH(OH)，R2＝H)；D.Seebach，E.Dziadulewicz，L.Behrendt，S.Cantoreggi，R.Fitzi，Liebigs Ann.Chem.1989，1215-1232(R1＝Me，Et，R2＝H)。
A3: see A.P.Kozikowski, Y.Liao, W.Tueckmantel, S.Wang, S.Pshsenichkin, bioorg.Med.chem.Lett.1996, 6, 2559-1＝H；R2＝CHCHO，CH2OH，CH2CH2OH，CH2COOH，COOH)；Isono，J.Am.Chem.Soc，1969，91，7490(R1＝H；R2＝Et)；P.J.Blythin，M.J.Green，M.J.Mary，H.Shue，J.Org.Chem.1994，59，6098-6100；S.Hanessian，N.Bernstein，R.-Y.Yang，R.Maquire，Bioorg.Chem.Lett.1994，9，1437-1442(R1＝H；R2＝Ph)。
A4: see e.g., Emmer, Tetrahedron 1992, 48, 7165-; M.P.Meyer, P.L.Feldman, H.Rapoport, J.org.chem.1985, 50, 5223-1＝H；R2＝H)；A.J.Bose，M.S.Manhas，J.E.Vincent，I.F.Fernandez，J.Org.Chem.1982，47，4075-4081(R1＝H；R2＝NHCOCH2OPh)；D.L.Boger，J.B.Meyers，J.Org.Chem.1991，56，5385-5390(R1＝H；R2＝NHCOCH2Ph)；K.-D.Kampe，TetrahedronLett.1969，117-120(R1＝CH2OH；R2＝Ph)；M.D.Andrews，M.G.Maloney，K.L.Owen，J.Chem.Soc.Perkin Trans.1，1996，227-228(R1＝CH2OH；R2＝H)。
A5: see c.bishang, c.weber, j.inglis, c.a.schiffer, w.f.van Gunsteren, j.a.robinson j.am.chem.soc.1995, 117, 7904 (r.b. 1＝CH3；R2＝H)；S.Takano，M.Morija，Y.Iwabuki，K.Ogasawara，Tetrahedron Lett.1989，30，3805-3806(R1＝H；R2＝COOH)；M.D.Bachi，R.Breiman，H.Meshulam，J.Org.Chem.1983，48，1439-1444(R1＝H；R2＝CH(Et)COOH)；D.S.Kemp，T.P.Curran，Tetrahedron Lett.1988，29，4931-4934；D.S.Kemp，T.P.Curran，W.M.Davies，J.Org.Chem.1991，56，6672-6682(R1＝H；R2＝CH2OH)；F.Manfre，J.-M.Kern，J.-F.Biellmann，J.Org.Chem.1992，57，2060-2065(R1＝H；R2＝H，CH＝CH2，CCH)；B.W.Bycroft，S.R.Chabra，J.Chem.Soc.Chem.Commun.1989，423-425(R1＝H；R2＝CH2COOtBu；Y.Xu，J.Choi，M.I.Calaza，S.Turner，H.Rapoport，J.Org.Chem.1999，64，4069-4078(R1＝H；R2＝3-pyridyl)；E.M.Khalil，W.J.Ojala，A.Pradham，V.D.Nair，W.B.Gleason，J.Med.Chem.1999，42，628-637；E.M.Khalil，N.L.Subasinghe，R.L.Johnson，Tetrahedron Lett.1996，37，3441-3444(R1＝allyl；R2＝H)；A.DeNicola，J.-L.Luche，Tetrahedron Lett.1992，33，6461-6464；S.Thaisrivongs，D.T.Pals，J.A.Lawson，S.Turner，D.W.Harris，J.Med.Chem.1987，30，536-54l；E.M.Khalil，N.L.Subasinghe，R.L.Johnson，Tetrahedron Lett.1996，37，3441-3444；A.Lewis，J.Wilkie，T.J.Rutherford，D.Gani，J.Chem.Soc.Perkin Trans.1，1998，3777-3794(R1＝Me；R2＝H)；A.Lewis，J.Wilkie，T.J.Rutherford，D.Gani，J.Chem.Soc.Perkin Trans.1，1998，3777-3794(R1＝CH2COOMe；R2＝H)；N.L.Subasinghe，E.M.Khalil，R.L.Johnson，Tetrahedron Lett.1997，38，1317-1320(R1＝CH2CHO；R2＝H)；D.J.Witter，S.J.Famiglietti，J.C.Gambier，A.L.Castelhano，Bioorg.Med.Chem.Lett.1998，8，3137-3142；E.H.Khalil，W.H.Ojada，A.Pradham，V.D.Nair，W.B.Gleason，J.Med.Chem.1999，42，628-637(R1＝CH2CH2CHO；R2＝H)。
A6: see DeNardo, Farmaco Ed.Sci.1977, 32, 522-529 (R)1＝H；R3＝H)；P.J.T.Floris，N.Terhuis，H.Hiemstra，N.W.Speckamp，Tetrahedron，1993，49，8605-8628；S.Kanemasa，N.Tomoshige，O.Tsuge，Bull.Chem.Soc.Jpn.1989，62，3944-3949(R1＝H；R3＝H)；Sucrow，Chem.Ber.1979，112，1719.
A7: see Fichter, j.prakt.chem.1906, 74, 310 (R)1＝Me；R4＝Ph)。
A8: see l.lapantsias, g.milias, k.froussios, m.kolovos, Synthesis 1983, 641-673; nedev, h.naharicoa, tetrahedron lett.1993, 34, 4201-; d.y.jackson, c.quan, d.r.artis, t.rawson, b.blackburn, j.med.chem.1997, 40, 3359-3368; konopinska, H.Bartosz-Bechowski, G.Rosinski, W.Sobotka, Bull.pol.Acad.Sci.chem.1993, 41, 27-40; J.Hondrelis, G.Lonergan, S.Voliotis, J.Matsukas, Tetrahedron 1990, 46, 565-; t.nakamura, h.matsuyama，H.Kanigata，M.Iyoda，J.Org.Chem.1992，57，3783-3789；C.E.O’Connell，K.Ackermann，C.A.Rowell，A.Garcia，M.D.Lewis，C.E.Schwartz，Bioorg.Med.Chem.Lett.1999，9，2095-2100；G.Lowe，T.Vilaivan，J.Chem.Soc.Perkin Trans.1997，547-554；B.Bellier，I.McCourt-Tranchepain，B.Ducos，S.Danascimenta，H.Mundal，J.Med.Chem.1997，40，3947-3956；M.Peterson，R.Vince J.Med.Chem.1991，34，2787-2797；E.M.Smith，G.F.Swiss，B.R.Neustadt，E.H.Gold，J.A.Sommer，j.Med.Chem.1988，31，875-885；E.Rubini，C.Gilon，Z.Selinger，M.Chorev，Tetrahedron 1986，42，6039-6045(R1＝H；R5＝OH)；C.R.Noe，M.Knollmueller，H.Voellenkle，M.Noe-Letschnig，A.Weigand，J.Mühl，Pharmazie，1996，51，800-804(R1＝CH3；R5＝OH)；J.Kitchin，R.C.Berthell，N.Cammack，S.Dolan，D.N.Evans，J.Med.Chem.1994，37，3703-3716；D.Y.Jackson，C.Quan，D.R.Artis，T.Rawson，B.Blackburn，J.Med.Chem.1997，40，3359-3368(R1＝H；R5＝OBn)；J.E.Baldwin，A.R.Field，C.C.Lawrence，K.D.Merritt，C.J.Schofield，Tetrahedron Lett.1993，34，7489-7492；K.Hashimoto，Y.Shima，H.Shirahama，Heterocycles1996，42，489-492(R1＝H；R5＝OTs)；T.R.Webb，C.Eigenbrot，J.Org.Chem.1991，56，3009-3016；D.C.Cafferty，C.A.Slate，B.M.Nakhle，H.D.Graham，T.L.Anstell，Tetrahedron 1995，51，9859-9872(R1＝H；R5＝NH2)；T.R.Webb，C.Eigenbrot，J.Org.Chem.1991，56，3009-3016(R1＝H；R5＝CH2NH2)；J.K.Thottathil，J.L.Moniot，Tetrahedron Lett.1986，27，151-154(R1＝H；R5＝Ph)；K.Plucinska，T.Kataoka，M.Yodo，W.Cody，J.Med.Chem.1993，36，1902-1913(R1＝H；R5＝SBn)；J.Krapcho，C.Turk，D.W.Cushman，J.R.Powell，J.Med.Chem.1988，31，1148-1160(R1＝H；R5＝SPh)；A.J.Verbiscar，B.Witkop，J.Org.Chem.1970，35，1924-1927(R1＝H；R5＝SCH2(4-OMe)C6H4)；S.I.Klein，J.M.Denner，B.F.Molino，C.Gardner，R.D’Alisa，Bioorg.Med.Chem.Lett.1996，6，2225-2230(R1＝H；R5＝O(CH2)3Ph)；R.Zhang，F.Brownewell，J.S.Madalengoita，Tetrahedron Lett.1999，40，2707-2710(R1＝H；R5＝CH2COOBn)。
A9: see Blake, J.Am.chem.Soc.1964, 86, 5293-5297; cooper, R.T.Gallagher, D.T.Knight, J.chem.Soc.chem.PerkinTrans.1, 1993, 1313-1318; knight, a.w.sibley, j.chem.soc.perkin trans.1, 1997, 2179, 2188 (R)1＝H；R6＝H)；Blake，J.Am.Chem.Soc.1964，86，5293-5297；Y.Yamada，T.Ishii，M.Kimura，K.Hosaka，Tetrahedron Lett.1981，1353-1354(R1＝H；R6＝OH)；Y.Umio，Yakugaku Zasshi，1958，78，727(R1＝H；R6＝iPr)；Miyamoto，Yakugaku Zasshi，1957，77，580-584；Tanaka，Proc.Jpn.Acad.1957，33，47-50(R1＝H；R6＝CH(CH3)CH2N(CH3)2)；L.E.Overman，B.N.Rodgers，J.E.Tellew，W.C.Trenkle，J.Am.Chem.Soc.1997，119，7159-7160(R1＝H；R6＝allyl)；Ohki，Chem.Pharm.Bull.1976，24，1362-1369(R1＝CH3；R6＝H)。
A10: see J.Mulzer, A.Meier, J.Buschmann, P.Luger, Synthesis 1996, 123-one 132 (R)1＝H；R7＝CH＝CH2)；J.Cooper，P.T.Gallagher，D.W.Knight，J.Chem.Soc.Chem.Commun.1988，509-510；E.G_tschi，C.Jenny，P.Reindl，F.Ricklin，Helv.Chim.Acta 1996，79，2219-2234(R1＝H；R7＝OH)；N.A.Sasaki，R.Pauli，C.Fontaine，A.Chiaroni，C.Riche，P.Potier，Tetrahedron Lett.1994，35，241-244(R1＝H；R7＝COOH)；R.Cotton，A.N.C.Johnstone，M.North，Tetrahedron 1995，51，8525-8544(R1＝H；R7＝COOMe)；J.S.Sabol，G.A.Flynn，D.Friedrich，E.W.Huber，Tetrahedron Lett.1997，38，3687-3690(R1＝H；R7＝CONH2)；P.P.Waid，G.A.Flynn，E.W.Huber，J.S.Sabol，Tetrahedron Lett.1996，37，409l-4094(R1＝H；R7＝(4-BnO)C6H4)；N.A.Sasaki，R.Pauli，P.Potier，TetrahedronLett.1994，35，237-240(R1＝H；R7＝SO2Ph)；R.J.Heffner，J.Jiang，M.Jouillié，J.Am.Chem.Soc.1992，114，10181-10189；U.Schmidt，H.Griesser，A.Lieberknecht，J.H_usler，Angew.Chem.1981，93，272-273(R1＝H；R7＝OAryl)；H.Mosberg，A.L.Lomize，C.Wang，H.Kroona，D.L.Heyl，J.Med.Chem.1994，37，4371-4383(R1＝H；R7＝4-OHC6H4)；S.A.Kolodziej，G.V.Nikiforovich，R.Sceean，M.-F.Lignon，J.Martinez，G.R.Marshall，J.Med.Chem.1995，38，137-149(R1＝H；R7＝SCH2(4-Me)C6H4)。
A11: see Kuhn, Osswald, chem. Ber.1956, 89, 1423-; patchett, Witkop, J.Am.chem.Soc.1957, 79, 185-189; benz, Helv. Chim. acta 1974, 57, 2459-; wessig, Synlett, 1999, 9, 1465-1467; E.M.Smit, G.F.Swiss, B.R.Neustadt, E.H.gold, J.A.Sommer, J.Med.chem.1988, 31, 875-; krapcho, c.turk, d.w.cushman, j.r.powel l, j.m.deforret, j.med.chem.1988, 31, 1148 (R) 1＝H；R6＝H)；D.BenIshai，S.Hirsh，Tetrahedron 1988，44，5441-5450(R1＝H；R6＝CH3)；M.W.Holladay，C.W.Lin，C.S.Garvey，D.G.Witte，J.Med.Chem.1991，34，455-457(R1＝H；R6＝allyl)；P.Barralough，P.Hudhomme，C.A.Spray，D.W.Young，Tetrahedron 1995，51，4195-4212(R1＝H；R6＝Et)；J.E.Baldwin，M.Rudolf，Tetrahedron Lett.1994，35，6163-6166；J.E.Baldwin，S.J.Bamford，A.M.Fryer，M.Rudolf，M.E.Wood，Tetrahedron 1997，53，5233-5254(R1＝H；R6＝CH2COOtBu)；P.Gill，W.D.Lubell，J.Org.Chem.1995，60，2658-2659(R1＝H；R6＝CH3；Bn；allyl；CH2COOMe)；M.J.Blanco，F.J.Sardina，J.Org.Chem.1998，63，3411-3466(R1＝H；R6＝OCH2OMe)。
A12: see Ahmed, Cheeseman, Tetrahedron 1977, 33, 2255-; J.S.New, J.P.Yev ich, J.heterocyclic.chem.1984, 21, 1355-1360; r.kikumoto, y.tamao, k.ohkubo, t.tezuka, s.tonomara, j.med.chem.1980, 23, 1293-1299; blankley, j.s.kaltenbronn, d.e.john, a.werner, l.r.bennett, j.med.chem.1987, 30, 992-; klutcho, C.J.Blankley, R.W.Fleming, J.M.Hinkley, R.E.Werner, J.Med.chem.1986, 29, 1953-1＝H；R8＝H)；L.J.Beeley，C.J.M.Rockwell，Tetrahedron Lett.1990，31，417-420(R1＝COOEt；R8＝H)。
A13: see g.flowet, w.brieher, t.majewski, k.mahan, j.med.chem.1991, 43, 2089-; g.galienda, p.grieco, e.perissuti, v.santagada, faraco, 1996, 51, 197-; mcconsey, m.j.hawkins, p.andrade-Gordon, m.f.addo, b.e.maryanoff, bioorg.med.chem.lett.1999, 9, 1423-; g.b.jones, s.b.heatton, b.j.chapman, m.guzel, Tetrahedron: asymmetry 1997, 8, 3625-; m.asami, h.watanabe, k.honda, s.inoue, Tetrahedron: asymmetry 1998, 9, 4165-; k.gross, Y.M.Yun, P.Beak, J.org.chem.1997, 62, 7679-1＝H；R6＝H；R8＝H)；K.Gross，Y.M.Yun，P.Beak，J.Org.Chem.1997，62，7679-7689(R1＝H；R6＝H；R8＝6-Cl)；Ch.Noe，M.Knollmueller，C.Schoedl，M.L.Berger，Sci.Pharm.1996，64，577-590；E.Reiman，W.Erdle，H.Unger，Pharmazie，1994，54，418-421(R1＝H；R6＝CH2COOH；R8＝H)；V.Collot，M.Schmitt，A.K.Marwah，B.Norberg，J.-J.Bourgignon，Tetrahedron Lett.1997，38，8033-8036(R1＝H；R6＝Ph；R8＝H)；L.V.Dunkerton，H.Chen，B.P.McKillican，Tetrahedron Lett.1988，29，2539-2542(R1＝C(CH3)2CH＝CH2；R6＝H；R8＝H)；E.J.Corey，J.Am.Chem.Soc.1970，92，2476-2488；Neunhoeffer，Lehmann，Chem.Ber.1961，94，2960-2963(R1＝CH3；R6＝H；R8＝H)。
A14: amino acids of class A14 can be prepared according to scheme 1.
Scheme 1
i：NaH，BrCH(R1)COOMe，DMF；ii：LiOHx1H2O，MeOH，H2O; iii: polyphosphoric Acid (PPA):
iv: NaH, ClCOOMe, THF; v: enzymatic breakdown (e.g., lipase); vi: NaOH, MeOH, H2O, heating;
vii：FmocOSu，Na2CO3aqueous solution, dioxane
A15: see D.S. Perlow, J.M.Erb, N.P.Gould, R.D.Tung, R.M.Freidinger, J.org.chem.1992, 57, 4394-; D.Y.Jackson, C.Quan, D.R.Artis, T.Rawson, B.Blackburn, J.Med.chem.1997, 40, 3359-3368 (R.Y.Jackson, C.Quan, D.R.Artis, T.Rawson, B.Blackburn, J.Med.chem.1997, 40, 3359-3368)1＝H；R2＝H)；H.H.Wasserman，K.Rodrigues，K.Kucharczyk，Tetrahedron Lett.1989，30，6077-6080(R1＝H；R2＝COOH)。
A16: see Beyerman, Boekee, Recl.Trav.Chim.Pays-Bas, 1959, 78, 648-; free, a.r.day, j.org.chem.1960, 25, 2105-; d.r. adams, p.d. bailey, i.d. collier, j.d. heferman, s.strokes, j.chem.soc.chem.commun.1996, 349-; baldwin, r.m.adlington, c.r.a.godfrey, d.w.collins, j.d.vaughan，J.Chem.Soc.Chem.Commun.1993，1434-1435；Y.Matsumura，Y.Takeshima，H.Ohita，Bull.Chem.Soc.Jpn.1994，67，304-306(R1＝H；R6＝H)；C.Herdeis，W.Engel，Arch.Pharm.1991，324，670(R1＝COOMe；R6＝CH3)。
A17, a 18: see c.r.davies, j.s.davies, j.chem.soc.perkin Trans 1, 1976, 2390-; bevan, J.chem.Soc.G 1971, 514-522; umezawa, K.Nakazawa, Y.Ikeda, H.Naganawa, S.Kondo, J.org.chem.1999, 64, 3034-1＝R3＝H)；P.D.Williams，M.G.Bock，R.D.Tung，V.M.Garsky，D.S.Parlow，J.Med.Chem，1992，35，3905-3918；K.Tamaki，K.Tanzawa，S.Kurihara，T.Oikawa，S.Monma，Chem.Pharm.Bull.1995，43，1883-1893(R1＝R5＝H；R3＝COOBn)；K.J.Hale，J.Cai，V.Delisser，S.Manaviazar，S.A.Peak，Tetrahedron 1996，52，1047-1068；M.H.Chen，O.P.Goel，J.-W.Hyun，J.Magano，J.R.Rubin，Bioorg.Med.Chem.Lett.1999，9，1587-1592(R1＝R5＝H；R3＝COOtBu)；R.Baenteli，I.Brun，P.Hall，R.Metternich，Tetrahedron Lett.1999，40，2109-2112(R1＝R5＝H；R3＝COR)；K.J.Hale，N.Jogiya，S.Manaviazar，Tetrahedron 1998，39，7163-7166(R1＝H；R3＝COOBn；R5＝OBn)；T.Kamenecka，S.J.Danishewsky，Angew.Chem.Int.Ed.Engl.1998，37，2995-2998(R1＝H；R3＝COO(CH2)2SiMe3；R5＝OSiMe2tBu.
A19: see Beilstein, accession number 648833 (R)1＝R4＝R8H). Such compounds may be prepared according to scheme 2.
Scheme 2.
i：NaH，CH2(COOMe)2，DMSO；ii：NaH，R1-X, DMSO; iii: NaOH aqueous solution; MeOH, 75 °; iv: DBU, Mel, DMF;
v：LDA，BocN＝NBoc；vi：TFA，CH2Cl2；vii：CbzCl，Na2CO3Solution dioxane; viii: enzymatic breakdown (e.g., lipase); then DBU, Mel, DMF; bc NaH, R4-X；THF；x：Pd/C，H2，EtOH；xi：LiOHx1H2O，MeOH，H2O；xii：FmoocOSu，Na2CO3Aqueous solution, dioxane
A20: see D.Hagiwara, H.Miyake, N.Igari, M.Karino, Y.Maeda, J.Med.chem.1994, 37, 2090-1＝H；R9＝OH)；Y.Arakawa，M.Yasuda，M.Ohnishi，S.Yoshifuji，Chem.pharm.Bulll.1997，45，255-259(R1＝H；R9＝COOH)；P.J.Murray，I.D.Starkey，Tetrahedron Lett.1996，37，1875-1878(R1＝H；R9＝(CH2)2NHCOCH2Ph)；K.Clinch，A.Vasella，R.Schauer，Tetrahedron Lett.1987，28，6425-6428(R1＝H；R9＝NHAc)。
A21: see a. golubev, n.sewald, k.burger, Tetrahedron lett.1995, 36, 2037-; machetti, F.M.Cordero, F.DeSarrio, A.Guarna, A.Brandi, Tetrahedron Lett.1996, 37, 4205-; ornstein, d.d.schoepp, m.b.arnold, j.d.leaner, d.lodge, j.med.chem.1991, 34, 90-97; r1＝R6＝H)；P.D.Leeson，B.J.Williams，R.Baker，T.Ludduwahetty，K.W.Moore，M.Rowley，J.Chem.Soc.Chrm.Commun.1990，1578-1580；D.I.C.Scopes，N.F.Hayes，D.E.Bays，D.Belton，J.Brain，J.Med.Chem.1992，35，490-501；H.Kessler，M.Kuehn，T.L_schner，Liebigs Ann.Chem.1986，1-20(R1＝R6＝H)；C.Herdeis，W.Engel，Arch.Pharm.1992，7，419-424(R1＝R6＝Bn)；C.Herdeis，W.Engel，Arch.Pharm.1992，411-418(R1＝COOMe；R6＝H)；C.Herdeis，W.Engel，Arch.Pharm.1992，419-424(R1＝COOMe；R6＝Bn)。
A22: see p.d. leeson, b.j.williams, r.baker, t.ladduwahetty, k.w. moore, m.rowley, J. chem.Soc.chem.Comm.1990, 1578-1580 (R)1＝H；R10＝NHOBn)。
A23: see Beyerman, Boekee, Recl. Tra. Chim. Pays-Bas 1959, 78, 648-; d.r.adams, p.d.bailey, i.d.colliier, j.d.heffennan, s.stokes j.chem.soc.chem.commun.1996, 349-; baldwin, r.m.adlington, c.godfrey, d.w.collins, j.g.vaughan, j.chem.soc.chem.comm.1993, 1434-1＝R6＝H)；C.Herdeis，W.Engel，Arch.Pharm.1993，297-302(R1＝COOMe；R6＝H)。
A24: see plineinger, Leonh _ user, chem. be.1959, 92, 1579-; D.W.Knight, N.Lewis, A.C.Share, D.Haigh, J.chem.Soc.Perkin Trans.11998, 22, 3673-; drummond, g.johnson, d.g.nickel, d.f.ortwine, r.f.bruns, b.welbaum, j.med.chem.1989, 32, 2116-; M.P.Moyer, P.L.Feldman, H.Rapoport, J.org.chem.1985, 50, 5223- 1＝R6＝H)；McElvain，Laughton，J.Am.Chem.Soc.1951，73，448-451(R1＝H；R6＝Ph)；McElvain，Laughton，J.Am.Chem.Soc.1951，73，448-451(R1＝Ph；R6＝H)；
A25: see l.y.hu, t.r.ryder, s.s.nikam, e.millerman, b.g.szoke, m.f.rafferty, bioorg.med.chem.lett.1999, 9, 1121-; lumma, r.d.hartman, w.s.saari, e.l.engelhardt, v.j.lotti, c.a.stone, j.med.chem.1981, 24, 93-101; hosten, m.j.o.antenenuis, ball.soc.chim.belg.1988, 97, 48-50; C.F.Bigge, S.J.Hays, P.M.Novak, J.T.Drummond, G.Johnson, T.P.Bobovski, Tetrahedron Lett.1989, 30, 5193-; aebishcher, P.Frey, H.P.Haerter, P.L.Herrling, W.Muller, Helv.Chim.acta 1989, 72,1043-1051；W.J.Hoeckstra，B.E.Maryanoff，B.P.Damiano，P.Andrade-Gordon，J.H.Cohen，M.J.Constanzo，B.J.Haertlein，L.R.Hecker，B.L.Hulshizer，J.A.Kauffman，P.Keane，J.Med.Chem.1999，42，5254-5265(R1＝H；R11＝H)；B.D.Dorsey，R.B.Levin，S.L.McDaniel，J.P.Vacca，J.P.Guare，J.Med.Chem.1994，37，3443-3451；M.Cheng，B.De，S.Pikul，N.G.Almstaed，M.G.Natchus，M.V.Anastasio，S.J.McPhail，C.J.Snider，Y.O.Taiwo，L.Chen，C.M.Dunaway，J.Med.Chem.2000，43，369-380；R.Kuwano，Y.Ito，J.Org.Chem.1999，64，1232-1237(R1＝H；R11＝COOtBu)；J.Kitchin，R.C.Bethell，N.Cammack，S.Dolan，D.N.Evans，J.Med.Chem.1994，37，3707-3716(R1＝H；R11＝COOPh)；C.F.Bigge，S.J.Hays，P.M.Novak，J.T.Drummond，G.Johnson，T.P.Bobovski，J.Med.Chem.1990，33，2916-2924(R1＝H；R11＝COOtBu；(CH2)3COOEt；(CH2)3PO(Me)OH；CH2PO(OH)2；(CH2)2PO(OEt)2；(CH2)2PO(OH)2)。
compounds of class a25 may also be prepared according to scheme 3:
scheme 3
i: lawesson reagent, toluene, 80 °; ii: DBU, Mel, DMF; iii: NaBH4Or NaCNBH3，MeOH；iv：Boc2O，THF；
v：LiOHx1H2O，MeOH，H2O；vi：Pd/C，H2，EtOH；vii：FmocOSu，Na2CO3Aqueous solution, dioxane
A26: see Koegel, j.biol.chem.1953, 201, 547 (R)1＝R12＝H)。
A27: see g.makara, g.r.marshall, Tetrahedron lett.1997, 38, 5069-; r.n. patel, a.banerjee, r.l.hanson, d.b.brzowski, l.w.parker, l.j.szarka, Tetrahedron: asymmetry1999, 10, 31-36 (R)1＝H；R13＝OH，OtBu)；J.E.Johanson，B.D.Christie，H.Rapoport，J.Org.Chem.1981，46，4914-4920；N.Moss，J.-S.Duceppe，J.-M-Ferland，J.Gauthier，J.Med.Chem.1996，39，2178-2187(R1＝H；R13＝CONHMe)；G.M.Makara，G.R.Marshall，Tetrahedron Lett.1997，38，5069-5072(R1＝H；R13＝SCH2(4-MeO)C6H4)。
A28: see a. golubev, n.sewald, k.burger, Tetrahedron lett.1995, 36, 2037-; ornstein, d.d.schoepp, m.b.arnold, j.d.leaner, d.lodge, j.med.chem.1991, 34, 90-97 (r.l.ornstein, d.d.schoepp, m.b.arnold, j.d.leaner, d.lodge, j.med.chem.1991, 34, 90-97 (r.d. 1＝R6＝H)；P.D.Leeson，B.J.Williams，R.Baker，T.Ladduwahetty，K.W.Moore，M.Rowley，J.Chem.Soc.Chem.Commun.1990，22，1578-1580；C.Herdeis，W.Engel，Arch.Pharm.1991，324，670(R1＝H；R6＝Me)；C.Herdeis，W.Engel，Arch.Pharm.1991，324，670(R1＝COOMe；R6＝H，Me)。
A29: see Kawase, Masami, chem.Pharm.Bull.1997, 45, 1248-1253; I.G.C.Coutts, J.A.Hadfield, P.R.Huddleston, J.chem.Res.Miniprint, 1987, 9, 2472-; I.G.C.Coutts, J.A.Hadfield, P.R.Huddleston, J.chem.Res.Miniprint, 1987, 9, 2472-; v.j.hrubi, w.l.cody, a.m.castrucci, m.e.hadley, collection.czech.chem.commu.1988, 53, 2549-; r.t.shuman, r.b.rothenberger, c.s.campbell, g.f.smith, d.s.gifford-Moore, p.d.gesellchen, j.med.chem.1993, 36, 314-; M.Kawase, Y.Okada, H.Miyamae, Heterocycles, 1998, 48, 285-294 (R)1＝R8＝H)；Kawase，Masami，Chem.Pharm.Bull.1997，45，1248-1253(R1＝H；R8＝6，7-(MeO2)；D.F.Ortwine，T.C.Malone，C.F.Bigge，J.T.Drummond，C.Humblet，J.Med.Chem.1992，35，1345-1370(R1＝H；R8＝7-CH2PO(OEt)2)；E.J.Corey，D.Y.Gin，Tetrahedron Lett.1996，37，7163-7166(R1＝CH2SCOOtBu)；P.Dostert，M.Varasi，A.DellaTorre，C.Monti，V.Rizzo，Eur.J.Med.Chim.Ther.1992，27，57-59(R1＝Me；R8＝6，7-(OH)2)；Z.Czarnocki，D.Suh，D.B.McLean，P.G.Hultin，W.A.Szarek，Can.J.Chem.1992，70，1555-1561；B.Sch_nenberger，A.Brossi，Helv.Chim.Acta 1986，69，1486-1497(R1＝Me；R8＝6-OH；7-MeO)；Hahn，Stiel，Chem.Ber.1936，69，2627；M.Chrzanowska，B.Sch_nenberger，A.Brossi，J.L.Flippen-Anderson，Helv.Chim.Acta 1987，70，1721-1731；T.Hudlicky，J.Org.Chem.1981，46，1738-1741(R1＝Bn；R8＝6，7-(OH)2)；A.I.Meyers，M.A.Gonzalez，V.Struzka，A.Akahane，J.Guiles，J.S.Warmus，TetrahedronLett.1991，32，5501-5504(R1＝CH2(3，4-methylenedioxy)C6H3；R8＝6，7-(OMe)2)。
A30 and A31 can be prepared according to schemes 4 and 5.
Scheme 4
i: NaH, tert-butyl N-benzoyl glycine ester, DMF; ii: NaH, pd (o), toluene; iii: TFA, CH2Cl2(ii) a iv: polyphosphoric acid
v: NaOH aqueous solution; MeOH, 75 ° then aqueous hydrochloric acid: vi: DBU, Mel, DMF; vii: lithium hexamethyldisilazide, THF, chlorotrimethylsilane, -78 °; then R1-X; viii: enzymatic breakdown (e.g. lipase) followed by separation in methyl ester: DBU, Mel, DMF; ix: NaOH aqueous solution; MeOH, heated; x: fmocosu, Na2CO3Aqueous solution, dioxane
Scheme 5
i：Boc2O，Na2CO3Aqueous solution, ═ dioxane; ii: DBU, Mel, DMF; iii: lithium hexamethyldisilazide THF, chlorotrimethylsilane, -78 °; then R2-X；iv：LiOHx1H2O，MeOH，H2O；v：TFA，CH2Cl2；vi：FmocOSu，Na2CO3Aqueous solution, dioxane
A32 can be prepared as described in the following references: p.w.schiller, g.weltrowska, t.m. -d.nguyen, c.lemieux, n.nga, j.med.chem.1991, 34, 3125-; v.s.goodfellow, m.v.marathon, k.g.kuhlman, t.d.fitzpatrick, d.cuadrato, j.med.chem.1996, 39, 1472-; G.Caliendo, F.Fiorino, P.Grieco, E.Perissutt, S.Deluca, A.Guiliano, G.Santelli, D.Califono, B.Severino, V.Santagada, Farmaco, 1999, 54, 785-; V.S.Goodfellow, M.V.Marathe, K.G.Kuhlman, T.D.Fitzpatrick, D.Cuadro, J.Med.chem.1996, 39, 1472-1＝R8＝H)；D.Tourwe，E.Mannekens，N.T.Trang，P.Verheyden，H.Jaspers，J.Med.Chem.1998，41，5167-5176；A.-K.Szardenings，M.Gordeev，D.V.Patel，Tetrahedron Lett.1996，37，3635-3638；W.Wiczk，K.Stachowiak，P.Skurski，L.Lankiewicz，A.Michniewicz，A.Roy，J.Am.Chem.Soc.1996，118，8300-8307；K.Verschuren，G.Toth，D.Tourwe，M.Lebl.，G.van Binst，V.Hrubi，Synthesis 1992，458-460(R1＝H；R8＝6-OH)；P.L.Ornstein，M.B.Arnold，N.K.Augenstein，J.W.Paschal，J.Org.Chem.1991，56，4388-4392(R1＝H；R8＝6-MeO)；D.Ma，Z.Ma，A.P.Kozikowski，S.Pshenichkin，J.T.Wroblenski，Bioorg.Med.Lett.1998，8，2447-2450(R1＝H；R8＝6-COOH)；U.Sch_llkopf，R.Hinrichs，R.Lonsky，Angew.Chem.1987，99，137-138(R1＝Me；R8＝H)；B.O.Kammermeier，U.Lerch，C.Sommer，Synthesis 1992，1157-1160(R1＝COOMe；R8＝H)；T.Gees，W.B.Schweizer，D.Seebach，Helv.Chim.Acta 1993，76，2640-2653(R1＝Me；R8＝6，7-(MeO2)。
A33: see Hinton, Mann, J.chem.Soc.1959, 599-.
A34: see g.p.zecchini, m.p.paradisi, j.heterocyclic.chem.1979, 16, 1589-; S.Cerrini, J.chem.Soc.PerkinTrans.1, 1979, 1013-; P.L.Ornstein, J.W.Pascal, P.D.Gesellchen, J.org.chem.1990, 55, 738-741; G.M.Kscan, A.M.Yan, C.G.Diefenbacher, J.L.Stanton, J.Med.chem.1985, 28, 1606-1611; J.A.Robl, D.S.Karanewsky, M.M.Asaad, Tetrahedron letter.1995, 36, 1593-; s.katayama, n.ae, r.nagata, Tetrahedron: asymmetry 1998, 9, 4295- 1＝R8＝H)；K.Hino，Y.Nagai，H.Uno，Chem.Pharm.Bull.1988，36，2386-2400(R1＝Me；R8＝H)。
A35: see Beilstein accession number: 530775, 883013 (R)1＝R8＝H)。
A36: see r.w.carling, p.d.leeson, a.m.moseley, r.baker, a.c.foster, j.med.chem.1992, 35, 1942-1953; S.Kano, T.Ebata, S.Shibuya, J.chem.Soc.Perkin Trans.1, 1980, 2105-1＝R8＝H)；R.W.Carling，P.D.Leeson，A.M.Moseley，R.Baker，A.C.Foster，J.Med.Chem.1992，35，1942-1953(R1＝H；R8＝5-Cl；7-Cl)。
A37: see Nagarajan, Indian J.chem.1973, 11, 112 (R)1＝CH2COOMe；R8＝H)。
A38: see r.pauly, n.a.sasaki, p.potire, tetrahedron lett.1994, 35, 237-; J.Podlech, D.Seebach, Liebigs Ann.org.Bioorg.chem.1995, 7, 1217-; K.C.Nicolaou, G. -Q.Shi, K.Namoto,F.Bernal，J.Chem.Soc.Chem.Commun.1998，1757-1758(R1＝H；R2＝H)。
a39: see Beilstein, registration Number 782885.
A40: see F.P.J.C.Rutjes, N.M.Terhiuis, H.Hiemstra, N.W.Speckamp, Tetrahedron 1993, 49, 8605-8628 (R.P.J.C.Rutjes, N.M.Terhiursa, N.W.Speckamp, Tetrahedron 1993, 49, 8605-86281＝H；R3Bn); such compounds may be prepared according to scheme 6.
Scheme 6
i：BocNHNH2，NaCNBH3，MeOH，AcOH；ii：CbzCl，Et3N.CH2Cl2；iii：TFA，CH2Cl2(ii) a Then pyridine DMAP is heated; iv: breakdown (e.g. lipase) v: DBU, Mel, DMF; vi: lawesson reagent toluene, 75 °; vii: DBU, Mel, DMF; viii: NaBH4Or NaCNBH3，MeOH；ix：R3Introduction of x by reactive amination, alkylation or acylation: liohx1H2O，MeOH，H2O；xi：Pd/C，H2，EtOH；xii：FmocOSu，Na2CO3Aqueous solution, dioxane
A41: such compounds may be prepared according to scheme 7.
Scheme 7
i: breakdown (e.g. lipase) and then separation as methyl ester: DBU, Mel, DMF;
ii：NaH，R4-X，THF；iii：LiOHx1H2O，MeOH，H2O；iv：Pd/C，H2，EtOH；
v：FmocOSu，Na2CO3Aqueous solution, dioxane
A42-A46: such compounds may be prepared according to schemes 8-12. Key intermediates 34 and alpha-amino acid syntheses involving this building block include: R.M.Williams, M. -N.im, Tetrahedron Lett.1988, 29, 6079-; R.M.Williams, M. -N.im, J.am.chem.Soc.1991, 113, 9276-; delllaria, b.d.santarsiero, Tetrahedron lettt.1988, 29, 6079-; delllaria, b.d.santarsiero, j.org.chem.1989, 54, 3916-; baldwin, v.lee, c.j.schofield, Synlett 1992, 249-; baldwin, v.lee, c.j.schofield, Heterocycles 1992, 34, 903-.
i: lithium hexamethyldisilazide, THF, chlorotrimethylsilane, -78 °; then R5-X; ii: HBr; iii: DBU, Mel, DMF; iv: DIBAL-H, THF; v: EtOH, pyridinium p-toluenesulfonate, molecular sieve 4A; vi: lithium hexamethyldisilazide THF, -78 °, 33; vii: Pd/C, H2EtOH; then DBU, Mel, DMF; then TFA, CH2Cl2(ii) a viii: hclaq., THF; then Na (OAc)3BH, AcOH, dichloroethane; ix; liohx1H2O，MeOH，H2O；x：FmocOSu，Na2CO3Aqueous solution, dioxane
Scheme 9
i: lithium hexamethyldisilazide, THF, chlorotrimethylsilane, -78 °; then R 6-X; ii: HBr, iii: DBU, Mel, DMF; iv: DIBAL-H, THF; v: EtOH, pyridinium p-toluenesulfonate, molecular sieve 4A; vi: lithium hexamethyldisilazide THF, -78 °, 39; vii: Pd/C, H2EtOH; then DBU, Mel, DMF; then TFA, CH2Cl2(ii) a viii: hclaq., THF; however, the device is not suitable for use in a kitchenLast Na (OAc)3BH, AcOH, dichloroethane; viii: boc2O，Et3N，CH2Cl2；ix:Bu4NFx10H2O, THF; ix: pyridinium chlorochromate; x: liohx1H2O，MeOH，H2O；xi：TFA，CH2Cl2；xii：FmocOSu，Na2CO3Aqueous solution, dioxane
Scheme 10
i: HBr; ii: DBU, Mel, DMF; iii: DIBAL-H, THF: iv: EtOH, pyridinium p-toluenesulfonate, molecular sieve 4A; v: lithium hexamethyldisilazide THF, -78 °, 43; vi: Pd/C, H2EtOH; then DBU, Mel, DMF; then TFA, CH2Cl2(ii) a vii: hcag, THF; then Na (OAc)3BH, AcOH, dichloroethane; vii: liohx1H2O，MeOH，H2O；ix：FmocOSu，Na2CO3Aqueous solution, dioxane
Scheme 11
i: HBr; ii: DBU, Mel, DMF; iii: DIBAL-H, THF; iv: EtOH, pyridinium p-toluenesulfonate, molecular sieve 4A; v: lithium hexamethyldisilazide, THF, -78 °, 47; vi: Pd/C, H2EtOH; then DBU, Mel, DMF; then TFA, CH2Cl2(ii) a vii: hclaq., THF; then Na (OAc)3BH, AcOH, dichloroethane; viii Boc2O，Et3N，CH2Cl2；ix：Bu4NFx10H2O, THF; x: pyridinium chlorochromate xi: liohx1H 2O，MeOH，H2O；xii：TFA，CH2Cl2；xiii：FmocOSu，Na2CO3Aqueous solution, dioxane
Scheme 12
i: HBr; ii: DBU, Mel, DMF; iii: DIBAL-H, THF; iv: EtOH, pyridinium p-toluenesulfonate, molecular sieve 4A; v: lithium hexamethyldisilazide, THF, -78 °, 51; vi: Pd/C, H2EtOH; then DBU, Mel, DMF; then TFA, CH2Cl2(ii) a vii: HCl aq. thf; then Na (OAc)3BH, AcOH, dichloroethane; viii: boc2O，Et3N，CH2Cl2；ix：Bu4NFx10H2O, THF; x: pyridinium chlorochromate; xi: liohx1H2O，MeOH，H2O；xii：TFA，CH2Cl2；xiii：FmocOSu，Na2CO3Aqueous solution, dioxane
A47: see P.Barraclough, R.D.Farrant, D.Kettle, S.Smith, J.chem.Res.Miniprint 1991, 11, 2876-2884 (R.Barraclough, R.D.Farrant, D.Kettle, S.Smith, J.Chem.Res.Miniprint 1991, 11, 2876)1＝R11＝H，Bn，(CH2)2PO(OEt)2)。
A48: see A.Nouvet, M.Binard, F.Lamato, J.Martinez, R.Lazaro, Tetrahedron 1999, 55, 4685-1＝R12＝H)。
A49: see m.y.kolleganov, i.g.kolleganova, m.d.mitrofanova, l.i.martynnko, p.p.nazarov, v.i.spitsyn, bull.acad.sci.ussr div.chem.sci (engl.trans.)1983, 32, 1293-materials 1299; akad Nauk SSSR Ser. Khim 1983, 6, 1293-1299; V.P.Vasilev, T.D.Orlova, S.F.Ledenkov, J.Gen.chem USSR (Engl. Trans.1989, 59, 1629-1＝H；R12＝CH(COOH)CH2COOH). Compounds of class a49 may also be prepared according to scheme 13.
Scheme 13
i：NaH，CbzNH(CH2)2Br，THF；ii：Pd/C，H2，EtOH；iii：EDCl，CH2Cl2Diisopropylethylamine iv: NaH, R12-X，THF；v：LiOHx1H2O，MeOH，H2O；vi：TFA，CH2Cl2；vii：FmocOSu，Na2CO3Aqueous solution, dioxane
A50 and a 51: these types of compounds can be prepared according to schemes 14 and 15.
Scheme 14
i: HBr; ii: DBU, Mel, DMF; iii: DIBAL-h.thf; iv: EtOH, pyridinium p-toluenesulfonate, molecular sieve 4A; v: lithium hexamethyldisilazide, THF, -78 °, 59; vi: Pd/C, H2EtOH; then DBU, Mel, DMF; then TFA, CH2Cl2(ii) a vii: HCl aq. thf; then Na (OAc)3BH, AcOH, dichloroethane; viii: liohx1H2O，MeOH，H2O；ix：FmocOSu，Na2CO3Aqueous solution, dioxane
Scheme 15
i: HBr; ii: DBU, Mel, DMF; iii: DIBAH, THF; iv: EtOH, pyridinium p-toluenesulfonate, molecular sieve 4A; v: lithium hexamethyldisilazide, THF, -78 °, 63 vi: Pd/C, H2EtOH; then DBU, Mel, DMF; then TFA, CH2Cl2(ii) a vii: HCl aq., THF; then Na (OAc)3BH, AcOH, dichloroethane viii: boc2O，Et3N，CH2Cl2；ix：Bu4NFx10H2O, THF; x: 1 pyridinium chlorochromate; xi: liohx1H2O，MeOH，H2O；xii：TFA，CH2Cl2；xiii：FmocOsu，Na2CO3Aqueous solution, dioxane
A53: see P.Barraclough, R.D.Farrant, D.Kettle, S.Smith, J.chem.Res.Miniprint 1991, 11, 2876-2884 (R.Barraclough, R.D.Farrant, D.Kettle, S.Smith, J.Chem.Res.Miniprint 1991, 11, 2876)1＝R11＝H；R1＝H；R11＝Bn，(CH2)3PO(OH)2)；(CH2)3PO(Et)2)；J.I.Levin，J.F.DiJoseph，L.M.Killar；A.Sung，T.Walter，Bioorg.Med.Chem.Lett.1998，8，2657-2662(R1＝H；R11＝4CF3OC6H4CO)。
A52 and a 54: such compounds may be prepared according to schemes 16 and 17.
Scheme 16
i: iBuMgCl, THF; ii: NaH, THF; iii: lithium hexamethyldisilazide THF, chlorotrimethylsilane-78 °; then R 6-X; iv: naohaq., MeOH, 75 °; then hclaq.; v: DBU, Mel, DMF; vi: lithium hexamethyldisilazide, THF, chlorotrimethylsilane, -78 °; then R1-x; vii: breakdown (e.g. lipase) then DBU, Mel, DMF: viii: liohx1H2O，MeOH，H2O；ix TFA，CH2Cl2；x：FmocOSu，Na2CO3Aqueous solution, dioxane
Scheme 17
i：NaN3，DMSO；ii：NaH，THF，CH2＝CHCOOBn；iii：Pd/C，H2，EtOH；iv：EDCl，CH2Cl2Diisopropylethylamine; v: NaH, R12-X，THF；vi：LiOHx1H2O，MeOH，H2O；vii：TFA，CH2Cl2；viii：FmocOSu，Na2CO3Aqueous solution, dioxane
A55 and a 56: such compounds may be prepared according to schemes 18 and 19.
Scheme 18
i：NaH，THF，CbzNH(CH2)3Br，ii：Pd/C，H2EtOH; then toluene, heating iii: breakdown (e.g. lipase) iv: DBU, Mel, DMF; v: NaH, R12-X，THF；vi：LiOHx1H2O，MeOH，H2O；vii：TFA，CH2Cl2；viii：FmocOSu，Na2CO3Aqueous solution, dioxane
Scheme19
i: HBr; ii: DBU, Mel, DMF; iii: DIBAL-H, THF; iv: EtOH, pyridinium p-toluenesulfonate, molecular sieve 4A; v: lithium hexamethyldisilazide, THF, -78 °, 86; vi: Pd/C, H2EtOH; then DBU, Mel, DMF; then TFA, CH2Cl2(ii) a vii: HCl aq., THF; then Na (OAc)3BH, AcOH, dichloroethane viii: liohx1H2O，MeOH，H2O；ix：FmocOSu，Na2CO3Aqueous solution, dioxane
A57: such compounds may be prepared according to scheme 20.
Scheme 20
i: NaOMe, MeOH; ii: NaH, THF; iii: NaOH aq., MeOH, 75 °; then HCl aq, iv: DBU, Mel, DMF; v: lithium hexamethyldisilazide THF, chlorotrimethylsilane, -78 °; then R 1-X; vi: breakdown (e.g. lipase) followed by isolation of DBU, Mel, DMF as methyl ester; vii: liohx1H2O，MeOH，H2O；viii：TFA，CH2Cl2；ix：FmocOSu，Na2CO3Aqueous solution, dioxane
A58: see C. -H.Lee, H.Kohn, J.org.chem.1990, 55, 6098-1＝R8＝H)。
A59: can be prepared according to scheme 21.
Scheme 21
i: NaOMe, MeOH; ii: NaH, THF; iii: NaOH aq., MeOH, 75 °; then hclaq.; iv: DBU, Mel, DMF; v: lithium hexamethyldisilazide, THF, chlorotrimethylsilane, -78 °; then R1-X; vi: breakdown (e.g. lipase) followed by isolation of DBU, Mel, DMF as methyl ester; vii: liohx1H2O，MeOH，H2O；viii：TFA，CH2Cl2；ix：FmocOSu，Na2CO3Aqueous solution, dioxane
A60: such compounds may be prepared according to scheme 22.
Scheme 22
i: NaH, DMSO; ii: naohaq., MeOH, 75 °; then hclaq.; iii: DBU, Mel, DMF; iv: NaOMe (2.2 equiv.), R1-X；v：Raney-Ni，H2，EtOH；vi：CbzCl，Et3N，CH2Cl2；vii：NaH，Br(CH2)2Br, THF; viii: breakdown (e.g. lipase) then DBU, Mel, DMF; ix: Pd/C, H2，EtOH；x：NaH，R14-X，THF；xi：LiOHx1H2O，MeOH，H2O；xii：TFA，CH2Cl2；xiii：FmocOSu，Na2CO3Aqueous solution, dioxane
A61: see D.R. Armour, K.M. Morriss, M.S. Congreve, A.B.Hawcock, bioorg.Med.chem.Lett.1997, 7, 2037-1＝R12＝H)。
A62: such compounds may be prepared according to scheme 23.
Scheme 23
i: breakdown (e.g. lipase) then DBU, Mel, DMF; ii: lithium hexamethyldisilazide, THF, chlorotrimethylsilane-78 °; then R 6-X；iii：LiOHx1H2O，MeOH，H2O；iv：TFA，CH2Cl2；v：FmocOSu，
Na2CO3Aqueous solution, dioxane
A63: see s.e. gibson, n.guillo, r.j.middleton, a.thuilliez, m.j.tozer, j.chem.soc.perkin trans.1, 1997, 4, 447-456; S.E.Gibson, N.Guillo, S.B.Kalindjan, M.J.Tozer, bioorg.Med.chem.Lett, 1997, 7, 1289-one 1292 (R.E.Gibson, N.Guillo., S.B.Kalindjan, M.J.Tozer, Med.chem.Lett, 1997, 7, 1289-one)1＝H；R8＝H)；Beilstein Registry Number：459155(R1＝H；R8＝4，5-MeO2)。
A64: such compounds may be prepared according to scheme 24.
Scheme 24
i：NaH，DMSO；ii：Pd/C，H2EtOH; iii: iBuOCOCl, diisopropylethylamine, CH2Cl2(ii) a Then, nitridizing methane; iv: HBr, CH2Cl2(ii) a v: NaH, THF; vi: NaOH aq.meoh, 75 °; then hclaq.; vii: DBU, Mel, DMF; viii: lithium diisopropylamide, THF, chlorotrimethylsilane, -78 °; then R1-X; ix: breakdown (e.g., lipase); then isolated as methyl ester: DBU, Mel, DMF; x: UOHx1H2O，MeOH，H2O；xi：TFA，CH2Cl2；xii：FmocOSu，Na2CO3Aqueous solution, dioxane
A65 and a 67: these types of compounds can be prepared according to schemes 25 and 26.
Scheme 25
i：NaH，DMSO，BrCH(R1)COOMe；ii：LiOHx1H2O，MeOH，H2O; iii: polyphosphoric acid; iv: NaH, CCOOMe, THF; v: breakdown (e.g. lipase) followed by isolation of DBU, Mel, DMF as methyl ester; vi: liohx1H2O，MeOH，H2O；vii：TFA，CH2Cl2；viii：FmocOSu，Na2CO3Aqueous solution, dioxane
Scheme 26
i：NaH，THF，CH2l2；ii：NaH，DMSO；iii：Bu4NFx10H2O, THF; iv: methanesulfonyl chloride, Et3N，CH2Cl2(ii) a Then nah.thf; v: naohaq., MeOH, 75 °; then hclaq.; vi: DBU, Mei, DMF; vii: lithium hexamethyldisilazide, THF, chlorotrimethylsilane-78 °; then R 1-X；viii：Pd/C，H2，EtOH；ix：NaH，THF，R14-X; x: breakdown (e.g. lipase) followed by isolation of DBU, Mel, DMF as methyl ester; xi: liohx1H2O，MeOH，H2O；xii：TFA，CH2Cl2；xiii：FmocOSu，Na2CO3Aqueous solution, dioxane
A66: see G.L.Grunewald, L.H.Dahanukar, J.Heterococcus.chem.1994, 31, 1609-1＝H；R8＝H，8-NO2；C(1)＝O)。
A68: see Griesbeck, H.Mauder, I.M ü iller, chem.Ber.1992, 11, 2467-2476; (R)1＝R8＝H；C(1)＝O)。
A69：R.Kreher，W.Gerhardt，Liebigs Ann.Chem.1981，240-247(R1＝R8＝H)。
As listed above, the structural unit A70 belongs to the class of open-chain alpha-substituted alpha-amino acids, A71 and A72 to the class of corresponding beta-amino acid analogs, and A73-A104 to the class of cyclic analogs of A70.
Building blocks of the A70 and A73-A104 types have been synthesized by several different conventional methods: by cycloaddition of ketones with imines [2+2] (I.Ojima, H.J.C.Chen, X.Quin, Terahydron Lett.1988, 44, 5307-; by asymmetric aldol reaction (Y.Ito, M.Sawamura, E.Shirakawa, K.Hayashikazi, T.Hayashi, Tetrahedron Lett.1988, 29, 235-; by the oxazolidinedione method (J.S. Amato, L.M.We instock, S.Karady, US 4508921A; M.Gander-Coquoz, D.Seebach, Helv.Chim.acta 1988, 71, 224-; α, α -disubstituted α -ketoesters by Schmidt-rearrangement (G.I.Georg, X.Guan, J.Kant, Tetrahedron Lett.1988, 29, 403-; asymmetric synthesis with chiral Ni (II) -derived Schiff bases (Y.N.Belokon, V.I.Bakhmutov, N.I.Chernoglazolva, K.A.Kochetov, S.V.Vitt, N.S.Garbarnkaya, V.M.Belikov, J.chem.Soc.Perkin Trans.1, 1988, 305-; by bis-lactonamide ether synthesis (U.S. Sch _ llkopf, R.Hinrichs, R.Lonsky, Angew.chem.1987, 99, 137-; degradation of racemic amino acids by the microbial degradation (K.Sakashita, I.Watanabe, JP 62/253397A2) and by the hydantoin method in combination with a chiral auxiliary from L-phenylalanine amide (D.Obrecht, C.Spiegler, P.Sch. nholzer, K.M muller, H.Heimgartner, F.Stierli, Helv.Chim.acta 1992, 75, 1666. 1696; D.Obrecht, U.Bohdal, J.Daly, C.Lehmann, P.Schholzer, K.M muller, Tehedron 1995, 51, 10883-10900; D.Obrechmann, C.Lehmann, C.Schffeeuhol, Schholzezer, K.M. Acutan, Bumper, C.Schffer, C.Offecht, C.7. Schffechhol, Spander, C.7. Schffechhol, C.7. Schffer, C.7. Schffechhol. The latter process is particularly useful in the preparation of enantiomers of structural units of the A70 class (see scheme 27) and the A73-A104 class (see scheme 28) in pure form.
Scheme 27
i：KCN，(NH4)2CO3，EtOH/H2O；ii：Ba(OH)2，H2O; iii: naoh, PhCOCl, dioxane; then DCC, CH2Cl2；iv：NaH，DMF，R18-X or R19-X; v: l-phenylalanine cyclohexylamine, N-methylpyrrolidone 70 °; vi: CH (CH)3SO3H, MeOH, 80 °; vii: 6N aqueous HCl dioxane 100 °; viii: me3SiCl，DlEA，CH2Cl2(ii) a Then FmocCl
The process described in scheme 27 consists in using KCN, (NH) in an ethanol/water mixture4)2CO3Treatment of the appropriate ketone 126(E.Ware, J.chem.Res.1950, 46, 403; L.H.Goodson, I.L.Honigberg, J.J.Lehmann, W.H.Burton, J.Org.chem.1960, 25, 1920; S.N.Rastogi, J.S.Bindra, N.Anand, Ind.J.Cgram.1971, 1175) affords the corresponding hydantoin 127 which is reacted with Ba (OH)2Hydrolysis of the water at 120-. The Shotten-Bowman acylation reaction (Houben-Wey, 'Methoden der Organischen Chemie', Volume XI/2, Stickstoff-Verbindungen II und III ', Georg Tieme Verlag, Stuttgart, pp 339) was carried out followed by cyclization with N, N' -dicyclohexylcarbodiimide to give dihydrooxazolone 129(D.Obrecht, U.Bohdal, C.Broger, D.Bur, C.Lehmann, R.Ruffiex, P.Sch _ nholzer, C.Spiegler, Helv.Chim.acta 1995, 78, 5631; D.Obrechlt, C.Spiegler, P.Sch _ nzeller, K.M, H.Hegamner, F.Stierli, Helv.1666, Chi 96). Alternatively, the dihydrooxazolone 129 can be prepared starting from amino acids 130 and 131, by a Showden Bowman acylation reaction and cyclization with N, N' -dicyclohexylcarbodiimide to yield dihydrooxazolones 132 and 133 and by alkylation to 129(D.Obrecht, U.Bohdal, C.Broger, D.Burr, C.Lehmann, R.Ruffeiux, P.Sch _ nholzer, C.Spiegler, Helv.Chim.acta 1995, 78, 563-580; D.Obrecht, C.Spiegler, P.Sch _ nholzer, K.M. Huimgartnner, F.Stierli, Helv.Chim.acta 1992, 75, 1666-1696) (see scheme 1). Treatment of 129(D.Obrecht, U.Bohdal, C.) with L-phenylalanine cyclohexanamide Broger, D.Bur, C.Lehmann, R.Ruffieux, P.Sch _ nholzer, C.Spiegler, Helv.Chim.acta 1995, 78, 563-. Treatment of 134 and 135 with methanesulfonic acid in methanol at 80 ℃ gives esters 136a and 136b, which are converted into the corresponding Fmoc-protected final building blocks 137a and 137 b.
116
Scheme 28
i：KCN，(NH4)2CO3，EtOH/H2O；ii：Ba(OH)2，H2O: iii: NaOH, PhCOCl, dioxane then DCC, CH2Cl2(ii) a iv: l-hydrocinnamic acid cyclohexanamide N-methylpyrrolidone, 70 °; v: CH (CH)3SO3H, MeOH, 80 °; vi: 6N hclaq., 100 ° dioxane; vii: me3SiCl，DIEA，CH2Cl2；FmocCl
The acetolactam (139) can be prepared starting from the corresponding ketone 138 according to the conventional methods described in scheme 28 (D.Obrecht, U.Bohdal, C.Broger, D.Burr, C.Lehmann, R.Ruffeioux, P.Sch. nholzer, C.Spiegler, Helv.Chim.acta 1995, 78, 563-580; D.Obrecht, C.Spiegler, P.Sch. nholzer, K.M muller, H.Heimgartner, F.Stierli, Helv.Chim.acta 1992, 75, 1666-1696), A73-A104 can be prepared starting from the corresponding ketone 138 to form the acetolactam (139) (E.Waodson, J.Chem.Res.1950, 46, 403; L.H.Goodson, I.L.Hodgmg, J.196man.W.1965, Burtmann, H.H.H.Scorker, H.19, H.J.5631, H.J.19832-H.H.H.H.H.H.7-Chedyson, I.H.H.H.H.197, H.15, H.H.H.H.H.H.H.H.H.H.H.H.H.H.H.H.H.H.H.15, H.H.H.H.H.H.H.H.H.H.H.H.H.H.H.H.H.H.H.H.H.H.H.H.S.H.H.H.H.H.H.H.H.H.H.H.H.H.H.H.H.H.H 2) Racemic amino acid 140 is obtained which is subjected to schottky-bowman-acylation and cyclization with N, N' -dicyclohexylcarbodiimide to yield dihydrooxazolone 141. With L-phenylalanine ringCaproamide reaction (D.Obrecht, U.Bohdal, C.Broger, D.Bur, C.Lehmann, R.Ruffieux, P.Sch. nholzer, C.Spiegler, Helv.Chim.acta 1995, 78, 563-580) gives diastereomeric peptides 142 and 143 which are separated by flash chromatography or crystallization. Treatment of 142 and 143 with methanesulfonic acid in methanol at 80 ℃ gives esters 144a and 144b, which are converted into the corresponding suitably protected amino acid precursors 145a and 145b, ready for peptide synthesis.
A71: such amino acid building blocks (see formula 147) can be prepared from the corresponding disubstituted succinate 146 by the Curtius-rearrangement shown in scheme 29.
Scheme 29
i: diphenylphosphoryl azide, toluene, 80 °; then benzyl alcohol
A71: see D.Seebach, S.Abele.T.Sifferlen, M.Haenggi, S.Gruner, P.Seiler, Helv.Chim.acta 1998, 81, 2218-18And R19 form：-(CH2)2-；-(CH2)3-；-(CH2)4-；-(CH2)5-；R20＝H)；L.Ducrie，S.Reinelt，P.Seiler，F.Diederich，D.R.Bolin，R.M.Campbell，G.L.Olson，Helv.Chim.Acta 1999，82，2432-2447；C.N.C.Drey，R.J.Ridge，J.Chem.Soc.Perkin Trans.1，1981，2468-2471；U.P.Dhokte，V.V.Khau，D.R.Hutchinson，M.J.Martinelli，Tetrahedron Lett.1998，39，8771-8774(R18＝R19＝Me；R20＝H)；D.L.Varie，D.A.Hay，S.L.Andis，T.H.Corbett，Bioorg.Med.Chem.Lett.1999，9，369-374(R18＝R19＝Et)；Testa，J.Org.Chem.1959，24，1928-1936(R18＝Et；R19＝Ph)；M.Haddad，C.Wakselman，J.Fluorine Chem.1995，73，57-60(R18＝Me；R19＝CF3；R20＝H)；T.Shono，K.Tsubata，N.Okinaga，J.Org.Chem.1984，49，1056-1059(R18＝R19＝R20＝Me)；K.Ikeda，Y.Terao，M.Sekiya，Chem.Pharm.Bull.1981，29，1747-1749(R18And R19 form：-(CH2)5-；R20＝Me)。
Amino acid building blocks of class A72 can suitably be prepared according to scheme 30 by the Arndt-Eisterrt C1-homologation of compounds of class A70.
Scheme 30
i: iBuOCOCl, diisopropylethylamine, CH 2Cl2(ii) a Then the methyl azide is used as a catalyst,
a72: see Y.V.Zeifman, J.Gen.chem.USSR (Engl. Trans.)1967, 37, 2355-18＝R19＝CF3)；W.R.Schoen，J.M.Pisano，K.Pendergast，M.J.Wyvratt，M.H.Fisher，J.Med.Chem.1994，37，897-906；S.Thaisrivongs，D.T.Pals，D.W.DuCharme，S.Turner，G.L.DeGraaf，J.Med.Chem.1991，34，655-642；T.K.Hansen，H.Thoegersen，B.S.Hansen，Bioorg.Med.Chem.Lett.1997，7，2951-2954；R.J.DeVita，R.Bochis，A.J.Frontier，A.Kotliar，M.H.Fisher，J.Med.Chem.1998，41，1716-1728；D.Seebach，P.E.Ciceri，M.Overhand，B.Jaun，D.Rigo，Helv.Chim.Acta 1996，79，2043-2066；R.P.Nargund，K.H.Barakat，K.Cheng，W.Chan，B.R.Butler，A.A.Patchett，Bioorg.Med.Chem.Lett.1996，6，1265-1270(R18＝R19＝Me)；E.Altmann，K.Nebel，M.Mutter，Helv.Chim.Acta 1991，74，800-806(R18＝Me；R19＝COOMe)。
A73: such compounds can be prepared according to the methods described in the following references: mapeli, G.Tarocy, F.Schwitzer, C.H.Stammer, J.org.chem.1989, 54, 145-149 (R.21＝4-OHC6H4)；F.Elrod，E.M.Holt，C.Mapelli，C.H.Stammer，J.Chem.Soc.Chem.Commun.1988，252-253(R21＝CH2COOMe)；R.E.Mitchell，M.C.Pirrung，G.M.McGeehan，Phytochemistry 1987，26，2695(R21＝CH2OH)，J.Bland，A.Batolussi，C.H.Stammer，J.Org.Chem.1988，53，992-995(R21＝CH2NH2). Other derivatives of a73 have been described in the following documents: T.Wakamiya, Y.Oda, H.Fujita, T.Shiba, Tetrahedron Lett.1986, 27.2143-2134; U.S. Sch _ llkopf, B.Hupfeld, R.Gull, Angew.chem.1986, 98, 755-; J.E.Baldwin, R.M.Adlington, B.J.Rawlings, Tetrahedron Lett.1985, 26, 481-484; d.kalvin, K.Ramalinggram, R.Woodard, Synth.Comm.1985, 15, 267-272 and L.M.Izquierdo, I.Arenal, M.Bernabe, E.Alvarez, tetrahedron Lett.1985, 41, 215-220.
A74: such compounds can be prepared according to conventional methods described in scheme 28 starting from the corresponding cyclobutanone.
A75 and a 76: such compounds can be prepared using the following methods: hughes, J.Clardy, J.org.chem.1988, 53, 4793-; e.a. bell, m.y.qureshi, r.j.pryce, d.h.janzen, p.lemke, j.clardy, j.am.chem.soc.1980, 102, 1409; Y.Gaoni, Tetrahedron Lett.1988, 29, 1591-; allan, J.R.Haurahan, T.W.Hambley, G.A.R.Johnston, K.N.Mewett, A.D.Mitrovic, J.Med.chem.1990, 33, 2905- 23＝COOH)；G.W.Fleet，J.A.Seijas，M.VasquezTato，Tetrahedron 1988，44，2077-2080(R23＝CH2OH)。
A77: such compounds may be prepared according to J.H.Burckhalter, G.Schmied, J.Pharm.Sci.1966, 55, 443-23Aryl).
A78: such compounds may be prepared according to the general formulae J.C.Watkins, P.Kroosgard-Larsen, T.Honor, TIPS 1990, 11, 25-33; trigalo, d.brisson, r.azerad, Tetrahedron lett.1988, 29, 6109 (r.b.24COOH).
A79: such compounds can be prepared according to conventional methods described in scheme 28 starting from the corresponding pyrrolidin-3-one.
A80-A82: such compounds may be prepared according to d.m. walker, e.w. logusch, Tetrahedron lett.1989, 30, 1181-1184; morimoto, K.Achiwa, chem.pharm.Bull.1989, 35, 3845-3849; j.yosh imura, S.Kondo, M.Ihara, H.Hashimoto, Carbohydrate Res.1982, 99, 129-142.
A83: such compounds can be prepared according to the general method described in scheme 28 starting from the corresponding pyrazolin-4-ones.
A84: such compounds may be prepared according to r.m. binder, b.h. butcher, d.h. buxton, d.j.howells, j.med.chem.1971, 14, 892-893; D.Obrecht, U.Bohdal, C.Broger, D.Burr, C.Lehmann, R.Ruffieux, P.Sch _ nholzer, C.Spiegler, Helv.Chim.acta 1995, 78, 563-.
A85: such compounds can be prepared according to the conventional methods described in scheme 28, starting from the corresponding 1, 2-indane-1, 3-dione.
A86: such compounds can be prepared according to the general methods described in scheme 28, starting from the corresponding 1, 2-indan-2-ones.
A87: such compounds and their analogues may be prepared according to c.cativiela, m.d.diazde Villegas, a.avenoza, j.m.peregrina, Tetrahedron 1993, 47, 10987-; cativiela, p.lopez, j.a.mayoral, tetrahedron ansymmetry 1990, 1, 379; c.cativiela, j.a.mayoral, a.avenoza, m.gonzalez, m.a.rey, Synthesis 1990, 1114.
A87 and a 88: such compounds may be prepared according to l.munda, j.chem.soc.1961, 4372; J.Ansell, D.Morgan, H.C.price, Tetrahedron Lett.1978, 47, 4615-one 4616.
A89: such compounds can be prepared according to conventional methods described in scheme 28 starting from the corresponding piperidin-3-ones.
A90: such compounds can be prepared according to conventional methods described in scheme 28, starting from the corresponding tetrahydrothiopyran-3-one.
A91: such compounds can be prepared according to conventional methods described in scheme 28, starting from the corresponding tetrahydropyran-3-one.
A92: such compounds can be prepared according to conventional methods described in scheme 28 starting from the corresponding piperidine-2, 5-dione.
A93: such compounds can be prepared according to the conventional methods described in scheme 28 starting from the corresponding cyclohexanone.
A94: such compounds may be prepared according to j.org.chem.1990, 55, 4208.
A95: such compounds may be prepared according to N.J.Lewis, R.L.Inlos, J.Hes, R.H.Matthews, G.Milo, J.Med.chem.1978, 21, 1070-.
A96: such compounds can be prepared according to conventional methods described in scheme 28, starting from the corresponding tetrahydropyran-4-one.
A97: such compounds can be prepared according to conventional methods described in scheme 28 starting from the corresponding piperidine-2, 4-dione.
A98: such compounds can be prepared according to the general procedure described in scheme 28 starting from the corresponding 1-tetralone (D.Obrecht, C.Spiegler, P.Sch. nholzer, K.M muler, H.Heimgartner, F.Stierli, Helv.Chim. acta 1992, 75, 1666-.
A99: such compounds can be prepared according to the conventional methods described in scheme 28 starting from the corresponding tetrahydronaphthalene-1, 4-dione mono-diethyl acetal.
A100: such compounds can be prepared according to conventional methods described in scheme 28 starting from the corresponding tetrahydroquinolin-4-one.
A101: such compounds can be prepared according to conventional methods described in scheme 28, starting from the corresponding tetrahydroquinoline-2, 4-dione.
A102: such compounds can be prepared according to the following references: ishizumi, N.Ohashi, N.Tanno, J.org.chem.1987, 52, 4477-; D.Obrecht, U.Bohdal, C.Broger, D.Burr, C.Lehmann, R.Ruffieux, P.Sch _ nholzer, C.Spiegler, Helv.Chim.acta 1995, 78, 563-; obrecht, C.Spiegler, P.Sch _ nholzer, K.M muller, H.Heimgartner, F.Stierli, Helv.Chim.acta 1992, 75, 1666-; D.R.Haines, R.W.Fuller, S.Ahmad, D.T.Vistica, V.E.Marquez, J.Med.chem.1987, 30, 542-; t.decks, p.a.crooks, r.d.waigh, j.pharm.sci 1984, 73, 457-; blair, L.N.Mander, Austr.J.chem.1979, 32, 1055-.
The general description of the building blocks for classes (b) - (p) is: S.Hanessian, G.McNaughton-Smith, H.G.Lombart, W.D.Lubell, Tetrahedron 1997, 38, 12789-; obrecht, M.Altorfer, J.A.Robinson, "Novel Peptide Mimetic assembling Blocks and Strategies for achieving Lead filing", adv.Med.Chem.1999, Vol.4, 1-68
(b1) Templates for classes can be prepared according to schemes 31 and 32.
Scheme 31
i: the 150 is treated with a dehydrogenation reagent, such as thionyl chloride in methanol, at elevated temperature, preferably under reflux.
ii: the introduction of Boc, for example using di-tert-butyl dicarbonate and triethylamine in a suitable solvent such as dichloromethane; any other suitable N-protecting groups (not shown in scheme 31) may be introduced in a similar manner.
iii: the product formed is reacted with phthalimide, diethyl azidodicarboxylate and triphenylphosphine under standard Mitsunobu conditions (Mitsunobu, o.; Wada, m.; Sano, t.j.j.am.chem.soc.1972, 94, 672), suitably to yield 151.
iv: treat 151 with trifluoroacetic acid in dichloromethane.
v: 152 coupling with Cbz-Asp (tBu) OH using reagents such as HBTU and 1-hydroxybenzotriazole (HOBt) using bases such as diisopropylethylamine in DMF under standard peptide coupling conditions gives 153.
vi: conveniently by using H2And a catalyst such as Pd/C in a solvent such as ethanol, DMF and ethyl acetate to remove the Cbz-group.
vii: suitably by treatment with hydrazine in a suitable solvent such as ethanol, at elevated temperature, preferably at about 80 c, and with CH 2Cl2Trifluoroacetic acid in (a) cleaves the product formed and phthalimide groups are cleaved from the resulting product.
viii: the amino acid formed is suitably protected with a reagent such as 9-fluorenylmethoxycarbonyl chloride or 9-fluorenylmethoxycarbonyl succinimide in a suitable solvent or solvent mixture such as dioxane and water, or dichloromethane using a base such as sodium carbonate or triethylamine to form 154, e.g. Bisang, c.; weber, c.; robinson, J.A.Helv.Chim.acta 1996, 79, 1825-.
Scheme 32
i: the 150 th is treated with a dehydrogenation reagent such as thionyl chloride in a suitable solvent such as methanol at elevated temperature, preferably under reflux.
ii: the resulting amino acid ester is N-protected under standard conditions for the introduction of the Cbz-group, for example using benzyloxycarbonyl chloride and triethylamine in a suitable solvent such as dichloromethane.
iii: this Cbz-protected amino acid methyl ester is treated with trimethylsilyl chloride and a base such as triethylamine in a solvent such as tetrahydrofuran, cooled, preferably to about-78 deg.C, and then reacted with a strong base such as lithium diisopropylamide or lithium hexamethyldisilylazide and tert-butyl bromoacetate to give 155, a mixture of diastereomers as described in Bisang, C.; jiang, l.; freund, e.; emery, f.; bauch, C.; matile, H,; pluschke, g.; robinson, J.A.J.am.chem.Soc.1998, 120, 7439-7449; emery, f.; bi sang, c.; favre, m.; jiang, l.; robinson, J.A.J.chem.Soc.chem.Commun.1996, 2155-2156.
iv: 155 was reacted with phthalimide, diethyl azidodicarboxylate and triphenylphosphine under standard Mitsunobu conditions (Mitsunobu, o.; Wada, m.; Sano, t.j.j.am.chem.soc.1972, 94, 672).
v: the resulting product used H2And a suitable catalyst such as Pd/C in a solvent such as ethyl acetate, DMF or ethanol; separation of the diastereomers follows and gives 156.
vi: 156 was coupled with Fmoc-Asp (allyl) OH under standard peptide coupling conditions using reagents such as HATU, HOAt and bases such as diisopropylethylamine in suitable reagents such as DMF.
vii: cyclization, preferably using DBU in DMF, gives 157.
viii: the phthalimide group is suitably cleaved from the resulting product by hydrazinolysis, for example by treatment with a suitable solvent such as methylhydrazine in DMF.
ix: the product formed is suitably protected with a reagent such as 9-fluorenylmethoxycarbonyl chloride or 9-fluorenylmethoxycarbonyl succinimide in a suitable solvent or solvent mixture such as dioxane and water, or dichloromethane using a base such as sodium carbonate or triethylamine to give 158.
x: removal of the allyl ester group using, for example, palladium (O) as a catalyst, gives 159.
(b2) Templates for classes can be prepared according to scheme 33.
Scheme 33
i: 160 (obtainable from vitamin C, e.g. as described in Hubschwerlen, C. (Synthesis 1986, 962) was treated with phthalimide, diethyl azidodicarboxylate and triphenylphosphine under standard Mitsunobu conditions (Mitsunobu, O.; Wada, M.; Sano, T.J. J.Am.Chem.Soc.1972, 94, 672).
ii: the phthalimide group is suitably cleaved from the product by hydrazinolysis, for example by treatment with methylhydrazine in a suitable solvent such as DMF.
iii: the amino group is protected by treatment with a benzoylating reagent such as benzoic anhydride or benzoyl chloride and a base such as triethylamine or 4-dimethylaminopyridine in a suitable solvent such as dichloromethane or DMF.
iv: for example with K2S2O8And Na2HPO4The 2, 4-dimethoxybenzyl group is removed in aqueous acetonitrile at elevated temperature, for example at about 80 ℃.
v: the tert-butoxycarbonyl group is introduced using, for example, di-tert-butyloxycarbonyl dicarbonate, triethylamine and a catalytic amount of 4-dimethylaminopyridine in a suitable solvent such as dichloromethane.
vi: with aqueous sodium carbonate in tetrahydrofuran, followed by acidification.
vii: esterification of the carboxylic acid group with diazomethane in a suitable solvent such as diethyl ether is suitable to give 161.
viii by using H as appropriate2Hydrogenation in a solvent such as DMF in the presence of a catalyst such as Pd/C to remove the Cbz-group affords 161, for example as described in Pfeifer, m.; robinson, j.a.j.chem.soc.chem.commun.1998, 1977.
ix: 161 with Cbz-asp (tbu) OH under standard peptide coupling conditions in DMF with reagents such as HBTU and 1-hydroxybenzotriazole using bases such as diisopropylethylamine to give 162, for example as described in Pfeifer, m.; robinson, j.a.j.chem.soc.chem.commun.1998, 1977.
x: for example by using H2And a catalyst such as Pd/C, under standard conditions to remove the Cbz-group to give 163, for example as described in Pfeifer, m.; robinson, j.a.j.chem.soc.chem.commun.1998, 1977.
xi: t-butyl esters and t-butyloxycarbonyl groups are cleaved off using trifluoroacetic acid in dichloromethane or 4N hydrochloric acid in dioxane, as appropriate.
xii: the intermediate free amino acid formed is suitably protected with a reagent such as 9-fluorenylmethoxycarbonyl chloride or 9-fluorenylmethoxycarbonyl succinimide in a suitable solvent or solvent mixture such as dioxane and water, or dichloromethane using a base such as sodium carbonate or triethylamine to give 164, for example as described in Pfeifer, m.; robinson, j.a.j.chem.soc.chem.commun.1998, 1977.
(c1) Templates for classes can be prepared according to schemes 34-37.
Scheme 34
i: 166 can be synthesized by 165 according to P.Waldmeier, "Solid-supported synthesis of high purity sub-synthesized templates for the synthesis of β -turn stabilized cyclic peptide libraries", PhD-thesis, University of Zurich, 1996. To cleave off the phthalimide group, 166 is suitably subjected to hydrazinolysis, for example by treatment with hydrazine hydrate in a suitable solvent such as ethanol at elevated temperature, for example at about 80 ℃.
ii: the intermediate aminonitrile is suitably saponified with aqueous sodium hydroxide under basic conditions, for example in a suitable solvent such as ethanol, at elevated temperature, preferably under reflux, to give 167.
iii: the resulting intermediate free amino acids are suitably protected with reagents such as 9-fluorenylmethoxycarbonyl chloride or 9-fluorenylmethoxycarbonyl succinimide in a suitable solvent or solvent mixture such as dioxane and water, or dichloromethane using a base such as sodium carbonate or triethylamine to give 168, for example as described in p.waldmeier, "Solid-supported synthesis of high purity sub-synthesized templates for the synthesis of β -turn stabilized cyclic peptide complexes", PhD-thesis, University of Zurich, 1996.
iv: preferably, region 167 is selectively brominated with bromine in acetic acid and dichloromethane. HNO in acetic acid in a similar manner3Treatment may introduce R37＝NO2Used in H2SO4The treatment with hydroxymethylphthalimide in (1) may introduce R37＝CH2-NPht。
v: the amino group is suitably Cbz-protected with a reagent such as benzyloxycarbonyl chloride or succinimide in a suitable solvent such as dioxane and in the presence of a base such as aqueous sodium hydroxide.
vi: the carboxylic acid group is preferably esterified with DBU and methyl iodide in DMF to afford 169.
vii: lower alkyl, substituted lower alkyl and aryl substituents (R.sub.alkyl, and aryl substituents) are suitably introduced by palladium (O) -catalysed Stille- (Stille, J.K.Angew.chem.1986, 68, 504) and Suzuki-coupling (Oh-e, T.; Mijaura, N.; Suzuki, A.J.org.chem.1993, 58, 2201)37). The substituent R may be introduced using any other functionalization known for aryl bromides37。
viii: for example, using H in a suitable solvent such as ethanol, DMF and ethyl acetate2And a catalyst such as Pd/C to remove the Cbz-group.
ix: the ester group is suitably hydrolysed under acidic conditions, for example with 25% aqueous hydrobromic acid in a suitable solvent such as dioxane at elevated temperature, preferably at about 100 ℃.
x: the intermediate free amino acid formed is suitably protected with a reagent such as 9-fluorenylmethoxycarbonyl chloride or 9-fluorenylmethoxycarbonyl succinimide in a suitable solvent or solvent mixture such as dioxane and water, or dichloromethane using a base such as sodium carbonate or triethylamine to give 170.
Scheme 35
i: preferably 171 is bis ortho brominated with excess bromine in acetic acid and dichloromethane. HNO used in acetic acid in a similar manner3Treatment may introduce R37＝R38＝NO2Used in H2SO4The treatment with hydroxymethylphthalimide in (1) may introduce R37＝R38＝CH2-NPht。
ii: the amino group is protected, suitably by Cbz-protection, with a reagent such as benzyloxycarbonyl chloride or succinimide, in the presence of a base such as aqueous sodium hydroxide, in a suitable solvent such as dioxane.
iii: the carboxylic acid group is preferably esterified with DBU and methyl iodide in DMF to give 172.
iv: lower alkyl, substituted lower alkyl and aryl substituents (R.sub.alkyl, and aryl substituents) are introduced, for example, by palladium (O) -catalyzed Stille- (Stille, J.K.Angew.chem.1986, 68, 504) and Suzuki-coupling (Oh-e, T.; Mijaura, N.; Suzuki, A.J.org.chem.1993, 58, 2201)37＝R38). The substituent R may be introduced using any other functionalization known for aryl bromides 37And R38。
v: for example by using H in a suitable solvent such as ethanol, DMF or ethyl acetate2And a catalyst such as Pd/C to remove 173 Cbz-groups.
vi: the ester group is suitably hydrolysed under acidic conditions, for example with 25% aqueous hydrobromic acid in a suitable solvent such as dioxane at elevated temperature, preferably at about 100 ℃.
vii: the intermediate free amino acid formed is suitably protected with a reagent such as 9-fluorenylmethoxycarbonyl chloride or 9-fluorenylmethoxycarbonyl succinimide in a suitable solvent or solvent mixture such as dioxane and water, or dichloromethane using a base such as sodium carbonate or triethylamine to give 174.
Scheme 36
i: the 166 methoxy group is cleaved off, preferably by treatment with an excess of boron tribromide in a suitable solvent such as dichloromethane.
ii: the cyano group is hydrolyzed under acidic conditions, preferably with 25% aqueous hydrochloric acid, in a suitable solvent such as dioxane at elevated temperature, preferably at about 100 ℃.
iii: the resulting acid is treated with a dehydrating reagent such as thionyl chloride in a suitable solvent such as dioxane to afford 175.
iv: 175 is treated with a suitable triflating reagent, preferably triflic acid, in a suitable solvent such as dichloromethane in the presence of a base such as 2, 6-di-tert-butyl-pyridine.
v: the intermediate is suitably heated in a suitable solvent such as methanol.
vi: by alkylation, introducing lower alkyl or aryl-lower alkyl (R)35) 177 is obtained. The substituents R can be introduced using any other functionalization of the known phenol groups35。
vii: lower alkyl or aryl groups (R.sub.alkyl or aryl) are suitably introduced by palladium (O) -catalysed Suzuki-coupling (Oh-e, T.; Mijaura, N.; Suzuki, A.J.Org.Chem.1993, 58, 2201)36) To obtain 178. Any other functionality known for aryl bromides may be usedIntroduction of substituent R36。
viii: the ester group is suitably hydrolysed under acidic conditions with 25% aqueous hydrobromic acid in a suitable solvent such as dioxane at an elevated temperature, for example about i00 ℃.
ix: cleavage of the phthalimide group is suitably carried out, for example, by hydrazinolysis with hydrazine hydrate in a suitable solvent, such as ethanol.
x: the intermediate free amino acid formed is suitably protected with a reagent such as 9-fluorenylmethoxycarbonyl chloride or 9-fluorenylmethoxycarbonyl succinimide in a suitable solvent or solvent mixture such as dioxane and water, or dichloromethane using a base such as sodium carbonate or triethylamine to give 179.
Scheme 37
i: 175 is brominated using a reagent such as bromine in a mixture of acetic acid and dichloromethane at a temperature of about 0 ℃ to about room temperature.
ii: benzoylation of the hydroxy group using a suitable acylating agent such as benzoyl chloride or benzoic anhydride, a base such as pyridine or triethylamine and a suitable solvent such as dichloromethane affords 180.
iii: treated 180 with methanol and a catalytic amount of an acidic catalyst such as camphorsulfonic acid under heat.
iv: introduction of lower alkyl or aryl-lower alkyl (R) by alkylation using a base such as sodium hydride or potassium tert-butoxide in a solvent such as tetrahydrofuran, dimethoxyethane or DMF35) To obtain 181.
v: lower alkyl, substituted lower alkyl and aryl substituents (R.sub.alkyl, and aryl substituents) are introduced, for example, by palladium (O) -catalyzed Stille- (Stille, J.K.Angew.chem.1986, 68, 504) and Suzuki-coupling (Oh-e, T.; Mijaura, N.; Suzuki, A.J.org.chem.1993, 58, 2201)38). Known pairs can be usedAny other functionalization of the aryl bromides to introduce substituents R38。
vi: to cleave the benzyloxy group, the intermediate is suitably heated with sodium cyanide and methanol adsorbed on alumina.
vii: treatment with a suitable triflating agent, preferably triflic anhydride, in a suitable solvent such as dichloromethane in the presence of a base such as 2, 6-di-tert-butyl-pyridine.
viii: lower alkyl and aryl substituents (R.J.Org.Chem.1993, 58, 2201) are introduced, for example, by palladium (O) -catalysed Stille- (Stille, J.K.Angew.Chem.1986, 68, 504) and Suzuki-coupling (Oh-e, T.; Mi jaura, N.; Suzuki, A.J.Org.Chem.1993, 58, 2201) 36) Yielding 182. The substituent R may be introduced using any other functionalization known for aryl bromides36。
ix: the bromination is carried out under standard conditions, for example using bromine, in acetic acid and dichloromethane, at temperatures of from about 0 ℃ to about room temperature.
x: lower alkyl, substituted lower alkyl and aryl substituents (R.sub.alkyl, and aryl substituents) are introduced, for example, by palladium (O) -catalyzed Sti lle- (Stille, J.K.Angew. chem.1986, 68, 504) and Suzuki-coupling (Oh-e, T.; Mijaura, N.; Suzuki, A.J.org. chem.1993, 58, 2201)37) And 184 is obtained. The substituent R may be introduced using any other functionalization known for aryl bromides37。
xi: the ester group is hydrolysed under acidic conditions, suitably using 25% aqueous hydrobromic acid, in a suitable solvent such as dioxane at elevated temperature, for example at about 100 ℃.
xii: for example, the phthalimide group is suitably cleaved by hydrazinolysis with hydrazine hydrate in a suitable solvent, such as ethanol.
xiii: the intermediate free amino acid formed is suitably protected with a reagent such as 9-fluorenylmethoxycarbonyl chloride or 9-fluorenylmethoxycarbonyl succinimide in a suitable solvent or solvent mixture such as dioxane and water, or dichloromethane using a base such as sodium carbonate or triethylamine to afford 185.
(c2) Templates for classes can be prepared as shown in schemes 38 and 39.
Scheme 38
i: preparation of 3, 7-dimethoxyphenothiazine 186, followed by Muller, K.; obrecht, d.; kniersinger, a.; spiegler, c.; bannwarth, w.; trzec iak, a.; englert, g.; labhardt, a.; schnholzer, p.perspectives in Medicinal Chemistry, Editor Testa, b.; kyburz, e.; fuhrer, w.; giger, r., Weinheim, New York, Basel, Cambridge: verlag Helvetica Chimica Acta, 1993, 513-; bannwarth, w.; gerber, f.; grieder, a.; kniersinger, a.; muller, K.; obrecht.d.; trzeciak, a.can.pat.appl.ca2101599 (page 131) is converted to 187. Suitably by reaction with H in a suitable solvent such as ethanol, DMF or ethyl acetate2And a catalyst such as Pd/C splits the benzyl group from 187.
ii: using a suitable alkylating agent (R) in the presence of a phase transfer catalyst such as TDA-I43-X'; x' ═ OTf, Br, I) and strong bases such as sodium amide in liquid ammonia or sodium hydride in tetrahydrofuran, dioxane or DMF, lower alkyl groups (R) being introduced by alkylation43). In a similar manner, substituted lower alkyl (R) groups may be introduced43) (ii) a Thus, R may be introduced, for example, by treatment with an appropriate 2-haloacetic acid and the corresponding 3-halopropionic acid derivative 43＝CH2COOR55And CH2CH2COOR55. The substituents R can be introduced using any other functionalization of the diarylamines known per se43。
iii: the methoxy group cleaved 188 is suitably treated with an excess of boron tribromide in a suitable solvent such as dichloromethane at a temperature of from about-20 ℃ to about room temperature.
iv: is composed ofIntroducing lower alkyl, substituted lower alkyl or aryl-lower alkyl substituents (R)39And R40) The intermediate bisphenol derivative is suitably reacted with formula R in tetrahydrofuran, dioxane or DMF in the presence of a phase transfer catalyst such as TDA-I and in the presence of a strong base such as sodium hydride39-and R40-X '(X' ═ OTf, Br, I) reagent reaction. The substituents R can be introduced using any other functionalization of the known phenol groups39And R40。
v: 188 and the cyano group in the corresponding 189 are suitably hydrolysed under acidic conditions, for example with 25% aqueous hydrochloric acid, in a suitable solvent such as dioxane at elevated temperature, for example at about 100 ℃.
vi: the phthalimide group of the intermediate is suitably cleaved by hydrazinolysis, for example using hydrazine hydrate in a suitable solvent such as ethanol.
vii: the free amino group is suitably protected with a reagent such as 9-fluorenylmethoxycarbonyl chloride or 9-fluorenylmethoxycarbonyl succinimide in a suitable solvent or solvent mixture such as dioxane and water, or dichloromethane using a base such as sodium carbonate or triethylamine to give 190 and the corresponding 191.
Scheme 39
i: the cyano group in 188 is suitably hydrolysed under acidic conditions, for example with 25% aqueous hydrochloric acid, in a suitable solvent such as dioxane at elevated temperature, for example at about 100 ℃.
iii: the phthalimide group of this intermediate is suitably cleaved by hydrazinolysis, for example using hydrazine hydrate in a suitable solvent such as ethanol, to give 192.
iii: the double ortho bromination of 192 is preferably carried out with excess bromine in acetic acid and dichloromethane. HNO used in acetic acid in a similar manner3Treatment may introduce R41＝R42＝NO2Used in H2SO4The treatment with hydroxymethylphthalimide in (1) may introduce R4＝R42＝CH2-NPht. The introduction of the substituent R by any other functionalization known for electrophilic aromatic substitution can be used41And R42。
iv: the amino group is protected, suitably by Cbz-protection, with a reagent such as benzyloxycarbonyl chloride or succinimide, in the presence of a base such as aqueous sodium hydroxide, in a suitable solvent such as dioxane.
v: the carboxylic acid group is preferably esterified with DBU and methyl iodide in DMF to afford 193.
vi: the 192 region is preferentially selectively brominated with bromine in acetic acid and dichloromethane. HNO in acetic acid in a similar manner3Treatment may introduce R41＝NO2Used in H2SO4The treatment with hydroxymethylphthalimide in (1) may introduce R 41＝CH2-NPht. The introduction of the substituent R by any other functionalization known for electrophilic aromatic substitution can be used41。
vii: the amino group is suitably Cbz-protected with a reagent such as benzyloxycarbonyl chloride or succinimide in a suitable solvent such as dioxane and in the presence of a base such as aqueous sodium hydroxide.
viii: the carboxylic acid group is preferably esterified with DBU and methyl iodide in DMF to give 194.
ix: lower alkyl, substituted lower alkyl and aryl substituents are introduced, as is the substituent (R) for 194, suitably via palladium (O) -catalysed Stille- (Stille, J.K.Angew.chem.1986, 68, 504) and Suzuki-coupling (Oh-e, T.; Mijaura, N.; Suzuki, A.J.org.chem.1993, 58, 2201)41) And, for 193, is a substituent (R)41And R42). The substituent R may be introduced using any other functionalization known for aryl bromides41And R42。
x: example (b)Such as using H in a suitable solvent such as ethanol, DMF and ethyl acetate2And a catalyst such as Pd/C to remove the Cbz-group.
xi: the ester group is suitably hydrolysed under acidic conditions, for example with 25% aqueous hydrochloric acid in a suitable solvent such as dioxane at elevated temperature, preferably at about 100 ℃.
xii: the intermediate free amino acids formed are suitably protected with reagents such as 9-fluorenylmethoxycarbonyl chloride or 9-fluorenylmethoxycarbonyl succinimide in a suitable solvent or solvent mixture such as dioxane and water, or dichloromethane using a base such as sodium carbonate or triethylamine to give 195 and 196.
(c3) Templates for classes can be prepared as shown in schemes 40 and 41.
Scheme 40
i: 197 may be prepared from commercially available resorufin and follows the mieler, k.; obrecht, d.; kniersinger, a.; spiegler, c.; bannwarth, w.; trzeciak, a.; englert, g.; labhardt, a.; schnholzer, p.perspectives in medical Chemistry, Editor Testa, b.; kyburz, e.; fuhrer, w.; giger, r., Weinheim, New York, Basel, Cambridge: VerlagHelvetica Chimica Acta, 1993, 513-; bannwarth, w.; gerber, f.; grieder, a.; kniersinger, a.; muller, K.; obrecht.d.; trzeciak, a.can.pat.appl.ca2101599 (page 131) translates to 198. To cleave off the benzyl group 198 is suitably hydrogenated, for example using H in a suitable solvent such as ethanol, DMF or ethyl acetate2And catalysts such as Pd/C.
ii: using a strong base such as sodium amide in liquid ammonia or sodium hydride in tetrahydrofuran, dioxane or DMF in the presence of a phase transfer catalyst such as TDA-I by using R43Alkylation of-X '(X' ═ OTf, Br, I) introduces lower alkyl (R)43). In a similar manner can be introducedOr substituted lower alkyl (R)43) (ii) a Thus, R may be introduced, for example, by treatment with an appropriate 2-haloacetic acid and the corresponding 3-halopropionic acid derivative 43＝CH2COOR55And CH2CH2COOR55. The substituents R can be introduced using any other functionalization of the known diarylamino groups43。
iii: the methoxy groups of 199 are cleaved by treatment with excess boron tribromide, suitably in dichloromethane, at a temperature of from about-20 ℃ to about room temperature.
iv: the intermediate bisphenol derivative is suitably reacted with a compound of formula R in tetrahydrofuran, dioxane or DMF in the presence of a phase transfer catalyst such as TDA-I and in the presence of a strong base such as sodium hydride39-and R40-X '(X' ═ OTf, Br, I) reaction. The substituents R can be introduced using any other functionalization of the known phenol groups39And R40。
v: 199 and correspondingly 200 are suitably hydrolysed under acidic conditions, for example with 25% aqueous hydrochloric acid, in a suitable solvent such as dioxane at elevated temperature, for example at about 100 ℃.
vi: the phthalimide group is suitably cleaved by hydrazinolysis, for example using hydrazine hydrate in a suitable solvent such as ethanol.
vii: this free amino group is suitably protected with a reagent such as 9-fluorenylmethoxycarbonyl chloride or 9-fluorenylmethoxycarbonyl succinimide in a suitable solvent or solvent mixture such as dioxane and water, or dichloromethane using a base such as sodium carbonate or triethylamine to afford 201 and the corresponding 202.
Scheme 41
i: 199 the cyano group is suitably hydrolysed under acidic conditions, for example with 25% aqueous hydrochloric acid, in a suitable solvent such as dioxane at elevated temperature, for example at about 100 ℃.
ii: the phthalimide group of this intermediate is suitably cleaved by hydrazinolysis, for example using hydrazine hydrate in a suitable solvent such as ethanol, to give 203.
iii: the bis-ortho-bromination of 203 is preferably performed with excess bromine in acetic acid and dichloromethane. HNO used in acetic acid in a similar manner3Treatment may introduce R41＝R42＝NO2Used in H2SO4The treatment with hydroxymethylphthalimide in (1) may introduce R41＝R42＝CH2-NPht. Any other functionalization by electrophilic aromatic substitution can be used to introduce the substituent R41And R42。
iv: the amino group is protected, suitably by Cbz-protection, with a reagent such as benzyloxycarbonyl chloride or succinimide, in the presence of a base such as aqueous sodium hydroxide, in a suitable solvent such as dioxane.
v: esterification of the carboxylic acid groups, preferably with DBU and methyl iodide in DMF, gives 204.
vi: preferably, region 203 is selectively brominated with bromine in acetic acid and dichloromethane. HNO in acetic acid in a similar manner3Treatment may introduce R41＝NO2Used in H2SO4The treatment with hydroxymethylphthalimide in (1) may introduce R 41＝CH2-NPht。
vii: the amino group is suitably Cbz-protected with a reagent such as benzyloxycarbonyl chloride or succinimide in a suitable solvent such as dioxane and in the presence of a base such as aqueous sodium hydroxide.
viii: the carboxylic acid group is preferably esterified with DBU and methyl iodide in DMF to give 205.
ix: suitably by palladium (O) -catalysed Stille- (Stille, J.K. Angew. chem.1986, 68, 504) and Suzuki-coupling (Oh-e, T.; Mi jaura, N.; Suzuki, A.J. Org. chem.1993, 58, 2201),introduction of lower alkyl, substituted lower alkyl and aryl substituents, for 205 is substituent (R)41) And, for 204, is a substituent (R)41And R42). The substituent R may be introduced using any other functionalization known for aryl bromides41And R42。
x: for example, using H in a suitable solvent such as ethanol, DMF and ethyl acetate2And a catalyst such as Pd/C to remove the Cbz-group.
xi: the ester group is suitably hydrolysed under acidic conditions, for example with 25% aqueous hydrochloric acid in a suitable solvent such as dioxane at elevated temperature, preferably at about 100 ℃.
xii: the intermediate free amino acids formed are suitably protected with reagents such as 9-fluorenylmethoxycarbonyl chloride or 9-fluorenylmethoxycarbonyl succinimide in a suitable solvent or solvent mixture such as dioxane and water, or dichloromethane using a base such as sodium carbonate or triethylamine to give 206 and 207.
Template (d) may be prepared according to the general rules of D.Obrecht, U.Bohdal, C.Lehmann, P.Sch _ nholzer, K.M uller, Tetrahedron 1995, 51, 10883; D.Obrecht, C.Abrecht, M.Altorfer, U.Bohdal, A.Grieder, M.Kleber, P.Pfyffer, K.Mimuller, Helv.Chim.acta 1996, 79, 1315-.
Templates (e1) and (e 2): see r.mueller, l.revesz, Tetrahedron lett.1994, 35, 4091; H. lubell, w.d.lubell, j.org.chem.1996, 61, 9437; l.colombo, m.digiacomo, g.papeo, o.carogo, c.scolaticco, l.manzoni, Tetrahedron lett.1994, 35, 4031.
Template (e 3): see s.hanessian, b.ronan, a.laoui, bioorg.med.chem.lett.1994, 4, 1397.
Template (e 4): see s.hanessian, g.mcnaughton-Smith, bioorg.med.chem.lett.1996, 6, 1567.
Template (f): see T.P.Curran, P.M.McEnay, Tetrahedron Lett.1995, 36, 191-194.
Template (g): see D.Gramberg, C.Weber, R.Beeli, J.Inglis, C.Bruns, J.A.Robinson, Helv.chem.acta 1995, 78, 1588-; kim, J.P.Dumas, J.P.Germanas, J.org.chem.1996, 61, 3138-.
Template (h): see s.de Lombart, l.blanchard, l.b.stamford, d.m.specbeck, m.d.grim, t.m.jenson, h.r.rodriguez, Tetrahedron lett.1994, 35, 7513-.
Template (i 1): see J.A.Robl, D.S.Karanewski, M.M.Asaad, Tetrahedron Lett.1995, 5, 773-.
Template (i 2): see t.p.burkholder, t.b.le, e.l.giroux, g.a.flunn, bioorg.med.chem.lett.1992, 2, 579.
Templates (i3) and (i 4): see l.m. simpkins, j.a. robl, m.p.cimatersi, d.e.ryono, j.stevenson, c.q.sun, e.w.petrillo, d.s.karanewski, m.m.asaad, j.e.bird, t.r.schaeffer, n.c.tripppodo, extracts of papers, 210th am.chem.soc Meeting, Chicago, I11, MEDI 064 (1995).
Template (k): see d.benishai, a.r.mcmurray, Tetrahedron 1993, 49, 6399.
Template (l): see e.g. von Roedern, h.kessler, angelw.chem.int.ed.engl.1994, 33, 687-.
Template (m): see R.Gonzalez-Munizz, M.J.Dominguez, M.T.Garcia-Lopez, Tetrahedron 1992, 48, 5191-.
Template (n): see f.esser, a.copy, h.briem, h.k _ pen, k. -h.pook, int.j.pept.res.1995, 45, 540-.
Template (o): see n.de la fig, i.alkorta, t.garcia-Lopez, r.herranz, r.gonzalez-Muniz, Tetrahedron 1995, 51, 7841.
Template (p): see U.S. Slomcynska, D.K. Chalmers, F.Cornille, M.L.Smythe, D.D.Benson, K.D.Moeller, G.R.Marshall, J.org.Chem.1996, 61, 1198-.
The β -hairpin peptidomimetics of the invention can be used in various fields to inhibit the growth of microorganisms and/or cancer cells or to kill them.
For example, they can be used as disinfectants for goods such as food, cosmetics, pharmaceuticals and other nutrient-containing goods or as preservatives or to prevent microbial growth on surfaces [ j.m. schierholz, c.fleck, j.beuth, g.silver, j.anitimicrob.chemi., 2000, 46, 45-50 ]. The beta-hairpin peptidomimetics of the invention are also useful for treating or preventing diseases associated with microbial infections in plants and animals.
For use as disinfectants or preservatives, these β -hairpin peptidomimetics can be added to the desired substance singly, or in mixtures of several β -hairpin peptidomimetics or mixed with other antimicrobial agents. These β -hairpin peptidomimetics may be administered per se or may be administered in a suitable dosage form together with carriers, diluents or excipients well known in the art, conveniently in a form suitable for oral, topical, transdermal, injection, buccal, transmucosal, pulmonary or inhalation administration, such as tablets, dragees, capsules, solutions, liquids, gels, plasters, creams, ointments, syrups, slurries, suspensions, aerosols, nebulisers or suppositories.
When used to treat or prevent infections or diseases or cancers associated with such infections, these β -hairpin peptidomimetics can be administered singly, in a mixture of several β -hairpin peptidomimetics, in admixture with other antimicrobial, antibiotic or anticancer agents or in admixture with other pharmaceutically active agents. These β -hairpin peptidomimetics are administered as such or in a pharmaceutical composition.
Pharmaceutical compositions containing the β -hairpin peptidomimetics of the invention and a pharmaceutically inert carrier may be prepared by conventional mixing, dissolving, granulating, coating tableting, levigating, emulsifying, encapsulating, entrapping or lyophilizing processes. Pharmaceutical compositions may be formulated in conventional manner with one or more pharmaceutically acceptable carriers, diluents, excipients or adjuvants which facilitate processing of the active β -hairpin peptidomimetic into a pharmaceutically acceptable formulation. The appropriate dosage form depends on the chosen method of administration.
For topical administration, the β -hairpin peptidomimetics of the invention can be formulated into solutions, gels, ointments, creams, suspensions, and the like, all of which are well known in the art.
Systemic dosage forms include those designed for administration by injection, such as subcutaneous, intravenous, intramuscular, intrathecal, or intraperitoneal injection, as well as those designed for transdermal, transmucosal, oral, or pulmonary administration.
For injection, the β -hairpin peptidomimetics of the invention can be formulated in a suitable solution, preferably in a physiologically compatible buffer, such as Hink's solution, Ringer's solution or physiological saline buffer. The solution may contain formulating agents such as adsorbing, stabilizing and/or dispersing agents. Alternatively, the β -hairpin peptidomimetics of the invention may be in powder form and used after mixing with a suitable carrier, such as sterile pyrogen-free water.
For transmucosal administration, penetrants appropriate to the barrier to be permeated are used in the dosage forms known in the art.
For oral administration, these compounds can be readily formulated by mixing the active β -hairpin peptidomimetics of the invention with pharmaceutically acceptable carriers well known in the art. These carriers enable the β -hairpin peptidomimetics of the invention to be formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions and the like, for oral ingestion by a patient in need of treatment. For oral dosage forms such as powders, capsules and tablets, suitable excipients include fillers such as sugars, for example lactose, sucrose, mannitol and sorbitol; cellulose preparations such as corn starch, wheat starch, rice starch, potato starch, gelatin, tragacanth, methyl cellulose, hydroxypropylmethyl-cellulose, sodium carboxymethylcellulose, and/or polyvinylpyrrolidone (PVP); granulating agent; and a binder. If desired, disintegrating agents may be added, such as cross-linked polyvinylpyrrolidone, agar, or alginic acid or a salt thereof, such as alginate. The solid dosage forms may be sugar coated or enteric coated using standard techniques, if desired.
For oral liquid preparations such as suspensions, elixirs and solutions, suitable carriers, excipients or diluents include water, glycols, oils, alcohols and the like. In addition, flavoring agents, preservatives, coloring agents, and the like may be added.
For buccal administration, the compositions may be conveniently formulated in the form of tablets, lozenges and the like.
For administration by inhalation, the β -hairpin peptidomimetics of the invention may be conveniently delivered in the form of an aerosol spray from pressurized packs or a nebulizer, with a suitable propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane, carbon dioxide, or another suitable gas. In the case of a pressurized aerosol, the dosage unit may be determined by providing a valve to release a metered amount. For example, gelatin capsules and cartridges for use in an inhaler or insufflator may be formulated containing a powder mix of the β -hairpin peptidomimetic of the invention and a suitable powder base such as lactose or starch.
These compounds may also be formulated in rectal or vaginal compositions such as suppositories, with suitable suppository bases such as cocoa butter or other glycerides.
In addition to the dosage forms described above, the β -hairpin peptidomimetics of the invention can also be formulated as stock preparations. These long acting dosage forms may be administered by implantation (e.g., subcutaneously or intramuscularly) or by intramuscular injection. To produce these depot formulations, the β -hairpin peptidomimetics of the invention can be formulated with suitable polymeric or hydrophobic materials (e.g., as an emulsion in an acceptable oil) or ion exchange resins, or as insoluble salts.
In addition, other pharmaceutical delivery systems may be used, such as liposomes and emulsions, as are well known in the art. Certain organic solvents such as dimethylsulfoxide also can be used. Furthermore, the β -hairpin peptidomimetics of the invention can be delivered using a sustained release system, such as a semi-permeable matrix containing a solid polymer of the therapeutic agent. Various sustained release materials are identified and known to those skilled in the art. Sustained release capsules, depending on their chemical nature, can release the compound for a period of weeks to less than 100 days. Additional protocols for protein stabilization may be used, depending on their chemical nature and the physiological stability of the therapeutic agent.
Since the β -hairpin peptidomimetics of the invention may contain charged residues, they may be included in any of the above dosage forms as a free base or as a pharmaceutically acceptable salt. Pharmaceutically acceptable salts tend to be more soluble in aqueous and other protic solvents than the corresponding free base forms.
The β -hairpin peptidomimetics of the invention, or compositions thereof, are generally used in amounts effective to achieve the desired purpose. It will be appreciated that the amount used will depend on the particular application.
For example, for use as a disinfectant or preservative, an antimicrobially effective amount of a β -hairpin peptidomimetic of the invention or a composition thereof is applied or added to the material to be disinfected or preserved. By antimicrobially effective amount is meant an amount of the β -hairpin peptidomimetics or compositions of the invention that inhibits the growth or lethality of the target microbiota. Although this antimicrobially effective amount will depend on the particular application, for use as a disinfectant or preservative, the β -hairpin peptidomimetics of the invention or compositions thereof are often added or applied in relatively low amounts to the material to be disinfected or preserved. Typically, the β -hairpin peptidomimetics of the invention comprise less than about 5% by weight, preferably less than 1% by weight, more preferably less than 0.1% by weight of the disinfectant solution or material to be preserved. For specific applications, one of ordinary skill in the art will be able to determine an antimicrobially effective amount of a particular β -hairpin peptidomimetic of the invention without undue experimentation, such as the in vitro assays provided in the examples.
For use in treating or preventing microbial infections or diseases and cancers associated with infections, the β -hairpin peptidomimetics of the invention or compositions thereof are administered or applied in a therapeutically effective amount. By therapeutically effective amount is meant an amount effective to ameliorate symptoms, or to ameliorate, treat or prevent microbial infections or diseases associated therewith. Determination of a therapeutically effective amount is within the ability of those skilled in the art, particularly in view of the detailed discussion provided herein.
In the case of disinfectants and preservatives, therapeutically effective dosages can be determined for topical administration to treat or prevent bacterial, yeast, fungal or other infections, for example, using in vitro tests provided in these examples. Treatment may be performed while the infection is visible, or even invisible. One of ordinary skill in the art can determine, without experimentation, a therapeutically effective amount to treat a topical infection.
For systemic administration, a therapeutically effective dose can be initially evaluated by in vitro testing. For example, a dose can be formulated in animal models to achieve a circulating range of β -hairpin peptidomimetic concentrations that includes the IC measured in cell culture50(i.e., the concentration of test compound that is 50% lethal to the cell culture), the MIC determined in the cell culture (i.e., the concentration of test compound that is 100% lethal to the cell culture). This information can be used to more accurately determine useful doses in humans.
Initial dosages can also be determined from in vivo data, such as animal models, using techniques well known in the art. One of ordinary skill in the art can readily optimize human administration based on animal data.
The dosage administered as an antimicrobial agent can be individually adjusted to provide plasma levels of the β -hairpin peptidomimetics of the invention sufficient to maintain the therapeutic effect. A typical patient dose range by injection is about 0.1-5mg/kg/day, preferably about 0.5-1 mg/kg/day. Therapeutically effective plasma levels may be achieved by administering multiple doses per day.
In the case of topical administration or selective uptake, the effective local concentration of the β -hairpin peptidomimetics of the invention may not be correlated with plasma concentrations. One skilled in the art would be able to optimize a therapeutically effective topical dose without undue experimentation.
The amount of β -hairpin peptidomimetic administered will, of course, depend on the subject being treated, the weight of the patient, the severity of the disease, the mode of administration, and the judgment of the pharmacist.
Although the infection may be detectable or even undetectable, the antimicrobial treatment may be repeated intermittently. Such treatment may be provided alone or in admixture with other drugs such as antibiotics or other antimicrobial agents.
Generally, a therapeutically effective dose of the β -hairpin peptidomimetics described herein will provide a therapeutic effect without substantial toxicity.
Haemolysis of erythrocytes is often used to assess the toxicity of related compounds such as protegrin or tachyplesin. Values are shown as% lysis of red blood cells observed at a concentration of 100. mu.g/ml. Typical values determined for cationic peptides such as protegrin and tachplysin are 30-40%, the mean MIC-value for many pathogens is 1-5 μ g/ml. Generally, the β -hairpin peptidomimetics of the invention will show hemolysis at 0.5-10%, usually 1-5%, at active levels compared to those mentioned above for protegrin and tachplesin. The preferred compounds thus exhibit low MIC-values and low% haemolysis of erythrocytes observed at a concentration of 100 μ g/ml.
Toxicity of the beta-hairpin peptidomimetics of the invention herein can be determined by standard pharmaceutical procedures in cell cultures or test animals, e.g., by determining LD50(total 50% lethal dose) or LD100(all 100% lethal doses). The dose ratio between toxic and therapeutic effects is the therapeutic index. Compounds with high therapeutic indices are preferred. The data obtained from these cell culture assays and animal studies can be used to formulate a range of dosages that are non-toxic for humans. The dosage of the β -hairpin peptidomimetics of the invention is preferably within a range of circulating concentrations that include an effective dose and are of little or no toxicity. The dosage may vary within a certain range depending on the dosage form used and the route of administration used. The precise dosage form, route of administration and dosage can be selected by The individual physician according to The condition of The patient (see, e.g., Fingl et al 1975, In: The pharmacological basis of Therapeutics, Ch.1, p.1).
The following examples illustrate the invention in more detail without intending to limit its scope in any way. The following abbreviations are used in these examples:
HBTU: 1-benzotriazol-1-yl-tetramethyluronium hexafluorophosphate
(Knorr et al Tetrahedron Lett.1989, 30, 1927-
HOBt: 1-hydroxybenzotriazoles
DIEA: diisopropylethylamine
HOAT: 7-aza-1-hydroxybenzotriazoles
HATU: o- (7-aza-benzotriazol-1-yl) -N, N, N ', N' -tetramethyluronium hexafluorophosphate Carpino et al Tetrahedron Lett.1994, 35, 2279-
Examples
1. Peptide synthesis
Coupling of the first protected amino acid residue
0.5g of 2-chlorotrityl chloride resin (Barlos et al Tetrahedron Lett.1989, 30, 3943-. The resin is suspended in CH2Cl2(2.5ml) and swollen at room temperature under constant stirring. The resin being used in CH2Cl20.415mMol (1 eq) of a (2.5ml) solution of the suitably protected amino acid residue (see below) and 284. mu.l (4 eq) of Diisopropylethylamine (DIEA) were first treated, the mixture was shaken at 25 ℃ for 15 minutes, poured onto the pre-swollen resin and stirred at 25 ℃ for 18 hours. The resin color turned purple and the solution remained yellowish. The resin was washed thoroughly (CH) 2Cl2/MeOH/DIEA：17/2/1；CH2Cl2、DMF；CH2Cl2；Et2O, 3 times each) and dried under vacuum for 6 hours.
The load is usually 0.6-0.7 mMol/g.
The following pre-loaded resins were prepared: Fmoc-GlyO-chlorotrityl resin; Fmoc-Arg (Pbf) O-chlorotrityl resin; Fmoc-Lys (Boc) O-chlorotrityl resin.
1.1. Step 1
The synthesis was performed using a Syro-peptide synthesizer (Multisyntech) with 24-96 reaction vessels. In each container 60mg (weight of resin before loading) of above resin was placed. The following reaction cycles were carried out in order:
step (ii) of Reagent Time of day
1 CH2Cl2Washing and swelling (Manual) 3X 1 min
2 DMF, washing and swelling 1X 5 minutes
3 40% piperidine/DMF 1X 5 minutes
4 DMF, washing 5X 2 minutes
5 5 equivalents Fmoc amino acid/DMF +5 equivalents HBTU +5 equivalents HOBt +5 equivalents DIEA 1X 120 minutes
6 DMF, washing 4X 2 minutes
7 CH2Cl2Washing (at the end of the synthesis) 3X 2 minutes
Repeating steps 3-6 to add the respective amino acids.
Cleavage of all protected peptide fragments
After completion of the synthesis, the resin was suspended in 1ml (0.39mMol) of 1% TFA in CH2Cl2(v/v) for 3 minutes, filtered and treated with 1ml (1.17mMol, 3 equiv.) of 20% DIEA in CH2Cl2(v/v) neutralizing the filtrate. This step was repeated 2 times to ensure that the cleavage was complete. The filtrate was evaporated to dryness and the product was totally deprotected by reverse phase-HPLC (column C) 18) Assays to monitor the efficiency of linear peptide synthesis.
Cyclization of linear peptides
100mg of all protected linear peptide was dissolved in DMF (9ml, concentration 10 mg/ml). 41.8mg (0.110mMol, 3 equiv.) of HATU, 14.9mg (0.110mMol, 3 equiv.) of HOAt and 1ml (0.584mMol) of 10% DIEA in DMF (v/v) were then added and the mixture was stirred at 20 ℃ for 16 h, followed by high vacuum concentration. The residue is in CH2Cl2And H2O/CH3CN (90/10: v/v). CH (CH)2Cl2Phase evaporation gave the complete protected cyclic peptide.
Deprotection and purification of cyclic peptides:
the resulting cyclic peptide was dissolved in 1ml of a solution containing 95% trifluoroacetic acid (TFA), 2.5% waterAnd 2.5% Triisopropylsilane (TIS). The mixture was left at 20 ℃ for 2.5 hours and then concentrated in vacuo. The residue is dissolved in H2O/acetic acid (75/25: v/v), the mixture was extracted with di-isopropyl ether.
The aqueous phase was dried in vacuo and the product was purified by preparative reverse phase HPLC.
After lyophilization, the product was obtained as a white powder and analyzed by ESI-MS. Analytical data including HPLC retention time and ESI-MS are shown in tables 1-7.
Analytical HPLC retention time (RT in minutes) was determined using a gradient a: (10% CH)3CN + 0.1% TFA and 90% H 2O + 0.1% TFA to 98% CH3CN + 0.1% TFA and 2% H2O + 0.1% TFA, held for 20 min) and gradient B: (10% CH)3CN + 0.1% TFA and 90% H2O + 0.1% TFA to 98% CH3CN + 0.1% TFA and 2% H2O + 0.1% TFA, held for 21 minutes) on a VYDAC 218TP104 (length 25cm) column.
Examples 1 to 7(n ═ 8) are shown in table 1. These peptides were synthesized starting with amino acid coupling to the resin at position P4. The starting resins were Fmoc-Arg (Pbf) O-chlorotrityl resin and Fmoc-Lys (Boc) O-chlorotrityl resin, which were prepared as described above. These linear peptides were synthesized on a solid support according to step 1 in the following order:
P5-P6-P7-P8-DPro-Pro-P1-P2-P3-P4-resin, cleaved, cyclized, deprotected and purified as shown. HPLC-retention time (min) was determined using gradient a.
Examples 8-31(n ═ 9) are shown in table 2. These peptides were synthesized starting with amino acid coupling to the resin at position P5. The starting resin was Fmoc-Arg (Pbf) O-chlorotrityl resin, which was prepared as described above. These linear peptides were synthesized on a solid support according to step 1 in the following order: P6-P7-P8-P9-DPro-Pro-P1-P2-P3-P4-P5-resin, cleaved, cyclized, deprotected and purified as shown. HPLC-retention time (min) was determined using gradient a.
Examples 32-58(n ═ 10) are shown in table 3. These peptides were synthesized starting with amino acid coupling to the resin at position P5. The starting resin was Fmoc-Arg (Pbf) O-chlorotrityl resin, which was prepared as described above. These linear peptides were synthesized on a solid support according to step 1 in the following order: P6-P7-P8-P9-DPro-Pro-P1-P2-P3-P4-P5-resin, cleaved, cyclized, deprotected and purified as shown. HPLC-retention time (min) was determined using gradient a.
Examples 59-70 (n-11) are shown in table 4. These peptides were synthesized starting with amino acid coupling to the resin at position P5. The starting resin was Fmoc-Arg (Pbf) O-chlorotrityl resin, which was prepared as described above. These linear peptides were synthesized on a solid support according to step 1 in the following order: P6-P7-P8-P9-DPro-Pro-P1-P2-P3-P4-P5-resin, cleaved, cyclized, deprotected and purified as shown. HPLC-retention time (min) was determined using gradient a.
Examples 71-84 (n-14) are shown in table 5. These peptides were synthesized starting with amino acid coupling to the resin at position P7. The starting resin was Fmoc-Arg (Pbf) O-chlorotrityl resin, which was prepared as described above. These linear peptides were synthesized on a solid support according to step 1 in the following order:
P8-P9-P10-P11-P12-P13-P14-DPro-Pro-P1-P2-P3-P4-P5-P6-P7-resin, cleaved, cyclized, deprotected and purified as shown. HPLC-retention time (min) was determined using gradient a.
Examples 85 to 95(n ═ 16) are shown in table 6. These peptides were synthesized starting with amino acid coupling to the resin at position P8. The starting resins were Fmoc-Arg (Pbf) O-chlorotrityl resin and Fmoc-Lys (Boc) O-chlorotrityl resin, which were prepared as described above. These linear peptides were synthesized on a solid support according to step 1 in the following order: P9-P10-P11-P12-P13-P13-P15-P16-DPro-Pro-P1-P2-P3-P4-P5-P6-P7-P8-resin, cleaved, cyclized, deprotected and purified as shown. HPLC-retention time (min) was determined using gradient a.
Examples 96 to 246, example 27Table 7 shows 6 (n-12). These peptides (except for example 177 and example 181) were synthesized starting with the grafting of an amino acid to the resin at position P6. The starting resins were Fmoc-Arg (Pbf) O-chlorotrityl resin and Fmoc-Lys (Boc) O-chlorotrityl resin, which were prepared as described above. These linear peptides were synthesized on a solid support according to step 1 in the following order: P7-P8-P9-P10-P11-P12-DPro-Pro-P1-P2-P3-P4-P5-P6-resin, cleaved, cyclized, deprotected and purified as shown. HPLC-retention time (min) was determined using gradient a.
Examples 177 to 181 (n-12) are shown in table 7. These peptides were synthesized starting with amino acid coupling to the resin at position P7. The starting resin was Fmoc-Arg (Pbf) O-chlorotrityl resin, which was prepared as described above. These linear peptides were synthesized on a solid support according to step 1 in the following order: P8-P9-P10-P11-P12-DPro-Pro-P1-P2-P3-P4-P5-P6-P7-resin, cleaved, cyclized, deprotected and purified as shown. HPLC-retention time (min) was determined using gradient a.
Example 247-. These peptides were synthesized starting with the amino acid grafted to the resin at position P6. The starting resins were Fmoc-Arg (Pbf) O-chlorotrityl resin and Fmoc-Lys (Boc) O-chlorotrityl resin, which were prepared as described above. These linear peptides were synthesized on a solid support according to step 1 in the following order: P7-P8-P9-P10-P11-P12-DPro-BB-P1-P2-P3-P4-P5-P6-resin, cleaved, cyclized, deprotected and purified as shown.
BB: gly (example 247); arg (pmc) (example 248); y (bzl) (example 249); phe (example 250); trp (example 251); leu (example 252); ile (example 253); cha (example 254); 2-Nal (example 255); 219a (example 256); 219b (example 257); 219c (example 258); 219d (example 259); 219e (example 260); 219f (example 261); 219g (example 262); 219h (example 263); 219i (example 264); 219k (example 265); 219l (example 266); 219m (example 267); 219n (example 268); 219o (example 269); 219p (example 270); 219q (example 271); 219r (example 272); 219s (example 273); 219t (example 274); 219u (example 275). Building blocks 219a-u are described below.
Example 277(n ═ 12) is shown in table 7. These peptides were synthesized starting with an amino acid at position P6 grafted with resin. The starting resin was Fmoc-Arg (Pbf) O-chlorotrityl resin, which was prepared as described above. These linear peptides were synthesized on a solid support according to step 1 in the following order: P7-P8-P9-P10-P11-P12- (c1-1) -P1-P2-P3-P4-P5-P6-resin, cleaved, cyclized, deprotected and purified as shown.
The structural unit (c1-1) is described below.
Example 278-. These peptides were synthesized starting with the amino acid grafted to the resin at position P6. The raw material resin is Fmoc-Arg (Pbf) O-chlorotrityl resin, Fmoc-Tyr (Bzl) O-chlorotrityl resin and Fmoc-DTyr (Bzl) O-chlorotrityl resin, the preparation of which is described above. These linear peptides were synthesized on a solid support according to step 1 in the following order: P7-P8-P9-P10-P11-P12-DPro-P1-P2-P3-P4-P5-P6-resin, cleaved as shown, cyclized, deprotected and purified. Using a gradient B (10% CH)3CN + 0.1% TFA and 90% H2O + 0.1% TFA to 98% CH3CN + 0.1% TFA and 2% H2O + 0.1% TFA, held for 21 minutes) was used to determine the analytical HPLC-retention time (RT in minutes).
The retention times (minutes) were as follows: example 278 (11.43); example 279 (11.64); example 280 (10.57); example 281 (10.04); example 282 (10.63); example 283 (10.00); example 284 (9.21).
Using a gradient CVYDAC C18-a column (length 15 cm); (8% CH)3CN + 0.1% TFA and 92% H2O + 0.1% TFA to 62.8% CH3CN + 0.1% TFA and 37.2% H2O + 0.1% TFA for 8 min to 100% CH3CN + 0.1% TFA for 9 minutes) the retention time (minutes) of example 285-300 was determined.
Example 285 (5.37; 5.57); example 286 (5.17); example 287 (5.0); example 288 (4.15; 4.37); example 289 (4.47; 4.72); example 290 (3.45; 3.72); example 291 (3.65; 3.82); example 292 (4.27); example 293 (4.10); example 294 (3.83; 4.13); example 296 (4.38; 4.67); example 297 (4.10; 4.32); example 298 (4.12); example 299 (4.47); example 300 (5.03).
Both doublets showing correct MS and chiral amino acid analysis. Only one peak was observed at 60 °.
Table 1: examples 1 to 7(n ═ 8)
a) % -purity of crude product. All compounds were purified by preparative HPLC-chromatography as indicated. The purity is more than 90 percent.
Examples Sequence of P1 P2 P3 P4 P5 P6 P7 P8 Form panel RTO(′) ％a) MS
1. SEQ ID NO：1 Tyr Val Arg Arg Arg Phe Leu Val DProLPro 18.6 76 1284.6
2. SEQ ID NO：2 Tyr Val Arg Lys Gly Phe Leu Val DProLPro 18.8 86 1157.4
3. SEQ ID NO：3 Trp Val Arg Lys Gly Phe Leu Trp DProLPro 22.0 70 1263.8
4. SEQ ID NO：4 Tyr Val Arg Arg Arg Trp Leu Val DProLPro 19.1 35 1323.6
5. SEQ ID NO：5 Tyr Val Tyr Arg Arg Phe Leu Val DProLPro 20.7 81 1287.6
6. SEQ ID NO：6 Lys Val Tyr Arg Arg Phe Len Val DProLPro 16.7 75 1256.6
7. SEQ ID NO：7 Lys Val Tyr Lys Gly Phe Leu Trp DProLPro 19.5 64 1216.5
Table 2: examples 8 to 29(n ═ 9)
a) % -purity of crude product. All compounds were purified by preparative HPLC-chromatography as indicated. The purity obtained is > 90%.
Examples Sequence of P1 P2 P3 P4 P5 P6 P7 P8 P9 Form panel RT(′) ％a) MS
8. SEQ ID NO：8 Arg Phe Leu Arg Arg Arg Leu Phe Arg DProLPro 10.5 35 1495.9
9. SEQ ID NO：9 Arg Tyr Leu Arg Arg Arg Leu Tyr Arg DProLPro 8.8 46 1527.9
10. SEQ ID NO：10 Arg Phe Phe Arg Arg Arg Leu Phe Arg DProLPro 10.0 26 1529.9
11. SEQ ID NO：11 Arg Tyr Tyr Arg Arg Arg Leu Tyr Arg DProLPro 8.0 90 1577.9
12. SEQ ID NO：12 Leu Phe Phe Arg Arg Arg Leu Phe Arg DProLPro 10.2 52 1502.9
13. SEQ ID NO：13 Leu Tyr Tyr Arg Arg Arg Leu Phe Arg DProLPro 8.4 30 1550.9
14. SEQ ID NO：14 Arg Phe Leu Phe Arg Arg Leu Leu Arg DProLPro 10.1 51 1468.9
15. SEQ ID NO：15 Arg Tyr Leu Tyr Arg Arg Leu Leu Arg DProLPro 8.8 55 1500.9
16. SEQ ID NO：16 Leu Phe Leu Phe Arg Arg Leu Phe Arg DProLPro 9.7 38 1459.9
17. SEQ ID NO：17 Leu Tyr Leu Tyr Arg Arg Leu Tyr Arg DProLPro 11.8 67 1507.9
18. SEQ ID NO：18 Arg Phe Leu Phe Arg Arg Leu Phe Leu DProLPro 10.3 57 1459.9
19. SEQ ID NO：19 Arg Tyr Leu Tyr Arg Arg Leu Tyr Leu DProLPro 11.7 66 1507.9
20. SEQ ID NO：20 Phe Leu Leu Phe Arg Arg Leu Phe Arg DProLPro 9.9 67 1459.9
21. SEQ ID NO：21 Tyr Leu Leu Tyr Arg Arg Leu Tyr Arg DProLPro 11.9 57 1507.9
22. SEQ ID NO：22 Arg Leu Leu Phe Arg Arg Leu Phe Phe DProLPro 10.1 68 1459.9
23. SEQ ID NO：23 Arg Leu Leu Tyr Arg Arg Leu Tyr Tyr DProLPro 11.5 63 1507.9
24. SEQ ID NO：24 Arg Phe Leu Arg Arg Phe Leu Phe Arg DProLPro 8.5 33 1502.9
25. SEQ ID NO：25 Arg Phe Leu Arg Arg Phe Phe Leu Arg DProLPro 10.3 30 1502.9
26. SEQ ID NO：26 Arg Tyr Leu Arg Arg Tyr Tyr Leu Arg DProLPro 12.6 65 1550.9
27. SEQ ID NO：27 Leu Tyr Leu Arg Arg Tyr Leu Tyr Arg DProLPro 10.1 29 1491.8
28. SEQ ID NO：28 Leu Leu Phe Phe Arg Arg Leu Phe Arg DPrpLPro 12.1 35 1443.8
29. SEQ ID NO：29 Leu Leu Tyr Tyr Arg Arg Leu Tyr Arg DProLPro 10.3 33 1491.8
30. SEQ ID NO：30 Arg Leu Phe Phe Arg Arg Leu Phe Leu DProLPro 12.1 35 1459.9
31. SEQ ID NO：31 Arg Leu Tyr Tyr Arg Arg Leu Tyr Leu DProLPro 10.3 33 1507.8
Table 3: examples 32 to 58(n ═ 10)
a) % -purity of crude product. All compounds were purified by preparative HPLC-chromatography as indicated. The purity obtained is > 90%.
Examples Sequence of P1 P2 P3 P4 P5 P6 P7 P8 P9 P10 Form panel RT(′) ％a) MS
32. SEQ ID NO：32 Arg Phe Leu Phe Arg Arg Arg Leu Phe Arg DProLPro 10.2 37 1643.0
33. SEQ ID NO：33 Arg Tyr Leu Tyr Arg Arg Arg Leu Tyr Arg DProLPro 8.3 41 1691.0
34. SEQ ID NO：34 Arg Phe Phe Phe Arg Arg Arg Leu Leu Arg DProLPro 10.1 45 1643.0
35. SEQ ID NO：35 Arg Tyr Tyr Tyr Arg Arg Arg Leu Leu Arg DProLPro 8.87 70 1691.0
36. SEQ ID NO：36 Arg Leu Phe Phe Arg Arg Arg Leu Phe Arg DProLPro 10.4 56 1643.0
37. SEQ ID NO：37 Leu Tyr Leu Tyr Arg Arg Arg Leu Tyr Arg DProLPro 9.6 35 1648.0
38. SEQ ID NO：38 Arg Phe Leu Phe Arg Arg Arg Leu Phe Leu DProLPro 11.1 50 1600.0
39. SEQ ID NO：39 Arg Tyr Leu Tyr Arg Arg Arg Leu Tyr Leu DProLPro 9.81 41 1648.0
40. SEQ ID NO：40 Leu Leu Phe Phe Arg Arg Arg Leu Phe Arg DProLPro 11.8 58 1600.0
41. SEQ ID NO：41 Arg Leu Phe Phe Arg Arg Arg Leu Phe Leu DProLPro 11.6 54 1600.0
42. SEQ ID NO：42 Leu Tyr Tyr Tyr Arg Arg Arg Leu Leu Arg DProLPro 9.9 51 1648.0
43. SEQ ID NO：43 Arg Phe Phe Phe Arg Arg Arg Leu Leu Leu DProLPro 11.3 49 1600.0
44. SEQ ID NO：44 Arg Tyr Tyr Tyr Arg Arg Arg Leu Leu Leu DProLPro 9.9 63 1648.0
45. SEQ ID NO：45 Arg Leu Leu Phe Arg Gly Arg Phe Phe Arg DProLPro 10.6 78 1543.9
46. SEQ ID NO：46 Arg Leu Leu Tyr Arg Gly Arg Tyr Tyr Arg DProLPro 9.1 45 1591.9
47. SEQ ID NO：47 Arg Phe Phe Phe Arg Gly Arg Leu Leu Arg DProLPro 10.4 43 1543.9
48. SEQ ID NO：48 Arg Tyr Tyr Tyr Arg Gly Arg Leu Leu Arg DProLPro 8.8 48 1591.9
49. SEQ ID NO：49 Leu Phe Leu Phe Arg Gly Arg Leu Phe Arg DProLPro 12.4 65 1500.9
50. SEQ ID NO：50 Leu Tyr Leu Tyr Arg Gly Arg Leu Tyr Arg DProLPro 10.3 58 1548.9
51. SEQ ID NO：51 Arg Phe Leu Phe Arg Gly Arg Leu Phe Leu DProLPro 12.3 42 1500.9
52. SEQ ID NO：52 Arg Tyr Leu Tyr Arg Gly Arg Leu Tyr Leu DProLPro 10.6 20 1548.9
53. SEQ ID NO：53 Leu Arg Phe Phe Arg Leu Arg Leu Phe Arg DProLPro 11.9 51 1600.0
54. SEQ ID NO：54 Leu Arg Tyr Tyr Arg Leu Arg Leu Tyr Arg DProLPro 9.9 50 1648.0
55. SEQ ID NO：55 Leu Leu Phe Phe Arg Gly Arg Leu Phe Arg DProLPro 12.5 50 1500.9
56. SEQ ID NO：56 Leu Leu Tyr Tyr Arg Gly Arg Leu Tyr Arg DProLPro 10.1 38 1548.9
57. SEQ ID NO：57 Arg Phe Leu Phe Arg Gly Arg Phe Arg Leu DProLPro 11.3 57 1543.9
58. SEQ ID NO：58 Arg Tyr Leu Tyr Arg Gly Arg Tyr Arg Leu DProLPro 10.8 56 1591.9
Table 4: examples 59 to 70(n ═ 11)
a) % -purity of crude product. All compounds were purified by preparative HPLC-chromatography as indicated. The purity is more than 90 percent.
Examples Sequence of P1 P2 P3 P4 P5 P6 P7 P8 P9 P10 P11 Form panel RTO(′) ％ MS
59. SEQ ID NO：59 Arg Leu Phe Leu Arg Arg Arg Phe Phe Arg Leu DProLPro 11.1 75 1756.2
60. SEQ ID NO：60 Arg Leu Tyr Leu Arg Arg Arg Tyr Tyr Arg Leu DProLPro 9.5 28 1804.2
61. SEQ ID NO：61 Leu Leu Phe Leu Arg Arg Arg Phe Phe Arg Arg DProLPro 10.8 65 1756.2
62. SEQ ID NO：62 Arg Leu Phe Leu Arg Arg Arg Leu Phe Arg Phe DProLPro 11.3 57 1756.2
63. SEQ ID NO：63 Phe Leu Phe Leu Arg Arg Arg Leu Phe Arg Arg DProLPro 11.1 76 1756.2
64. SEQ ID NO：64 Tyr Leu Tyr Leu Arg Arg Arg Leu Tyr Arg Arg DProLPro 9.5 70 1804.2
65. SEQ ID NO：65 Arg Arg Phe Leu Arg Gly Arg Phe Phe Leu Arg DProLPro 9.8 36 1700.1
66. SEQ ID NO：66 Leu Leu Tyr Tyr Arg Arg Leu Tyr Tyr Arg Arg DProLPro 9.9 47 1811.2
67. SEQ ID NO：67 Leu Tyr Leu Tyr Arg Arg Tyr Leu Tyr Arg Arg DProLPro 9.9 47 1811.2
68. SEQ ID NO：68 Arg Arg Phe Phe Arg Arg Leu Phe Phe Leu Leu DProLPro 12.4 46 1747.2
69. SEQ ID NO：69 Arg Leu Tyr Tyr Arg Arg Leu Tyr Tyr Arg Leu DProLPro 9.9 51 1811.2
70. SEQ ID NO：70 Arg Leu Phe Phe Arg Gly Arg Phe Phe Arg Leu DProLPro 10.5 26 1691.1
Table 5: examples 71-84(n ═ 14)
a) % -purity of crude product. All compounds were purified by preparative HPLC-chromatography. The purity is more than 90 percent.
Examples Sequence of P1 P2 P3 P4 P5 P6 P7 P8 P9 P10 P11 P12 P13 P14 Form panel RT(′) ％ MS
71. SEQ ID NO：71 Arg Tyr Leu Leu Tyr Arg Arg Arg Tyr Leu Leu Tyr Arg Arg DProLPro 9.4 48 2236.7
72. SEQ ID NO：72 Arg Leu Leu Tyr Tyr Arg Arg Arg Tyr Leu Leu Tyr Arg Arg DProLPro 9.4 29 2236.7
73. SEQ ID NO：73 Arg Leu Leu Leu Tyr Arg Arg Arg Tyr Leu Tyr Tyr Arg Arg DProLPro 9.4 50 2236.7
74. SEQ ID NO：74 Arg Phe Leu Phe Leu Arg Arg Arg Phe Phe Leu Phe Arg Arg DProLPro 10.9 78 2206.7
75. SEQ ID NO：75 Arg Tyr Leu Tyr Leu Arg Arg Arg Tyr Tyr Leu Tyr Arg Arg DProLPro 9.1 51 2286.7
76. SEQ ID NO：76 Arg Phe Leu Phe Leu Arg Arg Arg Phe Leu Phe Leu Arg Arg DProLPro 10.6 79 2172.7
77. SEQ ID NO：77 Arg Tyr Leu Tyr Leu Arg Arg Arg Tyr Leu Tyr Leu Arg Arg DProLPro 9.1 53 2236.7
78. SEQ ID NO：78 Arg Arg Leu Leu Phe Arg Arg Arg Phe Leu Leu Phe Phe Arg DProLPro 11.0 42 2172.7
79. SEQ ID NO：79 Arg Arg Leu Leu Tyr Arg Arg Arg Tyr Leu Leu Tyr Tyr Arg DProLPro 9.4 91 2236.7
80. SEQ ID NO：80 Arg Arg Leu Tyr Tyr Arg Arg Arg Tyr Leu Leu Tyr Tyr Arg DProLPro 9.3 72 2286.7
81. SEQ ID NO：81 Arg Arg Leu Leu Tyr Arg Arg Arg Tyr Leu Tyr Tyr Leu Arg DProLPro 9.5 65 2236.7
82. SEQ ID NO：82 Arg Arg Leu Phe Leu Arg Arg Arg Phe Phe Leu Phe Phe Arg DProLPro 11.1 34 2206.7
83. SEQ ID NO：83 Arg Arg Leu Tyr Leu Arg Arg Arg Tyr Tyr Leu Tyr Tyr Arg DProLPro 9.3 89 2286.7
84. SEQ ID NO：84 Arg Arg Leu Tyr Leu Arg Arg Arg Tyr Leu Tyr Leu Tyr Arg DPrpLPro 9.3 47 2236.7
Table 6: examples 85 to 95(n ═ 16)
a) % -purity of crude product. All compounds were purified by preparative HPLC-chromatography. The purity is more than 90 percent.
Examples Sequence of P1 P2 P3 P4 P5 P6 P7 P8 P9 P10 P11 P12 P13 P14 P15 P16 Form panel RT(′) ％ MS
85. SEQ ID NO：85 Lys Arg Leu Lys Tyr Val Arg Arg Arg Trp Leu Val Lys Val Leu Arg DPrLPro 13.7 70 2346.0
86. SEQ ID NO：86 Lys Arg Leu Lys Tyr Val Arg Arg Gly Trp Leu Val Lys Val Leu Arg DProLPro 13.9 38 2246.8
87. SEQ ID NO：87 Lys Arg Leu Lys Tyr Trp Arg Arg Arg Trp Tyr Val Lys Val Leu Arg DPrpLPro 13.6 34 2483.1
88. SEQ ID NO：88 Lys Arg Leu Tyr Tyr Trp Arg Arg Arg Trp Tyr Val Phe Val Leu Arg DProLPro 14.3 35 2537.1
89. SEQ ID NO：89 Lys Arg Leu Lys Tyr Trp Arg Arg Gly Trp Tyr Val Lys Val Leu Arg DProLPro 13.7 27 2383.9
90. SEQ ID NO：90 Lys Arg Leu Tyr Tyr Trp Arg Arg Gly Trp Tyr Val Phe Val Leu Arg DProLPro 14.6 39 2437.9
91. SEQ ID NO：91 Lys Arg Leu Tyr Tyr Trp Arg Arg Arg Trp Lys Val Phe Val Leu Arg DProLPro 13.9 22 2402.1
92. SEQ ID NO：92 Lys Arg Leu Lys Tyr Trp Arg Arg Gly Trp Lys Val Lys Val Leu Arg DProLPro 13.4 26 2348.9
93. SEQ ID NO：93 Tyr Lys Leu Arg Leu Lys Tyr Arg Arg Trp Lys Tyt Arg Val Lys Phe DProLPro 12.5 34 2402.1
94. SEQ ID NO：94 Tys Lys Leu Gln Leu Lys Trp Arg Arg Phe Lys Tyr Gln Val Lys Phe DProLPro 12.1 21 2348.9
95. SEQ ID NO：95 Tys Lys Leu Gln Leu Gln Lys Lys Gly Trp Gln Tyr Gln Val Lys Phe DProLPro 11.1 84 2383.9
Table 7: examples 96-128 (n-12);
a) % -purity of crude product. All compounds had a purity of > 90% after preparative HPLC-chromatography.
Examples Sequence of P1 P2 P3 P4 P5 P6 P7 P8 P9 P10 P11 P12 Form panel RT(′) ％ MS
96. SEQ ID NO：96 Leu Arg Leu Val Tyr Lys Gly Phe Leu Tyr Arg Val DProLPro 21.6 92 1703.1
97. SEO ID NO：97 Leu Arg Phe Val Tyr Lys Gly Phe Leu Tyr Arg Va1 DProLPro 21.6 95 1737.1
98. SEQ ID NO：98 Leu Arg Thr Val Tyr Lys Gly Phe Leu Tyr Arg Val DProLPro 20.0 93 1691.1
99. SEQ ID NO：99 Leu Arg Lys Val Arg Lys Gly Arg Leu Tyr Arg Val DProLPro 15.7 99 1720.2
100. SEQ ID NO：100 Leu Arg Lys Trp Tyr Lys Gly Phe Trp Tyr Arg Val DProLPro 17.6 60 1878.3
101. SEQ ID NO：101 Leu Arg Lys Val Tyr Arg Gly Phe Leu Tyr Arg Val DProLPro 17.8 61 1845.3
102. SEQ ID NO：102 Leu Lys Lys Val Tyr Arg Arg Phe Leu Lys Lys Val DProLPro 15.9 59 1754.3
103. SEQ ID NO：103 Leu Arg Leu Lys Tyr Arg Arg Phe Lys Tyr Arg Val DProLPro 20.5 36 1874.3
104. SEQ ID NO：104 Leu Arg Leu Glu Tyr Arg Arg Phe Glu Tyr Arg Val DProLPro 21.5 99 1876.2
105. SEQ ID NO：105 Leu Arg Leu Gln Tyr Arg Arg Phe Gln Tyr Arg Val DProLPro 21.5 58 1874.2
106. SEQ ID NO：106 Leu Arg Leu Lys Lys Arg Arg Trp Lys Tyr Arg Val DProLPro 18.1 51 1879.7
107. SEQ ID NO：107 Leu Arg Leu Lys Trp Arg Arg Lys Lys Tyr Arg Val DProLPro 20.2 28 1879.7
108. SEQ ID NO：108 Leu Arg Trp Lys Tyr Arg Arg Phe Lys Tyr Arg Val DProLPro 20.9 40 1948.7
109. SEQ ID NO：109 Lys Val Arg Phe Arg Arg Arg Lys Leu Lys Leu Arg DProLPro 15.7 75 1833.7
110. SEQ ID NO：110 Leu Arg Leu Gln Tyr Arg Arg Trp Gln Tyr Arg Val DProLPro 21.9 30 1913.3
111. SEQ ID NO：111 Leu Arg Leu Gln Trp Arg Arg Phe Gln Tyr Arg Val DProLPro 22.6 75 1897.3
112. SEQ ID NO：112 Leu Arg Leu Gln Lys Arg Arg Trp Gln Tyr Arg Val DProLPro 18.9 49 1878.3
113. SEQ ID NO：113 Leu Arg Leu Gln Trp Arg Arg Lys Gln Tyr Arg Val DProLPro 21.2 75 1878.3
114. SEQ ID NO：114 Phe Arg Leu Gln Tyr Arg Arg Phe Gln Tyr Arg Val DProLPro 22.3 50 1908.3
115. SEQ ID NO：115 Leu Arg Leu Gln Tyr Arg Arg Phe Gln Tyr Arg Phe DProLPro 22.4 99 1908.3
116. SEQ ID NO：116 Phe Arg Leu Gln Tyr Arg Arg Phe Gln Tyr Arg Phe DProLPro 22.9 99 1956.3
117. SEQ ID NO：117 Leu Arg Leu Gln Tyr Arg Arg Phe Gln Trp Arg Val DProLPro 22.7 15 1897.3
118. SEQ ID NO：118 Leu Arg Trp Gln Tyr Arg Arg Phe Gln Tyr Arg Val DProLPro 21.9 21 1947.3
1l9. SEQ ID NO：119 Gln Val Arg Phe Arg Arg Arg Lys Leu Gln Leu Arg DProLPro 17.2 46 1831.3
120. SEQ ID NO：120 Phe Arg Leu Lys Lys Arg Arg Trp Lys Tyr Arg Val DProLPro 10.5 52 1912.4
121. SEQ ID NO：121 Cha Arg Leu Lys Lys Arg Arg Trp Lys Tyr Arg Val DProLPro 10.6 36 1918.4
122. SEQ ID NO：122 hPhe Arg Leu Lys Lys Arg Arg Trp Lys Tyr Arg Val DProLPro 9.6 95 1926.4
123. SEQ ID NO：123 2Nal Arg Leu Lys Lys Arg Arg Trp Lys Tyr Arg Val DProLPro 9.6 69 1962.4
124. SEQ ID NO：124 1Nal Arg Leu Lys Lys Arg Arg Trp Lys Tyr Arg Val DProLPro 11.8 47 1962.4
125. SEQ ID NO：125 Nle Arg Leu Lys Lys Arg Arg Trp Lys Tyr Arg Val DProLPro 10.3 63 1878.4
126. SEQ ID NO：126 Leu Arg Phe Lys Lys Arg Arg Trp Lys Tyr Arg Val DProLPro 10.6 44 1912.4
127. SEQ ID NO：l27 Leu Arg Cha Lys Lys Arg Arg Trp Lys Tyr Arg Val DProLPro 10.8 41 1918.4
128. SEQ ID NO：128 Leu Arg Y(bzl) Lys Lys Arg Arg Trp Lys Tyr Arg Val DProLPro 11.5 23 2018.5
Table 7 (next): example 129-161(n ═ 12)
Examples Sequence of P1 P2 P3 P4 P5 P6 P7 P8 P9 P10 P11 P12 Form panel RT(′) ％ MS
129. SEQ ID NO：129 Leu Arg Trp Lys Lys Arg Arg Trp Lys Tyr Arg Val DProLPro 10.5 41 1951.4
130. SEQ ID NO：130 Leu Arg hPhe Lys Lys Arg Arg Trp Lys Tyr Arg Val DProLPro 10.6 32 1926.4
131. SEO ID NO：131 Leu Arg 2Nal Lys Lys Arg Arg Trp Lys Tyr Arg Val DProLPro 11.0 42 1962.4
132. SEQ ID NO：132 Leu Arg 1Nal Lys Lys Arg Arg Trp Lys Tyr Arg Val DProLPro 10.9 43 1962.4
133. SEQ ID NO：133 Leu Arg Val Lys Lys Arg Arg Trp Lys Tyr Arg Val DProLPro 10.0 47 1864.3
134. SEQ ID NO：134 Leu Arg Ile Lys Lys Arg Arg Trp Lys Tyr Arg Val DPrpLPro 10.3 34 1878.4
135. SEQ ID NO：135 Leu Arg Nle Lys Lys Arg Arg Trp Lys Tyr Arg Val DProLPro 10.3 90 1878.4
136. SEQ ID NO：136 Leu Arg Leu Lys Lys Arg Arg Trp Lys Tyr Arg Val DProLPro 9.9 48 1855.3
137. SEQ ID NO：137 Leu Arg Leu Lys Lys Arg Arg Y(Bzl) Lys Tyr Arg Val DProLPro 11.0 33 1945.4
138. SEQ ID NO：138 Leu Arg Leu Lys Lys Arg Arg hPhe Lys Tyr Arg Val DProLPro 10.3 52 1853.3
139. SEQ ID NO：139 Leu Arg Leu Lys Lys Arg Arg 2Nal Lys Tyr Arg Val DProLPro 10.5 53 1889.4
140. SEQ ID NO：140 Leu Arg Leu Lys Lys Arg Arg 1Nal Lys Tyr Arg Val DProLPro 10.5 34 1889.4
141. SEQ ID NO：141 Leu Arg Leu Lys Lys Arg Arg Val Lys Tyr Arg Val DProLPro 9.9 49 1889.4
142. SEQ ID NO：142 Leu Arg Leu Lys Lys Arg Arg Ile Lys Tyr Arg Val DProLPro 10.0 32 1791.3
143. SEQ ID NO：143 Leu Arg Leu Lys Lys Arg Arg Leu Lys Tyr Arg Val DProLPro 10.1 46 1805.3
144. SEQ ID NO：144 Leu Arg Leu Lys Lys Arg Arg Nle Lys Tyr Arg Val DProLPro 10.1 43 1805.3
145. SEQ ID NO：145 Leu Arg Leu Lys Lys Arg Arg His Lys Tyr Arg Val DProLPro 9.8 56 1829.3
146. SEQ ID NO：146 Leu Arg Leu Lys Lys Srg Arg Trp Lys Phe Arg Val DProLPro 10.9 45 1862.3
147. SEQ ID NO：147 Leu Arg Leu Lys Lys Arg Arg Trp Lys Y(Bzl) Arg Val DProLPro 11.4 15 1968.5
148. SEQ ID NO：148 Leu Arg Leu Lys Lys Arg Arg Trp Lys Trp Arg Val DProLPro 10.8 56 1901.4
149. SEQ ID NO：149 Leu Arg Leu Lys Lys Arg Arg Trp Lys hPhe Arg Val DProLPro 11.3 32 1876.4
150. SEQ ID NO：150 Leu Arg Leu Lys Lys Arg Arg Trp Lys 1Nal Arg Val DProLPro 11.6 24 1912.4
151. SEQ ID NO：151 Leu Arg Leu Lys Lys Arg Arg Trp Lys Val Arg Val DProLPro 10.6 48 1814.3
152. SEQ ID NO：152 Leu Arg Leu Lys Lys Arg Arg Trp Lys Ile Arg Val DProLPro 10.9 40 1828.3
153. SEQ ID NO：153 Leu Arg Leu Lys Lys Arg Arg Trp Lys Leu Arg Val DProLPro 10.7 18 1828.3
154. SEQ ID NO：154 Leu Arg Leu Lys Lys Arg Arg Trp Lys Nle Arg Val DProLPro 11.2 40 1828.3
155. SEQ ID NO：155 Leu Arg Leu Lys Lys Arg Arg Trp Lys Tyt Arg Phe DProLPro 10.6 35 1926.4
156. SEQ ID NO：156 Leu Arg Leu Lys Lys Arg Arg Trp Lys Tyr Arg Cha DProLPro 11.2 60 1932.5
157. SEQ ID NO：157 Leu Arg Leu Lys Lys Arg Arg Trp Lys Tyr Arg Y(Bzl) DProLPro 11.7 37 2032.5
158. SEQ ID NO：158 Leu Arg Leu Lys Lys Arg Arg Trp Lys Tyr Arg Trp DProLPro 10.4 69 1965.4
159. SEQ ID NO：159 Leu Arg Leu Lys Lys Arg Arg Trp Lys Tyr Arg hPhe DProLPro 10.8 95 1940.4
160. SEQ ID NO：160 Leu Arg Leu Lys Lys Arg Arg Trp Lys Tyr Arg 2Nal DProLPro 11.2 30 1976.5
161. SEQ ID NO：161 Leu Arg Leu Lys Lys Arg Arg Trp Lys Tyr Arg 1Nal DProLPro 11.3 89 1976.5
Table 7 (next): example 162-
Examples Sequence of P1 P2 P3 P4 P5 P6 P7 P8 P9 P10 P11 P12 Form panel RT(′) ％ MS
162. SEQ ID NO：162 Leu Arg Leu Lys Lys Arg Arg Trp Lys Tyr Arg Ile DProLPro 10.5 56 1g92.4
163. SEQ ID NO：163 Leu Arg Leu Lys Lys Arg Arg Trp Lys Tyr Arg Nle DProLPro 10.5 91 1892.4
164. SEQ ID NO：164 Leu Arg Leu Lys Lys Arg Arg Trp Lys Tyr Arg His DProLPro 8.6 88 1916.4
165. SEQ ID NO：165 Leu Trp Leu Lys Lys Arg Arg Trp Lys Tyr Arg Val DProLPro 10.4 55 1908.4
166. SEQ ID NO：166 Leu Leu Leu Lys Lys Arg Arg Trp Lys Tyr Arg Val DProLPro 10.6 88 1835.3
167. SEQ ID NO：167 Leu Thr Leu Lys Lys Arg Arg Trp Lys Tyr Arg Val DProLPro 10.4 94 1823.3
168. SEQ ID NO：168 Leu Gln Leu Lys Lys Arg Arg Trp Lys Tyr Arg Val DProLPro 10.4 55 1850.3
169. SEQ ID NO：169 Leu Arg Leu Leu Lys Arg Arg Trp Lys Tyr Arg Val DProLPro 10.9 62 1863.3
170. SEQ ID NO：170 Leu Arg Leu Arg Lys Arg Arg Trp Lys Tyr Arg Val DProLPro 10.3 45 1906.4
171. SEQ ID NO：171 Leu Arg Leu Thr Lys Arg Arg Trp Lys Tyr Arg Val DProLPro 10.4 94 1851.3
172. SEQ ID NO：172 Leu Arg Leu G1n Lys Arg Arg Trp Lys Tyr Arg Val DProLPro 10.3 76 1878.3
173. SEQ ID NO：173 Leu Arg Leu Lys Leu Arg Arg Trp Lys Tyr Arg Val DProLPro 11.9 43 1863.3
174. SEQ ID NO：174 Leu Arg Leu Lys His Arg Arg Trp Lys Tyr Arg Val DProLPro 10.5 53 1887.3
175. SEQ ID NO：175 Leu Arg Leu Lys Arg Arg Arg Trp Lys Tyr Arg Val DProLPro 10.4 37 1906.4
176. SEQ ID NO：176 Leu Arg Leu Lys Thr Arg Arg Trp Lys Tyr Arg Val DProLPro 11.4 45 1851.3
177. SEQ ID NO：177 Leu Arg Leu Lys Lys Leu Arg Trp Lys Tyr Arg Val DProLPro 10.8 58 1835.3
178. SEQ ID NO：178 Leu Arg Leu Lys Lys His Arg Trp Lys Tyr Arg Va1 DProLPro 10.2 46 1859.3
179. SEQ ID NO：179 Leu Arg Leu Lys Lys Lys Arg Trp Lys Tyr Arg Val DProLPro 10.3 53 1850.3
180. SEQ ID NO：180 Leu Arg Leu Lys Lys Thr Arg Trp Lys Tyr Arg Val DProLPro 10.4 82 1823.3
181. SEQ ID NO：181 Leu Arg Leu Lys Lys Gln Arg Trp Lys Tyr Arg Val DProLPro 10.4 36 1850.3
182. SEQ ID NO：182 Leu Arg Leu Lys Lys Arg Trp Trp Lys Tyr Arg Val DProLPro 10.8 70 1908.4
183. SEQ ID NO：183 Leu Arg Leu Lys Lys Arg His Trp Lys Tyr Arg Val DProLPro 10.3 74 1859.3
184. SEQ ID NO：184 Leu Arg Leu Lys Lys Arg Lys Trp Lys Tyr Arg Val DProLPro 10.2 50 1850.3
185. SEQ ID NO：185 Bip Arg Leu Lys Lys Arg Arg Trp Lys Tyr Arg Val DProLPro 11.4 39 1988.5
186. SEQ ID NO：186 4ClPhe Arg Leu Lys Lys Arg Arg Trp Lys Tyr Arg Val DProLPro 11.1 53 1946.8
187. SEQ ID NO：187 AmPhe Arg Leu Lys Lys Arg Arg Trp Lys Tyr Arg Val DProLPro 8.6 83 1927.4
188. SEQ ID NO：188 S(Bzl) Arg Leu Lys Lys Arg Arg Trp Lys Tyr Arg Val DProLPro 10.4 66 194Z.4
189. SEQ ID NO：189 T(Bzl) Arg Leu Lys Lys Arg Arg Trp Lys Tyr Arg Val DProLPro 10.8 51 1956.4
190. SEQ ID NO：190 Orn Arg Leu Lys Lys Arg Arg Trp Lys Tyr Arg Val DProLPro 8.4 84 1879.3
191. SEQ ID NO：191 Leu Arg Bip Lys Lys Arg Arg Trp Lys Tyr Arg Val DPrpLPro 11.3 39 1988.5
192. SEQ ID NO：192 Leu Arg 4ClPhe Lys Lys Arg Arg Trp Lys Tyr Arg Val DProLPro 10.9 50 1946.8
193. SEQ ID NO：193 Leu Arg AmPhe Lys Lys Arg Arg Trp Lys Tyr Arg Val DProLPro 9.2 82 1927.4
194. SEQ ID NO：194 Leu Arg S(Bzl) Lys Lys Arg Arg Trp Lys Tyr Arg Val DPrpLPro 10.7 80 1942.4
Table 7 (next): examples 195-227 (n =12)
Table 7 (next): example 228-
Examples Sequence of P1 P2 P3 P4 P5 P6 P7 P8 P9 P10 P11 P12 Form panel RT(′) ％ MS
228. SEQ ID NO：228 Leu Arg Leu Arg Lys Arg Arg Bip Lys Tyr Arg Val DProLPro 10.9 46 1943.4
229. SEQ ID NO：229 Leu Arg Leu Lys Lys Arg Arg Bip Arg Tyr Arg Val DProLPro 10.9 41 1943.4
230. SEQ ID NO：230 Leu Trp Leu Lys Lys Arg Arg Bip Lys Tyr Arg Val DProLPro 11.0 73 1945.4
231. SEQ ID NO：231 Leu Trp Leu Arg Lys Arg Arg Bip Lys Tyr Arg Val DProLPro 11.0 71 1973.5
232. SEQ ID NO：232 Leu Trp Leu Lys Lys Arg Arg Bip Arg Tyr Arg Val DProLPro 11.0 71 1973.5
233. SEQ ID NO：233 Leu Trp Leu Arg Lys Arg Arg Bip Lys Bip Arg Val DProLPro 12.4 60 2033.6
234. SEQ ID NO：234 Leu Trp Leu Lys Lys Arg Arg Bip Arg Bip Arg Val DProLPro 12.4 85 2033.6
235. SEQ ID NO：235 Leu Trp Leu Arg Lys Arg Arg Bip Arg Bip Arg Bip DProLPro 11.6 50 2185.7
236. SEQ ID NO：236 4ClPhe Arg Leu Lys Lys Arg Arg Bip Lys Tyr Arg Val DProLPro 10.7 39 1983.9
237. SEQ ID NO：237 4ClPhe Arg Leu Lys Lys Arg Arg Bip Lys Bip Arg Val DProLPro 13.0 36 2043.9
238. SEQ ID NO：238 4ClPhe Arg Leu Lys Lys Arg Arg Bip Lys Tyr Arg Bip DProLPro 12.9 52 2108.0
239. SEQ ID NO：239 4ClPhe Arg Leu Lys Lys Arg Arg Bip Lys Bip Arg Bip DProLPro 12.6 68 2168.1
240. SEQ ID NO：240 4ClPhe Arg Leu Arg Lys Arg Arg Bip Lys Tyr Arg Val DProLPro 11.7 46 2011.9
241. SEQ ID NO：241 4ClPhe Arg Leu Lys Lys Arg Arg Bip Arg Tyr Arg Val DProLPro 11.7 41 2011.9
242. SEQ ID NO；242 4ClPhe Trp Leu Lys Lys Arg Arg Bip Lys Tyr Arg Val DProLPro 11.8 48 2013.9
243. SEQ ID NO：243 4ClPhe Trp Leu Arg Lys Arg Arg Bip Lys Tyr Arg Val DProLPro 11.9 38 2041.9
244. SEQ ID NO：244 4ClPhe Trp Leu Lys Lys Arg Arg Bip Arg Tyr Arg Val DProLPro 11.9 74 2041.9
245. SEQ ID NO：245 4ClPhe Trp Leu Arg Lys Arg Arg Bip Lys Bip Arg Val DProLPro 13.2 66 2102.0
246. SEQ ID NO：246 4ClPhe Trp Leu Lys Lys Arg Arg Bip Arg Bip Arg Val DProLPro 13.2 49 2102.0
247. SEQ ID NO：247 Leu Arg Leu Lys Lys Arg Arg Trp Lys Tyr Arg Val DPro-Gly 9.5 58 1838.3
248. SEQ ID NO：248 Leu Arg Leu Lys Lys Arg Arg Trp Lys Tyr Arg Val DPro-Arg 9.3 57 1937.4
249. SEQ ID NO：249 Leu Arg Leu Lys Lys Arg Arg Trp Lys Tyr Arg Val DPro-Tyr 9.9 29 1944.4
250. SEQ ID NO：250 Leu Arg Leu Lys Lys Arg Arg Trp Lys Tyr Arg Val DPro-Phe 10.7 34 1928.4
251. SEQ ID NO：251 Leu Arg Leu Lys Lys Arg Arg Trp Lys Tyr Arg Val DPro-Trp 10.7 25 1967.5
252. SEQ ID NO：252 Leu Arg Leu Lys Lys Arg Arg Trp Lys Tyr Arg Val DPro-Leu 10.5 21 1894.4
253. SEQ ID NO：253 Leu Arg Leu Lys Lys Arg Arg Trp Lys Tyr Arg Val DPro-Ile 10.4 42 1894.4
254. SEQ ID NO：254 Leu Arg Leu Lys Lys Arg Arg Trp Lys Tyr Arg Val DPro-Cha 11.2 36 1934.5
255. SEQ ID NO：255 Leu Arg Leu Lys Lys Arg Arg Trp Lys Tyr Arg Val DPro-2Nal 11.4 27 1978.5
Table 7 (next): example 256-
All products were purified by preparative HPLC-chromatography. The purity is more than 90 percent.
Examples Sequence of P1 P2 P3 P4 P5 P6 P7 P8 P9 P10 P11 P12 Form panel MS
256. SEQ ID NO：256 Leu Arg Leu Lys Lys Arg Arg Trp Lys Tyr Arg Val DPro-A8’-1 1990.5
257. SEQ ID NO：257 Leu Arg Leu Lys Lys Arg Arg Trp Lys Tyr Arg Val DPro-A8’-2 2018.3
258. SEQ ID NO：258 Leu Arg Leu Lys Lys Arg Arg Trp Lys Tyr Arg Val DPro-A8’-3 2086.4
259. SEQ ID NO：259 Leu Arg Leu Lys Lys Arg Arg Trp Lys Tyr Arg Val DPro-A8’-4 2086.4
260. SEQ ID NO：260 Leu Arg Leu Lys Lys Arg Arg Trp Lys Tyr Arg Val DPro-A8’-5 1978.3
261. SEO ID NO：261 Leu Arg Leu Lys Lyg Arg Arg Trp Lys Tyr Arg Val DPro-A8’-6 2023.3
262. SEQ ID NO：262 Leu Arg Leu Lys Lys Arg Arg Trp Lys Tyr Arg Val DPro-A8’-7 1934.3
263. SEQ ID NO：263 Leu Arg Leu Lys Lys Arg Arg Trp Lys Tyr Arg Val DPro-A8’-8 1948.2
264. SEQ ID NO：264 Leu Arg Leu Lys Lys Arg Arg Trp Lys Tyr Arg Val DPro-A8’-9 1962.2
265. SEQ ID NO：265 Leu Arg Leu Lys Lys Arg Arg Trp Lys Tyr Arg Val DPro-A8’-10 1976.3
266. SEQ ID NO：266 Leu Arg Leu Lys Lys Arg Arg Trp Lys Tyr Arg Val DPro-A8’-11 1962.2
267. SEQ ID NO：267 Leu Arg Leu Lys Lys Arg Arg Trp Lys Tyr Arg Val DPro-A8’-12 2002.3
268. SEQ ID NO：268 Leu Arg Leu Lys Lys Arg Arg Trp Lys Tyr Arg Val DPro-A8’-13 2016.3
269. SEQ ID NO：269 Leu Arg Leu Lys Lys Arg Arg Trp Lys Tyr Arg Val DPro-A8’-14 1976.3
270. SEQ ID NO：270 Leu Arg Leu Lys Lys Arg Arg Trp Lys Tyr Arg Val DPro-A8’-15 1996.2
271. SEQ ID NO：271 Leu Arg Leu Lys Lys Arg Arg Trp Lys Tyr Arg Val DPro-A8’-16 2011.4
272. SEQ ID NO：272 Leu Arg Leu Lys Lys Arg Arg Trp Lys Tyr Arg Val DPrp-A8’-17 2049.3
273. SEQ ID NO：273 Leu Arg Leu Lys Lys Arg Arg Trp Lys Tyr Arg Val DPro-A8’-18 2063.4
274. SEQ ID NO：274 Leu Arg Leu Lys Lys Arg Arg Trp Lys Tyr Arg Val DPro-A8’-19 2072.3
275. SEQ ID NO：275 Leu Arg Leu Lys Lys Arg Arg Trp Lys Tyr Arg Val DPro-A8’-20 2046.4
276. SEQ ID NO：276 Leu Arg Leu Lys Lys Gly Arg Trp Lys Tyr Arg Val DProLPro 1779.2
277. SEQ ID NO：277 Leu Arg Leu Lys Lys Arg Arg Trp Lys Tyr Arg Val (c1)-1 2023.2
278. SEQID NO：278 Leu Tyr Leu Lys Lys Arg Arg rrp Lys Tyr Tyr Val DProLPro 1892.3
279. SEQ ID NO：279 Leu Trp Leu Lys Lys Arg Arg Trp Lys Tyr Tyr Val DProLPro 1915.4
280. SEQ ID NO：280 Atg Trp Leu Lys Lys Arg Arg Trp Lys Tyr Trp Val DProLPro 1981.4
281. SEQ ID NO：281 Arg Trp Leu Lys Lys Arg Arg Trp Lys Tyr Tyr Val DProLPro 1958.4
282. SEQ ID NO：282 Leu Trp Leu Lys Lys Arg Arg Trp Lys Tyr Tyr Arg DProLPro 1995.5
283. SEQ ID NO：283 Leu Trp Leu Lys Lys Arg Arg Trp Lys Tyr Tyr Arg DProLPro 1972.4
284. SEQ ID NO：284 Arg Trp Leu Lys Lys Arg Arg Trp Lys Tyr Tyr Arg DProLPro 2015.5
285. SEQ ID NO：285 Leu Arg Leu Lys Lys Y(Bzl) Arg Trp Lys Tyr Arg Val DProLPro 1975.5
286. SEQ ID NO：286 Leu Arg Leu Lys Lys DY(Bzl) Arg Trp Lys Tyr Arg Val DProLPro 1975.5
Table 7 (next): example 287-300(n ═ 12)
All products were purified by preparative HPLC-chromatography. The purity is more than 90 percent.
Examples Sequence of P1 P2 P3 P4 P5 P6 P7 P8 P9 P10 P11 P12 Form panel MS
287. SEQ ID NO：287 Bip Trp Leu Lys Lys Arg Arg Trp Lys Tyr Tyr Arg DProLPro 2082.6
288. SEQ ID NO：288 Thr Trp Leu Lys Lys Arg Arg Trp Lys Tyr Tyr Arg DProLPro 1960.4
289. SEQ ID NO：289 Arg Bip Leu Lys Lys Arg Arg Trp Lys Tyr Tyr Arg DProLPro 2052.5
290. SEQ ID NO：290 Arg Thr Leu Lys Lys Arg Arg Trp Lys Tyr Tyr Arg DProLPro 1930.4
291. SEQ ID NO：291 Arg Trp Thr Lys Lys Arg Arg Trp Lys Tyr Tyr Arg DProLPro 2003.4
292. SEQ ID NO：292 Arg Trp Leu Arg Lys Arg Arg Trp Lys Tyr Tyr Arg DProLPro 2043.5
293. SEQ ID NO：293 Arg Trp Leu Gln Lys Arg Arg Trp Lys Tyr Tyr Arg DProLPro 2015.4
294. SEQ ID NO：294 Lys Trp Leu Lys Lys Arg Arg Trp Lys Tyr Tyr Arg DProLPro 1987.5
295. SEQ ID NO：295 Tyr Trp Leu Lys Lys Arg Arg Trp Lys Tyr Tyr Arg DPrpLPro 2022.5
296. SEQ ID NO：296 Trp Trp Leu Lys Lys Arg Arg Trp Lys Tyr Tyr Arg DPrpLPro 2045.5
297. SEQ ID NO：297 Val Trp Leu Lys Lys Arg Arg Trp Lys Tyr Tyr Arg DProLPro 2082.4
298. SEQ ID NO：298 Gln Trp Leu Lys Lys Arg Arg Trp Lys Tyr Tyr Arg DProLPro 1987.4
299. SEQ ID NO：299 Cha Trp Leu Lys Lys Arg Arg Trp Lys Tyr Tyr Arg DProLPro 2012.5
300. SEQ ID NO：300 Y(bzl) Trp Leu Lys Lys Arg Arg Trp Lys Tyr Tyr Arg DProLPro 2112.6
1.2 step 2
Example 256-275 was also synthesized using step 2.
Peptide synthesis was performed by solid phase method using standard Fmoc chemistry on a peptide synthesizer-ABI 433A.
The first amino acid, Fmoc-Arg (Pbf) -OH (1.29g, 1.2 equiv.) was reacted with 2-chlorotrityl chloride resin (Barlos et al Tetrahedron Lett.1989, 30, 3943-3946) (2g, 0.83mmol/g) in CH with DIEA (1.12mL, 4 equiv.)2Cl2Coupling was carried out (20mL) while stirring at room temperature for 3 hours. Then using 3 XCH2Cl2/MeOH/DIEA(17∶2∶1)、3×CH2Cl2、2×DMF、2×CH2Cl2The resin was washed 2 XMeOH. Finally, the resin was dried under vacuum and the substitution level was determined by weight gain (-0.6 mmol/g).
The resin carrying the synthetic linear peptide, Fmoc-Arg (Pbf) -Trp (Boc) -Lys (Boc) -Tyr (tBu) -Arg (Pbf) -Val-DPro-212-Leu-Arg (Pbf) -Leu-Lys (Boc) -Arg (Pbf) -resin, preferably divided into aliquots and placed in different reaction vessels to perform the acylation reaction in a parallel fashion. The coupling and deprotection reactions in the following steps were monitored by Kaiser's test (Kaiser et al anal. biochemistry 1970, 43, 595). Removal of Alloc protecting groups:
to a linear peptide resin (100 mg per reaction vessel) was added Pd (PPh) under argon3)4(15mg, 0.5 eq.) followed by addition to CH2Cl2(10mL) and phenylsilane (17. mu.L, 30 equiv.). The reaction mixture was left in the dark for 1 hour, filtered and the resin was washed with CH2Cl2DMF and CH2Cl2Washing is carried out for 2 times.
Acylation of 4-amino-proline groups
To this resin is added the corresponding acylating agent (often a carboxylic acid (R)64’COOH, 3 equivalents), HBTU (22.3mg, 4 equivalents), HOBt (8mg, 4 equivalents) and DIEA (125. mu.L, 6 equivalents) in DMF (2mL) at room temperature for 1.5-2 hours. Putting treesFiltering with 2 XDMF and 3 XCH2Cl2And 2 xDMF.
Deprotection of the Na-Fmoc group:
deprotection of the Fmoc-group was accomplished by treating the resin with 20% piperidine in DMF for 20 min. The resin was then filtered and washed with DMF and CH 2Cl2Washing 3 times with DMF and CH2Cl2Washing is carried out for 2 times.
Cleavage of the peptide from the resin:
using AcOH: TFE: CH at room temperature2Cl2(2: 6, v/v/v) cleaving the linear side chain protected peptide from the resin for 2 hours. The resin was filtered off and washed 2 times with a mixture of AcOH: TFE: DCM, with CH2Cl2Washing is carried out for 1 time. The filtrate was then diluted with hexane (14 volumes) and concentrated. The evaporation was repeated 2 times with hexane to remove traces of AcOH. The residue was dried under vacuum. The yield of the linear protected peptide is typically about 40-50 mg.
Cyclization of the linearly protected peptide:
cyclization was performed in DMF at a concentration of 5mg/mL using HATU (13.12mg, 3 equiv.), HOAT (4.7mg, 3 equiv.), DIEA (153. mu.L, 6 equiv.). The reaction mixture was stirred at room temperature for 16 hours and the completion of the reaction was monitored by HPLC. After evaporation of DMF, CH was added to the residue3CN/H2O (90/10, v/v) and extracting the residue with DCM. The organic layer was washed 1 time with water and evaporated to dryness. And (5) drying in vacuum.
Cleavage of side chain protecting groups:
TFA, triisopropylsilane, H at room temperature2O (95: 2.5, v/v/v) the peptide was treated for 3 hours for final deprotection of the side chain protecting groups. TFA was then evaporated and the residue triturated with cold ether.
And (3) purification:
The crude peptide thus obtained was subjected to HPLC on a VYDAC C18 preparative column for 30 min using 5-60% CH3CN/H2O + 0.1% TFA asAnalysis and purification were performed for gradients at a flow rate of 10 ml/min. The purity of the final peptide was checked by analytical HPLC and by ESI-MS. The analytical data are shown in Table 7.
1.3. Step 3
Step 3 describes the synthesis of peptides with disulfide β -chain linkages.
a) n is 8: the synthesis of these peptides was started according to step 1 by coupling the amino acid to the resin at position P4. These linear peptides were synthesized on a solid support according to step 1 in the following order: P5-P6-P7-P8-DPro-Pro-P1-P2-P3-P4-resin with Fmoc-Cys (Acm) OH or Fmoc-hCys (Acm) OH inserted at positions P2 and P7. These linear peptides were cleaved and cyclized as described in step 1. The cyclized side chain-protected β -hairpin mimetic was dissolved in methanol (0.5ml) and a solution of iodine in methanol (1N, 1.5 equivalents) was added dropwise thereto at room temperature. The reaction mixture was stirred at room temperature for 4 hours and the solvent was evaporated. The crude product was then deprotected and purified as described in step 1.
b) n is 9: the synthesis of these peptides was started according to step 1 by coupling the amino acid to the resin at position P5. These linear peptides were synthesized on a solid support according to step 1 in the following order: P6-P7-P8-P9- DPro-Pro-P1-P2-P3-P4-P5-resin with Fmoc-Cys (Acm) OH or Fmoc-hCys (Acm) OH inserted at positions P2 and P8. These linear peptides were cleaved and cyclized as described in step 1. The cyclized side chain-protected β -hairpin mimetic was dissolved in methanol (0.5ml) and a solution of iodine in methanol (1N, 1.5 equivalents) was added dropwise thereto at room temperature. The reaction mixture was stirred at room temperature for 4 hours and the solvent was evaporated. The crude product was then deprotected and purified as described in step 1.
c) n is 10: the synthesis of these peptides was started according to step 1 by coupling the amino acid to the resin at position P5. These linear peptides were synthesized on a solid support according to step 1 in the following order: P6-P7-P8-P9-P10-DPro-Pro-P1-P2-P3-P4-P5-resin with Fmoc-Cys (Acm) OH or Fmoc-hCys (Acm) OH inserted at positions P3 and P8. These linear peptides were cleaved and cyclized as described in step 1. Solubilizing the cyclized side chain protected β -hairpin mimeticsIn methanol (0.5ml), a solution of iodine in methanol (1N, 1.5 equiv.) was added dropwise thereto at room temperature. The reaction mixture was stirred at room temperature for 4 hours and the solvent was evaporated. The crude product was then deprotected and purified as described in step 1.
d) n is 11: the synthesis of these peptides was started according to step 1 by coupling the amino acid to the resin at position P5. These linear peptides were synthesized on a solid support according to step 1 in the following order: P6-P7-P8-P9-P10-P11- DPro-Pro-P1-P2-P3-P4-P5-resin, or P6-P7-P8-P9-P10-P11-DPro-Pro-P1-P2-P3-P4, or P5-P6-P7-P8-P9-P10-P11DPro-Pro-P1-P2-P3-P4-P5-resin, wherein Fmoc-Cys (Acm) OH or Fmoc-hCys (Acm) OH is inserted at positions P2, P4, P8 and P10. These linear peptides were cleaved and cyclized as described in step 1. The cyclized side chain-protected β -hairpin mimetic was dissolved in methanol (0.5ml) and a solution of iodine in methanol (1N, 1.5 equivalents) was added dropwise thereto at room temperature. The reaction mixture was stirred at room temperature for 4 hours and the solvent was evaporated. The crude product was then deprotected and purified as described in step 1.
e) n is 12: the synthesis of these peptides was started according to step 1 by coupling the amino acid to the resin at position P6. These linear peptides were synthesized on a solid support according to step 1 in the following order: P7-P8-P9-P10-P11-P12-DPro-Pro-P1-P2-P3-P4-P5-P6 resin, or P7-P8-P9-P10-P11-DPro-Pro-P1-P2-P3-P4-P5-P6 resin, or P7-P8-P9-P10-P11-DPro-Pro-P1-P2-P3-P4-P5-P6-resin, wherein Fmoc-Cys (Acm) OH or Fmoc-hCys (Acm) OH is inserted at positions P2, P4, P9 and P11. These linear peptides were cleaved and cyclized as described in step 1. The cyclized side chain-protected β -hairpin mimetic was dissolved in methanol (0.5ml) and a solution of iodine in methanol (1N, 1.5 equivalents) was added dropwise thereto at room temperature. The reaction mixture was stirred at room temperature for 4 hours and the solvent was evaporated. The crude product was then deprotected and purified as described in step 1.
Example 301:
synthesis of NH on resin according to step 32Arg(Pbf)-Lys(Boc)-Lys(Boc)-Cys(Acm)-Arg(Pbf)-Leu-Pro-DPro-Val-Arg-Cys(Acm)-Lys(Boc)-Trp(Boc)-Arg(Pbf)-[SEQ IDNO：301]Coupled to a resin, cleaving and cyclizing the linear side chain protected peptide, followed by disulfide formation, deprotection, and preparative HPLC chromatography to afford the above product [ SEQ id no: 302]It is a white amorphous powder. ESI-MS: 1806.2([ M + H)]+)。
f) n is 14: the synthesis of these peptides was started according to step 1 by coupling the amino acid to the resin at position P7. These linear peptides were synthesized on a solid support according to step 1 in the following order: P8-P9-P10-P11-P12-P13-P14-DPro-Pro-P1-P2-P3-P4-P5-P6-P7-resin, or P8-P9-P10-P11-P12-P13-P14-DPro-Pro-P1-P2-P3-P4-P5-P6-P7-resin, or P8-P9-P10-P11-P12-P14-DPro-Pro-P1-P2-P3-P4-P5-P6-P7-resin, wherein Fmoc-Cys (Acm) OH or Fmoc-hCys (Acm) OH is inserted at positions P3, P5, P10 and P12. These linear peptides were cleaved and cyclized as described in step 1. The cyclized side chain-protected β -hairpin mimetic was dissolved in methanol (0.5ml) and a solution of iodine in methanol (1N, 1.5 equivalents) was added dropwise thereto at room temperature. The reaction mixture was stirred at room temperature for 4 hours and the solvent was evaporated. The crude product was then deprotected and purified as described in step 1.
g) n is 16: the synthesis of these peptides was started according to step 1 by coupling the amino acid to the resin at position P8. These linear peptides were synthesized on a solid support according to step 1 in the following order: P9-P10-P11-P12-P13-P14-P15-P16- DPro-Pro-P1-P2-P3-P4-P5-P6-P7-P8-resin, or P9-P10-P11-P12-P13-P14-P15-P16-DPro-Pro-P1-P2-P3-P4-P5-P6-P7-P8-resin, or P9-P10-P11-P12-P13-P14-P15-P16-DPro-Pro-P1-P2-P3-P4-P5-P6-P7-P8-resin, or P9-P10-P11-P12-P13-P14-P15-P16-DPro-Pro-P1-P2-P3-P4-P5-P6-P7-P8-resin, or P9-P10-P11-P12-P13-P14-P15-P16-DPro-Pro-P1-P2-P3-P4-P5-P6-P7-P8-resin, or P9-P10-P11-P12-P13-P14-P15-P16-DPro-Pro-P1-P2-P3-P4-P5-P6-P7-P8-resin, or P9-P10-P11-P12-P13-P14-P15-P16-DPro-Pro-P1-P2-P3-P4-P5-P6-P7-P8-resin, wherein Fmoc-Cys (Acm) OH or Fmoc-hCys (Acm) OH is inserted at positions P2, P4, P6, P11, P13 and P15. These linear peptides were cleaved and cyclized as described in step 1. The cyclized side chain-protected β -hairpin mimetic was dissolved in methanol (0.5ml) and a solution of iodine in methanol (1N, 1.5 equivalents) was added dropwise thereto at room temperature. The reaction mixture was stirred at room temperature for 4 hours and the solvent was evaporated. The crude product was then deprotected and purified as described in step 1.
1.4. Step 4
Step 4 describes the synthesis of peptides with amide β -chain linkages.
a) n is 8: the synthesis of these peptides was started according to step 1 by coupling the amino acid to the resin at position P4. These linear peptides were synthesized on a solid support according to step 1 in the following order: P5-P6-P7-P8- DPro-Pro-P1-P2-P3-P4-resin with Fmoc-Asp (O allyl) OH or Fmoc-Glu (O allyl) OH inserted at position P2 and Fmoc-Orn (alloc) OH or Fmoc-Lys (alloc) OH inserted at position P7. Alternatively, Fmoc-Orn (alloc) OH or Fmoc-Lys (alloc) OH is inserted at position P2 and Fmoc-Asp (Oallyl) OH or Fmoc-Glu (Oallyl) OH is inserted at position P7. These linear peptides were cleaved and cyclized and the allyl groups were removed as described in step 2. Cyclization as described in steps 1 and 2 followed by amide bonding, removal of these side chain protecting groups and purification of the product as described in steps 1 and 2.
b) n is 9: the synthesis of these peptides was started according to step 1 by coupling the amino acid to the resin at position P5. These linear peptides were synthesized on a solid support according to step 1 in the following order: P6-P7-P8-P9-DPro-Pro-P1-P2-P3-P4-P5-resin in which Fmoc-Asp (O allyl) OH or Fmoc-Glu (O allyl) OH is inserted at position P2 and Fmoc-Orn (alloc) OH or Fmoc-Lys (alloc) OH is inserted at position P8. Alternatively, Fmoc-Orn (alloc) OH or Fmoc-Lys (alloc) OH is inserted at position P2 and Fmoc-Asp (Oallyl) OH or Fmoc-Glu (Oallyl) OH is inserted at position P8. These linear peptides were cleaved and cyclized and the allyl groups were removed as described in step 2. Cyclisation as described in Steps 1 and 2 Amide linkages were then performed, these side chain protecting groups were removed and the product was purified as described in steps 1 and 2.
c) n is 10: the synthesis of these peptides was started according to step 1 by coupling the amino acid to the resin at position P5. These linear peptides were synthesized on a solid support according to step 1 in the following order: P6-P7-P8-P9-P10-DPro-Pro-P1-P2-P3-P4-P5-resin in which Fmoc-Asp (O allyl) OH or Fmoc-Glu (O allyl) OH is inserted at position P3 and Fmoc-Orn (alloc) OH or Fmoc-Lys (alloc) OH is inserted at position P8. Alternatively, Fmoc-Orn (alloc) OH or Fmoc-Lys (alloc) OH is inserted at position P3 and Fmoc-Asp (Oallyl) OH or Fmoc-Glu (Oallyl) OH is inserted at position P8. These linear peptides were cleaved and cyclized and the allyl groups were removed as described in step 2. Cyclization as described in steps 1 and 2 followed by amide bonding, removal of these side chain protecting groups and purification of the product as described in steps 1 and 2.
d) n is 11: the synthesis of these peptides was started according to step 1 by coupling the amino acid to the resin at position P5. These linear peptides were synthesized on a solid support according to step 1 in the following order: P6-P7-P8-P9-P10-P11-DPro-Pro-P1-P2-P3-P4-P5-resin, or P6-P7-P8-P9-P10-P11- DPro-Pro-P1-P2-P3-P4-P5-resin, or P6-P7-P8-P9-P10-P11-DPro-Pro-P1-P2-P3-P4-P5-resin; wherein Fmoc-Asp (O allyl) OH or Fmoc-Glu (O allyl) OH is inserted at position P2 and/or P4 and Fmoc-Orn (alloc) OH or Fmoc-Lys (alloc) OH is inserted at position P8 and/or P10. Alternatively, Fmoc-Orn (alloc) OH or Fmoc-Lys (alloc) OH is inserted at position P2 and/or P4 and Fmoc-Asp (O allyl) OH or Fmoc-Glu (O allyl) OH is inserted at position P8 and/or P10. These linear peptides were cleaved and cyclized and the allyl groups were removed as described in step 2. Cyclization as described in steps 1 and 2 followed by amide bonding, removal of these side chain protecting groups and purification of the product as described in steps 1 and 2.
e) n is 12: the synthesis of these peptides was started according to step 1 by coupling the amino acid to the resin at position P6. These linear peptides were synthesized on a solid support according to step 1 in the following order: P7-P8-P9-P10-P11-P12-DPro-Pro-P1-P2-P3-P4-P5-P6 resin, or P7-P8-P9-P10-P11-P12-DPro-Pro-P1-P2-P3-P4-P5-P6 resin, or P7-P8-P9-P10-P11-P12-DPro-Pro-P1-P2-P3-P4-P5-P6 resin; wherein Fmoc-Asp (O allyl) OH or Fmoc-Glu (O allyl) OH is inserted at position P2 and/or P4 and Fmoc-Orn (alloc) OH or Fmoc-Lys (alloc) OH is inserted at position P9 and/or P11. Alternatively, Fmoc-Orn (alloc) OH or Fmoc-Lys (alloc) OH is inserted at position P2 and/or P4 and Fmoc-Asp (O allyl) OH or Fmoc-Glu (O allyl) OH is inserted at position P9 and/or P11. These linear peptides were cleaved and cyclized and the allyl groups were removed as described in step 2. Cyclization as described in steps 1 and 2 followed by amide bonding, removal of these side chain protecting groups and purification of the product as described in steps 1 and 2.
f) n is 14: the synthesis of these peptides was started according to step 1 by coupling the amino acid to the resin at position P7. These linear peptides were synthesized on a solid support according to step 1 in the following order: P8-P9-P10-P11-P12-P3-P14-DPro-Pro-P1-P2-P3-P4-P5-P6-P7-resin, or P8-P9-Pl0-P11-P12-P13-P14-DPro-Pro-P1-P2-P3-P4-P5-P6-P7-resin, or P8-P9-P10-P11-P12-R14-DPro-Pro-P1-P2-P3-P4-P5-P6-P7-resin; wherein Fmoc-Asp (O allyl) OH or Fmoc-Glu (O allyl) OH is inserted at position P3 and/or P5 and Fmoc-Orn (alloc) OH or Fmoc-Lys (alloc) OH is inserted at position P10 and/or P12. Alternatively, Fmoc-Orn (alloc) OH or Fmoc-Lys (alloc) OH is inserted at position P3 and/or P5 and Fmoc-Asp (O allyl) OH or Fmoc-Glu (O allyl) OH is inserted at position P10 and/or P12. These linear peptides were cleaved and cyclized and the allyl groups were removed as described in step 2. Cyclization as described in steps 1 and 2 followed by amide bonding, removal of these side chain protecting groups and purification of the product as described in steps 1 and 2.
g) n is 16: the synthesis of these peptides was started according to step 1 by coupling the amino acid to the resin at position P7. These linear peptides were synthesized on a solid support according to step 1 in the following order: P8-P9-P10-P11-P12-P13-P14-P15-P16- DPro-Pro-P1-P2-P3-P4-P5-P6-P7-resin, or P8-P9-P10-P11-P12-P13-P14-P15-P16-DPro-Pro-P1-P2-P3-P4-P5-P6-P7-resin, or P9-P9-P10-P11-P12-P4-P5-P16-DPro-Pro-P1-P2-P3-P4-P5-P6-P7-resin, or P8-P9-P10-P11-P12-P13-P14-P15-P16-DPro-Pro-P1-P2-P3-P4-P5-P6-P7-resin, or P8-P9-P10-P11-P12-P13-P14-P15-P16-DPro-Pro-P1-P2-P3-P4-P5-P6-P7-resin, or P8-P9-P10-P11-P12-P13-P14-P15-P16-DPro-Pro-P1-P2-P3-P4-P5-P6-P7-resin, or P8-P9-P10-P11-P12-P13-P14-P15-P16-DPro-Pro-P1-P2-P3-P4-P5-P6-P7-resin; wherein Fmoc-Asp (O allyl) OH or Fmoc-Glu (O allyl) OH is inserted at positions P2 and/or P4 and/or P6 and Fmoc-Orn (alloc) OH or Fmoc-Lys (alloc) OH is inserted at positions P11 and/or P13 and/or P15. Alternatively, Fmoc-Orn (alloc) OH or Fmoc-Lys (alloc) OH is inserted at positions P2 and/or P4 and/or P6, and Fmoc-Asp (Oallyl) OH or Fmoc-Glu (Oallyl) OH is inserted at positions P11 and/or P13 and/or P15. These linear peptides were cleaved and cyclized and the allyl groups were removed as described in step 2. Cyclization as described in steps 1 and 2 followed by amide bonding, removal of these side chain protecting groups and purification of the product as described in steps 1 and 2.
Example 302:
preparation of NH according to step 22Arg(Pbf)-Trp(Boc)-Lys(Boc)-Tyr(tBu)-Arg(Pbf)-DPro-212-Leu-Arg(Pbf)-Leu-Lys(Boc)-Lys(Boc)-Arg(Pbf)-[SEQ ID NO：303]It is coupled to a resin to cleave and cyclize the linear peptide.
The Alloc-group is removed from building block 212 as described in step 2, the resulting amine half is reacted with excess pyridine and glutaric anhydride in DMAP and the solvent is removed. The resulting acid was coupled with the other half of the amine mentioned above in DMF and in the presence of TATU, HOAt and DIEA. These protecting groups were removed as described in step 2 and the product was purified by preparative HPLC chromatography as described in step 2 to give the above product [ SEQ ID NO: 304]It is a white amorphous powder. ESI-MS: 3882.3([ M + H)]+)。
2. Synthesis of the template
The synthesis of (2S, 4S) -4- [ (allyloxy) carbonylamino ] -1- [ (9H-fluoren-9-yl) methoxycarbonyl ] -proline (212) and (2S, 4R) -4- [ (allyloxy) carbonylamino ] -1- [ (9H-fluoren-9-yl) methoxy-carbonyl ] proline (217) is shown in schemes 42 and 43.
Scheme 42
i：SOCl2，MeOH；ii：Boc2O，DMAP，Et3N；iii：pNO2C6H4SO2Cl，Et3N；iv：NaN3，DMF；v：SnCl2dioxane/H2O；vi：ClCOOCH2CH＝CH2，aq.NaHCO3Dioxane vii: LiOH, MeOH, H2O；viii：TFA，CH2Cl2；ix：Fmoc-OSu，DIEA
(2S, 4S) -4- [ (allyloxy) carbonylamino ] -1- [ (9H-fluoren-9-yl) methoxycarbonyl ] -proline (212)
i, ii: thionyl chloride (38ml, 2.5 equiv., 0.45mol) was added dropwise to a solution of (2S, 4R) -4-hydroxyproline (30g, 0.18mol) in pure methanol (300ml) at 0 ℃. The solution was heated to reflux and stirred under nitrogen for 3 hours. The solution was then concentrated by rotary evaporation and the ester was precipitated by addition of diethyl ether. After filtration the white solid is washed with diethyl ether and then dried under HV: (2S, 4R) -4-hydroxyproline-methyl ester hydrochloride as a white solid (29.9g, 90%). TLC (CH) 2Cl2MeOH/water 70: 28: 2): rf0.82.[α]D 20＝-24.5(c＝1.01，MeOH)。IR(KBr)：3378s(br.)，2950m，2863w，1745s，1700s，1590m，1450s，1415s，1360s，1215s，1185s，1080m，700m。1H-NMR(300MHz，MeOH-d4)4.66-4.55(mm，2H，H-C(4)，H-C(2))；3.85(s，3H，H3C-O)；3.45(dd，J＝12.2，3.8，1H，H-C(5))；3.37-3.25(m，1H，H-C(5))；2.44-2.34(m，1H，H-C(3))，2.27-2.12(m，1H，H-C(3))。13C-NMR(75MHz，MeOH-d4)：170.8(s，COOMe)；70.8(d，C(4))；59.6(d，C(2))；55.2(t，C(5))；54.2(q，Me)；38.7(t，C(3))。CI-MS(NH3)：146.1([M-Cl]+)。
30g (0.17mmol) of the above intermediate were dissolved in CH2Cl2(300ml), cooled to 0 ℃ and triethylamine (45ml, 1.5 eq, 0.25mol) was added dropwise. Di-tert-butyldicarbonate (54.0g, 1.5 eq, 0.25mmol) was then added as CH2Cl2(15ml) and 4-N, N-dimethylaminopyridine (2.50g, 0.1 eq, 17 mmol). The solution was stirred at room temperature overnight. The solution was then treated with 1N aqueous citric acid, saturated NaHCO3Washed with an aqueous solution and dried (Na)2SO4) The residue was evaporated and dried under high vacuum: (2S, 4R) -4-hydroxy-1- [ (tert-butoxy) carbonyl]Proline-methyl ester (209) as a white solid (39.6g, 78%). TLC (CH)2Cl2/MeOH 9∶1)：Rf 0.55.[α]D 24＝-55.9(c＝0.983，CHCl3)。IR(KBr)：3615w，3440w(br.)，2980m，2950m，2880m，1750s，1705s，1680s，1480m，1410s，1370s，1340m，1200s，1160s，1130m，1090m，1055w，960w，915w，895w，855m，715m.1H-NMR(300MHz，CDCl3)：4.47-4.37(m，2H，H-C(4)，H-C(2))；3.73(s，3H，H3C-O))；3.62(dd，J＝11.8，4.1，1H，H-C(5))；3.54-3.44(m，1H，H-C(5))；2.32-2.25(m，1H，H-C(3))；2.10-2.03(m，1H，H-C(3))；1.46+1.41(2s， 9H，tBu)。13C-NMR(75MHz，CDCl3)：173.6(s，COOMe)；154.3+153.9(2s，COOtBu)；80.3(s，C-tBu)；70.0+69.3(2d，C(4))；57.9+57.4(2d，C(2))；54.6(t，C(5))；51.9(q，Me)；39.0+38.4(2t，C(3))；28.1+27.6(2q，tBu)。CI-MS：246.2([M+H]+)；190.1([M-tBu+H]+)；146.1([M-BOC+H]+)。
iii, iv: 39g (0.16mol) of 209 were dissolved in CH at 0 DEG C2Cl2(300ml), followed by the addition of 4-nitrobenzenesulfonyl chloride (46g, 1.3 eq, 0.21mol) and Et3N (33ml, 1.5 eq, 0.24 mol). The solution was then stirred overnight and gradually warmed to room temperature with 1N hydrochloric acid, saturated NaHCO3Washed with aqueous solution and dried (Na)2SO4). The solvent was evaporated and the crude product was purified on silica gel with (2: 1) hexane/AcOEt by filtration. The product was crystallized from hexane/AcOEt: (2S, 4S) -4- [ (p-nitrobenzyl) sulfonyloxy]-1- [ (tert-butoxy) carbonyl ]Proline methyl ester as white crystals (46.4g, 65%). TLC (Hexane/AcOEt 1: 1): rf 0.78.M.p.：93-95℃.[α]D 20＝-32.3°(c＝0.907，CHCl3)。IR(KBr)：3110w，3071w，2971w，1745s，1696s，1609s，1532s，1414s，1365s，1348m，1289n，1190m，1173m，1122s，1097w，1043w，954w，912w，755w，578w，1H-NMR(600MHz，CDCl3)：8.42-8.34(m，2H，H-C(Nos))；8.11-8.04(m，2H，H-C(Nos))；5.14(s，1H，H-C(4))；4.39-4.28(m，1H，H-C(2))；3.70-3.56(m，5H，H2-C(5)，H3C-O)；2.58-2.38(m，1H，H-C(3))；2.25-2.11(m，1H，H-C(3))；1.37+1.33(2s，9H，tBu)。13C-NMR(150MHz，CDCl3)：172.4+172.2(2s，COOMe)；153.6+153.0(2s，COOtBu)；150.8+142.0(2s，C(Nos))；129.0+124.6(2d，C(Nos))；80.4(s，C-tBu)；80.8+79.9(2d，C(4))；57.1+56.9(2d，C(2))；52.2+51.7(2t，C(5))；52.3(q，Me)；37.1+35.9(2t，C(3))；28.0(q，tBu)。ESI-MS(MeOH+NaI)：453.0([M+Na]+)。
38g (88mmol) of the above intermediate was dissolved in DMF (450ml) and then heated to 40 ℃ whereupon sodium azide (34g, 6 equivalents, 0.53mol) was added and the solution stirred overnight. DMF was evaporated and the solid was suspended in diethyl ether. The suspension was washed with water and dried (Na)2SO4). The solvent was evaporated and the product was dried under high vacuum: (2S, 4S) -4-azido-1- [ (tert-butoxy) carbonyl]Proline methyl ester (210) yellow oil (21.1g, 88%). [ alpha ] to]D 20＝-36.9(c＝0.965，CHCl3)。1H-NMR(600MHz，CDCl3)：4.46-4.25(2m，1H，H-C(2))；4.20-4.10(m，1H，H-C(4))；3.80-3.65(m，4H，H-C(5)，H3C-O)；3.53-3.41(m，1H，H-C(5))；2.54-2.39(m，1H，H-C(3))；2.21-2.12(m，1H，H-C(3))；1.47+1.41(2s，9H，tBu)。13C-NMR(150MHz，CDCl3)：172.2+171.9(2s，COOMe)；153.9+153.4(2s，COOtBu)；80.5(s，C-tBu)；59.2+58.2(2d，C(4))；57.7+57.3(2d，C(2))；52.4+52.2(2q，Me)；51.2+50.7(2t，C(5))；36.0+35.0(2t，C(3))；28.3+28.2(2q，tBu)。EI-MS(70ev)：270.1([M]+)；227.1([M-CO2+H]+)；169.1([M-BOC+H]+)。
v, vi: 21.1g (78mmol) of the above intermediate was dissolved in a (3: 1) -dioxane/water mixture (500ml) at 0 ℃ and SnCl was added2(59.2g, 4 equivalents, 0.31mol), the solution was stirred for 30 minutes and gradually warmed to room temperature and stirred for an additional 5 hours. With solid NaHCO3After adjusting its pH to 8, allyl chloroformate (41.5ml, 5 equivalents, 0.39mol) was added, and the solution was stirred at room temperature overnight. The reaction mixture was evaporated and extracted with AcOEt. The organic phase was washed with brine and dried (Na)2SO4) The solvent was evaporated and the product was dried under high vacuum: (2S, 4S) -4- [ (allyloxy) carbonylamino group]-1- [ (tert-butoxy) carbonyl]Proline methyl ester (211) as clear thick oil (22.3g, 87%). [ alpha ] to ]D 20＝-30.2°(c＝1.25，CHCl3)。1H-NMR(300MHz，CDCl3)：5.98-5.77(m，1H，H-C(β)(Alloc))；5.32-5.12(m，2H，H2-C(γ)(Alloc)；4.59-4.46(m，2H，H2-C(α)(Alloc))；4.40-4.16(m，2H，H-C(4)，H-C(2))；3.80-3.53(m，4H，H-C(5)，H3C-O)；3.53-3.31(m，1H，H-C(5))；2.54-2.17(m，1H，H-C(3))；1.98-1.84(m，1H，H-C(3))；1.41+1.37(2s，9H，tBu)。ESI-MS(MeOH+CH2Cl2)：351.2([M+Na]+)；229.0([M-BOC+H]+)。
vii-ix: 22g, 67mmol) of 211 are dissolved in a (4: 1) -methanol/water mixture (100ml) and LiOH (5g, 2 equiv., 134mmol) is added at room temperature and the solution is filteredThe solution was stirred for 3.5 hours. The reaction mixture was evaporated and extracted with 1N hydrochloric acid (100ml) and AcOEt. The solvent was removed and the resulting solid was dissolved in 1: 1TFA/CH2Cl2(200ml) and stirred for 2 hours. The solvent was evaporated and the product was dried under high vacuum: (2S, 4S) -4- [ (allyloxy) carbonylamino group]Proline as clear oil (21g, 96%)1H-NMR(600MHz，MeOH-d4)：5.98-5.85(m，1H，H-C(β)(Alloc))；5.30(dd，J＝17.1，1.5Hz，1H，H-C(γ)(Alloc))；5.12(d，J＝10.7Hz，1H，H-C(γ)(Alloc))；4.54(d，J＝4.4Hz，2H，H2-C(α)(Alloc))；4.44(t，J＝8.9Hz，1H，H-C(2))；4.36-4.27(m，1H，H-C(4))；3.58(dd，J＝12.2，7.3Hz，1H，H-C(5))；3.34-3.32(m，1H，H-C(5))；2.73(ddd，J＝13.6，8.7，7.2Hz，1H，H-C(3))；2.23-2.15(m，1H，H-C(3))。13C-NMR(150MHz，MeOH-d4): 171.3(s, COOMe); 158.3(s, COO allyl); 134.1(d, C (β) (Alloc)); 118.0(t, C (γ) (Alloc)); 66.8(t, C (α) (Alloc)); 59.7(d, C (2)); 51.3(d, C (4)); 51.1(t, C (5)); 34.9(t, C (3)). ESI-MS (DCM + MeOH): 237.0([ M + Na ]]+)；215.0([M+H]+)。
15g (70mmol) of the above intermediate and 9-fluorenylmethoxycarbonylsuccinimide (28g, 1.2 equiv., 84mmol) were dissolved in DCM (700ml) and DIEA (48ml, 6 equiv., 0.42mol) was added and the solution was stirred at room temperature overnight. The solvent was removed and the residue was dissolved in AcOEt, washed with 1N hydrochloric acid and dried (Na)2SO4). After evaporation, the crude product was purified on silica gel by filtration with a (3: 1) hexane/AcOEt to AcOEt gradient. The solvent was evaporated and the residue was crystallized from hexane at-20 ℃. The product was dried under high vacuum:
(2S, 4S) -4- [ (allyloxy) carbonylamino group]-1- [ (9H-fluoren-9-yl) methoxycarbonyl]-proline (212) as white solid (23.8mg, 78%) [ alpha ]]D 20＝-27.0(c＝1.1，CHCl3)。IR(KBr)：3321w(br.)，3066w，2953w，1707s，1530m，1451s，1422s，1354m，1250m，1205m，1173m，1118m，1033m，977m，936m，759m，739s，621m，597w，571w，545s.1H-NMR (300MHz，MeOH-d4)：7.88-7.78(m，2H，H-C(4‘)(Fmoc))；7.71-7.61(m，2H，H-C(1‘)(Fmoc))；7.49-7.29(m，4H，H-C(3‘)(Fmoc)，H-C(2‘)(Fmoc))；6.08-5.68(m，1H，H-C(β)(Alloc))；5.41-5.17(m，2H，H2-C(γ)(Alloc)；4.58(s，2H，H2-C(α)(Alloc))；4.74-4.17(m，5H，H2-C(10‘)(Fmoc)，H-C(9‘)(Fmoc)，H-C(4)，H-C(2))；3.94-3.73(m，1H，H-C(5))；3.41-3.26(m，1H，H-C(5))；2.74-2.54(m，1H，H-C(3))；2.12-1.92(m，1H，H-C(3))。ESI-MS(DCM+MeOH)：459.3([M+Na]+)；437.3([M+H]+)。
Scheme 43
i：Ac2O，AcOH；ii：SOCl2，MeOH；iii:Boc2O，DMAP，Et3N；vi：pNO2C6H4SO2Cl，Et3N；v：NaN3，DMF；vi：SnCl2dioxane/H2O；vii：ClOOCH2CH＝CH2，aq.：NaHCO3And dioxane: viii: LiOH, MeOH, H2O；ix：TFA，CH2Cl2；x：Fmoc-OSu，DIEA
(2R, 4S) -4- [ (allyloxy) carbonylamino ] -1- [ (9H-fluoren-9-yl) methoxycarbonyl ] -proline (217)
i: a solution of acetic anhydride (1.02kg, 5.3eq, 10mol) in glacial acetic acid (3l) was heated to 50 ℃ and a portion of (2S, 4R) -4-hydroxyproline (208) (247g, 1.88mol) was added. The solution was refluxed for 5.5 hours, cooled to room temperature and the solvent was removed under reduced pressure to give a thick oil. The oil was then dissolved in 2N hydrochloric acid (3.5l) and heated to reflux for 4 hours, treated with carbon and filtered through celite. As the solution evaporated, a white needle formed, which was filtered. The product was dried under high vacuum: (2R, 4R) -4-hydroxyproline hydrochloride (213) white crystallized needle (220.9g, 70%). M.p.: at 117 deg.C]D 20+19.3 ° (c-1.04, water). IR (KBr): 3238s3017s, 2569m, 1712s, 1584m, 1376s, 1332m, 1255s, 1204m, 1181w, 1091w, 1066w, 994w, 725m, 499s.1H-NMR(600MHz，MeOH-d4)：9.64(s，1H，H-N)；8.89(s，1H，H-N)；4.55-4.53(m，1H，H-C(4))；4.51(dd，J＝10.4，3.6Hz，1H，H-C(2))；3.44-3.35(m，2H，H2-C(5))；2.54-2.48(m，1H，H-C(3))；2.40-2.34(m，1H，H-C(3))。13C-NMR(150MHz，MeOH-d4)：171.9(s，COOH)；70.3(d，C(4))；59.6(d，C(2))；55.0(t，C(5))；38.5(t，C(3))。EI-MS(NH3)：132.1([M-Cl]+). The filtrate was further concentrated to give an additional 59.5g (19%).
ii, iii: thionyl chloride (38ml, 2.5 equiv., 0.45mol) was added dropwise to a solution of 213(30g, 0.18mol) in pure methanol (550ml) at 0 ℃. The solution was refluxed under nitrogen for 3 hours. The solution was evaporated and the ester hydrochloride was precipitated by addition of diethyl ether. After filtration the white solid was washed with diethyl ether and dried under high vacuum: (2R, 4R) -4-Hydroxyproline methyl ester hydrochloride as a white solid (29g, 89%). [ alpha ] to ]D 20＝+8.6°(c＝0.873，MeOH)。IR(KBr)：3388s(br.)，2980s(br.)，1730s，1634m，1586s，1384s，1248s，1095s，1064s，1030m，877m.1H-NMR(3O0MHz，MeOH-d4)：4.59-4.44(m，2H，H-C(4)，H-C(2))；3.81(s，3H，H3C-O)；3.37-3.31(m，2H，H2-C(5))；2.50-2.37(m，1H，H-C(3))，2.37-2.27(m，1H，H-C(3))。13C-NMR(75MHz，MeOH-d4)：17O.9(s，COOMe)；7O.2(d，C(4))；59.8(d，C(2))；55.1(t，C(5))；))；54.1(q，C(Me))；38.4(t，C(3))。EI-MS(NH3)：146.1([M-Cl]+)。
10g (55mmol) of the above intermediate were dissolved in CH2Cl2(100ml), cooled to 0 ℃ and triethylamine (15.2ml, 2 eq, 0.11 mol.) is added dropwise followed by di-tert-butyldicarbonate (18.0g, 1.5 eq, 83mmol) in CH2Cl2(10ml) and 4-N, N-dimethylaminopyridine (0.67g, 0.1 eq, 5 mmol). In thatThe solution was stirred at room temperature overnight. The solution was treated with 1M aqueous citric acid and saturated NaHCO3Washed with an aqueous solution and dried (Na)2SO4) The solvent was evaporated and dried under high vacuum: (2R, 4R) -4-hydroxy-1- [ (tert-butoxy) -carbonyl]Proline methyl ester (214) as a white solid (13g, 97%). [ alpha ] to]D 20＝+13.0°(c＝1.06，CHCl3)。IR(KBr)：3466s(br.)，2985s，2930m，1729s，1679s，1424s，1283m，1262m，1122s，1089s，969m，770m.1H-NMR(300MHz，CDCl3)：4.43-4.26(m，2H，H-C(4)，H-C(2))；3.80+3.79(2s，3H，H3C-O))；3.76-3.47(m，2H，H2-C(5))；2.44-2.24(m，1H，H-C(3))；2.16-2.03(m，1H，H-C(3))；1.47+1.43(2s，9H，tBu)。ESI-MS：268.1([M+Na]+)。
iv, v: 214(12.2g, 50mmol) was dissolved in CH2Cl2(130ml), cooled to 0 ℃ and added 4-nitrobenzenesulfonyl chloride (14.3g, 1.3 eq, 65mmol) and Et3N (10.3ml, 1.5 eq, 75 mmol). The reaction mixture was stirred overnight and gradually warmed to room temperature. The solution was treated with 1N hydrochloric acid and saturated NaHCO3Washed with an aqueous solution and dried (Na)2SO4) The solvent was evaporated and the crude product was purified on silica gel by filtration with a mixture of (2: 1) -hexane/AcOEt: 18g (84%). The product was then crystallized from hexane/AcOEt: (2R, 4R) -4- [ (p-nitrobenzyl) sulfonyloxy]-1- [ (tert-butoxy) carbonyl]Proline-methyl ester as white crystals (13.7g, 64%). TLC (Hexane/AcOEt 1: 1): r f0.76.M.p.：113-115℃.[α]D 20＝+21.6°(c＝0.924，CHCl3)。IR(KBr)：3112s(br.)，2981s，2955s，2882m，1755s，1683s，1532s，1413s，1375s，1348s，1192s，928s，911s，759m，745s，610s.1H-NMR(600MHz，CDCl3)：8.45-8.35(m，2H，H-C(Nos))；8.15-8.06(m，2H，H-C(Nos))；5.27-5.16(m，1H，H-C(4))；4.53-4.32(m，1H，H-C(2))；3.75-3.60(m，5H，H2-C(5)，H3C-O)；2.59-2.35(m，2H，H2-C(3))；1.42+1.39(2s，9H，tBu)。13C-NMR(150MHz，CDCl3)：171.8+171.6(s，COOMe)；153.8+153.4(s，COOtBu)；151.0+142.6(s，C(Nos))；129.2+124.7(d，C(Nos))；81.0(s，C-tBu)；80.8+79.7(d，C(4))；57.4+57.1(d，C(2))；52.6+52.5+52.3+51.8(t，C(5)，q，Me)；37.2+36.3(t，C(3))；28.5+28.3(q，tBu)。ESI-MS(DCM+MeOH+NaI)：453.2([M+Na]+)。
13g (30mmol) of the above intermediate was dissolved in DMF (200ml), heated to 40 ℃ and sodium azide (14.3g, 6 equivalents, 180mmol) was added and the reaction mixture was stirred overnight. The reaction mixture was evaporated and the residue was suspended in diethyl ether. The suspension was filtered, the filtrate was washed with water and the organic phase was dried (Na)2SO4). The solvent was evaporated and the product was dried under high vacuum: (2R, 4S) -4-azido-1- [ (tert-butoxy) carbonyl]Proline methyl ester (215) as yellow oil (8.15g, 99%). [ alpha ] to]D 20＝+42.8°(c＝1.05，CHCl3)。1H-NMR(300MHz，CDCl3)：4.58-4.37(m，1H，H-C(2))；4.34-4.23(m，1H，H-C(4))；3.92-3.51(m，5H，H2-C(5)，H3C-O)；2.52-2.33(m，1H，H-C(3))；2.33-2.20(m，1H，H-C(3))；1.56+1.51(2s，9H，tBu)。CI-MS(NH3)：288.2([M+NH4]+)；271.1([M+H]+)。
vi, vii: 215(8g, 30mmol) was dissolved in a mixture of (3: 1) -dioxane/water (400ml), cooled to 0 ℃ and added SnCl2(22.4g, 4 eq, 120mmol), the reaction mixture was stirred at 0 ℃ for 30 minutes, gradually warmed to room temperature and stirred for a further 5 hours. After conditioning with solid NaHCO3The pH of the solution was adjusted to 8 and allyl chloroformate (15.7ml, 5 equivalents, 150mmol) was added. The reaction mixture was stirred at room temperature overnight, evaporated and extracted with AcOEt and the organic phase washed with brine. The organic phase was dried (Na)2SO4) Thereafter, the solvent was evaporated and the product was dried under high vacuum: (2R, 4S) -4- [ (allyloxy) carbonylamino group]-1- [ (tert-butoxy) carbonyl]Proline-methyl ester as clear thick oil (216) (8.7g, 89%). [ alpha ] to ]D 20＝+41.9°(c＝0.928，CHCl3)。1H-NMR(300MHz，CDCl3)：5.98-5.87(m，1H，H-C(β)(Alloc))；5.34-5.02(m，2H，H2-C(γ)(Alloc)；4.62-4.49(m，2H，H2-C(α)(Alloc))；4.41-4.23(m，2H，H-C(4)，H-C(2))；3.82-3.66(m，4H，H-C(5)，H3C-O)；3.43-3.20(m，1H，H-C(5))；2.33-2.07(m，2H，H2-C(3))；1.43+1.39(2s，9H，tBu)。CI-MS(NH3)：329.1([M+H]+)。
vii-x: 216(8.4g, 25mmol) was dissolved in a (4: 1) -methanol/water mixture (100ml) at room temperature, LiOH (2.2g, 2 equiv., 50mmol) was added and the solution was stirred overnight. Methanol was evaporated and the residue poured into 1N hydrochloric acid (100ml) and extracted with AcOEt. The solvent was removed and the residue was dissolved in (1: 1) -TFA/CH2Cl2The mixture (200ml) was stirred for 2 hours. The solvent was evaporated and the product was dried under high vacuum: (2R, 4R) -4- [ (allyloxy) carbonylamino group]Proline as clear oil (5.2g, 96%)1H-NMR(300MHz，MeOH-d4)：6.04-5.88(m，1H，H2-C(β)(Alloc))；5.38-5.19(m，2H，H2-C(γ)(Alloc)；4.64-4.54(m，3H，H2-C(α)(Alloc)，H-C(4))；4.39-4.22(m，1H，H-C(2))；3.71-3.60(m，1H，H-C(5))；3.45-3.32(m，1H，H-C(5))；2.51-2.41(m，2H，H2-C(3))。CI-MS(NH3)：215.1([M+H]+)。
200mg (0.86mmol) of the above intermediate and 9-fluorenylmethoxycarbonylsuccinimide (440mg, 1.5 equiv., 1.3mmol) were dissolved in CH2Cl2(10ml) DIEA (466. mu.l, 4 eq., 3.44mmol) was added and the solution was stirred at room temperature overnight. The solvent was removed and the residue was dissolved in AcOEt, washed with 1N hydrochloric acid and dried (Na)2SO4). After evaporation, the crude product was first purified by filtration on silica gel with a gradient (3: 1) of hexane/AcOEt to AcOEt. Solvent and CH2Cl2Co-evaporation, the product was dried under high vacuum: (2R, 4S) -4- [ (allyloxy) carbonylamino group]-1- [ (9H-fluoren-9-yl) methoxy-carbonyl]Proline (217) as white solid (90mg, 33%) [ alpha ]]D 20＝+29.3°(c＝1.08，CHCl3)。IR(KBr)：3314s(br.)，3066s(br.)，2952s(br.)，1708s(br.)，1536m，1424s，1353s，1126m，1030m，909m，759m，738s，620m.1H-NMR(300MHz，CDCl3)：8.74(s，1H，H-N)；7.79-7.66(m，2H，H-C(4‘)(fmoc))；7.62-7.49(m，2H，H-C(1‘)(fmoc))；7.44-7.22(m，4H，H-C(3‘)(fmoc)，H-C(2‘)(fmoc))；6.03-5.74(m，1H，H-C(β)(Alloc))；5.41-5.07(m，2H，H2-C(γ)(Alloc)；4.74-4.17(m，7H，H2-C(10‘)(fmoc)，H-C(9‘)(fmoc)，H-C(4)，H-C(2)，H2-C(α)(Alloc))；3.91-3.76(m，1H，H-C(5))；3.48-3.25(m，1H，H-C(5))；2.45-2.08(m，2H，H2-C(3))。ES I-MS(MeOH)：437.3([M+H]+)；ESI-MS(MeOH+Na)：459.1([M+Na]+)。
2.3. Starting from derivatives 210 and 215, key precursors 219a-u and 221a-u can be prepared according to scheme 44.
R64: n-hexyl (219a, 221 a); n-heptyl (219b, 221 b); 4- (phenyl) benzyl (219c, 221 c); diphenylmethyl (219d, 221 d); 3-amino-propyl (219e, 221 e); 5-amino-pentyl (219f, 221 f); methyl (219g, 221 g); ethyl (219h, 221 h); isopropyl (219I, 221I); isobutyl (219k, 221 k); n-propyl (219l, 221 l); cyclohexyl (219m, 221 m); cyclohexylmethyl (219n, 221 n); n-butyl (219o, 221 o); phenyl (219p, 221 p); benzyl (219q, 221 q); (3-indolyl) methyl (219r, 221 r); 2- (3-indolyl) ethyl (219s, 221 s); (4-phenyl) phenyl (219t, 221 t); n-nonyl group (219u, 221 u).
Scheme 44
i：SnCl2dioxane/H2O；ii：R64COCl, diisopropylethylamine, CH2Cl2；iii：LiOHx1H2O，MeOH，H2O；iv：TFA，CH2Cl2；v：FmocOSu，Na2CO3Aqueous solution, dioxane
i, ii: the typical steps are as follows:
to a solution of 78mmol of azides 210 and 215 in a (3: 1) -dioxane/water mixture (500ml) at 0 deg.C was added SnCl2(59.2g, 4 eq, 0.31mol), the solution was stirred for 30 minutes. The reaction mixture was gradually warmed to room temperature and stirred for an additional 5 hours. With solid NaHCO3After adjusting the pH to 8, the reaction mixture was treated with CH2Cl2Extraction, drying of the organic fraction (MgSO)4) Evaporated and the residue dried under reduced pressure. Dissolving the residue in CH 2Cl2(300ml) was cooled to 4 ℃ with an ice bath and DIEA (20.0ml, 117mmol) and the appropriate acid chloride R were added at 4 ℃64’COCl (101.0mmol) in CH2Cl2(50ml) solution. The reaction mixture was stirred at 4 ℃ for 1 h and at room temperature for 18 h, using aqueous HCl (0.5N, 200ml) and CH2Cl2And (4) extracting. The organic portion was dried (MgSO)4) Evaporating and dissolving the residue in SiO2Gradient chromatography over ethyl acetate/hexane afforded 218a-u and 220a-u, which were converted to the final products 219a-u and 221a-u as described previously for 216 to 217. The overall yield is 50-60%.
Template (b 1):
synthesis of (2S, 6S, 8aR) -8a- { [ (tert-butyl) oxycarbonyl ] methyl } perhydro-5, 8-dioxo- { [ (9H-fluoren-9-yl) methoxycarbonyl ] amino } -pyrrolo [1, 2-a ] pyrazine-6-acetic acid (222):
to a degassed mixture of dichloromethane/methanol (9: 1, 3ml) was added 250mg (0.414mmol) of { (2S, 6S, 8aR) -8a- [ (tert-butyl) oxycarbonyl (2S, 6S, 8aR) -8a- [ (tert-butyl) oxy) under argon]Methyl } perhydro-5, 8-dioxo- { [ (9H-fluoren-9-yl) methoxycarbonyl]Amino } -pyrrolo [1, 2-a)]25mg (0.0216mmol) of tetrakis (triphenylphosphine) were added to a stirred solution of pyrazine-6-allyl acetate) Palladium, 0.05ml acetic acid and 0.025ml N-methylmorpholine. The reaction mixture was stirred at room temperature for 48 hours and poured into water and dichloromethane. The organic phase was dried (MgSO) 4) Evaporating and dissolving the residue in SiO2Chromatography on dichloromethane/methanol (9: 1) gave 180mg (77%) (2S, 6S, 8aR) -8a- { [ (tert-butyl) oxycarbonyl]Methyl } perhydro-5, 8-dioxo- { [ (9H-fluoren-9-yl) -methoxycarbonyl]Amino } -pyrrolo [1, 2-a)]Pyrazine-6-acetic acid (222) as a white powder.
1H-NMR(300MHz，DMSO-d6)：8.30(s，1H)；7.88(d，J＝7.2，2H)；7.67(d，J＝7.4，2H)；7.62(br.s，1H)；7.41(t，J＝7.2，2H)；7.33(t，J＝7.4，2H)；4.35-4.2(m，5H)；3.55(br.d，J＝6.3，2H)；2.8-2.55(m，3H)；2.45-2.25(m，2H)；2.1-1.95(m，1H)；1.35(s，9H)；MS(ESI)：586.1(M+Na)+，564.1(M+H)+。
Template (c 1):
the test procedures are described in W.Bannwarth, A.Knierzinger, K.Muller, D.Obrecht, A.Trzeciak, EP 0592791A 2, 1993.
3. Biological method
3.1. Preparation of peptides
The lyophilized peptide was weighed on a microbalance (Mettler MT5) and dissolved in sterile water containing 0.01% acetic acid. Tachyplesin was purchased from Bachem Ltd. (BubendorfSwitzerland).
3.2. Antimicrobial activity of these peptides.
The antimicrobial activity of these peptides was determined by standard NCCLS broth microdilution (see 1 below) in a total volume of 100 μ l in sterile 96-well plates (Nunclon polystyrene microtiter plates). Inocula of the microorganisms were prepared using 0.5Mcfarland standards and then diluted into Mueller-Hinton (MH) meatIn the soup, about 10 is obtained for bacteria6Colony Forming Unit (CFU)/ml, or 5X 10 for Candida3An aliquot of this inoculum (50 μ Ι) was added at two-fold dilution to 50 μ Ι of MH broth containing the peptide. The microorganisms used were Escherichia coli (ATCC 25922), Pseudomonas aeruginosa (Pseudomonas aeruginosa) (ATCC 27853), Staphylococcus aureus (ATCC 29213 and ATCC 25923) and Candida albicans. Selected quantities of the peptides were screened for activity against a larger group of gram-negative strains. These strains were: escherichia coli ATCC 43827 and the clinical divisions of the genus Pseudomonas (Pseudomonas aeruginosa V0714482, Pseudomonas aeruginosa 15288, Pseudomonas aeruginosa V0215328 and Pseudomonas aeruginosa V0916085) and Acinetobacter (Acinetobacter V0419905/1, Acinetobacter V1221143/1 and Acinetobacter V1221193/1). The antimicrobial activity of these peptides is expressed as the Minimum Inhibitory Concentration (MIC) in μ g/ml, where no visible growth is observed after 18-20 hours of microtiter plate culture at 37 ℃.
3.3. Antimicrobial activity of these peptides in 1% salt
The salt sensitivity of these peptides was determined by the microtiter serial dilution assay described above. Only MH broth was replaced with MH broth containing 1% NaCl.
3.4. Antimicrobial activity of these peptides in human serum
Serum binding of these peptides was determined by the microtiter serial dilution assay described above. MH broth was replaced only with MH broth (BioWhittaker) containing 90% human serum.
3.5. Hemolysis of blood
The peptide was assayed for hemolytic activity against human red blood cells (hRBC). Fresh hRBC were washed 3 times with Phosphate Buffered Saline (PBS) by centrifugation at 2000Xg for 10 minutes. Peptides were incubated with 20% v/v hRBC at a concentration of 100. mu.g/ml for 1 hour at 37 ℃. The final red blood cell concentration was about 0.9X 109And/ml. In BS alone and H with corresponding 0.1% Triton X-1002In the case of O, the values of 0% and corresponding 100% cell lysis were determined. Will make theseSamples were centrifuged and the supernatant diluted 20-fold in PBS buffer and the Optical Density (OD) of the samples at 540nM was determined. The 100% dissolution value (OD)540H2O) to obtain an OD of about 1.6-2.0. The percent hemolysis is calculated as follows: (OD)540peptide/OD540H2O)×100％。
3.6. Cytotoxicity assays
The cytotoxicity of these peptides on HELA cells (Acc57) and MCF-7 cells (Acc115) was determined using the MTT reduction assay (see 2 and 3 below). Briefly, the method is as follows: HELA cells and MCF-7 cells in RPMI1640+ 5% fetal calf serum at 37 deg.C in microtiter plates with 5% CO 2And growing for 48 hours. The total number of cells was finally 106Cells/well. The cell culture supernatant was decanted and fresh RPMI1640 medium containing 5% fetal bovine serum and peptides serially diluted at 12.5, 25 and 50 μ g/ml was pipetted into these wells. Each peptide concentration was determined in 3 replicates. At 37 deg.C, 5% CO2Next, the cells were cultured continuously for 20-24 hours, and then the wells were washed 3 times with fresh RPMI medium, and finally 100. mu.l of MTT reagent (0.5 mg/ml in RPMI 1640) was added to each well. They were incubated at 37 ℃ for 2 hours, and then the wells were washed 1 time with PBS. To each well, 100. mu.l of isopropanol was added and the absorbance (OD) of the lysate at 595nm was measured595Peptides). 100% growth value (OD) was determined from wells containing HELA or MCF-7 cells with RPMI1640+ 5% fetal bovine serum but no peptide595Media). 0% growth value (OD)595Empty wells) were obtained from wells without HELA or MCF-7 cells. The% MTT reduction per peptide concentration was calculated as follows: (OD)595peptide-OD595void)/(OD595Culture Medium-OD595Empty wells) x 100% and plotted for each peptide concentration. EC of peptide50Defined as the concentration at which 50% inhibition of MTT reduction was observed and calculated for each peptide.
Reference to the literature
1.National Committee for Clinical Laboratory Standards.1993.Methods for dilution antimicrobial susceptibility testsfor bacteria that grow aerobically，3rd ed.Approved standardM7-A3.National Committee for Clinical laboratory standards，Villanova，Pa.
2.Mossman T.J Immunol Meth 1983，65，55-63
3.Berridge MV，Tan AS.Archives of Biochemistry &Biophysics 1993，303，474-482
3.7. Results
TABLE 8 minimum inhibitory concentration (MIC in μ g/ml) and% hemolysis at a concentration of 100 μ g/ml peptide
Examples Escherichia coli ATCC25922 Pseudomonas putida ATCC27853 Staphylococcus aureus ATCC29213 Staphylococcus aureus ATCC25923 Candida albicans Hemolytic hRBC
11 25 100 100 100 100 0.2
36 25 25 25 50 25 0.5
40 25 50 25 50 25 1.2
59 4.7 50 25 50 25 3.0
63 6.2 50 12.5 25 12.5 3.0
71 12.5 100 12.5 12.5 50 1.2
87 6.2 6.2 9.4 9.4 12.5 3.7
101 12.5 50 ＞50 ＞50 50 0.2
103 9.4 25 25 25 12.5 18.3
105 6.2 9.4 12.5 6.2 6.2 31.0
106 12.5 6.2 25 12.5 12.5 1.4
107 25 6.2 12.5 9.4 12.5 10.4
109 50 25 50 50 12.5 3.2
112 25 50 25 25 25 2.6
Examples Escherichia coli ATCC25922 Pseudomonas putida ATCC27853 Staphylococcus aureus ATCC29213 Staphylococcus aureus ATCC25923 Candida albicans Hemolytic hRBC
113 50 100 100 100 100 9.2
119 50 25 ＞100 100 50 3.5
120 18.8 9.4 18.8 9.4 12.5 1.1
121 25 25 6.2 6.2 6.2 7.1
126 25 25 25 50 25 2.6
128 6.2 12.5 6.2 6.2 12.5 13.9
133 6.2 6.2 12.5 25 12.5 1.1
134 12.5 6.2 12.5 25 12.5 1.2
137 25 6.2 6.2 6.2 6.2 3.1
139 25 6.2 12.5 9.4 6.2 3.5
140 12.5 6.2 12.5 12.5 6.2 2.7
141 25 12.5 25 25 12.5 2.0
142 25 12.5 50 25 12.5 2.3
146 12.5 12.5 25 12.5 6.2 30.1
147 50 25 25 25 12.5 1.9
148 25 12.5 12.5 9.4 6.2 3.9
150 25 12.5 12.5 12.5 12.5 29.3
151 50 50 100 50 25 4.9
152 25 25 50 25 12.5 29.1
154 12.5 12.5 25 12.5 12.5 31.5
155 6.2 12.5 6.2 12.5 6.2 10.1
156 50 12.5 12.5 6.2 12.5 35.2
158 12.5 6.2 12.5 12.5 12.5 10.5
159 12.5 12.5 12.5 12.5 12.5 21.7
161 25 12.5 6.2 6.2 12.5 3.7
163 12.5 12.5 12.5 12.5 12.5 24.6
Examples Escherichia coli ATCC25922 Pseudomonas putida ATCC27853 Staphylococcus aureus ATCC29213 Staphylococcus aureus ATCC25923 Candida albicans Hemolytic hRBC
165 6.2 12.5 25 18 12.5 0.2
168 12.5 12.5 25 25 12.5 1.1
172 6.2 25 25 25 12.5 1.0
173 12.5 25 6.2 12.5 12.5 27.4
175 12.5 6.2 12.5 12.5 12.5 2.4
177 25 12.5 25 25 12.5 4.1
182 12.5 6.2 6.2 25 12.5 6.2
185 12.5 6.2 6.2 6.2 12.5 17.6
186 6.2 3.1 6.2 6.2 6.2 11.5
187 12.5 100 50 100 25 0.3
197 12.5 3.1 6.2 6.2 6.2 3.4
203 6.2 6.2 6.2 6.2 6.2 33.0
205 6.2 6.2 12.5 6.2 6.2 27.0
206 6.2 6.2 12.5 12.5 6.2 8.5
207 50 50 25 50 25 0.1
208 12.5 6.2 6.2 6.2 12.5 18.4
209 12.5 6.2 12.5 12.5 18.8 6.4
210 12.5 6.2 25 25 25 1.9
214 12.5 6.2 12.5 12.5 12.5 1.0
216 12.5 6.2 12.5 25 12.5 1.4
217 18.8 6.2 12.5 25 12.5 1.7
218 25 6.2 25 25 25 2.2
219 12.5 12.5 50 50 25 2.6
220 12.5 18.8 25 25 12.5 2.3
222 12.5 6.2 12.5 12.5 6.2 2.2
223 6.2 12.5 12.5 25 12.5 2.7
Examples Escherichia coli ATCC25922 Pseudomonas putida ATCC27853 Staphylococcus aureus ATCC29213 Staphylococcus aureus ATCC25923 Candida albicans Hemolytic hRBC
224 6.2 12.5 18.8 25 12.5 3.7
225 6.2 12.5 12.5 25 12.5 4.4
228 12.5 6.2 6.2 6.2 12.5 6.3
229 12.5 6.2 3.1 6.2 6.2 4.8
230 6.2 6.2 6.2 9.4 12.5 1.7
232 6.2 12.5 9.4 6.2 9.4 1.5
233 9.4 12.5 9.4 6.2 12.5 37
234 6.2 12.5 6.2 3.1 12.5 33.9
242 6.2 12.5 6.2 12.5 12.5 19.4
244 3.1 12.5 6.2 6.2 12.5 22.7
250 6.2 6.2 12.5 12.5 12.5 0.7
251 6.2 9.4 6.2 12.5 12.5 4.1
254 12.5 6.2 6.2 12.5 12.5 11.7
256 3.1 3.1 6.2 6.2 6.2 2.7
257 6.2 6.2 6.2 6.2 25 19.6
258 6.2 6.2 6.2 6.2 12.5 23.6
259 6.2 6.2 6.2 6.2 12.5 18.0
267 12.5 6.2 6.2 12.5 12.5 3.4
277 25 18.8 3.1 6.2 6.2 12.7
278 12.5 25 50 50 50 5.3
279 12.5 12.5 50 50 50 4.9
280 12.5 12.5 50 100 25 1.8
281 12.5 4.7 100 100 50 1.1
282 12.5 12.5 25 50 25 1.6
283 12.5 4.7 100 100 50 1.0
284 6.2 1.6 12.5 12.5 12.5 0.7
Examples Escherichia coli ATCC25922 Pseudomonas putida ATCC27853 Staphylococcus aureus ATCC29213 Staphylococcus aureus ATCC25923 Candida albicans Hemolytic hRBC
287 25 50 12.5 25 25 28.5
288 25 1.5 100 100 100 1.1
289 50 3.1 25 25 25 1.7
292 25 6.2 50 100 25 1.3
293 25 12.5 100 100 100 1.3
294 25 3.1 100 100 50 1.5
295 25 6.5 50 100 50 2.0
296 12.5 6.2 25 50 25 1.9
297 25 3.1 100 100 50 0.9
298 25 3.1 100 200 50 1.0
299 50 6.2 25 100 50 2.5
300 25 12.5 12.5 25 50 6.5
301 25 50.0 50.0 25 50.0 0.5
302 6.2 3.1 3.1 6.2 6.2 3.4
TABLE 9 minimum inhibitory concentration (MIC in μ g/ml) in Mueller-Hinton broth with 1% NaCl
Examples Escherichia coli ATCC25922 Pseudomonas putida ATCC 27853 Staphylococcus aureus ATCC 29213 Staphylococcus aureus ATCC 25923 Candida albicans
106 100 50 100 100 100
197 12.5 6.2 18.8 12.5 12.5
230 25 50 50 50 18.8
250 12.5 50 100 50 50
229 50 18.8 25 25 12.5
256 6.2 6.2 25 25 25
The assay showed that several compounds preferred for gram-negative bacteria were resistant to several pseudomonas strains shown in table 10.
TABLE 10 minimum inhibitory concentration (MIC in μ g/ml) against Pseudomonas strains
MIC(μg/ml) Example 197 Example 284 Example 283 Example 288 Example 289 Example 292 Example 296 Example 297 Example 298
Escherichia coli ATCC 25922 12.5 6.2 25 25 25 25 12.5 25 25
Escherichia coli ATCC 43827 12.5 12.5 12.5 12.5 25 25 12.5 12.5 12.5
Pseudomonas aeruginosa ATCC 278853 3.1 1.6 3.1 3.1 6.2 6.2 3.1 3.1 3.1
Pseudomonas aeruginosa V0714482 12.5 3.1 4.7 3.1 6.2 12.5 12.5 4.7 3.1
Pseudomonas aeruginosa 15288 12.5 3.1 25 6.2 6.2 12.5 12.5 6.2 4.7
Pseudomonas aeruginosa V0215328 12.5 3.1 6.2 3.1 6.2 12.5 12.5 6.2 3.1
Pseudomonas aeruginosa V0916085 9.4 1.6 3.1 6.2 6.2 6.2 6.2 3.1 3.1
Acinetobacter V0419905/1 12.5 6.2 6.2 6.2 12.5 12.5 6.2 6.2 6.2
Acinetobacter V1221143/1 12.5 3.1 6.2 6.2 6.2 6.2 6.2 6.2 9.4
Acinetobacter V1221193/1 12.5 3.1 3.1 6.2 3.1 6.2 3.1 6.2 6.2
Table 11: anticancer Activity (EC)50Value) in μ g/ml
Examples Hela(μg/ml) MCF(μg/ml) Hemolytic hRBC
80 337 nd nd
106 43 39 1.4
170 24 41 nd
197 20 23 3.4
229 13 25 4.8
230 23 32 1.7
285 11 11 4.2
286 nd 23 17.1
Sequence listing
<110>POLYPHOR LIMITED
<120> t template fixed peptidomimetics
<130>P724PCT-II
<140>PCT/EP 02/01711
<141>2002-02-18
<150>PCT/EP 01/02072
<151>2001-02-23
<160>304
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Tyr Val Arg Arg Arg Phe Leu Val Xaa Pro
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Tyr Val Arg Lys Gly Phe Leu Val Xaa Pro
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<223> Xaa is D-Pro
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Trp Val Arg Lys Gly Phe Leu Trp Xaa Pro
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<213> Artificial sequence
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<223> description of artificial sequences: cyclic peptides
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Tyr Val Arg Arg Arg Trp Leu Val Xaa Pro
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<210>5
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Tyr Val Tyr Arg Arg Phe Leu Val Xaa Pro
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Lys Val Tyr Arg Arg Phe Leu Val Xaa Pro
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Lys Val Tyr Lys Gly Phe Leu Trp Xaa Pro
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Arg Phe Leu Arg Arg Arg Leu Phe Arg Xaa Pro
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<220>
<223> Xaa is D-Pro
<400>9
Arg Tyr Leu Arg Arg Arg Leu Tyr Arg Xaa Pro
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<223> Xaa is D-Pro
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Arg Phe Phe Arg Arg Arg Leu Phe Arg Xaa Pro
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<213> Artificial sequence
<220>
<223> description of artificial sequences: cyclic peptides
<220>
<223> Xaa is D-Pro
<400>11
Arg Tyr Tyr Arg Arg Arg Leu Tyr Arg Xaa Pro
1 5 10
<210>12
<211>11
<212>PRT
<213> Artificial sequence
<220>
<223> description of artificial sequences: cyclic peptides
<220>
<223> Xaa is D-Pro
<400>12
Leu Phe Phe Arg Arg Arg Leu Phe Arg Xaa Pro
1 5 10
<210>13
<211>11
<212>PRT
<213> Artificial sequence
<220>
<223> Xaa is D-Pro
<220>
<223> description of artificial sequences: cyclic peptides
<400>13
Leu Tyr Tyr Arg Arg Arg Leu Tyr Arg Xaa Pro
1 5 10
<210>14
<211>11
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<213> Artificial sequence
<220>
<223> description of artificial sequences: cyclic peptides
<220>
<223> Xaa is D-Pro
<400>14
Arg Phe Leu Phe Arg Arg Leu Leu Arg Xaa Pro
1 5 10
<210>15
<211>11
<212>PRT
<213> Artificial sequence
<220>
<223> description of artificial sequences: cyclic peptides
<220>
<223> Xaa is D-Pro
<400>15
Arg Tyr Leu Tyr Arg Arg Leu Leu Arg Xaa Pro
1 5 10
<210>16
<211>11
<212>PRT
<213> Artificial sequence
<220>
<223> description of artificial sequences: cyclic peptides
<220>
<223>Xaa id D-Pro
<400>16
Leu Phe Leu Phe Arg Arg Leu Phe Arg Xaa Pro
1 5 10
<210>17
<211>11
<212>PRT
<213> Artificial sequence
<220>
<223> description of artificial sequences: cyclic peptides
<220>
<223> Xaa is D-Pro
<400>17
Leu Tyr Leu Tyr Arg Arg Leu Tyr Arg Xaa Pro
1 5 10
<210>18
<211>11
<212>PRT
<213> Artificial sequence
<220>
<223> description of artificial sequences: cyclic peptides
<220>
<223> Xaa is D-Pro
<400>18
Arg Phe Leu Phe Arg Arg Leu Phe Leu Xaa Pro
1 5 10
<210>19
<211>11
<212>PRT
<213> Artificial sequence
<220>
<223> description of artificial sequences: cyclic peptides
<220>
<223> Xaa is D-Pro
<400>19
Arg Tyr Leu Tyr Arg Arg Leu Tyr Leu Xaa Pro
1 5 10
<210>20
<211>11
<212>PRT
<213> Artificial sequence
<220>
<223> description of artificial sequences: cyclic peptides
<220>
<223> Xaa is D-Pro
<400>20
Phe Leu Leu Phe Arg Arg Leu Phe Arg Xaa Pro
1 5 10
<210>21
<211>11
<212>PRT
<213> Artificial sequence
<220>
<223> description of artificial sequences: cyclic peptides
<220>
<223> Xaa is D-Pro
<400>21
Tyr Leu Leu Tyr Arg Arg Leu Tyr Arg Xaa Pro
1 5 10
<210>22
<211>11
<212>PRT
<213> Artificial sequence
<220>
<223> description of artificial sequences: cyclic peptides
<220>
<223> Xaa is D-Pro
<400>22
Arg Leu Leu Phe Arg Arg Leu Phe Phe Xaa Pro
1 5 10
<210>23
<211>11
<212>PRT
<213> Artificial sequence
<220>
<223> description of artificial sequences: cyclic peptides
<220>
<223> Xaa is D-Pro
<400>23
Arg Leu Leu Tyr Arg Arg Leu Tyr Tyr Xaa Pro
1 5 10
<210>24
<211>11
<212>PRT
<213> Artificial sequence
<220>
<223> description of artificial sequences: cyclic peptides
<220>
<223> Xaa is D-Pro
<400>24
Arg Phe Leu Arg Arg Phe Leu Phe Arg Xaa Pro
1 5 10
<210>25
<211>11
<212>PRT
<213> Artificial sequence
<220>
<223> description of artificial sequences: cyclic peptides
<220>
<223> Xaa is D-Pro
<400>25
Arg Phe Leu Arg Arg Phe Phe Leu Arg Xaa Pro
1 5 10
<210>26
<211>11
<212>PRT
<213> Artificial sequence
<220>
<223> description of artificial sequences: cyclic peptides
<220>
<223> Xaa is D-Pro
<400>26
Arg Tyr Leu Arg Arg Tyr Tyr Leu Arg Xaa Pro
1 5 10
<210>27
<211>11
<212>PRT
<213> Artificial sequence
<220>
<223> description of artificial sequences: cyclic peptides
<220>
<223> Xaa is D-Pro
<400>27
Leu Tyr Leu Arg Arg Tyr Leu Tyr Arg Xaa Pro
1 5 10
<210>28
<211>11
<212>PRT
<213> Artificial sequence
<220>
<223> description of artificial sequences: cyclic peptides
<220>
<223> Xaa is D-Pro
<400>28
Leu Leu Phe Phe Arg Arg Leu Phe Arg Xaa Pro
1 5 10
<210>29
<211>11
<212>PRT
<213> Artificial sequence
<220>
<223> description of artificial sequences: cyclic peptides
<220>
<223> Xaa is D-Pro
<400>29
Leu Leu Tyr Tyr Arg Arg Leu Tyr Arg Xaa Pro
1 5 10
<210>30
<211>11
<212>PRT
<213> Artificial sequence
<220>
<223> description of artificial sequences: cyclic peptides
<220>
<223> Xaa is D-Pro
<400>30
Arg Leu Phe Phe Arg Arg Leu Phe Leu Xaa Pro
1 5 10
<210>31
<211>11
<212>PRT
<213> Artificial sequence
<220>
<223> description of artificial sequences: cyclic peptides
<220>
<223> Xaa is D-Pro
<400>31
Arg Leu Tyr Tyr Arg Arg Leu Tyr Leu Xaa Pro
1 5 10
<210>32
<211>12
<212>PRT
<213> Artificial sequence
<220>
<223> description of artificial sequences: cyclic peptides
<220>
<223> Xaa is D-Pro
<400>32
Arg Phe Leu Phe Arg Arg Arg Leu Phe Arg Xaa Pro
1 5 10
<210>33
<211>12
<212>PRT
<213> Artificial sequence
<220>
<223> description of artificial sequences: cyclic peptides
<220>
<223> Xaa is D-Pro
<400>33
Arg Tyr Leu Tyr Arg Arg Arg Leu Tyr Arg Xaa Pro
1 5 10
<210>34
<211>12
<212>PRT
<213> Artificial sequence
<220>
<223> description of artificial sequences: cyclic peptides
<220>
<223> Xaa is D-Pro
<400>34
Arg Phe Phe Phe Arg Arg Arg Leu Leu Arg Xaa Pro
1 5 10
<210>35
<211>12
<212>PRT
<213> Artificial sequence
<220>
<223> description of artificial sequences: cyclic peptides
<220>
<223> Xaa is D-Pro
<400>35
Arg Tyr Tyr Tyr Arg Arg Arg Leu Leu Arg Xaa Pro
1 5 10
<210>36
<211>12
<212>PRT
<213> Artificial sequence
<220>
<223> description of artificial sequences: cyclic peptides
<220>
<223> Xaa is D-Pro
<400>36
Arg Leu Phe Phe Arg Arg Arg Leu Phe Arg Xaa Pro
1 5 10
<210>37
<211>12
<212>PRT
<213> Artificial sequence
<220>
<223> description of artificial sequences: cyclic peptides
<220>
<223> Xaa is D-Pro
<400>37
Leu Tyr Leu Tyr Arg Arg Arg Leu Tyr Arg Xaa Pro
1 5 10
<210>38
<211>12
<212>PRT
<213> Artificial sequence
<220>
<223> description of artificial sequences: cyclic peptides
<220>
<223> Xaa is D-Pro
<400>38
Arg Phe Leu Phe Arg Arg Arg Leu Phe Leu Xaa Pro
1 5 10
<210>39
<211>12
<212>PRT
<213> Artificial sequence
<220>
<223> description of artificial sequences: cyclic peptides
<220>
<223> Xaa is D-Pro
<400>39
Arg Tyr Leu Tyr Arg Arg Arg Leu Tyr Leu Xaa Pro
1 5 10
<210>40
<211>12
<212>PRT
<213> Artificial sequence
<220>
<223> description of artificial sequences: cyclic peptides
<220>
<223> Xaa is D-Pro
<400>40
Leu Leu Phe Phe Arg Arg Arg Leu Phe Arg Xaa Pro
1 5 10
<210>41
<211>12
<212>PRT
<213> Artificial sequence
<220>
<223> description of artificial sequences: cyclic peptides
<220>
<223> Xaa is D-Pro
<400>41
Arg Leu Phe Phe Arg Arg Arg Leu Phe Leu Xaa Pro
1 5 10
<210>42
<211>12
<212>PRT
<213> Artificial sequence
<220>
<223> description of artificial sequences: cyclic peptides
<220>
<223> Xaa is D-Pro
<400>42
Leu Tyr Tyr Tyr Arg Arg Arg Leu Leu Arg Xaa Pro
1 5 10
<210>43
<211>12
<212>PRT
<213> Artificial sequence
<220>
<223> description of artificial sequences: cyclic peptides
<220>
<223> Xaa is D-Pro
<400>43
Arg Phe Phe Phe Arg Arg Arg Leu Leu Leu Xaa Pro
1 5 10
<210>44
<211>12
<212>PRT
<213> Artificial sequence
<220>
<223> description of artificial sequences: cyclic peptides
<220>
<223> Xaa is D-Pro
<400>44
Arg Tyr Tyr Tyr Arg Arg Arg Leu Leu Leu Xaa Pro
1 5 10
<210>45
<211>12
<212>PRT
<213> Artificial sequence
<220>
<223> description of artificial sequences: cyclic peptides
<220>
<223> Xaa is D-Pro
<400>45
Arg Leu Leu Phe Arg Gly Arg Phe Phe Arg Xaa Pro
1 5 10
<210>46
<211>12
<212>PRT
<213> Artificial sequence
<220>
<223> description of artificial sequences: cyclic peptides
<220>
<223> Xaa is D-Pro
<400>46
Arg Leu Leu Tyr Arg Gly Arg Tyr Tyr Arg Xaa Pro
1 5 10
<210>47
<211>12
<212>PRT
<213> Artificial sequence
<220>
<223> description of artificial sequences: cyclic peptides
<220>
<223> Xaa is D-Pro
<400>47
Arg Phe Phe Phe Arg Gly Arg Leu Leu Arg Xaa Pro
1 5 10
<210>48
<211>12
<212>PRT
<213> Artificial sequence
<220>
<223> description of artificial sequences: cyclic peptides
<220>
<223> Xaa is D-Pro
<400>48
Arg Tyr Tyr Tyr Arg Gly Arg Leu Leu Arg Xaa Pro
1 5 10
<210>49
<211>12
<212>PRT
<213> Artificial sequence
<220>
<223> description of artificial sequences: cyclic peptides
<220>
<223> Xaa is D-Pro
<400>49
Leu Phe Leu Phe Arg Gly Arg Leu Phe Arg Xaa Pro
1 5 10
<210>50
<211>12
<212>PRT
<213> Artificial sequence
<220>
<223> description of artificial sequences: cyclic peptides
<220>
<223> Xaa is D-Pro
<400>50
Leu Tyr Leu Tyr Arg Gly Arg Leu Tyr Arg Xaa Pro
1 5 10
<210>51
<211>12
<212>PRT
<213> Artificial sequence
<220>
<223> description of artificial sequences: cyclic peptides
<220>
<223> Xaa is D-Pro
<400>51
Arg Phe Leu Phe Arg Gly Arg Leu Phe Leu Xaa Pro
1 5 10
<210>52
<211>12
<212>PRT
<213> Artificial sequence
<220>
<223> description of artificial sequences: cyclic peptides
<220>
<223> Xaa is D-Pro
<400>52
Arg Tyr Leu Tyr Arg Gly Arg Leu Tyr Leu Xaa Pro
1 5 10
<210>53
<211>12
<212>PRT
<213> Artificial sequence
<220>
<223> description of artificial sequences: cyclic peptides
<220>
<223> Xaa is D-Pro
<400>53
Leu Arg Phe Phe Arg Leu Arg Leu Phe Arg Xaa Pro
1 5 10
<210>54
<211>12
<212>PRT
<213> Artificial sequence
<220>
<223> description of artificial sequences: cyclic peptides
<220>
<223> Xaa is D-Pro
<400>54
Leu Arg Tyr Tyr Arg Leu Arg Leu Tyr Arg Xaa Pro
1 5 10
<210>55
<211>12
<212>PRT
<213> Artificial sequence
<220>
<223> description of artificial sequences: cyclic peptides
<220>
<223> Xaa is D-Pro
<400>55
Leu Leu Phe Phe Arg Gly Arg Leu Phe Arg Xaa Pro
1 5 10
<210>56
<211>12
<212>PRT
<213> Artificial sequence
<220>
<223> description of artificial sequences: cyclic peptides
<220>
<223> Xaa is D-Pro
<400>56
Leu Leu Tyr Tyr Arg Gly Arg Leu Tyr Arg Xaa Pro
1 5 10
<210>57
<211>12
<212>PRT
<213> Artificial sequence
<220>
<223> description of artificial sequences: cyclic peptides
<220>
<223> Xaa is D-Pro
<400>57
Arg Phe Leu Phe Arg Gly Arg Phe Arg Leu Xaa Pro
1 5 10
<210>58
<211>12
<212>PRT
<213> Artificial sequence
<220>
<223> description of artificial sequences: cyclic peptides
<220>
<223> Xaa is D-Pro
<400>58
Arg Tyr Leu Tyr Arg Gly Arg Tyr Arg Leu Xaa Pro
1 5 10
<210>59
<211>13
<212>PRT
<213> Artificial sequence
<220>
<223> description of artificial sequences: cyclic peptides
<220>
<223> Xaa is D-Pro
<400>59
Arg Leu Phe Leu Arg Arg Arg Phe Phe Arg Leu Xaa Pro
1 5 10
<210>60
<211>13
<212>PRT
<213> Artificial sequence
<220>
<223> description of artificial sequences: cyclic peptides
<220>
<223> Xaa is D-Pro
<400>60
Arg Leu Tyr Leu Arg Arg Arg Tyr Tyr Arg Leu Xaa Pro
1 5 10
<210>61
<211>13
<212>PRT
<213> Artificial sequence
<220>
<223> description of artificial sequences: cyclic peptides
<220>
<223> Xaa is D-Pro
<400>61
Leu Leu Phe Leu Arg Arg Arg Phe Phe Arg Arg Xaa Pro
1 5 10
<210>62
<211>13
<212>PRT
<213> Artificial sequence
<220>
<223> description of artificial sequences: cyclic peptides
<220>
<223> Xaa is D-Pro
<400>62
Arg Leu Phe Leu Arg Arg Arg Leu Phe Arg Phe Xaa Pro
1 5 10
<210>63
<211>13
<212>PRT
<213> Artificial sequence
<220>
<223> description of artificial sequences: cyclic peptides
<220>
<223> Xaa is D-Pro
<400>63
Phe Leu Phe Leu Arg Arg Arg Leu Phe Arg Arg Xaa Pro
1 5 10
<210>64
<211>13
<212>PRT
<213> Artificial sequence
<220>
<223> description of artificial sequences: cyclic peptides
<220>
<223> Xaa is D-Pro
<400>64
Tyr Leu Tyr Leu Arg Arg Arg Leu Tyr Arg Arg Xaa Pro
1 5 10
<210>65
<211>13
<212>PRT
<213> Artificial sequence
<220>
<223> description of artificial sequences: cyclic peptides
<220>
<223> Xaa is D-Pro
<400>65
Arg Arg Phe Leu Arg Gly Arg Phe Phe Leu Arg Xaa Pro
1 5 10
<210>66
<211>13
<212>PRT
<213> Artificial sequence
<220>
<223> description of artificial sequences: cyclic peptides
<220>
<223> Xaa is D-Pro
<400>66
Leu Leu Tyr Tyr Arg Arg Leu Tyr Tyr Arg Arg Xaa Pro
1 5 10
<210>67
<211>13
<212>PRT
<213> Artificial sequence
<220>
<223> description of artificial sequences: cyclic peptides
<220>
<223> Xaa is D-Pro
<400>67
Leu Tyr Leu Tyr Arg Arg Tyr Leu Tyr Arg Arg Xaa Pro
1 5 10
<210>68
<211>13
<212>PRT
<213> Artificial sequence
<220>
<223> description of artificial sequences: cyclic peptides
<220>
<223> Xaa is D-Pro
<400>68
Arg Arg Phe Phe Arg Arg Leu Phe Phe Leu Leu Xaa Pro
1 5 10
<210>69
<211>13
<212>PRT
<213> Artificial sequence
<220>
<223> description of artificial sequences: cyclic peptides
<220>
<223> Xaa is D-Pro
<400>69
Arg Leu Tyr Tyr Arg Arg Leu Tyr Tyr Arg Leu Xaa Pro
1 5 10
<210>70
<211>13
<212>PRT
<213> Artificial sequence
<220>
<223> description of artificial sequences: cyclic peptides
<220>
<223> Xaa is D-Pro
<400>70
Arg Leu Phe Phe Arg Gly Arg Phe Phe Arg Leu Xaa Pro
1 5 10
<210>71
<211>16
<212>PRT
<213> Artificial sequence
<220>
<223> description of artificial sequences: cyclic peptides
<220>
<223> Xaa is D-Pro
<400>71
Arg Tyr Leu Leu Tyr Arg Arg Arg Tyr Leu Leu Tyr Arg Arg Xaa Pro
1 5 10 15
<210>72
<211>16
<212>PRT
<213> Artificial sequence
<220>
<223> description of artificial sequences: cyclic peptides
<220>
<223> Xaa is D-Pro
<400>72
Arg Leu Leu Tyr Tyr Arg Arg Arg Tyr Leu Leu Tyr Arg Arg Xaa Pro
1 5 10 15
<210>73
<211>16
<212>PRT
<213> Artificial sequence
<220>
<223> description of artificial sequences: cyclic peptides
<220>
<223> Xaa is D-Pro
<400>73
Arg Leu Leu Leu Tyr Arg Arg Arg Tyr Leu Tyr Tyr Arg Arg Xaa Pro
1 5 10 15
<210>74
<211>16
<212>PRT
<213> Artificial sequence
<220>
<223> description of artificial sequences: cyclic peptides
<220>
<223> Xaa is D-Pro
<400>74
Arg Phe Leu Phe Leu Arg Arg Arg Phe Phe Leu Phe Arg Arg Xaa Pro
1 5 10 15
<210>75
<211>16
<212>PRT
<213> Artificial sequence
<220>
<223> description of artificial sequences: cyclic peptides
<220>
<223> Xaa is D-Pro
<400>75
Arg Tyr Leu Tyr Leu Arg Arg Arg Tyr Tyr Leu Tyr Arg Arg Xaa Pro
1 5 10 15
<210>76
<211>16
<212>PRT
<213> Artificial sequence
<220>
<223> description of artificial sequences: cyclic peptides
<220>
<223> Xaa is D-Pro
<400>76
Arg Phe Leu Phe Leu Arg Arg Arg Phe Leu Phe Leu Arg Arg Xaa Pro
1 5 10 15
<210>77
<211>16
<212>PRT
<213> Artificial sequence
<220>
<223> description of artificial sequences: cyclic peptides
<220>
<223> Xaa is D-Pro
<400>77
Arg Tyr Leu Tyr Leu Arg Arg Arg Tyr Leu Tyr Leu Arg Arg Xaa Pro
1 5 10 15
<210>78
<211>16
<212>PRT
<213> Artificial sequence
<220>
<223> description of artificial sequences: cyclic peptides
<220>
<223> Xaa is D-Pro
<400>78
Arg Arg Leu Leu Phe Arg Arg Arg Phe Leu Leu Phe Phe Arg Xaa Pro
1 5 10 15
<210>79
<211>16
<212>PRT
<213> Artificial sequence
<220>
<223> description of artificial sequences: cyclic peptides
<220>
<223> Xaa is D-Pro
<400>79
Arg Arg Leu Leu Tyr Arg Arg Arg Tyr Leu Leu Tyr Tyr Arg Xaa Pro
1 5 10 15
<210>80
<211>16
<212>PRT
<213> Artificial sequence
<220>
<223> description of artificial sequences: cyclic peptides
<220>
<223> Xaa is D-Pro
<400>80
Arg Arg Leu Tyr Tyr Arg Arg Arg Tyr Leu Leu Tyr Tyr Arg Xaa Pro
1 5 10 15
<210>81
<211>16
<212>PRT
<213> Artificial sequence
<220>
<223> description of artificial sequences: cyclic peptides
<220>
<223> Xaa is D-Pro
<400>81
Arg Arg Leu Leu Tyr Arg Arg Arg Tyr Leu Tyr Tyr Leu Arg Xaa Pro
1 5 10 15
<210>82
<211>16
<212>PRT
<213> Artificial sequence
<220>
<223> description of artificial sequences: cyclic peptides
<220>
<223> Xaa is D-Pro
<400>82
Arg Arg Leu Phe Leu Arg Arg Arg Phe Phe Leu Phe Phe Arg Xaa Pro
1 5 10 15
<210>83
<211>16
<212>PRT
<213> Artificial sequence
<220>
<223> description of artificial sequences: SEQ083
<220>
<223> Xaa is D-Pro
<400>83
Arg Arg Leu Tyr Leu Arg Arg Arg Tyr Tyr Leu Tyr Tyr Arg Xaa Pro
1 5 10 15
<210>84
<211>16
<212>PRT
<213> Artificial sequence
<220>
<223> description of artificial sequences: cyclic peptides
<220>
<223> Xaa is D-Pro
<400>84
Arg Arg Leu Tyr Leu Arg Arg Arg Tyr Leu Tyr Leu Tyr Arg Xaa Pro
1 5 10 15
<210>85
<211>18
<212>PRT
<213> Artificial sequence
<220>
<223> description of artificial sequences: cyclic peptides
<220>
<223> Xaa is D-Pro
<400>85
Lys Arg Leu Lys Tyr Val Arg Arg Arg Trp Leu Val Lys Val Leu Arg
1 5 10 15
Xaa Pro
<210>86
<211>18
<212>PRT
<213> Artificial sequence
<220>
<223> description of artificial sequences: cyclic peptides
<220>
<223> Xaa is D-Pro
<400>86
Lys Arg Leu Lys Tyr Val Arg Arg Gly Trp Leu Val Lys Val Leu Arg
1 5 10 15
Xaa Pro
<210>87
<211>18
<212>PRT
<213> Artificial sequence
<220>
<223> description of artificial sequences: cyclic peptides
<220>
<223> Xaa is D-Pro
<400>87
Lys Arg Leu Lys Tyr Trp Arg Arg Arg Trp Tyr Val Lys Val Leu Arg
1 5 10 15
Xaa Pro
<210>88
<211>18
<212>PRT
<213> Artificial sequence
<220>
<223> description of artificial sequences: cyclic peptides
<220>
<223> Xaa is D-Pro
<400>88
Lys Arg Leu Tyr Tyr Trp Arg Arg Arg Trp Tyr Val Phe Val Leu Arg
1 5 10 15
Xaa Pro
<210>89
<211>18
<212>PRT
<213> Artificial sequence
<220>
<223> description of artificial sequences: cyclic peptides
<220>
<223> Xaa is D-Pro
<400>89
Lys Arg Leu Lys Tyr Trp Arg Arg Gly Trp Tyr Val Lys Val Leu Arg
1 5 10 15
Xaa Pro
<210>90
<211>18
<212>PRT
<213> Artificial sequence
<220>
<223> description of artificial sequences: cyclic peptides
<220>
<223> Xaa is D-Pro
<400>90
Lys Arg Leu Tyr Tyr Trp Arg Arg Gly Trp Tyr Val Phe Val Leu Arg
1 5 10 15
Xaa Pro
<210>91
<211>18
<212>PRT
<213> Artificial sequence
<220>
<223> description of artificial sequences: cyclic peptides
<220>
<223> Xaa is D-Pro
<400>91
Lys Arg Leu Tyr Tyr Trp Arg Arg Arg Trp Lys Val Phe Val Leu Arg
1 5 10 15
Xaa Pro
<210>92
<211>18
<212>PRT
<213> Artificial sequence
<220>
<223> description of artificial sequences: cyclic peptides
<220>
<223> Xaa is D-Pro
<400>92
Lys Arg Leu Lys Tyr Trp Arg Arg Gly Trp Lys Val Lys Val Leu Arg
1 5 10 15
Xaa Pro
<210>93
<211>18
<212>PRT
<213> Artificial sequence
<220>
<223> description of artificial sequences: cyclic peptides
<220>
<223> Xaa is D-Pro
<400>93
Tyr Lys Leu Arg Leu Lys Tyr Arg Arg Trp Lys Tyr Arg Val Lys Phe
1 5 10 15
Xaa Pro
<210>94
<211>18
<212>PRT
<213> Artificial sequence
<220>
<223> description of artificial sequences: cyclic peptides
<220>
<223> Xaa is D-Pro
<400>94
Tyr Lys Leu Gln Leu Lys Trp Arg Arg Phe Lys Tyr Gln Val Lys Phe
1 5 10 15
Xaa Pro
<210>95
<211>18
<212>PRT
<213> Artificial sequence
<220>
<223> description of artificial sequences: cyclic peptides
<220>
<223> Xaa is D-Pro
<400>95
Tyr Lys Leu Gln Leu Gln Lys Lys Gly Trp Gln Tyr Gln Val Lys Phe
1 5 10 15
Xaa Pro
<210>96
<211>14
<212>PRT
<213> Artificial sequence
<220>
<223> description of artificial sequences: cyclic peptides
<220>
<223> Xaa is D-Pro
<400>96
Leu Arg Leu Val Tyr Lys Gly Phe Leu Tyr Arg Val Xaa Pro
1 5 10
<210>97
<211>14
<212>PRT
<213> Artificial sequence
<220>
<223> description of artificial sequences: cyclic peptides
<220>
<223> Xaa is D-Pro
<400>97
Leu Arg Phe Val Tyr Lys Gly Phe Leu Tyr Arg Val Xaa Pro
1 5 10
<210>98
<211>14
<212>PRT
<213> Artificial sequence
<220>
<223> description of artificial sequences: cyclic peptides
<220>
<223> Xaa is D-Pro
<400>98
Leu Arg Thr Val Tyr Lys Gly Phe Leu Tyr Arg Val Xaa Pro
1 5 10
<210>99
<211>14
<212>PRT
<213> Artificial sequence
<220>
<223> description of artificial sequences: cyclic peptides
<220>
<223> Xaa is D-Pro
<400>99
Leu Arg Lys Val Arg Lys Gly Arg Leu Tyr Arg Val Xaa Pro
1 5 10
<210>100
<211>14
<212>PRT
<213> Artificial sequence
<220>
<223> description of artificial sequences: cyclic peptides
<220>
<223> Xaa is D-Pro
<400>100
Leu Arg Lys Trp Tyr Lys Gly Phe Trp Tyr Arg Val Xaa Pro
1 5 10
<210>101
<211>14
<212>PRT
<213> Artificial sequence
<220>
<223> description of artificial sequences: cyclic peptides
<220>
<223> Xaa is D-Pro
<400>101
Leu Arg Lys Val Tyr Arg Gly Phe Leu Tyr Arg Val Xaa Pro
1 5 10
<210>102
<211>14
<212>PRT
<213> Artificial sequence
<220>
<223> description of artificial sequences: cyclic peptides
<220>
<223> Xaa is D-Pro
<400>102
Leu Lys Lys Val Tyr Arg Arg Phe Leu Lys Lys Val Xaa Pro
1 5 10
<210>103
<211>14
<212>PRT
<213> Artificial sequence
<220>
<223> description of artificial sequences: cyclic peptides
<220>
<223> Xaa is D-Pro
<400>103
Leu Arg Leu Lys Tyr Arg Arg Phe Lys Tyr Arg Val Xaa Pro
1 5 10
<210>104
<211>14
<212>PRT
<213> Artificial sequence
<220>
<223> description of artificial sequences: cyclic peptides
<220>
<223> Xaa is D-Pro
<400>104
Leu Arg Leu Glu Tyr Arg Arg Phe Glu Tyr Arg Val Xaa Pro
1 5 10
<210>105
<211>14
<212>PRT
<213> Artificial sequence
<220>
<223> description of artificial sequences: cyclic peptides
<220>
<223> Xaa is D-Pro
<400>105
Leu Arg Leu Gln Tyr Thr Thr Phe Gln Tyr Arg Val Xaa Pro
1 5 10
<210>106
<211>14
<212>PRT
<213> Artificial sequence
<220>
<223> description of artificial sequences: cyclic peptides
<220>
<223> Xaa is D-Pro
<400>106
Leu Arg Leu Lys Lys Arg Arg Trp Lys Tyr Arg Val Xaa Pro
1 5 10
<210>107
<211>14
<212>PRT
<213> Artificial sequence
<220>
<223> description of artificial sequences: cyclic peptides
<220>
<223> Xaa is D-Pro
<400>107
Leu Arg Leu Lys Trp Arg Arg Lys Lys Tyr Arg Val Xaa Pro
1 5 10
<210>108
<211>14
<212>PRT
<213> Artificial sequence
<220>
<223> description of artificial sequences: cyclic peptides
<220>
<223> Xaa is D-Pro
<400>108
Leu Arg Trp Lys Tyr Arg Arg Phe Lys Tyr Arg Val Xaa Pro
1 5 10
<210>109
<211>14
<212>PRT
<213> Artificial sequence
<220>
<223> description of artificial sequences: cyclic peptides
<220>
<223> Xaa is D-Pro
<400>109
Lys Val Arg Phe Arg Arg Arg Lys Leu Lys Leu Arg Xaa Pro
1 5 10
<210>110
<211>14
<212>PRT
<213> Artificial sequence
<220>
<223> description of artificial sequences: cyclic peptides
<220>
<223> Xaa is D-Pro
<400>110
Leu Arg Leu Gln Tyr Arg Arg Trp Gln Tyr Arg Val Xaa Pro
1 5 10
<210>111
<211>14
<212>PRT
<213> Artificial sequence
<220>
<223> description of artificial sequences: cyclic peptides
<220>
<223> Xaa is D-Pro
<400>111
Leu Arg Leu Gln Trp Arg Arg Phe Gln Tyr Arg Val Xaa Pro
1 5 10
<210>112
<211>14
<212>PRT
<213> Artificial sequence
<220>
<223> description of artificial sequences: cyclic peptides
<220>
<223> Xaa is D-Pro
<400>112
Leu Arg Leu Gln Lys Arg Arg Trp Gln Tyr Arg Val Xaa Pro
1 5 10
<210>113
<211>14
<212>PRT
<213> Artificial sequence
<220>
<223> description of artificial sequences: cyclic peptides
<220>
<223> Xaa is D-Pro
<400>113
Leu Arg Leu Gln Trp Arg Arg Lys Gln Tyr Arg Val Xaa Pro
1 5 10
<210>114
<211>14
<212>PRT
<213> Artificial sequence
<220>
<223> description of artificial sequences: cyclic peptides
<220>
<223> Xaa is D-Pro
<400>114
Phe Arg Leu Gln Tyr Arg Arg Phe Gln Tyr Arg Val Xaa Pro
1 5 10
<210>115
<211>14
<212>PRT
<213> Artificial sequence
<220>
<223> description of artificial sequences: cyclic peptides
<220>
<223> Xaa is D-Pro
<400>115
Leu Arg Leu Gln Tyr Arg Arg Phe Gln Tyr Arg Phe Xaa Pro
1 5 10
<210>116
<211>14
<212>PRT
<213> Artificial sequence
<220>
<223> description of artificial sequences: cyclic peptides
<220>
<223> Xaa is D-Pro
<400>4116
Phe Arg Leu Gln Tyr Arg Arg Phe Gln Tyr Arg Phe Xaa Pro
1 5 10
<210>117
<211>14
<212>PRT
<213> Artificial sequence
<220>
<223> description of artificial sequences: cyclic peptides
<220>
<223> Xaa is D-Pro
<400>117
Leu Arg Leu Gln Tyr Arg Arg Phe Gln Trp Arg Val Xaa Pro
1 5 10
<210>118
<211>14
<212>PRT
<213> Artificial sequence
<220>
<223> description of artificial sequences: cyclic peptides
<220>
<223> Xaa is D-Pro
<400>118
Leu Arg Trp Gln Tyr Arg Arg Phe Gln Tyr Arg Val Xaa Pro
1 5 10
<210>119
<211>14
<212>PRT
<213> Artificial sequence
<220>
<223> description of artificial sequences: cyclic peptides
<220>
<223> Xaa is D-Pro
<400>119
Gln Val Arg Phe Arg Arg Arg Lys Leu Gln Leu Arg Xaa Pro
1 5 10
<210>120
<211>14
<212>PRT
<213> Artificial sequence
<220>
<223> description of artificial sequences: cyclic peptides
<220>
<223> Xaa is D-Pro
<400>120
Phe Arg Leu Lys Lys Arg Arg Trp Lys Tyr Arg Val Xaa Pro
1 5 10
<210>121
<211>14
<212>PRT
<213> Artificial sequence
<220>
<223> description of artificial sequences: cyclic peptides
<220>
<223> Xaa is Cha (L-cyclohexylalanine) at position 1;
xaa is D-Pro at position 13
<400>121
Xaa Arg Leu Lys Lys Arg Arg Trp Lys Tyr Arg Val Xaa Pro
1 5 10
<210>122
<211>14
<212>PRT
<213> Artificial sequence
<220>
<223> description of artificial sequences: cyclic peptides
<220>
<223> Xaa is hPhe (L-homo-phenylalanine) at position 1;
xaa is D-Pro at position 13
<400>122
Xaa Arg Leu Lys Lys Arg Arg Trp Lys Tyr Arg Val Xaa Pro
1 5 10
<210>123
<211>14
<212>PRT
<213> Artificial sequence
<220>
<223> description of artificial sequences: cyclic peptides
<220>
<223> Xaa is 2-Nal (L-2-naphthylalanine) at position 1;
xaa is D-Pro at position 13
<400>123
Xaa Arg Leu Lys Lys Arg Arg Trp Lys Tyr Arg Val Xaa Pro
1 5 10
<210>124
<211>14
<212>PRT
<213> Artificial sequence
<220>
<223> description of artificial sequences: cyclic peptides
<220>
<223> Xaa is 1-Nal (L-1-naphthylalanine) at position 1;
xaa is D-Pro at position 13
<400>124
Xaa Arg Leu Lys Lys Arg Arg Trp Lys Tyr Arg Val Xaa Pro
1 5 10
<210>125
<211>14
<212>PRT
<213> Artificial sequence
<220>
<223> description of artificial sequences: cyclic peptides
<220>
<223> Xaa is Nle (L-norleucine) at position 1; xaa is D-Pro at position 13
<400>125
Xaa Arg Leu Lys Lys Arg Arg Trp Lys Tyr Arg Val Xaa Pro
1 5 10
<210>126
<211>14
<212>PRT
<213> Artificial sequence
<220>
<223> description of artificial sequences: cyclic peptides
<220>
<223> Xaa is D-Pro
<400>126
Leu Arg Phe Lys Lys Arg Arg Trp Lys Tyr Arg Val Xaa Pro
1 5 10
<210>127
<211>14
<212>PRT
<213> Artificial sequence
<220>
<223> description of artificial sequences: cyclic peptides
<220>
<223> Xaa is Cha (L-cyclohexylalanine) at position 3;
xaa is D-Pro at position 13
<400>127
Leu Arg Xaa Lys Lys Arg Arg Trp Lys Tyr Arg Val Xaa Pro
1 5 10
<210>128
<211>14
<212>PRT
<213> Artificial sequence
<220>
<223> description of artificial sequences: cyclic peptides
<220>
<223> Xaa is Y (Bzl) [ L-O-benzyltyrosine ] at position 3;
Xaa is D-Pro at position 13
<400>128
Leu Arg Xaa Lys Lys Arg Arg Trp Lys Tyr Arg Val Xaa Pro
1 5 10
<210>129
<211>14
<212>PRT
<213> Artificial sequence
<220>
<223> description of artificial sequences: cyclic peptides
<220>
<223> Xaa is D-Pro
<400>129
Leu Arg Trp Lys Lys Arg Arg Trp Lys Tyr Arg Val Xaa Pro
1 5 10
<210>130
<211>14
<212>PRT
<213> Artificial sequence
<220>
<223> description of artificial sequences: cyclic peptides
<220>
<223> Xaa is hPhe (L-homo-phenylalanine) at position 3;
xaa is D-Pro at position 13
<400>130
Leu Arg Xaa Lys Lys Arg Arg Trp Lys Tyr Arg Val Xaa Pro
1 5 10
<210>131
<211>14
<212>PRT
<213> Artificial sequence
<220>
<223> description of artificial sequences: cyclic peptides
<220>
<223> Xaa is 2-Nal (L-2-naphthylalanine) at position 3;
xaa is D-Pro at position 13
<400>131
Leu Arg Xaa Lys Lys Arg Arg Trp Lys Tyr Arg Val Xaa Pro
1 5 10
<210>132
<211>14
<212>PRT
<213> Artificial sequence
<220>
<223> description of artificial sequences: cyclic peptides
<220>
<223> Xaa is 1-Nal (L-1-naphthylalanine) at position 3;
xaa is D-Pro at position 13
<400>132
Leu Arg Xaa Lys Lys Arg Arg Trp Lys Tyr Arg Val Xaa Pro
1 5 10
<210>133
<211>14
<212>PRT
<213> Artificial sequence
<220>
<223> description of artificial sequences: cyclic peptides
<220>
<223> Xaa is D-Pro
<400>133
Leu Arg Val Lys Lys Arg Arg Trp Lys Tyr Arg Val Xaa Pro
1 5 10
<210>134
<211>14
<212>PRT
<213> Artificial sequence
<220>
<223> description of artificial sequences: cyclic peptides
<220>
<223> Xaa is D-Pro
<400>134
Leu Arg Ile Lys Lys Arg Arg Trp Lys Tyr Arg Val Xaa Pro
1 5 10
<210>135
<211>14
<212>PRT
<213> Artificial sequence
<220>
<223> description of artificial sequences: cyclic peptides
<220>
<223> Xaa is Nle (L-norleucine) at position 3; xaa is D-Pro at position 13
<400>135
Leu Arg Xaa Lys Lys Arg Arg Trp Lys Tyr Arg Val Xaa Pro
1 5 10
<210>136
<211>14
<212>PRT
<213> Artificial sequence
<220>
<223> description of artificial sequences: cyclic peptides
<220>
<223> Xaa is D-Pro
<400>136
Leu Arg Leu Lys Lys Arg Arg Tyr Lys Tyr Arg Val Xaa Pro
1 5 10
<210>137
<211>14
<212>PRT
<213> Artificial sequence
<220>
<223> description of artificial sequences: cyclic peptides
<220>
<223> Xaa is Y (Bzl) [ L-O-benzyltyrosine ] at position 8;
xaa is D-Pro at position 13
<400>137
Leu Arg Leu Lys Lys Arg Arg Xaa Lys Tyr Arg Val Xaa Pro
1 5 10
<210>138
<211>14
<212>PRT
<213> Artificial sequence
<220>
<223> description of artificial sequences: cyclic peptides
<220>
<223> Xaa is hPhe (L-homo-phenylalanine) at position 8;
Xaa is D-Pro at position 13
<400>138
Leu Arg Leu Lys Lys Arg Arg Xaa Lys Tyr Arg Val Xaa Pro
1 5 10
<210>139
<211>14
<212>PRT
<213> Artificial sequence
<220>
<223> description of artificial sequences: cyclic peptides
<220>
<223> Xaa is 2-Nal (L-2-naphthylalanine) at position 8;
xaa is D-Pro at position 13
<400>139
Leu Arg Leu Lys Lys Arg Arg Xaa Lys Tyr Arg Val Xaa Pro
1 5 10
<210>140
<211>14
<212>PRT
<213> Artificial sequence
<220>
<223> description of artificial sequences: cyclic peptides
<220>
<223> Xaa is 1-Nal (L-1-naphthylalanine) at position 8;
xaa is D-Pro at position 13
<400>140
Leu Arg Leu Lys Lys Arg Arg Xaa Lys Tyr Arg Val Xaa Pro
1 5 10
<210>141
<211>14
<212>PRT
<213> Artificial sequence
<220>
<223> description of artificial sequences: cyclic peptides
<220>
<223> Xaa is D-Pro
<400>141
Leu Arg Leu Lys Lys Arg Arg Val Lys Tyr Arg Cys Xaa Pro
1 5 10
<210>142
<211>14
<212>PRT
<213> Artificial sequence
<220>
<223> description of artificial sequences: cyclic peptides
<220>
<223> Xaa is D-Pro
<400>142
Leu Arg Leu Lys Lys Arg Arg Ile Lys Tyr Arg Val Xaa Pro
1 5 10
<210>143
<211>14
<212>PRT
<213> Artificial sequence
<220>
<223> description of artificial sequences: cyclic peptides
<220>
<223> Xaa is D-Pro
<400>143
Leu Arg Leu Lys Lys Arg Arg Leu Lys Tyr Arg Val Xaa Pro
1 5 10
<210>144
<211>14
<212>PRT
<213> Artificial sequence
<220>
<223> description of artificial sequences: cyclic peptides
<220>
<223> Xaa is Nle (L-norleucine) at position 8; xaa is D-Pro at position 13
<400>144
Leu Arg Leu Lys Lys Arg Arg Xaa Lys Tyr Arg Val Xaa Pro
1 5 10
<210>145
<211>14
<212>PRT
<213> Artificial sequence
<220>
<223> description of artificial sequences: cyclic peptides
<220>
<223> Xaa is D-Pro
<400>145
Leu Arg Leu Lys Lys Arg Arg His Lys Tyr Arg Val Xaa Pro
1 5 10
<210>146
<211>14
<212>PRT
<213> Artificial sequence
<220>
<223> description of artificial sequences: cyclic peptides
<220>
<223> Xaa is D-Pro
<400>146
Leu Arg Leu Lys Lys Arg Arg Trp Lys Phe Arg Val Xaa Pro
1 5 10
<210>147
<211>14
<212>PRT
<213> Artificial sequence
<220>
<223> description of artificial sequences: cyclic peptides
<220>
<223> Xaa is Y (Bzl) [ L-O-benzyltyrosine ] at position 10;
xaa is D-Pro at position 13
<400>147
Leu Arg Leu Lys Lys Arg Arg Trp Lys Xaa Arg Val Xaa Pro
1 5 10
<210>148
<211>14
<212>PRT
<213> Artificial sequence
<220>
<223> description of artificial sequences: cyclic peptides
<220>
<223> Xaa is D-Pro
<400>148
Leu Arg Leu Lys Lys Arg Arg Trp Lys Trp Arg Val Xaa Pro
1 5 10
<210>149
<211>14
<212>PRT
<213> Artificial sequence
<220>
<223> description of artificial sequences: cyclic peptides
<220>
<223> Xaa is hPhe (L-homo-phenylalanine) at position 10;
Xaa is D-Pro at position 13
<400>149
Leu Arg Leu Lys Lys Arg Arg Trp Lys Xaa Arg Val Xaa Pro
1 5 10
<210>150
<211>14
<212>PRT
<213> Artificial sequence
<220>
<223> description of artificial sequences: cyclic peptides
<220>
<223> Xaa is 1-Nal (L-1-naphthylalanine) at position 10;
xaa is D-Pro at position 13
<400>150
Leu Arg Leu Lys Lys Arg Arg Trp Lys Xaa Arg Val Xaa Pro
1 5 10
<210>151
<211>14
<212>PRT
<213> Artificial sequence
<220>
<223> description of artificial sequences: cyclic peptides
<220>
<223> Xaa is D-Pro
<400>151
Leu Arg Leu Lys Lys Arg Arg Trp Lys Val Arg Val Xaa Pro
1 5 10
<210>152
<211>14
<212>PRT
<213> Artificial sequence
<220>
<223> description of artificial sequences: cyclic peptides
<220>
<223> Xaa is D-Pro
<400>152
Leu Arg Leu Lys Lys Arg Arg Trp Lys Ile Arg Val Xaa Pro
1 5 10
<210>153
<211>14
<212>PRT
<213> Artificial sequence
<220>
<223> description of artificial sequences: cyclic peptides
<220>
<223> Xaa is D-Pro
<400>153
Leu Arg Leu Lys Lys Arg Arg Trp Lys Leu Arg Val Xaa Pro
1 5 10
<210>154
<211>14
<212>PRT
<213> Artificial sequence
<220>
<223> description of artificial sequences: cyclic peptides
<220>
<223> Xaa is Nle (L-norleucine) at position 10; xaa is D-Pro at position 13
<400>154
Leu Arg Leu Lys Lys Arg Arg Trp Lys Xaa Arg Val Xaa Pro
1 5 10
<210>155
<211>14
<212>PRT
<213> Artificial sequence
<220>
<223> description of artificial sequences: cyclic peptides
<220>
<223> Xaa is D-Pro
<400>155
Leu Arg Leu Lys Lys Arg Arg Trp Lys Tyr Arg Phe Xaa Pro
1 5 10
<210>156
<211>14
<212>PRT
<213> Artificial sequence
<220>
<223> description of artificial sequences: cyclic peptides
<220>
<223> Xaa is Cha (L-cyclohexylalanine) at position 12;
xaa is D-Pro at position 13
<400>156
Leu Arg Leu Lys Lys Arg Arg Trp Lys Tyr Arg Xaa Xaa Pro
1 5 10
<210>157
<211>14
<212>PRT
<213> Artificial sequence
<220>
<223> description of artificial sequences: cyclic peptides
<220>
<223> Xaa is Y (Bzl) [ L-O-benzyltyrosine ] at position 12;
xaa is D-Pro at position 13
<400>157
Leu Arg Leu Lys Lys Arg Arg Trp Lys Tyr Arg Xaa Xaa Pro
1 5 10
<210>158
<211>14
<212>PRT
<213> Artificial sequence
<220>
<223> description of artificial sequences: cyclic peptides
<220>
<223> Xaa is D-Pro
<400>158
Leu Arg Leu Lys Lys Arg Arg Trp Lys Tyr Arg Trp Xaa Pro
1 5 10
<210>159
<211>14
<212>PRT
<213> Artificial sequence
<220>
<223> description of artificial sequences: cyclic peptides
<220>
<223> Xaa is hPhe (L-homo-phenylalanine) at position 12;
xaa is D-Pro at position 13
<400>159
Leu Arg Leu Lys Lys Arg Arg Trp Lys Tyr Arg Xaa Xaa Pro
1 5 10
<210>160
<211>14
<212>PRT
<213> Artificial sequence
<220>
<223> description of artificial sequences: cyclic peptides
<220>
<223> Xaa is 2-Nal (L-2-naphthylalanine) at position 12;
xaa is D-Pro at position 13
<400>160
Leu Arg Leu Lys Lys Arg Arg Trp Lys Tyr Arg Xaa Xaa Pro
1 5 10
<210>161
<211>14
<212>PRT
<213> Artificial sequence
<220>
<223> description of artificial sequences: cyclic peptides
<220>
<223> Xaa is 1-Nal (L-1-naphthylalanine) at position 12;
xaa is D-Pro at position 13
<400>161
Leu Arg Leu Lys Lys Arg Arg Trp Lys Tyr Arg Xaa Xaa Pro
1 5 10
<210>162
<211>14
<212>PRT
<213> Artificial sequence
<220>
<223> description of artificial sequences: cyclic peptides
<220>
<223> Xaa is D-Pro
<400>162
Leu Arg Leu Lys Lys Arg Arg Trp Lys Tyr Arg Ile Xaa Pro
1 5 10
<210>163
<211>14
<212>PRT
<213> Artificial sequence
<220>
<223> description of artificial sequences: cyclic peptides
<220>
<223> Xaa is Nle (L-norleucine) at position 12; xaa is D-Pro at position 13
<400>163
Leu Arg Leu Lys Lys Arg Arg Trp Lys Tyr Arg Xaa Xaa Pro
1 5 10
<210>164
<211>14
<212>PRT
<213> Artificial sequence
<220>
<223> description of artificial sequences: cyclic peptides
<220>
<223> Xaa is D-Pro
<400>164
Leu Arg Leu Lys Lys Arg Arg Trp Lys Tyr Arg His Xaa Pro
1 5 10
<210>165
<211>14
<212>PRT
<213> Artificial sequence
<220>
<223> description of artificial sequences: cyclic peptides
<220>
<223> Xaa is D-Pro
<400>165
Leu Trp Leu Lys Lys Arg Arg Trp Lys Tyr Arg Val Xaa Pro
1 5 10
<210>166
<211>14
<212>PRT
<213> Artificial sequence
<220>
<223> description of artificial sequences: cyclic peptides
<220>
<223> Xaa is D-Pro
<400>166
Leu Leu Leu Lys Lys Arg Arg Trp Lys Tyr Arg Val Xaa Pro
1 5 10
<210>167
<211>14
<212>PRT
<213> Artificial sequence
<220>
<223> description of artificial sequences: cyclic peptides
<220>
<223> Xaa is D-Pro
<400>167
Leu Thr Leu Lys Lys Arg Arg Trp Lys Tyr Arg Val Xaa Pro
1 5 10
<210>168
<211>14
<212>PRT
<213> Artificial sequence
<220>
<223> description of artificial sequences: cyclic peptides
<220>
<223> Xaa is D-Pro
<400>168
Leu Gln Leu Lys Lys Arg Arg Trp Lys Tyr Arg Val Xaa Pro
1 5 10
<210>169
<211>14
<212>PRT
<213> Artificial sequence
<220>
<223> Xaa is D-Pro
<220>
<223> description of artificial sequences: cyclic peptides
<220>
<223> Xaa is D-Pro
<400>169
Leu Arg Leu Leu Lys Arg Arg Trp Lys Tyr Arg Val Xaa Pro
1 5 10
<210>170
<211>14
<212>PRT
<213> Artificial sequence
<220>
<223> description of artificial sequences: cyclic peptides
<220>
<223> Xaa is D-Pro
<400>170
Leu Arg Leu Arg Lys Arg Arg Trp Lys Tyr Arg Val Xaa Pro
1 5 10
<210>171
<211>14
<212>PRT
<213> Artificial sequence
<220>
<223> description of artificial sequences: cyclic peptides
<220>
<223> Xaa is D-Pro
<400>171
Leu Arg Leu Thr Lys Arg Arg Trp Lys Tyr Arg Val Xaa Pro
1 5 10
<210>172
<211>14
<212>PRT
<213> Artificial sequence
<220>
<223> description of artificial sequences: cyclic peptides
<220>
<223> Xaa is D-Pro
<400>172
Leu Arg Leu Gln Lys Arg Arg Trp Lys Tyr Arg Val Xaa Pro
1 5 10
<210>173
<211>14
<212>PRT
<213> Artificial sequence
<220>
<223> description of artificial sequences: cyclic peptides
<220>
<223> Xaa is D-Pro
<400>173
Leu Arg Leu Lys Leu Arg Arg Trp Lys Tyr Arg Val Xaa Pro
1 5 10
<210>174
<211>14
<212>PRT
<213> Artificial sequence
<220>
<223> description of artificial sequences: cyclic peptides
<220>
<223> Xaa is D-Pro
<400>174
Leu Arg Leu Lys His Arg Arg Trp Lys Tyr Arg Val Xaa Pro
1 5 10
<210>175
<211>14
<212>PRT
<213> Artificial sequence
<220>
<223> description of artificial sequences: cyclic peptides
<220>
<223> Xaa is D-Pro
<400>175
Leu Arg Leu Lys Arg Arg Arg Trp Lys Tyr Arg Val Xaa Pro
1 5 10
<210>176
<211>14
<212>PRT
<213> Artificial sequence
<220>
<223> description of artificial sequences: cyclic peptides
<220>
<223> Xaa is D-Pro
<400>176
Leu Arg Leu Lys Thr Arg Arg Trp Lys Tyr Arg Val Xaa Pro
1 5 10
<210>177
<211>14
<212>PRT
<213> Artificial sequence
<220>
<223> description of artificial sequences: cyclic peptides
<220>
<223> Xaa is D-Pro
<400>177
Leu Arg Leu Lys Lys Leu Arg Trp Lys Tyr Arg Val Xaa Pro
1 5 10
<210>178
<211>14
<212>PRT
<213> Artificial sequence
<220>
<223> description of artificial sequences: cyclic peptides
<220>
<223> Xaa is D-Pro
<400>178
Leu Arg Leu Lys Lys His Arg Trp Lys Tyr Arg Val Xaa Pro
1 5 10
<210>179
<211>14
<212>PRT
<213> Artificial sequence
<220>
<223> description of artificial sequences: cyclic peptides
<220>
<223> Xaa is D-Pro
<400>179
Leu Arg Leu Lys Lys Lys Arg Trp Lys Tyr Arg Val Xaa Pro
1 5 10
<210>180
<211>14
<212>PRT
<213> Artificial sequence
<220>
<223> description of artificial sequences: cyclic peptides
<220>
<223> Xaa is D-Pro
<400>180
Leu Arg Leu Lys Lys Thr Arg Trp Lys Tyr Arg Val Xaa Pro
1 5 10
<210>181
<211>14
<212>PRT
<213> Artificial sequence
<220>
<223> description of artificial sequences: cyclic peptides
<220>
<223> Xaa is D-Pro
<400>181
Leu Arg Leu Lys Lys Gln Arg Trp Lys Tyr Arg Val Xaa Pro
1 5 10
<210>182
<211>14
<212>PRT
<213> Artificial sequence
<220>
<223> description of artificial sequences: cyclic peptides
<220>
<223> Xaa is D-Pro
<400>182
Leu Arg Leu Lys Lys Arg Trp Trp Lys Tyr Arg Val Xaa Pro
1 5 10
<210>183
<211>14
<212>PRT
<213> Artificial sequence
<220>
<223> description of artificial sequences: cyclic peptides
<220>
<223> Xaa is D-Pro
<400>183
Leu Arg Leu Lys Lys Arg His Trp Lys Tyr Arg Val Xaa Pro
1 5 10
<210>184
<211>14
<212>PRT
<213> Artificial sequence
<220>
<223> description of artificial sequences: cyclic peptides
<220>
<223> Xaa is D-Pro
<400>184
Leu Arg Leu Lys Lys Arg Lys Trp Lys Tyr Arg Val Xaa Pro
1 5 10
<210>185
<211>14
<212>PRT
<213> Artificial sequence
<220>
<223> description of artificial sequences: cyclic peptides
<220>
<223> Xaa is Bip at position 1
([ L- (4-phenyl) phenylalanine ]; Xaa is D-Pro at position 13
<400>185
Xaa Arg Leu Lys Lys Arg Arg Trp Lys Tyr Arg Val Xaa Pro
1 5 10
<210>186
<211>14
<212>PRT
<213> Artificial sequence
<220>
<223> description of artificial sequences: cyclic peptides
<220>
<223> Xaa at position 1 is 4C1-Phe
(L-4-chlorophenylalanine); xaa at position 13 is
D-Pro
<400>186
Xaa Arg Leu Lys Lys Arg Arg Trp Lys Tyr Arg Val Xaa Pro
1 5 10
<210>187
<211>14
<212>PRT
<213> Artificial sequence
<220>
<223> description of artificial sequences: cyclic peptides
<220>
<223> Xaa is AmPhe (L-aminophenylalanine) at position 1;
xaa is D-Pro at position 13
<400>187
Xaa Arg Leu Lys Lys Arg Arg Trp Lys Tyr Arg Val Xaa Pro
1 5 10
<210>188
<211>14
<212>PRT
<213> Artificial sequence
<220>
<223> description of artificial sequences: cyclic peptides
<220>
<223> Xaa is S (Bzl) [ L-O-benzylserine ] at position 1;
xaa is D-Pro at position 13
<400>188
Xaa Arg Leu Lys Lys Arg Arg Trp Lys Tyr Arg Val Xaa Pro
1 5 10
<210>189
<211>14
<212>PRT
<213> Artificial sequence
<220>
<223> description of artificial sequences: cyclic peptides
<220>
<223> Xaa is T (Bzl) [ L-0-benzylthreonine ] at position 1;
xaa is D-Pro at position 13
<400>189
Xaa Arg Leu Lys Lys Arg Arg Trp Lys Tyr Arg Val Xaa Pro
1 5 10
<210>190
<211>14
<212>PRT
<213> Artificial sequence
<220>
<223> description of artificial sequences: cyclic peptides
<220>
<223> Xaa is Orn (L-ornithine) at position 1; xaa is D-Pro at position 13
<400>190
Xaa Arg Leu Lys Lys Arg Arg Trp Lys Tyr Arg Val Xaa Pro
1 5 10
<210>191
<211>14
<212>PRT
<213> Artificial sequence
<220>
<223> description of artificial sequences: cyclic peptides
<220>
<223> Xaa at position 3 is Bip
[ L- (4-phenyl) phenylalanine ]; xaa at position 13 is
D-Pro
<400>191
Leu Arg Xaa Lys Lys Arg Arg Trp Lys Tyr Arg Val Xaa Pro
1 5 10
<210>192
<211>14
<212>PRT
<213> Artificial sequence
<220>
<223> description of artificial sequences: cyclic peptides
<220>
<223> Xaa at position 3 is 4Cl-Phe
(L-4-chlorophenylalanine); xaa at position 13 is
D-Pro
<400>192
Leu Arg Xaa Lys Lys Arg Arg Trp Lys Tyr Arg Val Xaa Pro
1 5 10
<210>193
<211>14
<212>PRT
<213> Artificial sequence
<220>
<223> description of artificial sequences: cyclic peptides
<220>
<223> Xaa is AmPhe (aminophenylalanine) at position 3;
xaa is D-Pro at position 13
<400>193
Leu Arg Xaa Lys Lys Arg Arg Trp Lys Tyr Arg Val Xaa Pro
1 5 10
<210>194
<211>14
<212>PRT
<213> Artificial sequence
<220>
<223> description of artificial sequences: cyclic peptides
<220>
<223> Xaa is S (Bzl) [ L-O-benzyltyrosine ] at position 3;
xaa is D-Pro at position 13
<400>194
Leu Arg Xaa Lys Lys Arg Arg Trp Lys Tyr Arg Val Xaa Pro
1 5 10
<210>195
<211>14
<212>PRT
<213> Artificial sequence
<220>
<223> description of artificial sequences: cyclic peptides
<220>
<223> Xaa is T (Bzl) [ L-O-benzylthreonine ] at position 3;
xaa is D-Pro at position 13
<400>195
Leu Arg Xaa Lys Lys Arg Arg Trp Lys Tyr Arg Val Xaa Pro
1 5 10
<210>196
<211>14
<212>PRT
<213> Artificial sequence
<220>
<223> description of artificial sequences: cyclic peptides
<220>
<223> Xaa is Orn (L-ornithine) at position 3; xaa is D-Pro at position 13
<400>196
Leu Arg Xaa Lys Lys Arg Trp Trp Lys Tyr Arg Val Xaa Pro
1 5 10
<210>197
<211>14
<212>PRT
<213> Artificial sequence
<220>
<223> description of artificial sequences: cyclic peptides
<220>
<223> Xaa at position 8 is
Bip [ L- (4-phenyl) phenylalanine ]; xaa is D-Pro at position 13
<400>197
Leu Arg Leu Lys Lys Arg Arg Xaa Lys Tyr Arg Val Xaa Pro
1 5 10
<210>198
<211>14
<212>PRT
<213> Artificial sequence
<220>
<223> description of artificial sequences: cyclic peptides
<220>
<223> Xaa is 4Cl-Phe at position 8
(L-4-chlorophenylalanine); xaa at position 13 is
D-Pro
<400>198
Leu Arg Leu Lys Lys Arg Arg Xaa Lys Tyr Arg Val Xaa Pro
1 5 10
<210>199
<211>14
<212>PRT
<213> Artificial sequence
<220>
<223> description of artificial sequences: cyclic peptides
<220>
<223> Xaa is AmPhe (L-aminophenylalanine) at position 8;
xaa is D-Pro at position 13
<400>199
Leu Arg Leu Leu Lys Arg Arg Xaa Lys Tyr Arg Val Xaa Pro
1 5 10
<210>200
<211>14
<212>PRT
<213> Artificial sequence
<220>
<223> description of artificial sequences: cyclic peptides
<220>
<223> Xaa is S (Bzl) [ L-0-benzylserine ] at position 8;
xaa is D-Pro at position 13
<400>200
Leu Arg Leu Lys Lys Arg Arg Xaa Lys Tyr Arg Val Xaa Pro
1 5 10
<210>201
<211>14
<212>PRT
<213> Artificial sequence
<220>
<223> description of artificial sequences: cyclic peptides
<220>
<223> Xaa is T (Bzl) [ L-0-benzylthreonine ] at position 8;
xaa is D-Pro at position 13
<400>201
Leu Arg Leu Lys Lys Arg Arg Xaa Lys Tyr Arg Val Xaa Pro
1 5 10
<210>202
<211>14
<212>PRT
<213> Artificial sequence
<220>
<223> description of artificial sequences: cyclic peptides
<220>
<223> Xaa is Orn (L-ornithine) at position 8; xaa is D-Pro at position 13
<400>202
Leu Arg Leu Lys Lys Arg Arg Xaa Lys Tyr Arg Val Xaa Pro
1 5 10
<210>203
<211>14
<212>PRT
<213> Artificial sequence
<220>
<223> description of artificial sequences: cyclic peptides
<220>
<223> Xaa is Bip at position 10
[ L- (4-phenyl) phenylalanine ]; xaa at position 13 is
D-Pro
<400>203
Leu Arg Leu Lys Lys Arg Arg Trp Lys Xaa Arg Val Xaa Pro
1 5 10
<210>204
<211>14
<212>PRT
<213> Artificial sequence
<220>
<223> description of artificial sequences: cyclic peptides
<220>
<223> Xaa is 4C1-Phe at position 10
(L-4-chlorophenylalanine); xaa at position 13 is
D-Pro
<400>204
Leu Arg Leu Lys Lys Arg Arg Trp Lys Xaa Arg Val Xaa Pro
1 5 10
<210>205
<211>14
<212>PRT
<213> Artificial sequence
<220>
<223> description of artificial sequences: cyclic peptides
<220>
<223> Xaa is S (Bzl) [ L-O-benzylserine ] at position 10;
xaa is D-Pro at position 13
<400>205
Leu Arg Leu Lys Lys Arg Arg Trp Lys Xaa Arg Val Xaa Pro
1 5 10
<210>206
<211>14
<212>PRT
<213> Artificial sequence
<220>
<223> description of artificial sequences: cyclic peptides
<220>
<223> Xaa at position 10 is T (Bzl)
[ L-O-benzylthreonine ]; xaa is D-Pro at position 13
<400>206
Leu Arg Leu Lys Lys Arg Arg Trp Lys Xaa Arg Val Xaa Pro
1 5 10
<210>207
<211>14
<212>PRT
<213> Artificial sequence
<220>
<223> description of artificial sequences: cyclic peptides
<220>
<223> Xaa is Orn (L-ornithine) at position 10; xaa is D-Pro at position 13
<400>207
Leu Arg Leu Lys Lys Arg Arg Trp Lys Xaa Arg Val Xaa Pro
1 5 10
<210>208
<211>14
<212>PRT
<213> Artificial sequence
<220>
<223> description of artificial sequences: cyclic peptides
<220>
<223> Xaa at position 12 is Bip
[ L- (4-phenyl) phenylalanine ]; xaa at position 13 is
D-Pro
<400>208
Leu Arg Leu Lys Lys Arg Arg Trp Lys Tyr Arg Xaa Xaa Pro
1 5 10
<210>209
<211>14
<212>PRT
<213> Artificial sequence
<220>
<223> description of artificial sequences: cyclic peptides
<220>
<223> Xaa at position 12 is? cl-Phe
(L-4-chlorophenylalanine); xaa at position 13 is
D-Pro
<400>209
Leu Arg Leu Lys Lys Arg Arg Trp Lys Tyr Arg Xaa Xaa Pro
1 5 10
<210>210
<211>14
<212>PRT
<213> Artificial sequence
<220>
<223> description of artificial sequences: cyclic peptides
<220>
<223> Xaa at position 12 AmPhe
(L-aminophenylalanine); xaa at position 13 is
D-Pro
<400>210
Leu Arg Leu Lys Lys Arg Arg Trp Lys Tyr Arg Xaa Xaa Pro
1 5 10
<210>211
<211>14
<212>PRT
<213> Artificial sequence
<220>
<223> description of artificial sequences: cyclic peptides
<220>
<223> Xaa at position 12 is T (Bzl)
[ L-0-benzylthreonine ]; xaa is D-Pro at position 13
<400>211
Leu Arg Leu Lys Lys Arg Arg Trp Lys Tyr Arg Xaa Xaa Pro
1 5 10
<210>212
<211>14
<212>PRT
<213> Artificial sequence
<220>
<223> description of artificial sequences: cyclic peptides
<220>
<223> Xaa is Orn (L-ornithine) at position 12; xaa is D-Pro at position 13
<400>212
Leu Arg Leu Lys Lys Arg Arg Trp Lys Tyr Arg Xaa Xaa Pro
1 5 10
<210>213
<211>14
<212>PRT
<213> Artificial sequence
<220>
<223> description of artificial sequences: cyclic peptides
<220>
<223> Xaa is Orn (L-ornithine) at position 2; xaa is D-Pro at position 13
<400>213
Leu Xaa Leu Lys Lys Arg Arg Trp Lys Tyr Arg Val Xaa Pro
1 5 10
<210>214
<211>14
<212>PRT
<213> Artificial sequence
<220>
<223> description of artificial sequences: cyclic peptides
<220>
<223> Xaa is Orn (L-ornithine) at position 4; xaa is D-Pro at position 13
<400>214
Leu Arg Leu Xaa Lys Arg Arg Trp Lys Tyr Arg Val Xaa Pro
1 5 10
<210>215
<211>14
<212>PRT
<213> Artificial sequence
<220>
<223> description of artificial sequences: cyclic peptides
<220>
<223> Xaa is Orn (L-ornithine) at position 5; xaa is D-Pro at position 13
<400>215
Leu Arg Leu Lys Xaa Arg Arg Trp Lys Tyr Arg Val Xaa Pro
1 5 10
<210>216
<211>14
<212>PRT
<213> Artificial sequence
<220>
<223> description of artificial sequences: cyclic peptides
<220>
<223> Xaa is Orn (L-ornithine) at position 7; xaa is D-Pro at position 13
<400>216
Leu Arg Leu Lys Lys Arg Xaa Trp Lys Tyr Arg Val Xaa Pro
1 5 10
<210>217
<211>14
<212>PRT
<213> Artificial sequence
<220>
<223> description of artificial sequences: cyclic peptides
<220>
<223> Xaa is Orn (L-ornithine) at position 9; xaa is D-Pro at position 13
<400>217
Leu Arg Leu Lys Lys Arg Arg Trp Xaa Tyr Arg Val Xaa Pro
1 5 10
<210>218
<211>14
<212>PRT
<213> Artificial sequence
<220>
<223> description of artificial sequences: cyclic peptides
<220>
<223> Xaa is Orn (L-ornithine) at position 11; xaa is D-Pro at position 13
<400>218
Leu Arg Leu Lys Lys Arg Arg Trp Lys Tyr Xaa Val Xaa Pro
1 5 10
<210>219
<211>14
<212>PRT
<213> Artificial sequence
<220>
<223> description of artificial sequences: cyclic peptides
<220>
<223> Xaa is D-Pro
<400>219
Leu Arg Leu Lys Lys Arg Gln Trp Lys Tyr Arg Val Xaa Pro
1 5 10
<210>220
<211>14
<212>PRT
<213> Artificial sequence
<220>
<223> description of artificial sequences: cyclic peptides
<220>
<223> Xaa is D-Pro
<400>220
Leu Arg Leu Lys Lys Arg Arg Trp Tyr Tyr Arg Val Xaa Pro
1 5 10
<210>221
<211>14
<212>PRT
<213> Artificial sequence
<220>
<223> description of artificial sequences: cyclic peptides
<220>
<223> Xaa is D-Pro
<400>221
Leu Arg Leu Lys Lys Arg Arg Trp His Tyr Arg Val Xaa Pro
1 5 10
<210>222
<211>14
<212>PRT
<213> Artificial sequence
<220>
<223> description of artificial sequences: cyclic peptides
<220>
<223> Xaa is D-Pro
<400>222
Leu Arg Leu Lys Lys Arg Arg Trp Arg Tyr Arg Val Xaa Pro
1 5 10
<210>223
<211>14
<212>PRT
<213> Artificial sequence
<220>
<223> description of artificial sequences: cyclic peptides
<220>
<223> Xaa is D-Pro
<400>223
Leu Arg Leu Lys Lys Arg Arg Trp Thr Tyr Arg Val Xaa Pro
1 5 10
<210>224
<211>14
<212>PRT
<213> Artificial sequence
<220>
<223> description of artificial sequences: cyclic peptides
<220>
<223> Xaa is D-Pro
<400>224
Leu Arg Leu Lys Lys Arg Arg Trp Gln Tyr Arg Val Xaa Pro
1 5 10
<210>225
<211>14
<212>PRT
<213> Artificial sequence
<220>
<223> description of artificial sequences: cyclic peptides
<220>
<223> Xaa is D-Pro
<400>225
Leu Arg Leu Lys Lys Arg Arg Trp Lys Tyr Tyr Val Xaa Pro
1 5 10
<210>226
<211>14
<212>PRT
<213> Artificial sequence
<220>
<223> description of artificial sequences: cyclic peptides
<220>
<223> Xaa is D-Pro
<400>226
Leu Arg Leu Lys Lys Arg Arg Trp Lys Tyr Trp Val Xaa Pro
1 5 10
<210>227
<211>14
<212>PRT
<213> Artificial sequence
<220>
<223> description of artificial sequences: cyclic peptides
<220>
<223> Xaa is Bip at positions 8 and 10
[ L- (4-phenyl) phenylalanine ]; xaa is D-Pro at position 13
<400>227
Leu Arg Leu Lys Lys Arg Arg Xaa Lys Xaa Arg Val Xaa Pro
1 5 10
<210>228
<211>14
<212>PRT
<213> Artificial sequence
<220>
<223> description of artificial sequences: cyclic peptides
<220>
<223> Xaa is Bip at position 8
[ L- (4-phenyl) phenylalanine ]; xaa is D-Pro at position 13
<400>228
Leu Arg Leu Arg Lys Arg Arg Xaa Lys Tyr Arg Val Xaa Pro
1 5 10
<210>229
<211>14
<212>PRT
<213> Artificial sequence
<220>
<223> description of artificial sequences: cyclic peptides
<220>
<223> Xaa is Bip at position 8
[ L- (4-phenyl) phenylalanine ]; xaa at position 13 is
D-Pro
<400>229
Leu Arg Leu Lys Lys Arg Arg Xaa Lys Tyr Arg Val Xaa Pro
1 5 10
<210>230
<211>14
<212>PRT
<213> Artificial sequence
<220>
<223> description of artificial sequences: cyclic peptides
<220>
<223> Xaa is Bip at position 8
[ L- (4-phenyl) phenylalanine ]; xaa at position 13 is
D-Pro
<400>230
Leu Trp Leu Lys Lys Arg Arg Xaa Lys Tyr Arg Val Xaa Pro
1 5 10
<210>231
<211>14
<212>PRT
<213> Artificial sequence
<220>
<223> description of artificial sequences: cyclic peptides
<220>
<223> Xaa is Bip at position 8
[ L- (4-phenyl) phenylalanine ]; xaa at position 13 is
D-Pro
<400>231
Leu Trp Leu Arg Lys Arg Arg Xaa Lys Tyr Arg Val Xaa Pro
1 5 10
<210>232
<211>14
<212>PRT
<213> Artificial sequence
<220>
<223> description of artificial sequences: cyclic peptides
<220>
<223> Xaa is Bip at position 8
[ L- (4-phenyl) phenylalanine ]; xaa at position 13 is
D-Pro
<400>232
Leu Trp Leu Lys Lys Arg Arg Xaa Arg Tyr Arg Val Xaa Pro
1 5 10
<210>233
<211>14
<212>PRT
<213> Artificial sequence
<220>
<223> description of artificial sequences: cyclic peptides
<220>
<223> Xaa is Bip at positions 8 and 10
[ L- (4-phenyl) phenylalanine ]; xaa at position 13 is
D-Pro
<400>233
Leu Trp Leu Arg Lys Arg Arg Xaa Lys Xaa Arg Val Xaa Pro
1 5 10
<210>234
<211>14
<212>PRT
<213> Artificial sequence
<220>
<223> description of artificial sequences: cyclic peptides
<220>
<223> Xaa is Bip at positions 8 and 10
[ L- (4-phenyl) phenylalanine ]; xaa at position 13 is
D-Pro
<400>234
Leu Trp Leu Lys Lys Arg Arg Xaa Arg Xaa Arg Val Xaa Pro
1 5 10
<210>235
<211>14
<212>PRT
<213> Artificial sequence
<220>
<223> description of artificial sequences: cyclic peptides
<220>
<223> Xaa is Bip at positions 8, 10, 12
[ L- (4-phenyl) phenylalanine ]; xaa at position 13 is
D-Pro
<400>235
Leu Trp Leu Arg Lys Arg Arg Xaa Arg Xaa Arg Xaa Xaa Pro
1 5 10
<210>236
<211>14
<212>PRT
<213> Artificial sequence
<220>
<223> description of artificial sequences: cyclic peptides
<220>
<223> Xaa is 4Cl-Phe at position 1
(L-4-chlorophenylalanine); xaa in position 8 is
Bip [ L- (4-phenyl) phenylalanine ]; xaa is D-Pro at position 13
<400>236
Xaa Arg Leu Lys Lys Arg Arg Xaa Lys Tyr Arg Val Xaa Pro
1 5 10
<210>237
<211>14
<212>PRT
<213> Artificial sequence
<220>
<223> description of artificial sequences: cyclic peptides
<220>
<223> Xaa at position 1 is 4C1-Phe
(L-4-Chlorophenylalanine Xaa is Bip [ L- (4-phenyl) phenylalanine ] at positions 8 and 10; Xaa is D-Pro at position 13
<400>237
Xaa Arg Leu Lys Lys Arg Arg Xaa Lys Xaa Arg Val Xaa Pro
1 5 10
<210>238
<211>14
<212>PRT
<213> Artificial sequence
<220>
<223> description of artificial sequences: cyclic peptides
<220>
<223> Xaa is 4Cl-Phe at position 1
(L-4-chlorophenylalanine Xaa at positions 8 and 12 is
Is Bip [ L- (4-phenyl) phenylalanine ]; xaa is D-Pro at position 13
<400>238
Xaa Arg Leu Lys Lys Arg Arg Xaa Lys Tyr Arg Xaa Xaa Pro
1 5 10
<210>239
<211>14
<212>PRT
<213> Artificial sequence
<220>
<223> description of artificial sequences: cyclic peptides
<220>
<223> Xaa is 4Cl-Phe at position 1
(4-chlorophenylalanine); xaa is Bip [ L- (4-phenyl) phenylalanine ] at positions 8, 10, 12; xaa at position 13 is
D-Pro
<400>239
Xaa Arg Leu Lys Lys Arg Arg Xaa Lys Xaa Arg Xaa Xaa Pro
1 5 10
<210>240
<211>14
<212>PRT
<213> Artificial sequence
<220>
<223> description of artificial sequences: cyclic peptides
<220>
<223> Xaa is 4Cl-Phe at position 1
(4-chlorophenylalanine); xaa is Bip at position 8
[ L- (4-phenyl) phenylalanine ]; xaa at position 13 is
D-Pro
<400>240
Xaa Arg Leu Arg Lys Arg Arg Xaa Lys Tyr Arg Val Xaa Pro
1 5 10
<210>241
<211>14
<212>PRT
<213> Artificial sequence
<220>
<223> description of artificial sequences: cyclic peptides
<220>
<223> Xaa is 4Cl-Phe at position 1
(4-chlorophenylalanine); xaa is Bip at position 8
[ L- (4-phenyl) phenylalanine ]; xaa at position 13 is
D-Pro
<400>241
Xaa Arg Leu Lys Lys Arg Arg Xaa Arg Tyr Arg Val Xaa Pro
1 5 10
<210>242
<211>14
<212>PRT
<213> Artificial sequence
<220>
<223> description of artificial sequences: cyclic peptides
<220>
<223> Xaa is 4Cl-Phe at position 1
(L-4-chlorophenylalanine); xaa in position 8 is
Pib [ L- (4-phenyl) phenylalanine ]; xaa is D-Pro at position 13
<400>242
Xaa Trp Leu Lys Lys Arg Arg Xaa Lys Tyr Arg Val Xaa Pro
1 5 10
<210>243
<211>14
<212>PRT
<213> Artificial sequence
<220>
<223> description of artificial sequences: cyclic peptides
<220>
<223> Xaa at position 1 is aCl-Phe
(L-4-chlorophenylalanine); xaa in position 8 is
Bip [ L- (4-phenyl) phenylalanine ]; xaa is D-Pro at position 13
<400>243
Xaa Trp Leu Arg Lys Arg Arg Xaa Lys Tyr Arg Val Xaa Pro
1 5 10
<210>244
<211>14
<212>PRT
<213> Artificial sequence
<220>
<223> description of artificial sequences: cyclic peptides
<220>
<223> Xaa is 4Cl-Phe at position 1
(L-4-chlorophenylalanine); xaa in position 8 is
Bip [ L- (4-phenyl) phenylalanine ]; xaa is D-Pro at position 13
<400>244
Xaa Trp Leu Lys Lys Arg Arg Xaa Arg Tyr Arg Val Xaa Pro
1 5 10
<210>245
<211>14
<212>PRT
<213> Artificial sequence
<220>
<223> description of artificial sequences: cyclic peptides
<220>
<223> Xaa is 4Cl-Phe at position 1
(L-4-chlorophenylalanine); xaa in position 8 is
Bip [ L- (4-phenyl) phenylalanine ]; xaa is D-Pro at position 13
<400>245
Xaa Trp Leu Arg Lys Arg Arg Xaa Lys Xaa Arg Val Xaa Pro
1 5 10
<210>246
<211>14
<212>PRT
<213> Artificial sequence
<220>
<223> description of artificial sequences: cyclic peptides
<220>
<223> Xaa at position 1 is 4C1-Phe
(L-4-chlorophenylalanine); xaa is Bip [ L- (4-phenyl) phenylalanine ] at positions 8, 10; xaa is D-Pro at position 13
<400>246
Xaa Trp Leu Lys Lys Arg Arg Xaa Arg Xaa Arg Val Xaa Pro
1 5 10
<210>247
<211>14
<212>PRT
<213> Artificial sequence
<220>
<223> description of artificial sequences: cyclic peptides
<220>
<223> Xaa is D-Pro
<400>247
Leu Arg Leu Lys Lys Arg Arg Trp Lys Tyr Arg Val Xaa Gly
1 5 10
<210>248
<211>14
<212>PRT
<213> Artificial sequence
<220>
<223> description of artificial sequences: cyclic peptides
<220>
<223> Xaa is D-Pro
<400>248
Leu Arg Leu Lys Lys Arg Arg Trp Lys Tyr Arg Val Xaa Arg
1 5 10
<210>249
<211>14
<212>PRT
<213> Artificial sequence
<220>
<223> description of artificial sequences: cyclic peptides
<220>
<223> Xaa is D-Pro
<400>249
Leu Arg Leu Lys Lys Arg Arg Trp Lys Tyr Arg Val Xaa Tyr
1 5 10
<210>250
<211>14
<212>PRT
<213> Artificial sequence
<220>
<223> description of artificial sequences: cyclic peptides
<220>
<223> Xaa is D-Pro
<400>250
Leu Arg Leu Lys Lys Arg Arg Trp Lys Tyr Arg Val Xaa Phe
1 5 10
<210>251
<211>14
<212>PRT
<213> Artificial sequence
<220>
<223> description of artificial sequences: cyclic peptides
<220>
<223> Xaa is D-Pro
<400>251
Leu Arg Leu Lys Lys Arg Arg Trp Lys Tyr Arg Val Xaa Trp
1 5 10
<210>252
<211>14
<212>PRT
<213> Artificial sequence
<220>
<223> description of artificial sequences: cyclic peptides
<220>
<223> Xaa is D-Pro
<400>252
Leu Arg Leu Lys Lys Arg Arg Trp Lys Tyr Arg Val Xaa Leu
1 5 10
<210>253
<211>14
<212>PRT
<213> Artificial sequence
<220>
<223> description of artificial sequences: cyclic peptides
<220>
<223> Xaa is D-Pro
<400>253
Leu Arg Leu Lys Lys Arg Arg Trp Lys Tyr Arg Val Xaa Ile
1 5 10
<210>254
<211>14
<212>PRT
<213> Artificial sequence
<220>
<223> description of artificial sequences: cyclic peptides
<220>
<223> Xaa is D-Pro at position 13; xaa is Cha (L-cyclohexylalanine) at position 14
<400>254
Leu Arg Leu Lys Lys Arg Arg Trp Lys Tyr Arg Val Xaa Xaa
1 5 10
<210>255
<211>14
<212>PRT
<213> Artificial sequence
<220>
<223> description of artificial sequences: cyclic peptides
<220>
<223> Xaa is D-Pro at position 13; xaa at position 14 is
2-Nal (L-2-naphthylalanine)
<400>255
Leu Arg Leu Lys Lys Arg Arg Trp Lys Tyr Arg Val Xaa Xaa
1 5 10
<210>256
<211>14
<212>PRT
<213> Artificial sequence
<220>
<223> description of artificial sequences: cyclic peptides
<220>
<223> Xaa is D-Pro at position 13; xaa at position 14 is
4- (n-hexylcarbonylamino) -Pro
<400>256
Leu Arg Leu Lys Lys Arg Arg Trp Lys Tyr Arg Val Xaa Xaa
1 5 10
<210>257
<211>14
<212>PRT
<213> Artificial sequence
<220>
<223> description of artificial sequences: cyclic peptides
<220>
<223> Xaa is D-Pro at position 13; xaa at position 14 is
4- (n-hexylheptylamino) -Pro
<400>257
Leu Arg Leu Lys Lys Arg Arg Trp Lys Tyr Arg Val Xaa Xaa
1 5 10
<210>258
<211>14
<212>PRT
<213> Artificial sequence
<220>
<223> description of artificial sequences: cyclic peptides
<220>
<223> Xaa is D-Pro at position 13; xaa at position 14 is
4- (4-Phenylbenzylcarbonylamino) -Pro
<400>258
Leu Arg Leu Lys Lys Arg Arg Trp Lys Tyr Arg Val Xaa Xaa
1 5 10
<210>259
<211>14
<212>PRT
<213> Artificial sequence
<220>
<223> description of artificial sequences: cyclic peptides
<220>
<223> Xaa is D-Pro at position 13; xaa at position 14 is
4- (Diphenylmethylcarbonylamino) -Pro
<400>259
Leu Arg Leu Lys Lys Arg Arg Trp Lys Tyr Arg Val Xaa Xaa
1 5 10
<210>260
<211>14
<212>PRT
<213> Artificial sequence
<220>
<223> description of artificial sequences: cyclic peptides
<220>
<223> Xaa is D-Pro at position 13; xaa at position 14 is
4- (3-Aminopropylcarbonylamino) -Pro
<400>260
Leu Arg Leu Lys Lys Arg Arg Trp Lys Tyr Arg Val Xaa Xaa
1 5 10
<210>261
<211>14
<212>PRT
<213> Artificial sequence
<220>
<223> description of artificial sequences: cyclic peptides
<220>
<223> Xaa is D-Pro at position 13; xaa at position 14 is
4- (5-Aminopentylcarbonylamino) -Pro
<400>261
Leu Arg Leu Lys Lys Arg Arg Trp Lys Tyr Arg Val Xaa Xaa
1 5 10
<210>262
<211>14
<212>PRT
<213> Artificial sequence
<220>
<223> description of artificial sequences: cyclic peptides
<220>
<223> Xaa is D-Pro at position 13; xaa at position 14 is
4- (methylcarbonylamino) -Pro
<400>262
Leu Arg Leu Lys Lys Arg Arg Trp Lys Tyr Arg Val Xaa Xaa
1 5 10
<210>263
<211>14
<212>PRT
<213> Artificial sequence
<220>
<223> description of artificial sequences: cyclic peptides
<220>
<223> Xaa is D-Pro at position 13; xaa at position 14 is
4- (ethylcarbonylamino) -Pro
<400>263
Leu Arg Leu Lys Lys Arg Arg Trp Lys Tyr Arg Val Xaa Xaa
1 5 10
<210>264
<211>14
<212>PRT
<213> Artificial sequence
<220>
<223> description of artificial sequences: cyclic peptides
<220>
<223> Xaa is D-Pro at position 13; xaa at position 14 is
4- (isopropylcarbonylamino) -Pro
<400>264
Leu Arg Leu Lys Lys Arg Arg Trp Lys Tyr Arg Val Xaa Xaa
1 5 10
<210>265
<211>14
<212>PRT
<213> Artificial sequence
<220>
<223> description of artificial sequences: cyclic peptides
<220>
<223> Xaa is D-Pro at position 13; xaa at position 14 is
4- (isobutylcarbonylamino) -Pro
<400>265
Leu Arg Leu Lys Lys Arg Arg Trp Lys Tyr Arg Val Xaa Xaa
1 5 10
<210>266
<211>14
<212>PRT
<213> Artificial sequence
<220>
<223> description of artificial sequences: cyclic peptides
<220>
<223> Xaa is D-Pro at position 13; xaa at position 14 is
4- (n-Propylcarbonylamino) -Pro
<400>266
Leu Arg Leu Leu Lys Arg Arg Trp Lys Tyr Arg Val Xaa Xaa
1 5 10
<210>267
<211>14
<212>PRT
<213> Artificial sequence
<220>
<223> description of artificial sequences: cyclic peptides
<220>
<223> Xaa is D-Pro at position 13; xaa at position 14 is
4- (Cyclohexylcarbonylamino) -Pro
<400>267
Leu Arg Leu Lys Lys Arg Arg Trp Lys Tyr Arg Val Xaa Xaa
1 5 10
<210>268
<211>14
<212>PRT
<213> Artificial sequence
<220>
<223> description of artificial sequences: cyclic peptides
<220>
<223> Xaa is D-Pro at position 13; xaa at position 14 is
4- (Cyclohexylmethylcarbonylamino) -Pro
<400>268
Leu Arg Leu Lys Lys Arg Arg Trp Lys Tyr Arg Val Xaa Xaa
1 5 10
<210>269
<211>14
<212>PRT
<213> Artificial sequence
<220>
<223> description of artificial sequences: cyclic peptides
<220>
<223> Xaa is D-Pro at position 13; xaa at position 14 is
4- (n-butylcarbonylamino) -Pro
<400>269
Leu Arg Leu Lys Lys Arg Arg Trp Lys Tyr Arg Val Xaa Xaa
1 5 10
<210>270
<211>14
<212>PRT
<213> Artificial sequence
<220>
<223> description of artificial sequences: cyclic peptides
<220>
<223> Xaa is D-Pro at position 13; xaa at position 14 is
4- (pentylcarbonylamino) -Pro
<400>270
Leu Arg Leu Lys Lys Arg Arg Trp Lys Tyr Arg Val Xaa Xaa
1 5 10
<210>271
<211>14
<212>PRT
<213> Artificial sequence
<220>
<223> description of artificial sequences: cyclic peptides
<220>
<223> Xaa is D-Pro at position 13; xaa at position 14 is
4- (Benzylcarbonylamino) -Pro
<400>271
Leu Arg Leu Lys Lys Arg Arg Trp Lys Tyr Arg Val Xaa Xaa
1 5 10
<210>272
<211>14
<212>PRT
<213> Artificial sequence
<220>
<223> description of artificial sequences: cyclic peptides
<220>
<223> Xaa is D-Pro at position 13; xaa at position 14 is
4- (3-indolylmethyl) -Pro
<400>272
Leu Arg Leu Lys Lys Arg Arg Trp Lys Tyr Arg Val Xaa Xaa
1 5 10
<210>273
<211>14
<212>PRT
<213> Artificial sequence
<220>
<223> description of artificial sequences: cyclic peptides
<220>
<223> Xaa is D-Pro at position 13; xaa at position 14 is
4- [2- (3-indolyl) ethyl ] -Pro
<400>273
Leu Arg Leu Lys Lys Arg Arg Trp Lys Tyr Arg Val Xaa Xaa
1 5 10
<210>274
<211>14
<212>PRT
<213> Artificial sequence
<220>
<223> description of artificial sequences: cyclic peptides
<220>
<223> Xaa is D-Pro at position 13; xaa at position 14 is
4- (4-Phenylphenyl) -Pro
<400>274
Leu Arg Leu Lys Lys Arg Arg Trp Lys Tyr Arg Val Xaa Xaa
1 5 10
<210>275
<211>14
<212>PRT
<213> Artificial sequence
<220>
<223> description of artificial sequences: cyclic peptides
<220>
<223> Xaa is D-Pro at position 13; xaa at position 14 is
4- (n-nonyl-carbonylamino) -Pro
<400>275
Leu Arg Leu Lys Lys Arg Arg Trp Lys Tyr Arg Val Xaa Xaa
1 5 10
<210>276
<211>14
<212>PRT
<213> Artificial sequence
<220>
<223> description of artificial sequences: cyclic peptides
<220>
<223> Xaa is D-Pro
<400>276
Leu Arg Leu Lys Lys Gly Arg Trp Lys Tyr Arg Val Xaa Pro
1 5 10
<210>277
<211>13
<212>PRT
<213> Artificial sequence
<220>
<223> description of artificial sequences: template-immobilized peptidomimetics incorporating a chain of 12 amino acid residues
<220>
<223> Xaa is 5-aminomethyl-9, 9-dimethyl-3, 6-dimethoxyxanthene-4
Divalent radicals of-acetic acid
<400>277
Leu Arg Leu Lys Lys Arg Arg Trp Lys Tyr Arg Val Xaa
1 5 10
<210>278
<211>14
<212>PRT
<213> Artificial sequence
<220>
<223> description of artificial sequences: cyclic peptides
<220>
<223> Xaa is D-Pro
<400>278
Leu Tyr Leu Lys Lys Arg Arg Trp Lys Tyr Tyr Val Xaa Pro
1 5 10
<210>279
<211>14
<212>PRT
<213> Artificial sequence
<220>
<223> description of artificial sequences: cyclic peptides
<220>
<223> Xaa is D-Pro
<400>279
Leu Trp Leu Lys Lys Arg Arg Trp Lys Tyr Tyr Val Xaa Pro
1 5 10
<210>280
<211>14
<212>PRT
<213> Artificial sequence
<220>
<223> description of artificial sequences: cyclic peptides
<220>
<223> Xaa is D-Pro
<400>280
Arg Trp Leu Lys Lys Arg Arg Trp Lys Tyr Trp Val Xaa Pro
1 5 10
<210>281
<211>14
<212>PRT
<213> Artificial sequence
<220>
<223> description of artificial sequences: cyclic peptides
<220>
<223> Xaa is D-Pro
<400>281
Arg Trp Leu Lys Lys Arg Arg Trp Lys Tyr Tyr Val Xaa Pro
1 5 10
<210>282
<211>14
<212>PRT
<213> Artificial sequence
<220>
<223> description of artificial sequences: cyclic peptides
<220>
<223> Xaa is D-Pro
<400>282
Leu Trp Leu Lys Lys Arg Arg Trp Lys Tyr Tyr Arg Xaa Pro
1 5 10
<210>283
<211>14
<212>PRT
<213> Artificial sequence
<220>
<223> description of artificial sequences: cyclic peptides
<220>
<223> Xaa is D-Pro
<400>283
Leu Trp Leu Lys Lys Arg Arg Trp Lys Tyr Tyr Arg Xaa Pro
1 5 10
<210>284
<211>14
<212>PRT
<213> Artificial sequence
<220>
<223> description of artificial sequences: cyclic peptides
<220>
<223> Xaa is D-Pro
<400>284
Arg Trp Leu Lys Lys Arg Arg Trp Lys Tyr Tyr Arg Xaa Pro
1 5 10
<210>285
<211>14
<212>PRT
<213> Artificial sequence
<220>
<223> description of artificial sequences: cyclic peptides
<220>
<223> Xaa is Y (Bzl) [ L-O-benzylserine ] at position 6;
xaa is D-Pro at position 13
<400>285
Leu Arg Leu Lys Lys Xaa Arg Trp Lys Tyr Arg Val Xaa Pro
1 5 10
<210>286
<211>14
<212>PRT
<213> Artificial sequence
<220>
<223> description of artificial sequences: cyclic peptides
<220>
<223> Xaa is D-Y (Bzl) [ D-O-benzylserine ] at position 6;
xaa is D-Pro at position 13
<400>286
Leu Arg Leu Lys Lys Xaa Arg Trp Lys Tyr Arg Val Xaa Pro
1 5 10
<210>287
<211>14
<212>PRT
<213> Artificial sequence
<220>
<223> description of artificial sequences: cyclic peptides
<220>
<223> Xaa is Bip at position 1
[ L- (4-phenyl) phenylalanine ]; xaa at position 13 is
D-Pro
<400>287
Xaa Trp Leu Lys Lys Arg Arg Trp Lys Tyr Tyr Arg Xaa Pro
1 5 10
<210>288
<211>14
<212>PRT
<213> Artificial sequence
<220>
<223> description of artificial sequences: cyclic peptides
<220>
<223> Xaa is D-Pro
<400>288
Thr Trp Leu Lys Lys Arg Arg Trp Lys Tyr Tyr Arg Xaa Pro
1 5 10
<210>289
<211>14
<212>PRT
<213> Artificial sequence
<220>
<223> description of artificial sequences: cyclic peptides
<220>
<223> Xaa at position 2 is Bip
[ L- (4-phenyl) phenylalanine ]; xaa at position 13 is
D-Pro
<400>289
Arg Xaa Leu Lys Lys Arg Arg Trp Lys Tyr Tyr Arg Xaa Pro
1 5 10
<210>290
<211>14
<212>PRT
<213> Artificial sequence
<220>
<223> description of artificial sequences: cyclic peptides
<220>
<223> Xaa is D-Pro
<400>290
Arg Thr Leu Lys Lys Arg Arg Trp Lys Tyr Tyr Arg Xaa Pro
1 5 10
<210>291
<211>14
<212>PRT
<213> Artificial sequence
<220>
<223> description of artificial sequences: cyclic peptides
<220>
<223> Xaa is D-Pro
<400>291
Arg Trp Thr Lys Lys Arg Arg Trp Lys Tyr Tyr Arg Xaa Pro
1 5 10
<210>292
<211>14
<212>PRT
<213> Artificial sequence
<220>
<223> description of artificial sequences: cyclic peptides
<220>
<223> Xaa is D-Pro
<400>292
Arg Trp Leu Arg Lys Arg Arg Trp Lys Tyr Tyr Arg Xaa Pro
1 5 10
<210>293
<211>14
<212>PRT
<213> Artificial sequence
<220>
<223> description of artificial sequences: cyclic peptides
<220>
<223> Xaa is D-Pro
<400>293
Arg Trp Leu Gln Lys Arg Arg Trp Lys Tyr Tyr Arg Xaa Pro
1 5 10
<210>294
<211>14
<212>PRT
<213> Artificial sequence
<220>
<223> description of artificial sequences: cyclic peptides
<220>
<223> Xaa is D-Pro
<400>294
Lys Trp Leu Lys Lys Arg Arg Trp Lys Tyr Tyr Arg Xaa Pro
1 5 10
<210>295
<211>14
<212>PRT
<213> Artificial sequence
<220>
<223> description of artificial sequences: cyclic peptides
<220>
<223> Xaa is D-Pro
<400>295
Tyr Trp Leu Lys Lys Arg Arg Trp Lys Tyr Tyr Arg Xaa Pro
1 5 10
<210>296
<211>14
<212>PRT
<213> Artificial sequence
<220>
<223> description of artificial sequences: cyclic peptides
<220>
<223> Xaa is D-Pro
<400>296
Trp Trp Leu Lys Lys Arg Arg Trp Lys Tyr Tyr Arg Xaa Pro
1 5 10
<210>297
<211>14
<212>PRT
<213> Artificial sequence
<220>
<223> description of artificial sequences: cyclic peptides
<220>
<223> Xaa is D-Pro
<400>297
Val Trp Leu Lys Lys Arg Arg Trp Lys Tyr Tyr Arg Xaa Pro
1 5 10
<210>298
<211>14
<212>PRT
<213> Artificial sequence
<220>
<223> description of artificial sequences: cyclic peptides
<220>
<223> Xaa is D-Pro
<400>298
Gln Trp Leu Lys Lys Arg Arg Trp Lys Tyr Tyr Arg Xaa Pro
1 5 10
<210>299
<211>14
<212>PRT
<213> Artificial sequence
<220>
<223> description of artificial sequences: cyclic peptides
<220>
<223> Xaa is Cha (L-cyclohexylalanine) at position 1;
xaa is D-Pro at position 13
<400>299
Xaa Trp Leu Lys Lys Arg Arg Trp Lys Tyr Tyr Arg Xaa Pro
1 5 10
<210>300
<211>14
<212>PRT
<213> Artificial sequence
<220>
<223> description of artificial sequences: cyclic peptides
<220>
<223> Xaa is Y (Bzl) [ L-O-benzylserine ] at position 1;
xaa is D-Pro at position 13
<400>300
Xaa Trp Leu Lys Lys Arg Arg Trp Lys Tyr Tyr Arg Xaa Pro
1 5 10
<210>301
<211>14
<212>PRT
<213> Artificial sequence
<220>
<223> description of artificial sequences: linear branched chain protected peptides
<220>
<223>Xaa(1)＝Arg(Pbf)；(2)＝Lys(Boc)；(3)＝Lys(Boc)；
(4)＝Cys(Acm)；(5)＝Arg(Pbf)；(8)＝D-Pro；
(11)＝Cys(Acm)；(12)＝Lys(Boc)；(13)＝Trp(Boc)；
(14)＝Arg(Pbf)
<400>301
Xaa Xaa Xaa Xaa Xaa Leu Pro Xaa Val Arg Xaa Xaa Xaa Xaa
1 5 10
<210>302
<211>14
<212>PRT
<213> Artificial sequence
<220>
<223> description of artificial sequences: cyclic peptides
<220>
<221>DISULFID
<222>(3)..(10)
<220>
<223> Xaa is D-Pro
<400>302
Leu Arg Cys Lys Lys Arg Arg Trp Lys Cys Arg Val Xaa Pro
1 5 10
<210>303
<211>13
<212>PRT
<213> Artificial sequence
<220>
<223> description of artificial sequences: linear branched chain protected peptides
<220>
<220>
<223>Xaa(1)＝Arg(Pbf)：(2)＝Trp(Boc)；(3)＝Lys(Boc)；
(4)＝Tyr(tBu)；(5)＝Arg(Pbf)；(6)＝D-Pro；
(7)＝4-AllocNH-l-Fmoc-Pro；(9)＝Arg(Pbf)；
(11)＝Lys(Boc)；(12)＝Lys(Boc)；(13)＝Arg(PbF)
<400>303
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Leu Xaa Leu Xaa Xaa Xaa
1 5 10
<210>304
<211>14
<212>PRT
<213> Artificial sequence
<220>
<223> description of artificial sequences: dimeric template-immobilized peptidomimetics incorporating two chains of 12 amino acid residues
<220>
<223> Xaa is D-Pro at position 13; xaa at position 14 is
4-amino-Pro linked to another 4-amino-Pro via CO-trimethylene-CO as Leu Arg
Leu Lys Lys Arg Arg Trp Lys Tyr Arg Val D-Pro
A member of the 4-amino-Pro ring
<400>304
Leu Arg Leu Lys Lys Arg Arg Trp Lys Tyr Arg Val Xaa Xaa
1 5 10

Claims (51)

1. A compound of the general formula and pharmaceutically acceptable salts thereof
And
wherein
Is one of the groups of the formula
Wherein
Is B is of the formula-NR20CH(R71) -or a residue of an L- α -amino acid of a residue of an enantiomer of one of the groups a1-a69 as defined herein after;
is one of the following groups
R1Is H; lower alkyl or aryl-lower alkyl;
R2is H; an alkyl group; an alkenyl group; - (CH)2)m(CHR61)sOR55；
-(CH2)m(CHR61)sSR56；-(CH2)m(CHR61)sNR33R34；
-(CH2)m(CHR61)sOCONR33R75；-(CH2)m(CHR61)sNR20CONR33R82；
-(CH2)o(CHR61)sCOOR57；-(CH2)o(CHR61)sCONR58R59；
-(CH2)o(CHR61)sPO(OR60)2；-(CH2)o(CHR61)sSO2R62Or
-(CH2)o(CHR61)sC6H4R8；
R3Is H; an alkyl group; an alkenyl group; - (CH)2)m(CHR61)sOR55；
-(CH2)m(CHR61)sSR56；-(CH2)m(CHR61)sNR33R34；
-(CH2)m(CHR61)sOCONR33R75；-(CH2)m(CHR61)sNR20CONR33R82；
-(CH2)o(CHR61)sCOOR57；-(CH2)o(CHR61)sCONR58R59；
-(CH2)o(CHR61)sPO(OR60)2；-(CH2)o(CHR61)sSO2R62Or
-(CH2)o(CHR61)sC6H4R8；
R4Is H; an alkyl group; an alkenyl group; - (CH)2)m(CHR61)sOR55；
-(CH2)m(CHR61)sSR56；-(CH2)m(CHR61)sNR33R34；
-(CH2)m(CHR61)sOCONR33R75；-(CH2)m(CHR61)sNR20CONR33R82；
-(CH2)p(CHR61)sCOOR57；-(CH2)p(CHR61)sCONR58R59；
-(CH2)p(CHR61)sPO(OR60)2；-(CH2)p(CHR61)sSO2R62Or
-(CH2)o(CHR61)sC6H4R8；
R5Is an alkyl group; an alkenyl group; - (CH)2)o(CHR61)sOR55；
-(CH2)o(CHR61)sSR56；-(CH2)o(CHR61)sNR33R34；
-(CH2)o(CHR61)sOCONR33R75；-(CH2)o(CHR61)sNR20CONR33R82；
-(CH2)o(CHR61)sCOOR57；-(CH2)o(CHR61)sCONR58R59；
-(CH2)o(CHR61)sPO(OR60)2；-(CH2)o(CHR61)sSO2R62Or
-(CH2)o(CHR61)sC6H4R8；
R6Is H; an alkyl group; an alkenyl group; - (CH)2)o(CHR61)sOR55；
-(CH2)o(CHR61)sSR56；-(CH2)o(CHR61)sNR33R34；
-(CH2)o(CHR61)sOCONR33R75；-(CH2)o(CHR61)sNR20CONR33R82；
-(CH2)o(CHR61)sCOOR57；-(CH2)o(CHR61)sCONR58R59；
-(CH2)o(CHR61)sPO(OR60)2；-(CH2)o(CHR61)sSO2R62Or
-(CH2)o(CHR61)sC6H4R8；
R7Is an alkyl group; an alkenyl group; - (CH)2)q(CHR61)sOR55；
-(CH2)q(CHR61)sNR33R34；-(CH2)q(CHR61)sOCONR33R75；
-(CH2)q(CHR61)sNR20CONR33R82；-(CH2)r(CHR61)sCOOR57；
-(CH2)r(CHR61)sCONR58R59；-(CH2)r(CHR61)sPO(OR60)2；
-(CH2)r(CHR61)sSO2R62Or- (CH)2)r(CHR61)sC6H4R8；
R8Is H; cl; f; CF (compact flash)3；NO2(ii) a A lower alkyl group; a lower alkenyl group; an aryl group; aryl-lower alkyl; - (CH)2)o(CHR61)sOR55；-(CH2)o(CHR61)sSR56；
-(CH2)o(CHR61)NR33R34；-(CH2)o(CHR61)sOCONR33R75；
-(CH2)o(CHR61)sNR20CONR33R82；-(CH2)o(CHR61)sCOOR57；
-(CH2)o(CHR61)sCONR58R59；-(CH2)o(CHR61)sPO(OR60)2；
-(CH2)o(CHR61)sSO2R62Or- (CH)2)o(CHR61)sCOR64；
R9Is an alkyl group; an alkenyl group; - (CH)2)o(CHR61)sOR55；
-(CH2)o(CHR61)sSR56；-(CH2)o(CHR61)sNR33R34；
-(CH2)o(CHR61)sOCONR33R75；-(CH2)o(CHR61)sNR20CONR33R82；
-(CH2)o(CHR61)sCOOR57；-(CH2)o(CHR61)sCONR58R59；
-(CH2)o(CHR61)sPO(OR60)2；-(CH2)o(CHR61)sSO2R62Or
-(CH2)o(CHR61)sC6H4R8；
R10Is an alkyl group; an alkenyl group; - (CH)2)o(CHR61)sOR55；
-(CH2)o(CHR61)sSR56；-(CH2)o(CHR61)sNR33R34；
-(CH2)o(CHR61)sOCONR33R75；-(CH2)o(CHR61)sNR20CONR33R82；
-(CH2)o(CHR61)sCOOR57；-(CH2)o(CHR61)sCONR58R59；
-(CH2)o(CHR61)sPO(OR60)2；-(CH2)o(CHR61)sSO2R62Or
-(CH2)o(CHR61)sC6H4R8；
R11Is H; an alkyl group; an alkenyl group; - (CH)2)m(CHR61)sOR55；
-(CH2)m(CHR61)sNR33R34；-(CH2)m(CHR61)sOCONR33R75；
-(CH2)m(CHR61)sNR20CONR33R82；-(CH2)o(CHR61)sCOOR57；
-(CH2)o(CHR61)sCONR58R59；-(CH2)o(CHR61)sPO(OR60)2；
-(CH2)o(CHR61)sSO2R62Or- (CH)2)o(CHR61)sC6H4R8；
R12Is H; an alkyl group; an alkenyl group; - (CH)2)m(CHR61)sOR55；
-(CH2)m(CHR61)sSR56；-(CH2)m(CHR61)sNR33R34；
-(CH2)m(CHR61)sOCONR33R75；-(CH2)m(CHR61)sNR20CONR33R82；
-(CH2)r(CHR61)sCOOR57；-(CH2)r(CHR61)sCONR58R59；
-(CH2)r(CHR61)sPO(OR60)2；-(CH2)r(CHR61)sSO2R62Or
-(CH2)r(CHR61)sC6H4R8；
R13Is an alkyl group; an alkenyl group; - (CH)2)q(CHR61)sOR55；
-(CH2)q(CHR61)sSR56；-(CH2)q(CHR61)sNR33R34；
-(CH2)q(CHR61)sOCONR33R75；-(CH2)q(CHR61)sNR20CONR33R82；
-(CH2)q(CHR61)sCOOR57；-(CH2)q(CHR61)sCONR58R59；
-(CH2)q(CHR61)sPO(OR60)2；-(CH2)q(CHR61)sSO2R62Or
-(CH2)q(CHR61)sC6H4R8；
R14Is H; an alkyl group; an alkenyl group; - (CH)2)m(CHR61)sOR55；
-(CH2)m(CHR61)sNR33R34；-(CH2)m(CHR61)sOCONR33R75；
-(CH2)m(CHR61)sNR20CONR33R82；-(CH2)q(CHR61)sCOOR57；
-(CH2)q(CHR61)sCONR58R59；-(CH2)q(CHR61)sPO(OR60)2；
-(CH2)q(CHR61)sSOR62Or- (CH)2)q(CHR61)sC6H4R8；
R15Is an alkyl group; an alkenyl group; - (CH)2)o(CHR61)sOR55；
-(CH2)o(CHR61)sSR56；-(CH2)o(CHR61)sNR33R34；
-(CH2)o(CHR61)sOCONR33R75；-(CH2)o(CHR61)sNR20CONR33R82；
-(CH2)o(CHR61)sCOOR57；-(CH2)o(CHR61)sCONR58R59；
-(CH2)o(CHR61)sPO(OR60)2；-(CH2)o(CHR61)sSO2R62Or
-(CH2)o(CHR61)sC6H4R8；
R16Is an alkyl group; an alkenyl group; - (CH)2)o(CHR61)sOR55；
-(CH2)o(CHR61)sSR56；-(CH2)o(CHR61)sNR33R34；
-(CH2)o(CHR61)sOCONR33R75；-(CH2)o(CHR61)sNR20CONR33R82；
-(CH2)o(CHR61)sCOOR57；-(CH2)o(CHR61)sCONR58R59；
-(CH2)o(CHR61)sPO(OR60)2；-(CH2)o(CHR61)sSO2R62Or
-(CH2)o(CHR61)sC6H4R8；
R17Is an alkyl group; alkene(s)A group; - (CH)2)q(CHR61)sOR55；
-(CH2)q(CHR61)sSR56；-(CH2)q(CHR61)sNR33R34；
-(CH2)q(CHR61)sOCONR33R75；-(CH2)q(CHR61)sNR20CONR33R82；
-(CH2)q(CHR61)sCOOR57；-(CH2)q(CHR61)sCONR58R59；
-(CH2)q(CHR61)sPO(OR60)2；-(CH2)q(CHR61)sSO2R62Or
-(CH2)q(CHR61)sC6H4R8；
R18Is an alkyl group; an alkenyl group; - (CH)2)p(CHR61)sOR55；
-(CH2)p(CHR61)sSR56；-(CH2)p(CHR61)sNR33R34；
-(CH2)p(CHR61)sOCONR33R75；-(CH2)p(CHR61)sNR20CONR33R82；
-(CH2)p(CHR61)sCOOR57；-(CH2)p(CHR61)sCONR58R59；
-(CH2)p(CHR61)sPO(OR60)2；-(CH2)p(CHR61)sSO2R62Or
-(CH2)o(CHR61)sC6H4R8；
R19Is a lower alkyl group; - (CH)2)p(CHR61)sOR55；-(CH2)p(CHR61)sSR56；
-(CH2)p(CHR61)sNR33R34；-(CH2)p(CHR61)sOCONR33R75；
-(CH2)p(CHR61)sNR20CONR33R82；-(CH2)p(CHR61)sCOOR57；
-(CH2)p(CHR61)sCONR58R59；-(CH2)p(CHR61)sPO(OR60)2；
-(CH2)p(CHR61)sSO2R62Or- (CH)2)o(CHR61)sC6H4R8Or
R18And R19Together may form: - (CH)2)2-6-；-(CH2)2O(CH2)2-；
-(CH2)2S(CH2)2-or- (CH)2)2NR57(CH2)2-；
R20Is H; an alkyl group; alkenyl or aryl-lower alkyl;
R21Is H; an alkyl group; an alkenyl group; - (CH)2)o(CHR61)sOR55；
-(CH2)o(CHR61)sSR56；-(CH2)o(CHR61)sNR33R34；
-(CH2)o(CHR61)sOCONR33R75；-(CH2)o(CHR61)sNR20CONR33R82；
-(CH2)o(CHR61)sCOOR57；-(CH2)o(CHR61)sCONR58R59；
-(CH2)o(CHR61)sPO(OR60)2；-(CH2)o(CHR61)sSO2R62Or
-(CH2)o(CHR61)sC6H4R8；
R22Is H; an alkyl group; an alkenyl group; - (CH)2)o(CHR61)sOR55；
-(CH2)o(CHR61)sSR56；-(CH2)o(CHR61)sNR33R34；
-(CH2)o(CHR61)sOCONR33R75；-(CH2)o(CHR61)sNR20CONR33R82；
-(CH2)o(CHR61)sCOOR57；-(CH2)o(CHR61)sCONR58R59；
-(CH2)o(CHR61)sPO(OR60)2；-(CH2)o(CHR61)sSO2R62Or
-(CH2)o(CHR61)sC6H4R8；
R23Is an alkyl group; an alkenyl group; - (CH)2)o(CHR61)sOR55；
-(CH2)o(CHR61)sSR56；-(CH2)o(CHR61)sNR33R34；
-(CH2)o(CHR61)sOCONR33R75；-(CH2)o(CHR61)sNR20CONR33R82；
-(CH2)o(CHR61)sCOOR57；-(CH2)o(CHR61)sCONR58R59；
-(CH2)o(CHR61)sPO(OR60)2；-(CH2)o(CHR61)sSO2R62Or
-(CH2)o(CHR61)sC6H4R8；
R24Is an alkyl group; an alkenyl group; - (CH)2)o(CHR61)sOR55；
-(CH2)o(CHR61)sSR56；-(CH2)o(CHR61)sNR33R34；
-(CH2)o(CHR61)sOCONR33R75；-(CH2)o(CHR61)sNR20CONR33R82；
-(CH2)o(CHR61)sCOOR57；-(CH2)o(CHR61)sCONR58R59；
-(CH2)o(CHR61)sPO(OR60)2；-(CH2)o(CHR61)sSO2R62Or
-(CH2)o(CHR61)sC6H4R8；
R25Is H; an alkyl group; an alkenyl group; - (CH)2)m(CHR61)sOR55；
-(CH2)m(CHR61)sSR56；-(CH2)m(CHR61)sNR33R34；
-(CH2)m(CHR61)sOCONR33R75；-(CH2)m(CHR61)sNR20CONR33R82；
-(CH2)o(CHR61)sCOOR57；-(CH2)o(CHR61)sCONR58R59；
-(CH2)o(CHR61)sPO(OR60)2；-(CH2)o(CHR61)sSO2R62Or
-(CH2)o(CHR61)sC6H4R8；
R26Is H; an alkyl group; an alkenyl group; - (CH)2)m(CHR61)sOR55；
-(CH2)m(CHR61)sSR56；-(CH2)m(CHR61)sNR33R34；
-(CH2)m(CHR61)sOCONR33R75；-(CH2)m(CHR61)sNR20CONR33R82；
-(CH2)o(CHR61)sCOOR57；-(CH2)o(CHR61)sCONR58R59；
-(CH2)o(CHR61)sPO(OR60)2；-(CH2)o(CHR61)sSO2R62Or
-(CH2)o(CHR61)sC6H4R8Or
R25And R26Together may form: - (CH)2)2-6-；-(CH2)rO(CH2)r-；
-(CH2)rS(CH2)r-or- (CH)2)rNR57(CH2)r-；
R27Is H; an alkyl group; an alkenyl group; - (CH)2)o(CHR61)sOR55；
-(CH2)o(CHR61)sSR56；-(CH2)o(CHR61)sNR33R34；
-(CH2)o(CHR61)sCOOR57；-(CH2)o(CHR61)sCONR58R59；
-(CH2)o(CHR61)sOCONR33R75；-(CH2)o(CHR61)sNR20CONR33R82；
-(CH2)o(CHR61)sPO(OR60)2；-(CH2)o(CHR61)sSO2R62Or
-(CH2)o(CHR61)sC6H4R8；
R28Is an alkyl group; an alkenyl group; - (CH)2)o(CHR61)s-OR55；
-(CH2)o(CHR61)sSR56；-(CH2)o(CHR61)sNR33R34；
-(CH2)o(CHR61)sOCONR33R75；-(CH2)o(CHR61)sNR20CONR33R82；
-(CH2)o(CHR61)sCOOR57；-(CH2)o(CHR61)sCONR58R59；
-(CH2)o(CHR61)sPO(OR60)2；-(CH2)o(CHR61)sSO2R62Or
-(CH2)o(CHR61)sC6H4R8；
R29Is an alkyl group; an alkenyl group; - (CH)2)o(CHR61)sOR55；
-(CH2)o(CHR61)sSR56；-(CH2)o(CHR61)sNR33R34；
-(CH2)o(CHR61)sOCONR33R75；-(CH2)o(CHR61)sNR20CONR33R82；
-(CH2)o(CHR61)sCOOR57；-(CH2)o(CHR61)sCONR58R59；
-(CH2)o(CHR61)sPO(OR60)2；-(CH2)o(CHR61)sSO2R62Or
-(CH2)o(CHR61)sC6H4R8；
R30Is H; an alkyl group; alkenyl or aryl-lower alkyl;
R31is H; an alkyl group; an alkenyl group; - (CH)2)p(CHR61)sOR55；
-(CH2)p(CHR61)sNR33R34；-(CH2)p(CHR61)sOCONR33R75；
-(CH2)p(CHR61)sNR20CONR33R82；-(CH2)o(CHR61)sCOOR57；
-(CH2)o(CHR61)sCONR58R59；-(CH2)o(CHR61)sPO(OR60)2；
-(CH2)o(CHR61)sSO2R62Or- (CH)2)o(CHR61)sC6H4R8；
R32Is H; lower alkyl or aryl-lower alkyl;
R33is H; alkyl, alkenyl; - (CH)2)m(CHR61)sOR55；
-(CH2)m(CHR61)sNR34R63；-(CH2)m(CHR61)sOCONR75R82；
-(CH2)m(CHR61)sNR20CONR78R82；-(CH2)o(CHR61)sCOR64；
-(CH2)o(CHR61)s-CONR58R59，-(CH2)o(CHR61)sPO(OR60)2；
-(CH2)o(CHR61)sSO2R62Or- (CH)2)o(CHR61)sC6H4R8；
R34Is H; a lower alkyl group; aryl or aryl-lower alkyl;
R33and R34Together may form: - (CH)2)2-6-；-(CH2)2O(CH2)2-；
-(CH2)2S(CH2)2-or- (CH)2)2NR57(CH2)2-；
R35Is H; an alkyl group; an alkenyl group; - (CH)2)m(CHR61)sOR55；
-(CH2)m(CHR61)sNR33R34；-(CH2)m(CHR61)sOCONR33R75；
-(CH2)m(CHR61)sNR20CONR33R82；-(CH2)p(CHR61)sCOOR57；
-(CH2)p(CHR61)sCONR58R59；-(CH2)p(CHR61)sPO(OR60)2；
-(CH2)p(CHR61)sSO2R62Or- (CH)2)p(CHR61)sC6H4R8；
R36Is H, alkyl; an alkenyl group; - (CH)2)o(CHR61)sOR55；
-(CH2)p(CHR61)sNR33R34；-(CH2)p(CHR61)sOCONR33R75；
-(CH2)p(CHR61)sNR20CONR33R82；-(CH2)p(CHR61)sCOOR57；
-(CH2)p(CHR61)sCONR58R59；-(CH2)p(CHR61)sPO(OR60)2；
-(CH2)p(CHR61)sSO2R62Or- (CH)2)o(CHR61)sC6H4R8；
R37Is H; f; br; cl; NO2；CF3(ii) a A lower alkyl group;
-(CH2)p(CHR61)sOR55；-(CH2)p(CHR61)sNR33R34；
-(CH2)p(CHR61)sOCONR33R75；-(CH2)p(CHR61)sNR20CONR33R82；
-(CH2)o(CHR61)sCOOR57；-(CH2)o(CHR61)sCONR58R59；
-(CH2)o(CHR61)sPO(OR60)2；-(CH2)o(CHR61)sSO2R62or
-(CH2)o(CHR61)sC6H4R8；
R38Is H; f; br; cl; NO2；CF3(ii) a An alkyl group; an alkenyl group;
-(CH2)p(CHR61)sOR55；-(CH2)p(CHR61)sNR33R34；
-(CH2)p(CHR61)sOCONR33R75；-(CH2)p(CHR61)sNR20CONR33R82；
-(CH2)o(CHR61)sCOOR57；-(CH2)o(CHR61)sCONR58R59；
-(CH2)o(CHR61)sPO(OR60)2；-(CH2)o(CHR61)sSO2R62or
-(CH2)o(CHR61)sC6H4R8；
R39Is H; an alkyl group; alkenyl or aryl-lower alkyl;
R40is H; an alkyl group; alkenyl or aryl-lower alkyl;
R41is H; f; br; cl; NO2；CF3(ii) a An alkyl group; an alkenyl group;
-(CH2)p(CHR61)sOR55；-(CH2)p(CHR61)sNR33R34；
-(CH2)p(CHR61)sOCONR33R75；-(CH2)p(CHR61)sNR20CONR33R82；
-(CH2)o(CHR61)sCOOR57；-(CH2)o(CHR61)sCONR58R59；
-(CH2)o(CHR61)sPO(OR60)2；-(CH2)o(CHR61)sSO2R62or
-(CH2)o(CHR61)sC6H4R8；
R42Is H; f; br; cl; NO2；CF3(ii) a An alkyl group; an alkenyl group;
-(CH2)p(CHR61)sOR55；-(CH2)p(CHR61)sNR33R34；
-(CH2)p(CHR61)sOCONR33R75；-(CH2)p(CHR61)sNR20CONR33R82；
-(CH2)o(CHR61)sCOOR57；-(CH2)o(CHR61)sCONR58R59；
-(CH2)o(CHR61)sPO(OR60)2；-(CH2)o(CHR61)sSO2R62or
-(CH2)o(CHR61)sC6H4R8；
R43Is H; an alkyl group; an alkenyl group; - (CH) 2)m(CHR61)sOR55；
-(CH2)m(CHR61)sNR33R34；-(CH2)m(CHR61)sOCONR33R75；
-(CH2)m(CHR61)sNR20CONR33R82；-(CH2)o(CHR61)sCOOR57；
-(CH2)o(CHR61)sCONR58R59；-(CH2)o(CHR61)sPO(OR60)2；
-(CH2)o(CHR61)sSO2R62Or- (CH)2)o(CHR61)sC6H4R8；
R44Is an alkyl group; an alkenyl group; - (CH)2)r(CHR61)sOR55；
-(CH2)r(CHR61)sSR56；-(CH2)r(CHR61)sNR33R34；
-(CH2)r(CHR61)sOCONR33R75；-(CH2)r(CHR61)sNR20CONR33R82；
-(CH2)r(CHR61)sCOOR57；-(CH2)r(CHR61)sCONR58R59；
-(CH2)r(CHR61)sPO(OR60)2；-(CH2)r(CHR61)sSO2R62Or
-(CH2)r(CHR61)sC6H4R8；
R45Is H; an alkyl group; an alkenyl group; - (CH)2)o(CHR61)sOR55；
-(CH2)o(CHR61)sSR56；-(CH2)o(CHR61)sNR33R34；
-(CH2)o(CHR61)sOCONR33R75；-(CH2)o(CHR61)sNR20CONR33R82；
-(CH2)o(CHR61)sCOOR57；-(CH2)s(CHR61)sCONR58R59；
-(CH2)s(CHR61)sPO(OR60)2；-(CH2)s(CHR61)sSO2R62Or
-(CH2)s(CHR61)sC6H4R8；
R46Is H; an alkyl group; alkenyl or- (CH)2)o(CHR61)pC6H4R8；
R47Is H; an alkyl group; alkenyl or- (CH)2)o(CHR61)sOR55；
R48Is H; a lower alkyl group; lower alkenyl or aryl-lower alkyl;
R49is H; an alkyl group; an alkenyl group; - (CHR)61)sCOOR57；
(CHR61)sCONR58R59；(CHR61)sPO(OR60)2；-(CHR61)sSOR62Or
-(CHR61)sC6H4R8；
R50Is H; lower alkyl or aryl-lower alkyl;
R51is H; an alkyl group; an alkenyl group; - (CH)2)m(CHR61)sOR55；
-(CH2)m(CHR61)sSR56；-(CH2)m(CHR61)sNR33R34；
-(CH2)m(CHR61)sOCONR33R75；-(CH2)m(CHR61)sNR20CONR33R82；
-(CH2)o(CHR61)sCOOR57；-(CH2)o(CHR61)sCONR58R59；
-(CH2)o(CHR61)pPO(OR60)2；-(CH2)p(CHR61)sSO2R62Or
-(CH2)p(CHR61)sC6H4R8；
R52Is H; an alkyl group; an alkenyl group; - (CH)2)m(CHR61)sOR55；
-(CH2)m(CHR61)sSR56；-(CH2)m(CHR61)sNR33R34；
-(CH2)m(CHR61)sOCONR33R75；-(CH2)m(CHR61)sNR20CONR33R82；
-(CH2)o(CHR61)sCOOR57；-(CH2)o(CHR61)sCONR58R59；
-(CH2)o(CHR61)pPO(OR60)2；-(CH2)p(CHR61)sSO2R62Or
-(CH2)p(CHR61)sC6H4R8；
R53Is H; an alkyl group; an alkenyl group; - (CH)2)m(CHR61)sOR55；
-(CH2)m(CHR61)sSR56；-(CH2)m(CHR61)sNR33R34；
-(CH2)m(CHR61)sOCONR33R75；-(CH2)m(CHR61)sNR20CONR33R82；
-(CH2)o(CHR61)sCOOR57；-(CH2)o(CHR61)sCONR58R59；
-(CH2)o(CHR61)pPO(OR60)2；-(CH2)p(CHR61)sSO2R62Or
-(CH2)p(CHR61)sC6H4R8；
R54Is H; an alkyl group; an alkenyl group; - (CH)2)m(CHR61)sOR55；
-(CH2)m(CHR61)sNR33R34；-(CH2)m(CHR61)sOCONR33R75；
-(CH2)m(CHR61)sNR20CONR33R82；-(CH2)o(CHR61)COOR57；
-(CH2)o(CHR61)sCONR58R59Or- (CH)2)o(CHR61)sC6H4R8；
R55Is H; a lower alkyl group; a lower alkenyl group; aryl-lower alkyl;
-(CH2)m(CHR61)sOR57；-(CH2)m(CHR61)sNR34R63；
-(CH2)m(CHR61)sOCONR75R82；-(CH2)m(CHR61)sNR20CONR78R82；
-(CH2)o(CHR61)s-COR64；-(CH2)o(CHR61)COOR57or
-(CH2)o(CHR61)sCONR58R59；
R56Is H; a lower alkyl group; a lower alkenyl group; aryl-lower alkyl;
-(CH2)m(CHR61)sOR57；-(CH2)m(CHR61)sNR34R63；
-(CH2)m(CHR61)sOCONR75R82；-(CH2)m(CHR61)sNR20CONR78R82；
-(CH2)o(CHR61)s-COR64or- (CH)2)o(CHR61)sCONR58R59；
R57Is H; a lower alkyl group; a lower alkenyl group; aryl-lower alkyl or heteroaryl-lower alkyl;
R58is H; a lower alkyl group; a lower alkenyl group; an aryl group; a heteroaryl group; aryl-lower alkyl or heteroaryl-lower alkyl;
R59is H; a lower alkyl group; a lower alkenyl group; an aryl group; a heteroaryl group; aryl-lower alkyl or heteroaryl-lower alkyl or
R58And R59Together may form: - (CH)2)2-6-；-(CH2)2O(CH2)2-；
-(CH2)2S(CH2)2-or- (CH)2)2NR57(CH2)2-；
R60Is H; a lower alkyl group; a lower alkenyl group; aryl or aryl-lower alkyl;
R61is an alkyl group; an alkenyl group; an aryl group; a heteroaryl group; aryl-lower alkyl; heteroaryl-lower alkyl; - (CH) 2)mOR55；-(CH2)mNR33R34；-(CH2)mOCONR75R82；
-(CH2)mNR20CONR78R82；-(CH2)oCOOR37；-(CH2)oNR58R59Or
-(CH2)oPO(COR60)2；
R62Is a lower alkyl group; a lower alkenyl group; aryl, heteroaryl or aryl-lower alkyl;
R63is H; a lower alkyl group; a lower alkenyl group; aryl, heteroaryl; aryl-lower alkyl; heteroaryl-lower alkyl; -COR64；-COOR57；-CONR58R59；-SO2R62OR-PO (OR)60)2；
R34And R53Together may form: - (CH)2)2-6-；-(CH2)2O(CH2)2-；
-(CH2)2S(CH2)2-or- (CH)2)2NR57(CH2)2-；
R64Is H; a lower alkyl group; a lower alkenyl group; an aryl group; a heteroaryl group; aryl-lower alkyl; heteroaryl-lower alkyl; - (CH)2)p(CHR61)sOR65；-(CH2)p(CHR61)sSR66Or- (CH)2)p(CHR61)sNR34R63；-(CH2)p(CHR61)sOCONR75R82；
-(CH2)P(CHR61)sNR20CONR78R82；
R65Is H; a lower alkyl group; a lower alkenyl group; aryl, aryl-lower alkyl; heteroaryl-lower alkyl; -COR57；-COOR57or-CONR58R59；
R66Is H; a lower alkyl group; a lower alkenyl group; an aryl group; aryl-lower alkyl; heteroaryl-lower alkyl or-CONR58R59；
m is 2 to 4; o is 0 to 4; p is 1 to 4; q is 0 to 2; r is 1 or 2; s is 0 or 1;
and
independently have any of the meanings defined above
With the exception that B is-NR20CH(R71) And A is other than (a1) or (a2) of A80, A81, A90, A91, A95 or A96, and other than (f) and (m), but wherein
R2Is- (CH)2)m(CHR61)sO-；-(CH2)m(CHR61)sS-；
-(CH2)m(CHR61)sNR34-or- (CH)2)o(CHR61)sCO-；
R3Is- (CH)2)m(CHR61)sO-；-(CH2)m(CHR61)sS-；
-(CH2)m(CHR61)sNR34-or- (CH)2)o(CHR61)sCO-；
R4Is- (CH)2)m(CHR61)sO-；-(CH2)m(CHR61)sS-；
-(CH2)m(CHR61)sNR34-or- (CH)2)p(CHR61)sCO-；
R5Is- (CH)2)o(CHR61)sO-；-(CH2)o(CHR61)sS-；
-(CH2)o(CHR61)sNR34-or- (CH)2)o(CHR61)sCO-；
R6Is- (CH)2)o(CHR61)sO-；-(CH2)o(CHR61)sS-；
-(CH2)o(CHR61)sNR34-or- (CH)2)o(CHR61)sCO-；
R7Is- (CH)2)q(CHR61)sO-；-(CH2)q(CHR61)sNR34-or
-(CH2)r(CHR61)sCO-；
R8Is- (CH)2)o(CHR61)sO-；-(CH2)o(CHR61)sS-；
-(CH2)o(CHR61)sNR34-or- (CH)2)o(CHR61)sCO-；
R9Is- (CH)2)o(CHR61)sO-；-(CH2)o(CHR61)sS-；
-(CH2)o(CHR61)sNR34-or- (CH)2)o(CHR61)sCO-；
R10Is- (CH)2)o(CHR61)sO-；-(CH2)o(CHR61)sS-；
-(CH2)o(CHR61)sNR34-or- (CH)2)o(CHR61)sCO-；
R11Is- (CH)2)m(CHR61)sO-；-(CH2)m(CHR61)sNR34-or
-(CH2)o(CHR61)sCO-；
R12Is- (CH)2)m(CHR61)sO-；-(CH2)m(CHR61)sNR34-or
-(CH2)r(CHR61)sCO-；
R13Is- (CH)2)q(CHR61)sO-；-(CH2)q(CHR61)sS-；
-(CH2)q(CHR61)sNR34-or- (CH)2)q(CHR61)sCO-；
R14Is- (CH)2)m(CHR61)sO-；-(CH2)m(CHR61)sNR34-or
-(CH2)q(CHR61)sCO-；
R15Is- (CH)2)o(CHR61)sO-；-(CH2)o(CHR61)sS-；
-(CH2)o(CHR61)sNR34-or- (CH) 2)o(CHR61)sCO-；
R16Is- (CH)2)o(CHR61)sO-；-(CH2)o(CHR61)sS-；
-(CH2)o(CHR61)sNR34-or- (CH)2)o(CHR61)sCO-；
R17Is- (CH)2)q(CHR61)sO-；-(CH2)q(CHR61)sS-；
-(CH2)q(CHR61)sNR34-or- (CH)2)q(CHR61)sCO-；
R18Is- (CH)2)p(CHR61)sO-；-(CH2)p(CHR61)sS-；
-(CH2)p(CHR61)sNR34-or- (CH)2)p(CHR61)sCO-；
R19Is- (CH)2)p(CHR61)sO-；-(CH2)p(CHR61)sS-；
-(CH2)p(CHR61)sNR34-or- (CH)2)p(CHR61)sCO-；
R21Is- (CH)2)o(CHR61)sO-；-(CH2)o(CHR61)sS-；
-(CH2)o(CHR61)sNR34-or- (CH)2)o(CHR61)sCO-；
R22Is- (CH)2)o(CHR61)sO-；-(CH2)o(CHR61)sS-；
-(CH2)o(CHR61)sNR34-or- (CH)2)o(CHR61)sCO-；
R23Is- (CH)2)o(CHR61)sO-；-(CH2)o(CHR61)sS-；
-(CH2)o(CHR61)sNR34-or- (CH)2)o(CHR61)sCO-；
R24Is- (CH)2)o(CHR61)sO-；-(CH2)o(CHR61)sS-；
-(CH2)o(CHR61)sNR34-or- (CH)2)o(CHR61)sCO-；
R25Is- (CH)2)m(CHR61)sO-；-(CH2)m(CHR61)sS-；
-(CH2)m(CHR61)sNR34-or- (CH)2)o(CHR61)sCO-；
R26Is- (CH)2)m(CHR61)sO-；-(CH2)m(CHR61)sS-；
-(CH2)m(CHR61)sNR34-or- (CH)2)o(CHR61)sCO-；
R27Is- (CH)2)o(CHR61)sO-；-(CH2)o(CHR61)sS-；
-(CH2)o(CHR61)sNR34-or- (CH)2)o(CHR61)sCO-；
R28Is- (CH)2)m(CHR61)sO-；-(CH2)m(CHR61)sS-；
-(CH2)m(CHR61)sNR34-or- (CH)2)o(CHR61)sCO-；
R29Is- (CH)2)o(CHR61)sO-；-(CH2)o(CHR61)sS-；
-(CH2)o(CHR61)sNR34-or- (CH)2)o(CHR61)sCO-；
R31Is- (CH)2)p(CHR61)sO-；-(CH2)p(CHR61)sS-；
-(CH2)p(CHR61)sNR34-or- (CH)2)o(CHR61)sCO-；
R33Is- (CH)2)m(CHR61)sO-；-(CH2)m(CHR61)sNR34-or
-(CH2)o(CHR61)sCO-；
R37Is- (CH)2)p(CHR61)sO-；-(CH2)p(CHR61)sS-；
-(CH2)p(CHR61)sNR34-or- (CH)2)o(CHR61)sCO-；
R38Is- (CH)2)p(CHR61)sO-；-(CH2)p(CHR61)sS-；
-(CH2)p(CHR61)sNR34-or- (CH)2)o(CHR61)sCO-；
R41Is- (CH)2)p(CHR61)sO-；-(CH2)p(CHR61)sS-；
-(CH2)p(CHR61)sNR34-or- (CH)2)o(CHR61)sCO-；
R42Is- (CH)2)p(CHR61)sO-；-(CH2)p(CHR61)sS-；
-(CH2)p(CHR61)sNR34--Or- (CH)2)o(CHR61)sCO-；
R43Is- (CH)2)m(CHR61)sO；-(CH2)m(CHR61)sNR34-or
-(CH2)o(CHR61)sCO-；
R45Is- (CH)2)o(CHR61)sO-；-(CH2)o(CHR61)sS-；
-(CH2)o(CHR61)sNR34-or- (CH)2)s(CHR61)sCO-；
R47Is- (CH)2)o(CHR61)sO-；
R49Is- (CHR)61)sO-；-(CHR61)sS-；-(CHR61)sNR34-or
-(CHR61)sCO-；
R51Is- (CH)2)m(CHR61)sO-；-(CH2)m(CHR61)sS-；
-(CH2)m(CHR61)sNR34-or- (CH)2)o(CHR61)sCO-；
R52Is- (CH)2)m(CHR51)sO-；-(CH2)m(CHR61)sS-；
-(CH2)m(CHR61)sNR34-or- (CH)2)o(CHR61)sCO-；
R53Is- (CH)2)m(CHR61)sO-；-(CH2)m(CHR61)sS-；
-(CH2)m(CHR61)sNR34-or- (CH)2)o(CHR61)sCO-；
R54Is- (CH)2)m(CHR61)sO-；-(CH2)m(CHR61)sNR34-or
-(CH2)o(CHR61)sCO-；
R55Is- (CH)2)m(CHR61)sO-；-(CH2)m(CHR61)sNR34-or
-(CH2)o(CHR61)sCO-；
R56Is- (CH)2)m(CHR61)sO-；-(CH2)m(CHR61)sNR34-or
-(CH2)o(CHR61)sCO-；
R64Is- (CH)2)p(CHR61)sO-；-(CH2)p(CHR61)sS-or
-(CH2)p(CHR61)sNR34-；
m, o, p, q, r and s are as defined above;
provided that if more than one substituent R is present2-R19、R21 to R29、R31、R33、R37、R38、R41 to R43、R45、R47、R49、R51 to R56And R64Then only one of them has the just mentioned meaning and the other substituents have any of the previously mentioned meanings;
l is a direct bond or one of these linkers
L1：-(CH2)pCHR61[X(CH2)pCHR61]o-；
L2：-CO(CH2)pCHR61[X(CH2)pCHR61]oCO-；
L3：-CONR34(CH2)pCHR61[X(CH2)pCHR61]oNR34CO-；
L4：-O(CH2)pCHR61[X(CH2)pCHR61]oO-；
L5：-S(CH2)pCHR61[X(CH2)pCHR61]oS-；
L6：-NR34(CH2)pCHR61[X(CH2)pCHR61]oNR34-；
L7：-(CH2)oCHR61Y(CH2)oCHR61-；
L8：-CO(CH2)oCHR61Y(CH2)oCHR61CO-；
L9：-CONR34(CH2)oCHR61Y(CH2)oCHR61NR34CO-；
L10：-O(CH2)oCHR61Y(CH2)oCHR61O-；
L11：-S(CH2)oCHR61Y(CH2)oCHR61S-；
L12：-NR34(CH2)oCHR61Y(CH2)oCHR61NR34-；
L13：-CO(CH2)pCHR61[X(CH2)pCHR61]oNR34-；
L14：-CO(CH2)oCHR61Y(CH2)oCHR61NR34-；
L15 -NR34(CH2)pCHR61[X(CH2)pCHR61]oCO-; and
L16 -NR34(CH2)oCHR61Y(CH2)oCHR61CO-；
m, o, p, q, r and s are as defined above; x is O; s; NR (nitrogen to noise ratio)34；-NR32CONR34-or-OCOO-; and Y is-C6R67R68R69R70-；
R67Is H; cl; br; f; NO2；-NR34COR57(ii) a Lower alkyl or lower alkenyl;
R68is H; cl; br; f; NO2；-NR34COR57(ii) a Lower alkyl or lower alkenyl;
R69is H; cl; br; f; NO2；-NR34COR57(ii) a Lower alkyl or lower alkenyl; and
R70is H; cl; br; f; NO2；-NR34COR57(ii) a Lower alkyl or lower alkenyl;
Provided that R is67、R68、R69And R70At least two of which are H; and
other preconditions are
-(CH2)m(CHR61)sO-may be bound to linker L1, L2, L3, L7, L8, or L9;
-(CH2)o(CHR61)so-may be bound to linker L1, L2, L3, L7, L8, or L9;
-(CH2)p(CHR61)so-may be bound to linker L1, L2, L3, L7, L8, or L9;
-(CH2)q(CHR61)so-may be bound to linker L1, L2, L3, L7, L8, or L9;
-(CHR61)so-may be bound to linker L1, L2, L3, L7, L8, or L9;
-(CH2)m(CHR61)ss-may be bound to linker L1, L2, L3, L7, L8 or L9 or may be bound to- (CH)2)m(CHR61)sS-；-(CH2)o(CHR61)sS-；-(CH2)p(CHR61)sS-；-(CH2)q(CHR61)sS-or- (CHR)61)sS-disulfide bond formation;
-(CH2)o(CHR61)ss-may be bound to linker L1, L2, L3, L7, L8 or L9 or may be bound to- (CH)2)m(CHR61)sS-；-(CH2)o(CHR61)sS-；-(CH2)p(CHR61)sS-；-(CH2)q(CHR61)sS-or- (CHR)61)sS-disulfide bond formation;
-(CH2)p(CHR61)ss-may be bound to linker L1, L2, L3, L7, L8 or L9 or may be bound to- (CH)2)m(CHR61)sS-；-(CH2)o(CHR61)sS-；-(CH2)p(CHR61)sS-；-(CH2)q(CHR61)sS-or- (CHR)61)sS-disulfide bond formation;
-(CH2)q(CHR61)ss-may be bound to linker L1, L2, L3, L7, L8 or L9 or may be bound to- (CH)2)m(CHR61)sS-；-(CH2)o(CHR61)sS-；-(CH2)p(CHR61)sS-；-(CH2)q(CHR61)sS-or- (CHR)61)sS-disulfide bond formation;
-(CHR61)ss-may be bound to linker L1, L2, L3, L7, L8 or L9 or may be bound to- (CH)2)m(CHR61)sS-；-(CH2)o(CHR61)sS-；-(CH2)p(CHR61)sS-；-(CH2)q(CHR61)sS-or- (CHR)61)sS-disulfide bond formation;
-(CH2)m(CHR61)sNR34-may bind to linker L1, L2, L3, L7, L8 or L9;
-(CH2)o(CHR61)sNR34-may bind to linker L1, L2, L3, L7, L8 or L9;
-(CH2)p(CHR61)sNR34-may bind to linker L1, L2, L3, L7, L8 or L9;
-(CH2)q(CHR61)sNR34-may bind to linker L1, L2, L3, L7, L8 or L9;
-(CHR61)sNR34-may bind to linker L1, L2, L3, L7, L8 or L9;
-(CH2)o(CHR61)sCO-may be bound to linker L4, L5, L6, L10, L11 or L12;
-(CH2)p(CHR61)sCO-may be bound to linker L4, L5, L6, L10, L11 or L12;
-(CH2)q(CHR61)sCO-may be bound to linker L4, L5, L6, L10, L11 or L12;
-(CH2)r(CHR61)sCO-may be bound to linker L4, L5, L6, L10, L11 or L12;
-(CHR61)sCO-may be bound to linker L4, L5, L6, L10, L11 or L12;
-(CH2)m(CHR61)so-can be conjugated to linker L13 or L14 and the resulting conjugate can be conjugated to- (CH)2)m(CHR61)sCO-；-(CH2)o(CHR61)pCO-；-(CH2)q(CHR61)sCO-or- (CHR)61)sCO-binding;
-(CH2)o(CHR61)so-can be conjugated to linker L13 or L14 and the resulting conjugate can be conjugated to- (CH)2)o(CHR61)sCO-；-(CH2)o(CHR61)pCO-；-(CH2)q(CHR61)sCO-or- (CHR)61)sCO-binding;
-(CH2)p(CHR61)so-can be conjugated to linker L13 or L14 and the resulting conjugate can be conjugated to- (CH)2)o(CHR61)sCO-；-(CH2)o(CHR61)pCO-；-(CH2)q(CHR61)sCO-or- (CHR)61)sCO-binding;
-(CH2)q(CHR61)so-can be conjugated to linker L13 or L14 and the resulting conjugate can be conjugated to- (CH)2)o(CHR61)sCO-；-(CH2)o(CHR61)pCO-；-(CH2)q(CHR61)sCO-or- (CHR)61)sCO-binding;
-(CHR61)so-can be conjugated to linker L13 or L14 and the resulting conjugate can be conjugated to- (CH)2)o(CHR61)sCO-；-(CH2)o(CHR61)pCO-；-(CH2)q(CHR61)sCO-or- (CHR)61)sCO-binding;
-(CH2)m(CHR61)ss-can be conjugated to linker L13 or L14 and the resulting conjugate can be conjugated to- (CH)2)o(CHR61)sCO-；-(CH2)o(CHR61)pCO-；-(CH2)q(CHR61)sCO-or- (CHR)61)sCO-binding;
-(CH2)o(CHR61)ss-can be conjugated to linker L13 or L14 and the resulting conjugate can be conjugated to- (CH)2)o(CHR61)sCO-；-(CH2)o(CHR61)pCO-；-(CH2)q(CHR61)sCO-or- (CHR)61)sCO-binding;
-(CH2)p(CHR61)ss-can be conjugated to linker L13 or L14 and the resulting conjugate can be conjugated to- (CH) 2)o(CHR61)sCO-；-(CH2)o(CHR61)pCO-；-(CH2)q(CHR61)sCO-or- (CHR)61)sCO-binding;
-(CH2)q(CHR61)ss-can be conjugated to linker L13 or L14 and the resulting conjugate can be conjugated to- (CH)2)o(CHR61)sCO-；-(CH2)o(CHR61)pCO-；-(CH2)q(CHR61)sCO-or- (CHR)61)sCO-binding;
-(CHR61)ss-can be conjugated to linker L13 or L14 and the resulting conjugate can be conjugated to- (CH)2)o(CHR61)sCO-；-(CH2)o(CHR61)pCO-；-(CH2)q(CHR61)sCO-or- (CHR)61)sCO-binding;
-(CH2)m(CHR61)sNR34-may be conjugated to linker L13 or L14 and the resulting conjugate may be conjugated to- (CH)2)o(CHR61)sCO-；-(CH2)o(CHR61)pCO-；-(CH2)q(CHR61)sCO-or- (CHR)61)sCO-binding;
-(CH2)o(CHR61)sNR34-may be conjugated to linker L13 or L14 and the resulting conjugate may be conjugated to- (CH)2)o(CHR61)sCO-；-(CH2)o(CHR61)pCO-；-(CH2)q(CHR61)sCO-or- (CHR)61)sCO-binding;
-(CH2)p(CHR61)sNR34-may be conjugated to linker L13 or L14 and the resulting conjugate may be conjugated to- (CH)2)o(CHR61)sCO-；-(CH2)o(CHR61)pCO-；-(CH2)q(CHR61)sCO-or- (CHR)61)sCO-binding;
-(CH2)q(CHR61)sNR34-may be conjugated to linker L13 or L14 and the resulting conjugate may be conjugated to- (CH)2)o(CHR61)sCO-；-(CH2)o(CHR61)pCO-；-(CH2)q(CHR61)sCO-or- (CHR)61)sCO-binding;
-(CHR61)sNR34-may be conjugated to linker L13 or L14 and the resulting conjugate may be conjugated to- (CH)2)o(CHR61)sCO-；-(CH2)o(CHR61)pCO-；-(CH2)q(CHR61)sCO-or- (CHR)61)sCO-binding;
-(CH2)o(CHR61)sCO-may be conjugated to L15 or L16 and the resulting conjugate may be conjugated to- (CH)2)m(CHR61)sX-、-(CH2)o(CHR61)sX-、-(CH2)p(CHR61)sX-、-(CH2)q(CHR61)sX-or- (CHR)61)sX-binding;
-(CH2)p(CHR61)sCO-may be conjugated to L15 or L16 and the resulting conjugate may be conjugated to- (CH)2)m(CHR61)sX-、-(CH2)o(CHR61)sX-、-(CH2)p(CHR61)sX-、-(CH2)q(CHR61)sX-or- (CHR)61)sX-binding;
-(CH2)q(CHR61)sCO-may be conjugated to L15 or L16 and the resulting conjugate may be conjugated to- (CH)2)m(CHR61)sX-、-(CH2)o(CHR61)sX-、-(CH2)p(CHR61)sX-、-(CH2)q(CHR61)sX-or- (CHR)61)sX-binding;
-(CH2)r(CHR61)sCO-may be conjugated to L15 or L16 and the resulting conjugate may be conjugated to- (CH)2)m(CHR61)sX-、-(CH2)o(CHR61)sX-、-(CH2)p(CHR61)sX-、-(CH2)q(CHR61)sX-or- (CHR)61)sX-binding;
-(CHR61)sCO-may be conjugated to L15 or L16 and the resulting conjugate may be conjugated to- (CH) 2)m(CHR61)sX-、-(CH2)o(CHR61)sX-、-(CH2)p(CHR61)sX-、-(CH2)q(CHR61)sX-or- (CHR)61)sX-binding;
Z、Z1and Z2Independently is a chain of N alpha-amino acid residues, N being an integer from 8 to 16, the positions of said amino acid residues in said chain being counted starting from the N-terminal amino acid, whereby these amino acid residues, depending on their position in the chain, are Gly or Pro, Z, Z1And Z2Either a chain of formula-A-CO-, or a chain of formula-B-CO-, or a chain of one of the following types
C：-NR20CH(R72)CO-；
D：-NR20CH(R73)CO-；
E：-NR20CH(R74)CO-；
F：-NR20CH(R84) CO-; and
H：-NR20-CH(CO-)-(CH2)4-7-CH(CO-)-NR20-；
-NR20-CH(CO-)-(CH2)pSS(CH2)p-CH(CO-)-NR20-；
-NR20-CH(CO-)-(-(CH2)pNR20CO(CH2)p-CH(CO-)-NR20-; and
-NR20-CH(CO-)-(-(CH2)pNR20CONR20(CH2)p-CH(CO-)-NR20-；
R71is H; a lower alkyl group; a lower alkenyl group; - (CH)2)p(CHR61)sOR75；
-(CH2)p(CHR61)sSR75；-(CH2)p(CHR61)sNR33R34；
-(CH2)p(CHR61)sOCONR33R75；-(CH2)p(CHR61)sNR20CONR33R82；
-(CH2)o(CHR61)sCOOR75；-(CH2)pCONR58R59；
-(CH2)pPO(OR62)2；-(CH2)pSO2R62Or- (CH)2)o-C6R67R68R69R70R76；
R72Is H; a lower alkyl group; a lower alkenyl group; - (CH)2)p(CHR61)sOR85Or
-(CH2)p(CHR61)sSR85；
R73Is- (CH)2)oR77；-(CH2)rO(CH2)oR77；-(CH2)rS(CH2)oR77Or
-(CH2)rNR20(CH2)oR77；
R74Is- (CH)2)pNR78R79；-(CH2)pNR77R80；
-(CH2)pC(＝NR80)NR78R79；-(CH2)pC(＝NOR50)NR78R79；
-(CH2)pC(＝NNR78R79)NR78R79；-(CH2)pNR80C(＝NR80)NR78R79；
-(CH2)pN＝C(NR78R80)NR79R80；-(CH2)pC6H4NR78R79；
-(CH2)pC6H4NR77R80；-(CH2)pC6H4C(＝NR80)NR79R79；
-(CH2)pC6H4C(＝NOR50)NR78R79；
-(CH2)pC6H4C(＝NNR78R79)NR78R79；
-(CH2)pC6H4NR80C(＝NR80)NR78R79；
-(CH2)pC6H4N＝C(NR78R80)NR79R80；
-(CH2)rO(CH2)mNR78R79；-(CH2)rO(CH2)mNR77R80；
-(CH2)rO(CH2)pC(＝NR80)NR78R79；
-(CH2)rO(CH2)pC(＝NOR50)NR78R79；
-(CH2)rO(CH2)pC(＝NNR78R79)NR78R79；
-(CH2)rO(CH2)mNR80C(＝NR80)NR78R79；
-(CH2)rO(CH2)mN＝C(NR78R80)NR79R80；
-(CH2)rO(CH2)pC6H4CNR78R79；
-(CH2)rO(CH2)pC6H4C(＝NR80)NR78R79；
-(CH2)rO(CH2)pC6H4C(＝NOR50)NR78R79；
-(CH2)rO(CH2)pC6H4C(＝NNR78R79)NR78R79；
-(CH2)rO(CH2)pC6H4NR80C(＝NR80)NR78R79；
-(CH2)rS(CH2)mNR78R79；-(CH2)rS(CH2)mNR77R80；
-(CH2)rS(CH2)pC(＝NR80)NR78R79；
-(CH2)rS(CH2)pC(＝NOR50)NR78R79；
-(CH2)rS(CH2)pC(＝NNR78R79)NR78R79；
-(CH2)rS(CH2)mNR80C(＝NR80)NR78R79；
-(CH2)rS(CH2)mN＝C(NR78R80)NR79R80；
-(CH2)rS(CH2)pC6H4CNR78R79；
-(CH2)rS(CH2)pC6H4C(＝NR80)NR78R79；
-(CH2)rS(CH2)pC6H4C(＝NOR50)NR78R79；
-(CH2)rS(CH2)pC6H4C(＝NNR78R79)NR78R79；
-(CH2)rS(CH2)pC6H4NR80C(＝NR80)NR78R79；-(CH2)pNR80COR64；
-(CH2)pNR80COR77；-(CH2)pNR80CONR78R79Or
-(CH2)pC6H4NR80CONR78R79；
R75Is a lower alkyl group; lower alkenyl or aryl-lower alkyl;
R33and R75Together may form: - (CH)2)2-6-；-(CH2)2O(CH2)2-；
-(CH2)2S(CH2)2-or- (CH)2)2NR57(CH2)2-；
R76And R82Together may form: - (CH)2)2-6-；-(CH2)2O(CH2)2-；
-(CH2)2S(CH2)2-or- (CH)2)2NR57(CH2)2-；
R76Is H; a lower alkyl group; a lower alkenyl group; aryl-lower alkyl;
-(CH2)oOR72；-(CH2)oSR72；-(CH2)oNR33R34；-(CH2)oOCONR33R75；
-(CH2)oNR20CONR33R82；-(CH2)oCOOR75；
-(CH2)oCONR58R59；-(CH2)oPO(OR60)2；-(CH2)pSO2R62or
-(CH2)oCOR64；
R77is-C6R67R68R69R70R76Or a heteroaryl group of one of the formulae
R78Is H; a lower alkyl group; aryl or aryl-lower alkyl;
R78and R82Together may form: - (CH)2)2-6-；-(CH2)2O(CH2)2-；
-(CH2)2S(CH2)2-or- (CH)2)2NR57(CH2)2-；
R79Is H; a lower alkyl group; aryl or aryl-lower alkyl or
R78And R79Taken together, may be- (CH)2)2-7-；-(CH2)2O(CH2)2-or
-(CH2)2NR57(CH2)2-；
R80Is H or lower alkyl;
R81is H; lower alkyl or aryl-lower alkyl;
R82is H; a lower alkyl group; an aryl group; heteroaryl or aryl-lower alkyl;
R33And R82Together may form: - (CH)2)2-6-；-(CH2)2O(CH2)2-；
-(CH2)2S(CH2)2-or- (CH)2)2NR57(CH2)2-；
R83Is H; a lower alkyl group; aryl or-NR78R79；
R84Is- (CH)2)m(CHR61)sOH；-(CH2)pCONR78R79；
-(CH2)pNR80CONR78R79；-(CH2)pC6H4CONR78R79Or
-(CH2)pC6H4NR80CONR78R79；
R85Is lower alkyl or lower alkenyl;
with the proviso that Z, Z is present in said chain of n alpha-amino acid residues1And Z2In
-if n is 8, then the amino acid residues at positions 1-8 are:
-P1: class C or class D or class E or class F, or the residue is Pro;
-P2: class E or class D or class F;
-P3: class E or class C, or the residue is Pro;
-P4: e or formula-A-CO-;
-P5: e is of the formula or-B-CO-, or the residue is Gly;
-P6: class D, or the residue is Pro;
-P7: or class C or class D; and
-P8: class C or class D or class E or class F, or the residue is Pro; or
P2 and P7, taken together, may form a group of the H type; and may also be the D-isomer at P4 and P5;
-if n is 9, then the amino acid residues at positions 1-9 are:
-P1: class C or class D or class E or class F, or the residue is Pro;
-P2: class E or class D or class F;
-P3: class C or class D or class E, or the residue is Pro;
-P4: class E or class D, or the residue is Pro;
-P5: e, or the residue is Gly or Pro;
-P6: class D or E, or the residue is Gly or Pro;
-P7: class E or class D or class C, or the residue is Pro;
-P8: class E or class D; and
-P9: class C or D or class E or class F, or the residue is Pro or
-P2 and P8, taken together, may form a group of the H type; and may also be the D-isomer at P4, P5 and P6;
-if n is 10, the amino acid residues at positions 1-10 are:
-P1: class C or class D or class E or class F, or the residue is Pro;
-P2: class E or class D, or the residue is Pro;
-P3: class C or class E;
-P4: class E or class D or class F, or the residue is Pro;
-P5: e or F or of the formula-A-CO-, or the residue is Gly;
-P6: e is of the formula or-B-CO-, or the residue is Gly;
-P7: class D or E, or the residue is Gly or Pro;
-P8: class D or class E;
-P9: class E or class D or class C, or the residue is Pro; and
-P10: class C or D or E or F or
-P3 and P8, taken together, may form a group of the H type; and may also be the D-isomer at P5 and P6;
-if n is 11, the amino acid residues at positions 1-11 are:
-P1: class C or class D or class E or class F, or the residue is Pro;
-P2: class E or class C or class D;
-P3: class D or E, or the residue is Pro;
-P4: class E or class C or class F;
-P5: class E or class F, or the residue is Gly or Pro;
-P6: class E or class F, or the residue is Gly or Pro;
-P7: class E or class F, or the residue is Gly or Pro;
-P8: class D or E or class F;
-P9: class D or E, or the residue is Pro;
-P10: class E or class C or class D; and
-P11: class C or D or class E or class F, or the residue is Pro or
-P4 and P8 and/or P2 and P10, taken together, may form a group of the H type; and may also be the D-isomer at P5, P6 and P7;
-if n is 12, then the amino acid residues at positions 1-12 are:
-P1: class C or class D or class E or class F, or the residue is Pro;
-P2: class E or class D;
-P3: class C or class D, or the residue is Pro;
-P4: class E or class F or class D;
-P5: class E or class D or class C, or the residue is Gly or Pro;
-P6: e or F or of the formula-A-CO-, or the residue is Gly;
-P7: class E or class F or of formula-B-CO-;
-P8: class D or class C, or the residue is Pro;
-P9: class E or class D or class F;
-P10: class D or class C, or the residue is Pro;
-P11: class E or class D; and
-P12: class C or D or class E or class F, or the residue is Pro or
-P4 and P9 and/or P2 and P11, taken together, may form a group of the H type; and may also be the D-isomer at P6 and P7;
-if n is 13, then the amino acid residues at positions 1-13 are:
-P1: class C or class D or class E or class F, or the residue is Pro;
-P2: class E or class F or class D;
-P3: class C or class D or class E, or the residue is Pro;
-P4: class E or class C or class F;
-P5: class E or class D, or the residue is Gly or Pro;
-P6: class E or class F, or the residue is Gly or Pro;
-P7: class E or class F, or the residue is Pro;
-P8: class D or E or class F, or the residue is Pro;
-P9: class D or E, or the residue is Pro;
-P10: class E or class C or class F;
-P11: class C or E, or the residue is Pro;
-P12: class E or class D or class C; and
-P13: class C or D or class E or class F, or the residue is Pro or
P4 and P10 and/or P2 and P12, taken together, may form a group of the H type; and may also be the D-isomer at P6, P7 and P8;
-if n is 14, then the amino acid residues at positions 1-14 are:
-P1: class C or class D or class E or class F, or the residue is Pro;
-P2: class E or class C or class D, or the residue is Pro;
-P3: class C or class D or class E;
-P4: class D or C or E, or the residue is Pro;
-P5: class E or class D;
-P6: class E or class F, or the residue is Gly or Pro;
-P7: e or F or of the formula-A-CO-, or the residue is Gly;
-P8: e or F or of the formula-B-CO-, or the residue is Gly;
-P9: class D or E, or the residue is Pro;
-P10: class C or class D or class E;
-P11: class E or class D or class F, or the residue is Pro;
-P12: class D or class E;
-P13: class E or class C or class D, or the residue is Pro; and
-P14: class C or D or class E or class F, or the residue is Pro or
-P5 and P10 and/or P3 and P12, taken together, may form a group of the H type; and may also be the D-isomer at P7 and P8;
-if n is 15, then the amino acid residues at positions 1-15 are:
p1: class C or class D or class E or class F, or the residue is Pro;
p2: class E or class F or class D;
p3: class C or class D or class E, or the residue is Pro;
p4: class E or class D or class F;
p5: class C or class D or class E, or the residue is Pro;
p6: class E or class D or class F;
p7: class C or E, or the residue is Pro;
p8: class E or class F, or the residue is Gly or Pro;
p9: class E or class F, or the residue is Gly or Pro;
p10: class E or class D;
p11: class C or class D or class E, or the residue is Pro;
p12: class E or class C or class F;
P13: class D or E, or the residue is Pro;
p14: class E or class C or class D; and
p15: class C or D or class E or class F, or the residue is Pro or
P6 and P10 and/or P4 and P12 and/or P2 and P14, taken together, may form a group of the H class; and may also be the D-isomer at P7, P8 and P9; and
-if n is 16, then the amino acid residues at positions 1-16 are:
-P1: class D, or class E, or class C or class F, or the residue is Pro;
-P2: class E or class F or class D;
-P3: class C or class D or class E, or the residue is Pro;
-P4: class E or class D or class F;
-P5: class D or C or E, or the residue is Pro;
-P6: class E or class D;
-P7: class E or class F, or the residue is Gly or Pro;
-P8: e or F or of the formula-A-CO-, or the residue is Gly;
-P9: e is of the formula or-B-CO-, or the residue is Gly;
-P10: class D or E, or the residue is Pro;
-P11: class E or class C or class D;
-P12: class D or C or E, or the residue is Pro;
-P13: class E or class C or class F;
-P14: class C or class D or class E, or the residue is Pro;
-P15: class E or class C or class D; and
-P16: class C or D or class E or class F, or the residue is Pro or
-P6 and P11 and/or P4 and P13 and/or P2 and P15, taken together, may form a group of the H type; and may also be the D-isomer at P8 and P9.
2. The compound of claim 1, wherein is different from the group of formula (a 2);
R2-R19，R21-R29，R31，R35-R38，R41-R45，R51-R54and R76Is different from- (CH)2)m(CHR61)sOCONR33R75Or- (CH)2)m(CHR61)sNR20CONR33R82；
R33、R55、R55、R61And R64Is different from- (CH)2)m(CHR61)sOCONR75R82Or
-(CH2)m(CHR61)sNR20CONR78R82；
R33And R34Or R34And R63Taken together, other than-CH2-6-；
-(CH2)2O(CH2)2-、-(CH2)2S(CH2)2-or- (CH)2)2NR57(CH2)2-；
-(CH2)2NR57(CH2)2-or- (CH)2)rNR57(CH2)rR in (A-C)57Other than lower alkenyl or heteroaryl-lower alkyl;
R71is H, lower alkyl, lower alkenyl, - (CH)2)p(CHR61)sOR75、
-(CH2)p(CHR61)sSR75、-(CH2)pNRxRy、-(CH2)o(CHR61)sCOOR75、
-(CH2)pCONRxRy、-(CH2)pPO(OR62)2、-(CH2)pSO2R62Or
-(CH2)o-C6R67R68R69R70R76；
R74Is different from- (CH)2)pNR77R80、-(CH2)pC6H4NR77R80、
-(CH2)pO(CH2)mNR77R80、-(CH2)pS(CH2)mNR77R80、
-(CH2)pN＝C(NR78R80)NR79R80、
-(CH2)pC6H4N＝C(NR78R80)NR79R80、
-(CH2)pO(CH2)mN＝C(NR78R80)NR79R80、
-(CH2)pS(CH2)mN＝C(NR78R80)NR79R80、-(CH2)pNR80COR64Or
-(CH2)pNR80COR77；
Other than H52, H53, and H54;
at Z, Z1Or Z2In
-if n is 8, the amino acid residues at positions 1, 7 and 8 are:
-P1: form C or D or E, or the residue is Pro;
-P7: form C or D; and
-P8: form C or D or E, or the residue is Pro;
-if n is 9, the amino acid residues in positions 1 and 9 are:
-P1: form C or D or E, or the residue is Pro; and
-P9: form C or D or E, or the residue is Pro;
-if n is 10, the amino acid residues in positions 1 and 10 are:
-P1: form C or D or E, or the residue is Pro; and
-P10: form C or D or E;
-if n is 11, the amino acid residues in positions 1 and 11 are:
-P1: form C or D or E, or the residue is Pro; and
-P11: form C or D or E, or the residue is Pro;
-if n is 12, the amino acid residues at positions 1, 5 and 12 are:
-P1: form C or D or E, or the residue is Pro;
-P5: form E or D, or the residue is Gly or Pro; and
-P12: form C or D or E, or the residue is Pro;
-if n is 13, the amino acid residues at positions 1 and 13 are:
-P1: form C or D or E, or the residue is Pro; and
-P13: form C or D or E, or the residue is Pro;
-if n is 14, the amino acid residues in positions 1 and 14 are:
-P1: form C or D or E, or the residue is Pro; and
-P14: form C or D or E, or the residue is Pro;
-if n is 15, the amino acid residues at positions 1 and 15 are:
-P1: form C or D or E, or the residue is Pro; and
-P15: form C or D or E, or the residue is Pro;
-if n is 16, the amino acid residues in positions 1 and 16 are:
-P1: d or E or C, or the residue is Pro; and
-P16: type C or D or E, or the residue is Pro.
3. A compound according to claim 1 or 2, wherein
Are a group of formulae (a1) or (a 2).
4. A compound according to claim 3, wherein a is a group of one of the formulae a1-a 69;
R1is H or lower alkyl;
R2is H; a lower alkyl group; a lower alkenyl group; (CH)2)mOR55(wherein R is55Is lower alkyl or lower alkenyl); (CH)2)mSR56(wherein R is56Is lower alkyl or lower alkenyl); (CH)2)mNR33R34(wherein R is33Is lower alkyl or lower alkenyl; r34Is H or lower alkyl; or R33And R34Taken together are- (CH)2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-or- (CH)2)2NR57(CH2)2-; wherein R is57Is H or lower alkyl); (CH)2)mOCONR33R75(wherein R is33Is H or lower alkyl or lower alkenyl; r75Is a lower alkyl group; or R33And R75Taken together are- (CH)2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-or- (CH)2)2NR57(CH2)2-; wherein R is87Is H or lower alkyl); - (CH)2)mNR20CONR33R82(wherein R is20Is H or lower alkyl; r33Is H or lower alkyl or lower alkenyl; r82Is H or lower alkyl or R33And R82Taken together are- (CH)2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-or- (CH)2)2NR57(CH2)2-; wherein R is57Is H or lower alkyl); - (CH)2)oN(R20)COR64(wherein: R20Is H or lower alkyl; r64Is lower alkyl or lower alkenyl); - (CH)2)oCOOR57(wherein R is57Is lower alkyl or lower alkenyl); - (CH)2)oCONR58R59(wherein R is58Is lower alkyl or lower alkenyl; and R59Is H or lower alkyl or R58And R59Taken together are- (CH)2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-or- (CH)2)2NR57(CH2)2-; wherein R is57Is H or lower alkyl); - (CH)2)oPO(OR60)2(wherein R is 60Is lower alkyl or lower alkenyl); - (CH)2)oSO2R62(wherein R is62Is lower alkyl or lower alkenyl) or- (CH)2)qC6H4R8(wherein R is8Is H; f; cl; CF (compact flash)3(ii) a A lower alkyl group; lower alkenyl or lower alkoxy);
R3is H; a lower alkyl group; a lower alkenyl group; - (CH)2)mOR55(wherein R is55Is lower alkyl or lower alkenyl); - (CH)2)mSR56(wherein R is56Is lower alkyl or lower alkenyl); - (CH)2)mNR33R34(wherein R is33Is lower alkyl or lower alkenyl; r34Is H or lower alkyl or R33And R34Taken together are- (CH)2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-or- (CH)2)2NR57(CH2)2-; wherein R is57Is H or lower alkyl); - (CH)2)mOCONR33R75(wherein R is33Is H or lower alkyl or lower alkenyl; r75Is lower alkyl or R33And R75Taken together are- (CH)2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-or- (CH)2)2NR57(CH2)2-; wherein R is57Is H or lower alkyl); - (CH)2)mNR20CONR33R82(wherein R is20Is H or lower alkyl; r33Is H or lower alkyl or lower alkenyl; r82Is H or lower alkyl or R33And R82Taken together are- (CH)2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-or- (CH)2)2NR57(CH2)2-; wherein R is57Is H or lower alkyl); - (CH)2)oN(R20)COR64(wherein: R20Is H or lower alkyl; r64Is lower alkyl or lower alkenyl); - (CH)2)oCOOR57(wherein R is57Is lower alkyl or lower alkenyl); - (CH)2)oCONR58R59(wherein58Is lower alkyl or lower alkenyl; and R59Is H; lower alkyl or R58And R59Taken together are- (CH)2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-or- (CH) 2)2NR57(CH2)2-; wherein R is57Is H or lower alkyl); (CH)2)oPO(OR60)2(wherein R is60Is lower alkyl or lower alkenyl); - (CH)2)oSO2R62(wherein R is62Is lower alkyl or lower alkenyl) or- (CH)2)qC6H4R8(wherein R is8Is H; f; cl; CF (compact flash)3(ii) a A lower alkyl group; lower alkenyl or lower alkoxy);
R4is H; a lower alkyl group; a lower alkenyl group; - (CH)2)mOR55(wherein R is55Is lower alkyl or lower alkenyl); - (CH)2)mSR56(wherein R is56Is lower alkyl or lower alkenyl); - (CH)2)mNR33R34(wherein R is33Is lower alkyl or lower alkenyl; r34Is H or lower alkyl or R33And R34Taken together are- (CH)2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-or- (CH)2)2NR57(CH2)2-; wherein R is57Is H or lower alkyl); - (CH)2)mOCONR33R75(wherein R is33Is H or lower alkyl or lower alkenyl; r75: lower alkyl or R33And R75Taken together are- (CH)2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-or- (CH)2)2NR57(CH2)2-; wherein R is57Is H or lower alkyl); - (CH)2)mNR20CONR33R82(wherein R is20Is H or lower alkyl; r33Is H or lower alkyl or lower alkenyl; r82Is H or lower alkyl or R33And R82Taken together are- (CH)2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-or- (CH)2)2NR57(CH2)2-; wherein R is57Is H or lower alkyl); - (CH)2)mN(R20)COR64(wherein: R20Is H or lower alkyl; r64Is lowLower alkyl or lower alkenyl); - (CH)2)oCOOR57(wherein R is57Is lower alkyl or lower alkenyl); - (CH)2)oCONR58R59(wherein R is58Is lower alkyl or lower alkenyl; and R59Is H or lower alkyl or R 58And R59Taken together are- (CH)2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-or- (CH)2)2NR57(CH2)2-; wherein R is57Is H or lower alkyl); - (CH)2)oPO(OR60)2(wherein R is60Is lower alkyl or lower alkenyl); - (CH)2)oSO2R62(wherein R is62Is lower alkyl or lower alkenyl) or- (CH)2)qC6H4R8(wherein R is8Is H; f; cl; CF (compact flash)3(ii) a A lower alkyl group; lower alkenyl or lower alkoxy).
R5Is a lower alkyl group; a lower alkenyl group; - (CH)2)oOR55(wherein R is55Is lower alkyl or lower alkenyl); - (CH)2)oSR56(wherein R is56Is lower alkyl or lower alkenyl); - (CH)2)oNR33R34(wherein R is33Is lower alkyl or lower alkenyl; r34Is H or lower alkyl or R33And R34Taken together are- (CH)2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-or- (CH)2)2NR57(CH2)2-; wherein R is57Is H or lower alkyl); - (CH)2)oOCONR33R75(wherein R is33Is H or lower alkyl or lower alkenyl; r75Is lower alkyl or R33And R75Taken together are- (CH)2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-or- (CH)2)2NR57(CH2)2-; wherein R is57Is H or lower alkyl); (CH)2)oNR20CONR33R82(wherein R is20Is H or lower alkyl; r33Is H or lower alkyl or lower alkenyl; r82Is H or lower alkyl or R33And R82Taken together are- (CH)2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-or- (CH)2)2NR57(CH2)2-; wherein R is57Is H or lower alkyl); (CH)2)oN(R20)COR64(wherein: R20Is H or lower alkyl; r64: an alkyl group; an alkenyl group; an aryl group; and aryl-lower alkyl; heteroaryl-lower alkyl); - (CH)2)oCOOR57(wherein R is57Is lower alkyl or lower alkenyl); - (CH) 2)oCONR58R59(wherein R is58Is lower alkyl or lower alkenyl; and R59Is H or lower alkyl or R58And R59Taken together are- (CH)2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-or- (CH)2)2NR57(CH2)2-; wherein R is57Is H or lower alkyl); - (CH)2)oPO(OR60)2(wherein R is60Is lower alkyl or lower alkenyl); - (CH)2)oSO2R62(wherein R is62Is lower alkyl or lower alkenyl) or- (CH)2)qC6H4R8(wherein R is8Is H; f; cl; CF (compact flash)3(ii) a A lower alkyl group; lower alkenyl or lower alkoxy);
R6is H; a lower alkyl group; a lower alkenyl group; - (CH)2)oOR55(wherein R is55Is lower alkyl or lower alkenyl); - (CH)2)oSR56(wherein R is56Is lower alkyl or lower alkenyl); - (CH)2)oNR33R34(wherein R is33Is lower alkyl or lower alkenyl; r34Is H or lower alkyl or R33And R34Taken together are- (CH)2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-or- (CH)2)2NR57(CH2)2-; wherein R is57Is H or lower alkyl); - (CH)2)oOCONR33R75(wherein R is33Is H or lower alkyl or lower alkenyl; r75Is lower alkyl or R33And R75Taken together are- (CH)2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-or- (CH)2)2NR57(CH2)2-; wherein R is57Is H or lower alkyl); - (CH)2)oNR20CONR33R82(wherein R is20Is H or lower alkyl; r33Is H or lower alkyl or lower alkenyl; r82Is H or lower alkyl or R33And R82Taken together are- (CH)2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-or- (CH)2)2NR57(CH2)2-; wherein R is57Is H or lower alkyl); - (CH)2)oN(R20)COR64(wherein: R20Is H or lower alkyl; r64Is lower alkyl or lower alkenyl); - (CH) 2)oCOOR57(wherein R is57Is lower alkyl or lower alkenyl); - (CH)2)oCONR58R59(wherein R is58Is lower alkyl or lower chainAn alkenyl group; and R59Is H or lower alkyl or R58And R59Taken together are- (CH)2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-or- (CH)2)2NR57(CH2)2-; wherein R is57Is H or lower alkyl); - (CH)2)oPO(OR60)2(wherein R is60Is lower alkyl or lower alkenyl); - (CH)2)oSO2R62(wherein R is62Is lower alkyl or lower alkenyl) or- (CH)2)qC6H4R8(wherein R is8Is H; f; cl; CF (compact flash)3(ii) a A lower alkyl group; lower alkenyl or lower alkoxy);
R7is a lower alkyl group; a lower alkenyl group; - (CH)2)qOR55(wherein R is55Is lower alkyl or lower alkenyl); - (CH)2)qSR56(wherein R is56Is lower alkyl or lower alkenyl); - (CH)2)qNR33R34(wherein R is33Is lower alkyl or lower alkenyl; r34Is H or lower alkyl or R33And R34Taken together are- (CH)2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-or- (CH)2)2NR57(CH2)2-; wherein R is57Is H or lower alkyl); - (CH)2)qOCONR33R75(wherein R is33Is H or lower alkyl or lower alkenyl; r75Is lower alkyl or R33And R75Taken together are- (CH)2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-or- (CH)2)2NR57(CH2)2-; wherein R is57Is H or lower alkyl); (CH)2)qNR20CONR33R82(wherein R is20Is H or lower alkyl; r33Is H or lower alkyl or lower alkenyl; r82Is H or lower alkyl or R33And R82Taken together are- (CH)2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-or- (CH)2)2NR57(CH2)2-; wherein R is57Is H or lower alkyl); - (CH)2)qN(R20)COR64(wherein: R20Is H or lower alkyl; r 64Is lower alkyl or lower alkenyl); - (CH)2)rCOOR57(wherein R is57Is lower alkyl or lower alkenyl); - (CH)2)qCONR58R59(wherein R is58Is lower alkyl or lower alkenyl; and R59Is H or lower alkyl or R58And R59Taken together are- (CH)2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-or- (CH)2)2NR57(CH2)2-; wherein R is57Is H or lower alkyl); - (CH)2)rPO(OR60)2(wherein R is60Is lower alkyl or lower alkenyl); (CH)2)rSO2R62(wherein R is62Is lower alkyl or lower alkenyl) or- (CH)2)qC6H4R8(wherein R is8Is H; f; cl; CF (compact flash)3(ii) a A lower alkyl group; lower alkenyl or lower alkoxy);
R8is H; f; cl; CF (compact flash)3(ii) a A lower alkyl group; a lower alkenyl group; - (CH)2)oOR55(wherein R is55Is lower alkyl or lower alkenyl); (CH)2)oSR56(wherein R is56Is lower alkyl or lower alkenyl); - (CH)2)oNR33R34(wherein R is33Is lower alkyl or lower alkenyl; r34Is H or lower alkyl or R33And R34Taken together are- (CH)2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-or- (CH)2)2NR57(CH2)2-; wherein R is57Is H or lower alkyl); - (CH)2)oOCONR33R75(wherein R is33Is H or lower alkyl or lower alkenyl; r75Is lower alkyl or R33And R75Taken together are- (CH)2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-or- (CH)2)2NR57(CH2)2-; wherein R is57Is H or lower alkyl); - (CH)2)oNR20CONR33R82(wherein R is20Is H or lower alkyl; r33Is H or lower alkyl or lower alkenyl; r82Is H or lower alkyl or R33And R82Taken together are- (CH)2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-or- (CH)2)2NR57(CH2)2-; wherein R is 57Is H or lower alkyl); - (CH)2)oN(R20)COR64(wherein: R20Is H or lower alkyl; r64Is lower alkyl or lower alkenyl); - (CH)2)oCOOR57(wherein R is57Is lower alkyl or lower alkenyl); - (CH)2)oCONR58R59(wherein R is58Is lower alkyl or lower alkenyl; and R59Is H or lower alkyl or R58And R59Taken together are- (CH)2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-or- (CH)2)2NR57(CH2)2-; wherein R is57Is H or lower alkyl); - (CH)2)oPO(OR60)2(wherein R is60Is lower alkyl or lower alkenyl); - (CH)2)oSO2R62(wherein R is62Is lower alkyl or lower alkenyl) or- (CH)2)qC6H4R8(wherein R is8Is H; f; cl; CF (compact flash)3(ii) a A lower alkyl group; lower alkenyl or lower alkoxy);
R9is a lower alkyl group; a lower alkenyl group; - (CH)2)oOR55(wherein R is55Is lower alkyl or lower alkenyl); - (CH)2)oSR56(wherein R is56Is lower alkyl or lower alkenyl); - (CH)2)oNR33R34(wherein R is33Is lower alkyl or lower alkenyl; r34Is H or lower alkyl or R33And R34Taken together are- (CH)2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-or- (CH)2)2NR57(CH2)2-; wherein R is57Is H or lower alkyl); - (CH)2)oOCONR33R75(wherein R is33Is H or lower alkyl or lower alkenyl; r75Is lower alkyl or R33And R75Taken together are- (CH)2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-or- (CH)2)2NR57(CH2)2-; wherein R is57Is H or lower alkyl); - (CH)2)mNR20CONR33R82(wherein R is20Is H or lower alkyl; r33Is H or lower alkyl or lower alkenyl; r82Is H or lower alkyl or R 33And R82Taken together are- (CH)2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-or- (CH)2)2NR57(CH2)2-; wherein R is57Is H or lower alkyl); - (CH)2)oN(R20)COR64(wherein: R20Is H or lower alkyl; r64Is lower alkyl or lower alkenyl); - (CH)2)oCOOR57(wherein R is57Is lower alkyl or lower alkenyl); - (CH)2)oCONR58R59(wherein R is58Is lower alkyl or lower alkenyl; and R59Is H or lower alkyl or R58And R59Taken together are- (CH)2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-or- (CH)2)2NR57(CH2)2-; wherein R is57Is H or lower alkyl); - (CH)2)oPO(OR60)2(wherein R is60Is lower alkyl or lower alkenyl); - (CH)2)oSO2R62(wherein R is62Is lower alkyl or lower alkenyl) or- (CH)2)qC6H4R8(wherein R is8Is H; f; cl; CF (compact flash)3(ii) a A lower alkyl group; lower alkenyl or lower alkoxy);
R10is a lower alkyl group; a lower alkenyl group; - (CH)2)oOR55(wherein R is55Is lower alkyl or lower alkenyl); - (CH)2)oSR56(wherein R is56Is lower alkyl or lower alkenyl); - (CH)2)oNR33R34(wherein R is33Is lower alkyl or lower alkenyl; r34Is H or lower alkyl or R33And R34Taken together are- (CH)2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-or- (CH)2)2NR57(CH2)2-; wherein R is57Is H or lower alkyl); - (CH)2)oOCONR33R75(wherein R is33Is H or lower alkyl or lower alkenyl; r75Is lower alkyl or R33And R75Taken together are- (CH)2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-or- (CH)2)2NR57(CH2)2-; wherein R is57Is H or lower alkyl); - (CH)2)oNR20CONR33R82(wherein R is20Is H or lower alkyl; r33Is H or lower alkyl or lower alkenyl; r 82Is H or lower alkyl or R33And R82Taken together are- (CH)2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-or- (CH)2)2NR57(CH2)2-; wherein R is57Is H or lower alkyl); - (CH)2)oN(R20)COR64(wherein: R20Is H or lower alkyl; r64Is lower alkyl or lower alkenyl); - (CH)2)oCOOR57(wherein R is57Is lower alkyl or lower alkenyl); - (CH)2)oCONR58R59(wherein R is58Is lower alkyl or lower alkenyl; and R59Is H; lower alkyl or R58And R59Taken together are- (CH)2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-or- (CH)2)2NR57(CH2)2-; wherein R is57Is H or lower alkyl); - (CH)2)oPO(OR60)2(wherein R is60Is lower alkyl or lower alkenyl); - (CH)2)oSO2R62(wherein R is62Is lower alkyl or lower alkenyl) or- (CH)2)qC6H4R8(wherein R is8Is H; f; cl; CF (compact flash)3(ii) a A lower alkyl group; lower alkenyl or lower alkoxy);
R11is H; a lower alkyl group; a lower alkenyl group; - (CH)2)mOR55(wherein R is55Is lower alkyl or lower alkenyl); - (CH)2)mSR56(wherein R is56Is lower alkyl or lower alkenyl); - (CH)2)mNR33R34(wherein R is33Is lower alkyl or lower alkenyl; r34Is H or lower alkyl or R33And R34Taken together are- (CH)2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-or- (CH)2)2NR57(CH2)2-; wherein R is57Is H or lower alkyl); - (CH)2)mOCONR33R75(wherein R is33Is H or lower alkyl or lower alkenyl; r75Is lower alkyl or R33And R75Taken together are- (CH)2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-or- (CH)2)2NR57(CH2)2-; wherein R is57Is H or lower alkyl); - (CH)2)mNR20CONR33R82(wherein R is20Is H or lower alkyl; r 33Is H or lower alkyl or lower alkenyl; r82Is H or lower alkyl or R33And R82Taken together are- (CH)2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-or- (CH)2)2NR57(CH2)2-; wherein R is57Is H or lower alkyl); - (CH)2)mN(R20)COR64(wherein: R20Is H or lower alkyl; r64Is lower alkyl or lower alkenyl); - (CH)2)oCOOR57(wherein R is57Is lower alkyl or lower alkenyl); - (CH)2)oCONR58R59(wherein R is58Is lower alkyl or lower alkenyl; and R59Is H; lower alkyl or R58And R59Taken together are- (CH)2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-or- (CH)2)2NR57(CH2)2-; wherein R is57Is H or lower alkyl); - (CH)2)oPO(OR60)2(wherein R is60Is lower alkyl or lower alkenyl); - (CH)2)oSO2R62(wherein R is62Is lower alkyl or lower alkenyl) or- (CH)2)qC6H4R8(wherein R is8Is H; f; cl; CF (compact flash)3(ii) a A lower alkyl group; lower alkenyl or lower alkoxy);
R12is H; a lower alkyl group; a lower alkenyl group; - (CH)2)mOR55(wherein R is55Is lower alkyl or lower alkenyl); - (CH)2)mSR56(wherein R is56Is lower alkyl or lower alkenyl); - (CH)2)mNR33R34(wherein R is33Is lower alkyl or lower alkenyl; r34Is H or lower alkyl or R33And R34Taken together are- (CH)2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-or- (CH)2)2NR57(CH2)2-; wherein R is57Is H or lower alkyl); - (CH)2)mOCONR33R75(wherein R is33Is H or lower alkyl or lower alkenyl; r75Is lower alkyl or R33And R76Taken together are- (CH)2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-or- (CH)2)2NR57(CH2)2-; wherein R is57Is H or lower alkyl); - (CH) 2)mNR20CONR33R82(wherein R is20Is H or lower alkyl; r33Is H or lower alkyl or lower alkenyl; r82Is H or lower alkyl or R33And R82Taken together are- (CH)2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-or- (CH)2)2NR67(CH2)2-; wherein R is57Is H or lower alkyl); - (CH)2)mN(R20)COR64(wherein: R20Is H or lower alkyl; r64Is lower alkyl or lower alkenyl); - (CH)2)rCOOR57(wherein R is57Is lower alkyl or lower alkenyl); - (CH)2)rCONR58R59(wherein R is58Is lower alkyl or lower alkenyl; and R59Is H or lower alkyl or R58And R59Taken together are- (CH)2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-or- (CH)2)2NR57(CH2)2-; wherein R is57Is H or lower alkyl); - (CH)2)rPO(OR60)2(wherein R is60Is lower alkyl or lower alkenyl); - (CH)2)oSO2R62(wherein R is62Is lower alkyl or lower alkenyl) or- (CH)2)qC6H4R8(wherein R is8Is H; f; cl; CF (compact flash)3(ii) a A lower alkyl group; lower alkenyl or lower alkoxy);
R13is a lower alkyl group;a lower alkenyl group; - (CH)2)qOR55(wherein R is55Is lower alkyl or lower alkenyl); - (CH)2)qSR56(wherein R is56Is lower alkyl or lower alkenyl); - (CH)2)qNR33R34(wherein R is33Is lower alkyl or lower alkenyl; r34Is H or lower alkyl or R33And R34Taken together are- (CH)2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-or- (CH)2)2NR57(CH2)2-; wherein R is57Is H or lower alkyl); - (CH)2)qOCONR33R75(wherein R is33Is H or lower alkyl or lower alkenyl; r75Is lower alkyl or R33And R75Taken together are- (CH) 2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-or- (CH)2)2NR57(CH2)2-; wherein R is57Is H or lower alkyl); - (CH)2)qNR20CONR33R82(wherein R is20Is H or lower alkyl; r33Is H or lower alkyl or lower alkenyl; r82Is H or lower alkyl or R33And R82Taken together are- (CH)2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-or- (CH)2)2NR57(CH2)2-; wherein R is57Is H or lower alkyl); - (CH)2)qN(R20)COR64(wherein: R20Is H or lower alkyl; r64Is lower alkyl or lower alkenyl); - (CH)2)rCOO57(wherein R is57Is lower alkyl or lower alkenyl); - (CH)2)qCONR58R59(wherein R is58Is lower alkyl or lower alkenyl; and R59Is H or lower alkyl or R58And R59Taken together are- (CH)2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-or- (CH)2)2NR57(CH2)2-; wherein R is57Is H or lower alkyl); - (CH)2)rPO(OR60)2(wherein R is60Is lower alkyl or lower alkenyl); - (CH)2)rSO2R62(wherein R is62Is lower alkyl or lower alkenyl) or- (CH)2)qC6H4R8(wherein R is8Is H; f; cl; CF (compact flash)3(ii) a A lower alkyl group; lower alkenyl or lower alkoxy);
R14is H; a lower alkyl group; a lower alkenyl group; - (CH)2)mOR55(wherein R is55Is lower alkyl or lower alkenyl); - (CH)2)mSR56(wherein R is56Is lower alkyl or lower alkenyl); - (CH)2)mNR33R34(wherein R is33Is lower alkyl or lower alkenyl; r34Is H or lower alkyl or R33And R34Taken together are- (CH)2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-or- (CH)2)2NR57(CH2)2-; wherein R is57Is H or lower alkyl); - (CH)2)mOCONR33R75(wherein R is33Is H or lower alkyl or lower alkenyl; r 75Is lower alkyl or R33And R75Taken together are- (CH)2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-or- (CH)2)2NR57(CH2)2-; wherein R is57Is H or lower alkylRadical); - (CH)2)mNR20CONR33R82(wherein R is20Is H or lower alkyl; r33Is H or lower alkyl or lower alkenyl; r82Is H or lower alkyl or R33And R82Taken together are- (CH)2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-or- (CH)2)2NR57(CH2)2-; wherein R is57Is H or lower alkyl); - (CH)2)mN(R20)COR64(wherein: R20Is H; a lower alkyl group; r64Is lower alkyl or lower alkenyl); - (CH)2)oCOOR57(wherein R is57Is lower alkyl or lower alkenyl); - (CH)2)oCONR58R59(wherein R is58Is lower alkyl or lower alkenyl; and R59Is H or lower alkyl or R58And R59Taken together are- (CH)2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-or- (CH)2)2NR57(CH2)2-; wherein R is57Is H or lower alkyl); - (CH)2)oPO(OR60)2(wherein R is60Is lower alkyl or lower alkenyl); - (CH)2)oSO2R62(wherein R is62Is lower alkyl or lower alkenyl); - (CH)2)qC6H4R8(wherein R is8Is H; f; cl; CF (compact flash)3(ii) a A lower alkyl group; lower alkenyl or lower alkoxy);
R15is a lower alkyl group; a lower alkenyl group; - (CH)2)oOR55(wherein R is55Is lower alkyl or lower alkenyl); - (CH)2)oSR56(wherein R is56Is lower alkyl or lower alkenyl); - (CH)2)oNR33R34(wherein R is33Is lower alkyl or lower alkenyl; r34Is H or lower alkyl or R33And R34Taken together are- (CH)2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-or- (CH)2)2NR57(CH2)2-; wherein R is57Is H or lower alkyl); - (CH) 2)oOCONR33R75(wherein R is33Is H or lower alkyl or lower alkenyl; r75Is lower alkyl or R33And R75Taken together are- (CH)2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-or- (CH)2)2NR57(CH2)2-; wherein R is57Is H or lower alkyl); - (CH)2)oNR20CONR33R82(wherein R is20Is H or lower alkyl; r33Is H or lower alkyl or lower alkenyl; r82Is H or lower alkyl or R33And R82Taken together are- (CH)2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-or- (CH)2)2NR57(CH2)2-; wherein R is57Is H or lower alkyl); (CH)2)oN(R20)COR64(wherein: R20Is H or lower alkyl; r64Is lower alkyl or lower alkenyl); NR is particularly preferred20CO lower alkyl (R)20H or lower alkyl); - (CH)2)oCOOR57(wherein R is57Is lower alkyl or lower alkenyl); - (CH)2)oCONR58R59(wherein R is58Is lower alkyl or lower alkenyl; and R59Is H; lower alkyl or R88And R59Taken together are- (CH)2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-or- (CH)2)2NR57(CH2)2-; wherein R is57Is H or lower alkyl); - (CH)2)oPO(OR60)2(wherein R is60Is lower alkyl or lower alkenyl); - (CH)2)oSO2R62(wherein R is62Is lower alkyl or lower alkenyl) or- (CH)2)qC6H4R8(wherein R is8Is H; f; cl; CF (compact flash)3(ii) a A lower alkyl group; lower alkenyl or lower alkoxy);
R16is a lower alkyl group; a lower alkenyl group; - (CH)2)oOR55(wherein R is55Is lower alkyl or lower alkenyl); - (CH)2)oSR56(wherein R is56Is lower alkyl or lower alkenyl); - (CH)2)oNR33R34(wherein R is33Is lower alkyl or lower alkenyl; r 34Is H or lower alkyl or R33And R34Taken together are- (CH)2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-or- (CH)2)2NR57(CH2)2-; wherein R is57Is H or lower alkyl); - (CH)2)oOCONR33R75(wherein R is33Is H or lower alkyl or lower alkenyl; r75Is lower alkyl or R33And R75Taken together are- (CH)2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-or- (CH)2)2NR57(CH2)2-; wherein R is57Is H or lower alkyl); - (CH)2)oNR20CONR33R82(wherein R is20Is H or lower alkyl; r33Is H or lower alkyl or lower alkenyl; r82Is H or lowerAlkyl or R33And R82Taken together are- (CH)2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-or- (CH)2)2NR57(CH2)2-; wherein R is57Is H or lower alkyl); - (CH)2)oN(R20)COR64(wherein: R20Is H or lower alkyl; r64Is lower alkyl or lower alkenyl); - (CH)2)oCOOR57(wherein R is57Is lower alkyl or lower alkenyl); - (CH)2)oCONR58R59(wherein R is58Is lower alkyl or lower alkenyl; and R59Is H or lower alkyl or R58And R59Taken together are- (CH)2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-or- (CH)2)2NR57(CH2)2-; wherein R is57Is H or lower alkyl); - (CH)2)oPO(OR60)2(wherein R is60Is lower alkyl or lower alkenyl); - (CH)2)oSO2R62(wherein R is62Is lower alkyl or lower alkenyl) or- (CH)2)qC6H4R8(wherein R is8Is H; f; cl; CF (compact flash)3(ii) a A lower alkyl group; lower alkenyl or lower alkoxy);
R17is a lower alkyl group; a lower alkenyl group; - (CH)2)qOR55(wherein R is55Is lower alkyl or lower alkenyl); - (CH)2)qSR56(wherein R is56Is lower alkyl or lower alkenyl); - (CH) 2)qNR33R34(wherein R is33Is lower alkyl or lower alkenyl; r34Is H or lower alkyl or R33And R34Taken together are- (CH)2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-or- (CH)2)2NR57(CH2)2-; wherein R is57Is H or lower alkyl); - (CH)2)qOCONR33R75(wherein R is33Is H or lower alkyl or lower alkenyl; r75Is lower alkyl or R33And R75Taken together are- (CH)2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-or- (CH)2)2NR57(CH2)2-; wherein R is57Is H or lower alkyl); - (CH)2)qNR20CONR33R82(wherein R is20Is H or lower alkyl; r33Is H or lower alkyl or lower alkenyl; r82Is H or lower alkyl or R33And R82Taken together are- (CH)2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-or- (CH)2)2NR57(CH2)2-; wherein R is57Is H or lower alkyl); - (CH)2)qN(R20)COR64(wherein: R20Is H or lower alkyl; r64Is lower alkyl or lower alkenyl); - (CH)2)rCOOR57(wherein R is57Is lower alkyl or lower alkenyl); - (CH)2)qCONR58R59(wherein R is58Is lower alkyl or lower alkenyl; and R59Is H; lower alkyl or R58And R59Taken together are- (CH)2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-or- (CH)2)2NR57(CH2)2-; wherein R is57Is H or lower alkyl); - (CH)2)rPO(OR60)2(wherein R is60Is a lower alkaneAlkyl or lower alkenyl); - (CH)2)rSO2R62(wherein R is62Is lower alkyl or lower alkenyl) or- (CH)2)qC6H4R8(wherein R is8Is H; f; cl; CF (compact flash)3(ii) a A lower alkyl group; lower alkenyl or lower alkoxy).
5. A compound according to claim 3 or 4, wherein A is of formula A5 (R)2Is H), A8, A22, A25, A38 (R)2Is one of H), A42 and A50.
6. The compound of claim 5, wherein A is a group of the formula:
wherein R is20Is H or lower alkyl; and R64Is an alkyl group; an alkenyl group; an aryl group; aryl-lower alkyl or heteroaryl-lower alkyl.
7. A compound of claim 6, wherein R64Is n-hexyl; a n-heptyl group; 4- (phenyl) benzyl; a diphenylmethyl group; 3-amino-propyl; 5-amino-pentyl; a methyl group; an ethyl group; isopropyl group; an isobutyl group; n-propyl; a cyclohexyl group; a cyclohexylmethyl group; n-butyl; a phenyl group; a benzyl group; (3-indolyl) methyl; 2- (3-indolyl) ethyl; (4-phenyl) phenyl; or n-nonyl.
8. A compound according to claim 3, wherein a is a group of one of the formulae a70-a 104;
R20is H or lower alkyl;
R18is a lower alkyl group.
R19Is a lower alkyl group; a lower alkenyl group; - (CH)2)pOR55(wherein R is55Is lower alkyl or lower alkenyl); - (CH)2)pSR56(wherein R is56Is lowLower alkyl or lower alkenyl); - (CH)2)pNR33R34(wherein R is33Is lower alkyl or lower alkenyl; r34Is H or lower alkyl or R33And R34Taken together are- (CH)2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-or- (CH)2)2NR57(CH2)2-; wherein R is57Is H or lower alkyl); - (CH)2)pOCONR33R75(wherein R is33Is H or lower alkyl or lower alkenyl; r75Is lower alkyl or R33And R75Taken together are- (CH)2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-or- (CH) 2)2NR57(CH2)2-; wherein R is57Is H or lower alkyl); - (CH)2)pNR20CONR33R82(wherein R is20Is H or lower alkyl; r33Is H or lower alkyl or lower alkenyl; r82Is H or lower alkyl or R33And R82Taken together are- (CH)2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-or- (CH)2)2NR57(CH2)2-; wherein R is57Is H or lower alkyl); - (CH)2)pN(R20)COR64(wherein: R20Is H or lower alkyl; r64Is lower alkyl or lower alkenyl); - (CH)2)pCOOR57(wherein R is57Is lower alkyl or lower alkenyl); - (CH)2)pCONR58R59(wherein R is58Is lower alkyl or lower alkenyl; and R59Is H or lower alkyl or R58And R59Taken together are- (CH)2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-or- (CH)2)2NR57(CH2)2-; wherein R is57Is H or lower alkyl); - (CH)2)oPO(OR60)2(wherein R is60Is lower alkyl or lower alkenyl); - (CH)2)pSO2R62(wherein R is62Is lower alkyl or lower alkenyl) or- (CH)2)oC6H4R8(wherein R is8Is H; f; cl; CF (compact flash)3(ii) a A lower alkyl group; lower alkenyl or lower alkoxy);
R21is H; a lower alkyl group; a lower alkenyl group; - (CH)2)oOR55(wherein R is55Is lower alkyl or lower alkenyl); - (CH)2)oSR56(wherein R is56Is lower alkyl or lower alkenyl); - (CH)2)oNR33R34(wherein R is33Is lower alkyl or lower alkenyl; r34Is H or lower alkyl or R33And R34Taken together are- (CH)2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-or- (CH)2)2NR57(CH2)2-; wherein R is57Is H or lower alkyl); - (CH)2)oOCONR33R75(wherein R is33Is H or lower alkyl or lower alkenyl; r 75Is lower alkyl or R33And R75Taken together are- (CH)2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-or- (CH)2)2NR87(CH2)2-; wherein R is57Is H or lower alkyl); - (CH)2)oNR20CONR33R82(wherein R is20Is H or lower alkyl; r33Is H or lower alkyl or lower alkenyl; r82Is H or lower alkyl or R33And R82Taken together are- (CH)2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-or- (CH)2)2NR57(CH2)2-; wherein R is57Is H or lower alkyl); - (CH)2)oN(R20)COR64(wherein: R20Is H or lower alkyl; r64Is lower alkyl or lower alkenyl); - (CH)2)oCOOR57(wherein R is57Is lower alkyl or lower alkenyl); - (CH)2)oCONR58R59(wherein R is58Is lower alkyl or lower alkenyl; and R59Is H; lower alkyl or R58And R59Taken together are- (CH)2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-or- (CH)2)2NR57(CH2)2-; wherein R is57Is H or lower alkyl); - (CH)2)oPO(OR60)2(wherein R is60Is lower alkyl or lower alkenyl); (CH)2)oSO2R62(wherein R is62Is lower alkyl or lower alkenyl) or (CH)2)qC6H4R8(wherein R is8Is H; f; cl; CF (compact flash)3(ii) a A lower alkyl group; lower alkenyl or lower alkoxy);
R22is a lower alkyl group; a lower alkenyl group; - (CH)2)oOR55(wherein R is55Is lower alkyl or lower alkenyl); - (CH)2)oSR56(wherein R is56Is lower alkyl or lower alkenyl); - (CH)2)oNR33R34(wherein R is33Is lower alkyl or lower alkenyl; r34Is H or lower alkyl or R33And R34Taken together are- (CH)2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-or- (CH)2)2NR57(CH2)2-; wherein R is57Is H or lower alkyl); - (CH)2)oOCONR33R75(wherein R is 33Is H or lower alkyl or lower alkenyl; r75Is lower alkyl or R33And R75Taken together are- (CH)2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-or- (CH)2)2NR57(CH2)2-; wherein R is57Is H or lower alkyl); - (CH)2)oNR20CONR33R82(wherein R is20Is H or lower alkyl; r33Is H or lower alkyl or lower alkenyl; r82Is H or lower alkyl or R33And R82Taken together are- (CH)2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-or- (CH)2)2NR57(CH2)2-; wherein R is57Is H or lower alkyl); - (CH)2)oN(R20)COR64(wherein: R20Is H or lower alkyl; r64Is lower alkyl or lower alkenyl); - (CH)2)oCOOR57(wherein R is57Is lower alkyl or lower alkenyl); - (CH)2)oCONR58R59(wherein R is58Is lower alkyl or lower alkenyl; and R59Is H; lower alkyl or R58And R59Taken together are- (CH)2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-or- (CH)2)2NR57(CH2)2-; wherein R is57Is H or lower alkyl); - (CH)2)oPO(OR60)2(wherein R is60Is lower alkyl or lower alkenyl); - (CH)2)oSO2R62(wherein R is62Is lower alkyl or lower alkenyl) or- (CH)2)qC6H4R8(wherein R is8Is H; f; cl; CF; a lower alkyl group; lower alkenyl or lower alkoxy);
R23is H; a lower alkyl group; a lower alkenyl group; - (CH)2)oOR55(wherein R is55Is lower alkyl or lower alkenyl); - (CH)2)oSR56(wherein R is56Is lower alkyl or lower alkenyl); - (CH)2)oNR33R34(wherein R is33Is lower alkyl or lower alkenyl; r34Is H or lower alkyl or R33And R34Taken together are- (CH)2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-or- (CH) 2)2NR57(CH2)2-; wherein R is57Is H or lower alkyl); - (CH)2)oOCONR33R75(wherein R is33Is H or lower alkyl or lower alkenyl; r75Is lower alkyl or R33And R75Taken together are- (CH)2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-or- (CH)2)2NR57(CH2)2-; wherein R is57Is H or lower alkyl); - (CH)2)oNR20CONR33R82(wherein R is20Is H or lower alkyl; r33Is H or lower alkyl or lower alkenyl; r82Is H or lower alkyl or R33And R82Taken together are- (CH)2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-or- (CH)2)2NR57(CH2)2-; wherein R is57Is H or lower alkyl); - (CH)2)oN(R20)COR64(wherein: R20Is H or lower alkyl; r64Is lower alkyl or lower alkenyl); NR is particularly preferred20CO lower alkyl (R)20H or lower alkyl); - (CH)2)oCOOR57(wherein R is57Is lower alkyl or lower alkenyl); - (CH)2)oCONR58R59(wherein R is55Is lower alkyl or lower alkenyl; and R59Is H; lower alkyl or R58And R59Taken together are- (CH)2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-or- (CH)2)2NR57(CH2)2-; wherein R is57Is H or lower alkyl); - (CH)2)oPO(OR60)2(wherein R is60Is lower alkyl or lower alkenyl); - (CH)2)oSO2R62(wherein R is82Is lower alkyl or lower alkenyl) or- (CH)2)qC6H4R8(wherein R is8Is H; f; cl; CF (compact flash)3(ii) a A lower alkyl group; lower alkenyl or lower alkoxy);
R24is a lower alkyl group; a lower alkenyl group; - (CH)2)oOR55(wherein R is55Is lower alkyl or lower alkenyl); - (CH)2)oSR56(wherein R is56Is lower alkyl or lower alkenyl); - (CH) 2)oNR33R34(wherein R is33Is lower alkyl or lower alkenyl; r34Is H or lower alkyl or R33And R34Taken together are- (CH)2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-or- (CH)2)2NR57(CH2)2-; wherein R is57Is H or lower alkyl); -(CH2)oOCONR33R75(wherein R is33Is H or lower alkyl or lower alkenyl; r75Is lower alkyl or R33And R75Taken together are- (CH)2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-or- (CH)2)2NR57(CH2)2-; wherein R is57Is H or lower alkyl); - (CH)2)oNR20CONR33R82(wherein R is20Is H or lower alkyl; r33Is H or lower alkyl or lower alkenyl; r82Is H or lower alkyl or R33And R82Taken together are- (CH)2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-or- (CH)2)2NR57(CH2)2-; wherein R is57Is H or lower alkyl); - (CH)2)oN(R20)COR64(wherein: R20Is H or lower alkyl; r64Is lower alkyl or lower alkenyl); NR is particularly preferred20CO lower alkyl (R)20H or lower alkyl); - (CH)2)oCOOR57(wherein R is57Is lower alkyl or lower alkenyl); - (CH)2)oCONR58R59(wherein R is58Is lower alkyl or lower alkenyl; and R59Is H; lower alkyl or R58And R59Taken together are- (CH)2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-or- (CH)2)2NR57(CH2)2-; wherein R is57Is H or lower alkyl); - (CH)2)oPO(OR60)2(wherein R is60Is lower alkyl or lower alkenyl); - (CH)2)oSO2R62(wherein R is62Is lower alkylOr lower alkenyl) or- (CH)2)qC6H4R8(wherein R is8Is H; f; cl; CF (compact flash)3(ii) a A lower alkyl group; lower alkenyl or lower alkoxy);
R25is H; a lower alkyl group; a lower alkenyl group; - (CH) 2)mOR55(wherein R is55Is lower alkyl or lower alkenyl); - (CH)2)mNR33R34(wherein R is33Is lower alkyl or lower alkenyl; r34Is H or lower alkyl or R33And R34Taken together are- (CH)2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-or- (CH)2)2NR57(CH2)2-; wherein R is57Is H or lower alkyl); - (CH)2)mOCONR33R75(wherein R is33Is H or lower alkyl or lower alkenyl; r75Is lower alkyl or R33And R75Taken together are- (CH)2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-or- (CH)2)2NR57(CH2)2-; wherein R is57Is H or lower alkyl); - (CH)2)mNR20CONR33R82(wherein R is20Is H or lower alkyl; r33Is H or lower alkyl or lower alkenyl; r82Is H or lower alkyl or R33And R82Taken together are- (CH)2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-or- (CH)2)2NR57(CH2)2-; wherein R is57Is H or lower alkyl); - (CH)2)mN(R20)COR64(wherein: R20Is H or lower alkyl; r64Is lower alkyl or lower alkenyl); - (CH)2)oCOOR57(wherein R is57Is lower alkyl or lower alkenyl); - (CH)2)oCONR58R59(wherein R is58Is lower alkyl or lower alkenyl; and R59Is H; lower alkyl or R58And R59Taken together are- (CH)2)2-6-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-or- (CH)2)2NR57(CH2)2-; wherein R is57Is H or lower alkyl); - (CH)2)oPO(OR60)2(wherein R is60Is lower alkyl or lower alkenyl); - (CH)2)oSO2R62(wherein R is62Is lower alkyl or lower alkenyl) or- (CH)2)qC6H4R8(wherein R is8Is H; f; cl; CF (compact flash)3(ii) a A lower alkyl group; lower alkenyl or lower alkoxy);
R26is H; a lower alkyl group; a lower alkenyl group; - (CH) 2)mOR55(wherein R is55Is lower alkyl or lower alkenyl); - (CH)2)mNR33R34(wherein R is33Is lower alkyl or lower alkenyl; r34Is H or lower alkyl or R33And R34Taken together are- (CH)2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-or- (CH)2)2NR57(CH2)2-; wherein R is57Is H or lower alkyl); - (CH)2)mOCONR33R75(wherein R is33Is H or lower alkyl or lower alkenyl; r75Is lower alkyl or R33And R75Taken together are- (CH)2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-or- (CH)2)2NR57(CH2)2-; wherein R is57Is H or lower alkyl); - (CH)2)mNR20CONR33R82(wherein R is20Is H or lower alkyl; r33Is H or lower alkyl or lower alkenyl; r82Is H or lower alkyl or R33And R82Taken together are- (CH)2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-or- (CH)2)2NR57(CH2)2-; wherein R is57Is H or lower alkyl); - (CH)2)mN(R20)COR64(wherein: R20Is H or lower alkyl; r64Is lower alkyl or lower alkenyl); - (CH)2)oCOOR57(wherein R is57Is lower alkyl or lower alkenyl); - (CH)2)oCONR58R59(wherein R is58Is lower alkyl or lower alkenyl; and R59Is H; lower alkyl or R58And R59Taken together are- (CH)2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-or- (CH)2)2NR57(CH2)2-; wherein R is57Is H or lower alkyl); - (CH)2)oPO(OR60)2(wherein R is60Is lower alkyl or lower alkenyl); - (CH)2)oSO2R62(wherein R is62Is lower alkyl or lower alkenyl) or- (CH)2)qC6H4R8(wherein R is8Is H; f; cl; CF (compact flash)3(ii) a A lower alkyl group; lower alkenyl or lower alkoxy);
in addition, R25And R26Taken together are- (CH)2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-or- (CH) 2)2NR57(CH2)2-; wherein R is57Is H or lower alkyl);
R27is H; a lower alkyl group; a lower alkenyl group; - (CH)2)oOR55(wherein R is55Is lower alkyl or lower alkenyl); - (CH)2)oSR56(wherein R is56Is lower alkyl or lower alkenyl); - (CH)2)oNR33R34(wherein R is33Is lower alkyl or lower alkenyl; r34Is H or lower alkyl or R33And R34Taken together are- (CH)2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-or- (CH)2)2NR57(CH2)2-; wherein R is57Is H or lower alkyl); - (CH)2)oOCONR33R75(wherein R is33Is H or lower alkyl or lower alkenyl; r75Is lower alkyl or R33And R75Taken together are- (CH)2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-or- (CH)2)2NR57(CH2)2-; wherein R is57Is H or lower alkyl); - (CH)2)oNR20CONR33R82(wherein R is20Is H or lower alkyl; r33Is H or lower alkyl or lower alkenyl; r82Is H or lower alkyl or R33And R82Taken together are- (CH)2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-or- (CH)2)2NR57(CH2)2-; wherein R is57Is H or lower alkyl); - (CH)2)oN(R20)COR64(wherein: R20Is H or lower alkyl; r64Is lower alkyl or lower alkenyl); - (CH)2)oCOOR57(wherein R is57Is lower alkyl or lower alkenyl); - (CH)2)oCONR55R59(wherein R is58Is lower alkyl or lower alkenyl; and R59Is H; lower alkyl or R58And R59Taken together are- (CH)2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-or- (CH)2)2NR57(CH2)2-; wherein R is57Is H or lower alkyl); - (CH)2)oPO(OR60)2(wherein R is60Is lower alkyl or lower alkenyl); - (CH)2)oSO2R62(wherein R is62Is lower alkyl or lower alkenyl) or- (CH) 2)qC6H4R8(wherein R is8Is H; f; cl; CF (compact flash)3(ii) a A lower alkyl group; lower alkenyl or lower alkoxy);
R28is a lower alkyl group; a lower alkenyl group; - (CH)2)oOR55(wherein R is55Is lower alkyl or lower alkenyl); - (CH)2)oSR56(wherein R is56Is lower alkyl or lower alkenyl); - (CH)2)oNR33R34(wherein R is33Is lower alkyl or lower alkenyl; r34Is H or lower alkyl or R33And R34Taken together are- (CH)2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-or- (CH)2)2NR57(CH2)2-; wherein R is57Is H or lower alkyl); - (CH)2)oOCONR33R75(wherein R is33Is H or lower alkyl or lower alkenyl; r75Is lower alkyl or R33And R75Taken together are- (CH)2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-or- (CH)2)2NR57(CH2)2-; wherein R is57Is H or lower alkyl); - (CH)2)oNR20CONR33R82(wherein R is20Is H or lower alkyl; r33Is H or lower alkyl or lower alkenyl; r82Is H or lower alkyl or R33And R82Taken together are- (CH)2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-or- (CH)2)2NR57(CH2)2-; wherein R is57Is H or lower alkyl); - (CH)2)oN(R20)COR64(wherein: R20Is H or lower alkyl; r64Is lower alkyl or lower alkenyl); - (CH)2)oCOOR57(wherein R is57Is lower alkyl or lower alkenyl); - (CH)2)oCONR58R59(wherein R is58Is lower alkyl or lower alkenyl; and R59Is H; lower alkyl or R85And R59Taken together are- (CH)2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-or- (CH)2)2NR57(CH2)2-; wherein R is57Is H or lower alkyl); - (CH)2)oPO(OR60)2(wherein R is60Is lower alkyl or lower alkenyl); - (CH)2)oSO2R62(wherein R is 62Is lower alkyl or lower alkenyl) or- (CH)2)qC6H4R8(wherein R is8Is H; f; cl; CF (compact flash)3(ii) a A lower alkyl group; lower alkenyl or lower alkoxy);
R29is a lower alkyl group; a lower alkenyl group; - (CH)2)oOR55(wherein R is55Is lower alkyl or lower alkenyl); - (CH)2)oSR56(wherein R is56Is lower alkyl or lower alkenyl); - (CH)2)oNR33R34(wherein R is33Is lower alkyl or lower alkenyl; r34Is H or lower alkyl or R33And R34Taken together are- (CH)2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-or- (CH)2)2NR57(CH2)2-; wherein R is57Is H or lower alkyl); - (CH)2)oOCONR33R75(wherein R is33Is H or lower alkyl or lower alkenyl; r75Is lower alkyl or R33And R75Taken together are- (CH)2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-or- (CH)2)2NR57(CH2)2-; wherein R is57Is H or lower alkyl); - (CH)2)oNR20CONR33R82(wherein R is20Is H or lower alkyl; r33Is H or lower alkyl or lower alkenyl; r82Is H or lower alkyl or R33And R82Taken together are- (CH)2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-or- (CH)2)2NR57(CH2)2-; wherein R is57Is H or lower alkyl); - (CH)2)oN(R20)COR64(wherein: R20Is H or lower alkyl; r64Is lower alkyl or lower alkenyl); particularly preferred is NR20CO lower-alkyl (R)20H or lower alkyl); - (CH)2)oCOOR57(wherein R is57Is lower alkyl or lower alkenyl); - (CH)2)oCONR58R59(wherein R is58Is lower alkyl or lower alkenyl; and R59Is H(ii) a Lower alkyl or R58And R59Taken together are- (CH) 2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-or- (CH)2)2NR57(CH2)2-; wherein R is57Is H or lower alkyl); - (CH)2)oPO(OR60)2(wherein R is60Is lower alkyl or lower alkenyl); - (CH)2)oSO2R62(wherein R is62Is lower alkyl or lower alkenyl) or- (CH)2)qC6H4R8(wherein R is8Is H; f; cl; CF (compact flash)3(ii) a A lower alkyl group; lower alkenyl or lower alkoxy).
9. A compound of claim 8, wherein R23、R24And R29is-NR20-CO-lower alkyl, wherein R20Is H or lower alkyl.
10. The compound of claim 8 or 9, wherein a is of formula a74 (R)22Is H); a 75; a76; a77 (R)22Is H); a78; and a group of one of A79.
A compound according to any one of claims 3 to 10 wherein B is of the formula-NR20CH(R71) Or an enantiomer (R) of one of the radicals A52Is H); a8; a22; a25; a38 (R)2Is H); a42; a47; and a 50.
12. The compound of claim 11, wherein B-CO is Ala; arg; asn; cys; gln; gly; his; ile; leu; lys; met; phe; pro; ser; thr; trp; tyr; val; cit or n; tBuA; sar; t-BuG; 4 AmPhe; 3 AmPhe; 2 AmPhe; phe (mC (NH)2)＝NH；Phe(pC(NH2)＝NH；Phe(mNHC(NH2)＝NH；Phe(pNHC(NH2)＝NH；Phg；Cha；C4al；C5al；Nle；2-Nal；1-Nal；4Cl-Phe；3Cl-Phe；2Cl-Phe；3，4Cl2Phe；4F-Phe；3F-Phe；2F-Phe；Tic；Thi；Tza；Mso；AcLys；Dpr；A2Bu; dbu; abu; aha; aib; y (bzl); bip; s (bzl); t (bzl); hRha; hCys; hSer, hArg; hPhe; bpa; pip; OctG; MePhe; menle; MeAla; a MeIle; MeVal or MeLeu.
13. The compound of claim 11 or 12, wherein B is a group of formula A8 "having the (L) -configuration:
wherein R is20Is H or lower alkyl; and R64Is an alkyl group; an alkenyl group; an aryl group; aryl-lower alkyl or heteroaryl-lower alkyl.
14. The compound of claim 13, wherein R64Is n-hexyl; a n-heptyl group; 4- (phenyl) benzyl; diphenylmethyl, 3-amino-propyl; 5-amino-pentyl; a methyl group; an ethyl group; isopropyl group; an isobutyl group; n-propyl; a cyclohexyl group; a cyclohexylmethyl group; n-butyl; a phenyl group; a benzyl group; (3-indolyl) methyl; 2- (3-indolyl) ethyl; (4-phenyl) phenyl or n-nonyl.
15. A compound according to claim 1 or 2, wherein
Is a group of formula (b1) or (1);
R1is H or lower alkyl;
R20is H or lower alkyl.
R30Is H or methyl.
R31Is H; a lower alkyl group; a lower alkenyl group; - (CH)2)pOR55(wherein R is55Is lower alkyl orLower alkenyl); - (CH)2)pNR33R34(wherein R is33Is lower alkyl or lower alkenyl; r34Is H or lower alkyl or R33And R34Taken together are- (CH)2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-or- (CH)2)2NR57(CH2)2-; wherein R is57Is H or lower alkyl); - (CH)2)pOCONR33R75(wherein R is33Is H or lower alkyl or lower alkenyl; r75Is lower alkyl or R33And R75Taken together are- (CH)2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-or- (CH) 2)2NR57(CH2)2-; wherein R is57Is H or lower alkyl); - (CH)2)pNR20CONR33R82(wherein R is20Is H or lower alkyl; r33Is H or lower alkyl or lower alkenyl; r82Is H or lower alkyl or R33And R82Taken together are- (CH)2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-or- (CH)2)2NR57(CH2)2-; wherein R is57Is H or lower alkyl); - (CH)2)pN(R20)COR64(wherein: R20Is H or lower alkyl; r64Is lower alkyl or lower alkenyl); - (CH)2)oCOOR57(wherein R is57Is lower alkyl or lower alkenyl); (-CH)2)oCONR58R59(wherein R is58Is lower alkyl or lower alkenyl; and R59Is H; lower alkyl or R55And R59Taken together are- (CH)2)2-6；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-or- (CH)2)2NR57(CH2)2-; wherein R is57Is H or lower alkyl); - (CH)2)oPO(OR60)2(wherein R is60Is lower alkyl or lower alkenyl); - (CH)2)oSO2R62(wherein R is62Is lower alkyl or lower alkenyl) or- (CH)2)rC6H4R8(wherein R is8Is H; f; cl; CF (compact flash)3(ii) a A lower alkyl group; lower alkenyl or lower alkoxy); most preferably is-CH2CONR58R59(R58Is H or lower alkyl; r59Is lower alkyl or lower alkenyl);
R32is H or methyl;
R33is a lower alkyl group; a lower alkenyl group; - (CH)2)mOR55(wherein R is55Is lower alkyl or lower alkenyl); - (CH)2)mNR34R63(wherein R is34Is lower alkyl or lower alkenyl; r63Is H or lower alkyl or R34And R63Taken together are- (CH)2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-or- (CH)2)2NR57(CH2)2-; wherein R is57Is H or lower alkyl); (CH)2)mOCONR75R82(wherein R is75Is lower alkyl or lower alkenyl; r 82Is H or lower alkyl or R75And R82Taken together are- (CH)2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-or- (CH)2)2NR57(CH2)2-; wherein R is57Is H or lower alkyl); - (CH)2)mNR20CONR78R82(wherein R is20Is H or lower alkyl; r78Is H or lower alkyl or lower alkenyl; r82Is H or lower alkyl or R78And R82Taken together are- (CH)2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-or- (CH)2)2NR57(CH2)2-; wherein R is57Is H or lower alkyl); - (CH)2)mN(R20)COR64(wherein: R20Is H or lower alkyl; r64Is lower alkyl or lower alkenyl); - (CH)2)oCOOR57(wherein R is57Is lower alkyl or lower alkenyl); - (CH)2)oCONR58R59(wherein R is58Is lower alkyl or lower alkenyl; and R59Is H; lower alkyl or R58And R59Taken together are- (CH)2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-or- (CH)2)2NR57(CH2)2-; wherein R is57Is H or lower alkyl);
R34is H or lower alkyl;
R35is H; a lower alkyl group; a lower alkenyl group; - (CH)2)mOR55(wherein R is55Is lower alkyl or lower alkenyl); - (CH)2)mNR33R34(wherein R is33Is lower alkyl or lower alkenyl; r34Is H or lower alkyl or R33And R34Taken together are- (CH)2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-or- (CH)2)2NR57(CH2)2-; wherein R is57Is H or lower alkyl); - (CH)2)mOCONR33R75(wherein R is33Is H or lower alkyl or lower alkenyl; r75Is lower alkyl or R33And R75Taken together are- (CH)2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-or- (CH)2)2NR57(CH2)2-; wherein R is57Is H or lower alkyl); - (CH)2)mNR20CONR33R82(wherein R is20Is H or lower alkyl; r33Is H or lower alkyl or lower alkenyl; r 82Is H or lower alkyl or R33And R82Taken together are- (CH)2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-or- (CH)2)2NR57(CH2)2-; wherein R is57Is H or lower alkyl); - (CH)2)mN(R20)COR64(wherein: R20Is H or lower alkyl; r64Is lower alkyl or lower alkenyl); - (CH)2)oCOOR57(wherein R is57Is lower alkyl or lower alkenyl); - (CH)2)oCONR58R59(wherein R is58Is lower alkyl or lower alkenyl; and R59Is H; lower alkyl or R58And R59Taken together are- (CH)2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-or- (CH)2)2NR57(CH2)2-; wherein R is57Is H or lower alkyl);
R36is a lower alkyl group; lower alkenyl or aryl-lower alkyl;
R37is H; a lower alkyl group; a lower alkenyl group; - (CH)2)pOR55(wherein R is55Is lower alkyl or lower alkenyl); - (CH)2)pNR33R34(wherein R is33Is lower alkyl or lower alkenyl; r34Is H or lower alkyl or R33And R34Taken together are- (CH)2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-or- (CH)2)2NR57(CH2)2-; wherein R is57Is H or lower alkyl); - (CH)2)pOCONR33R75(wherein R is33Is H or lower alkyl or lower alkenyl; r75Is lower alkyl or R33And R75Taken together are- (CH)2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-or- (CH)2)2NR57(CH2)2-; wherein R is57Is H or lower alkyl); - (CH)2)pNR20CONR33R82(wherein R is20Is H or lower alkyl; r33Is H or lower alkyl or lower alkenyl; r82Is H or lower alkyl or R33And R82Taken together are- (CH)2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-or- (CH)2)2NR57(CH2)2-; wherein R is57Is H or lower alkyl); - (CH)2)pN(R20)COR64(wherein: R20Is H or lower alkyl; r 64Is lower alkyl or lower alkenyl); - (CH)2)oCOOR57(wherein R is57Is lower alkyl or lower alkenyl); - (CH)2)oCONR58R59(wherein R is58Is lower alkyl or lower alkenyl; and R59Is H; lower alkyl or R58And R59Taken together are- (CH)2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-or- (CH)2)2NR57(CH2)2-; wherein R is57Is H or lower alkyl); - (CH)2)oPO(OR60)2(wherein R is60Is lower alkyl or lower alkenyl); - (CH)2)oSO2R62(wherein R is62: lower alkyl or lower alkenyl) or- (CH)2)qC6H4R8(wherein R is8Is H; f; cl; CF (compact flash)3(ii) a A lower alkyl group; lower alkenyl or lower alkoxy); and
R38is H; a lower alkyl group; a lower alkenyl group; - (CH)2)pOR55(wherein R is55Is lower alkyl or lower alkenyl); - (CH)2)pNR33R34(wherein R is33Is lower alkyl or lower alkenyl; r34Is H or lower alkyl or R33And R34Taken together are- (CH)2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-or- (CH)2)2NR57(CH2)2-; wherein R is57Is H or lower alkyl); - (CH)2)pOCONR33R75(wherein R is33Is H or lower alkyl or lower alkenyl; r75Is lower alkyl or R33And R78Taken together are- (CH)2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-or- (CH)2)2NR57(CH2)2-; wherein R is57Is H or lower alkyl); - (CH)2)pNR20CONR33R82(wherein R is20Is H or lower alkyl; r33Is H or lower alkyl or lower alkenyl; r82Is H or lower alkyl or R33And R82Taken together are- (CH)2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-or- (CH)2)2NR57(CH2)2-; wherein R is57Is H or lower alkyl); - (CH)2)pN(R20)COR64(wherein: R20Is H or lower alkyl; r 64Is lower alkyl or lower alkenyl); - (CH)2)oCOOR57(wherein R is57Is lower alkyl or lower alkenyl); - (CH)2)oCONR58R59(wherein R is58Is lower alkyl or lower alkenyl; and R59Is H; lower alkyl or R58And R59Taken together are- (CH)2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-or- (CH)2)2NR57(CH2)2-; wherein R is57Is H or lower alkyl); - (CH)2)oPO(OR60)2(wherein R is60Is lower alkyl or lower alkenyl); - (CH)2)oSO2R62(wherein R is62Is lower alkyl or lower alkenyl) or- (CH)2)qC6H4R8(wherein R is8Is H; f; cl; CF (compact flash)3(ii) a A lower alkyl group; lower alkenyl or lower alkoxy).
16. The compound of claim 15, wherein R1Is H; r20Is H; r30Is H; r31Is carboxymethyl or lower alkoxycarbonylmethyl; r32Is H; r35Is methyl; r36Is a methoxy group; r37Is H and R38Is H.
17. A compound according to any one of claims 1 to 16, wherein the chain of α -amino acid residues Z, Z1And Z2In (1),
-if n is 8, then the amino acid residues at positions 1-8 are:
-P1: class C or class D or class E;
-P2: class E or class D;
-P3: class E;
-P4: class E or formula-A1-A69-CO-;
-P5: e or formula-B-CO-;
-P6: class D;
-P7: class E or class D and
-P8: class C or class D or class E;
-it may also be the D-isomer at P4 and P5;
-if n is 9, then the amino acid residues at positions 1-9 are:
-P1: class C or class D or class E;
-P2: class E or class D;
-P3: class C;
-P4: class E, or the residue is Pro;
-P5: class E, or the residue is Pro;
-P6: class D or E, or the residue is Pro;
-P7: class E or class D;
-P8: class E or class D and
-P9: class C or class D or class E;
-it may also be the D-isomer at P4, P5 and P6;
-if n is 10, the amino acid residues at positions 1-10 are:
-P1: class C or class D or class E;
-P2: class E or class D;
-P3: class C;
-P4: class E or class D;
-P5: class E or formula-A1-A69-CO-;
-P6: e or formula-B-CO-;
-P7: class D or class E;
-P8: class D;
-P9: class E or class D and
-P10: class C or class D or class E;
-it may also be the D-isomer at P5 and P6;
-if n is 11, the amino acid residues at positions 1-11 are:
-P1: class C or class D or class E;
-P2: class E or class D;
-P3: class D;
-P4: class E or class C;
-P5: class E, or the residue is Pro;
-P6: class E, or the residue is Pro;
-P7: class E, or the residue is Pro;
-P8: class D or class E;
-P9: class D;
-P10: class E or class D and
-P11: class C or class D or class E;
-it may also be the D-isomer at P5, P6 and P7;
-if n is 12, then the amino acid residues at positions 1-12 are:
-P1: class C or E or class D or class F;
-P2: class E or class D;
-P3: class C or class D;
-P4: class E;
-P5: class E or class C;
-P6: class E or class F or of formula-A1-A69-CO-;
-P7: e or formula-B-CO-;
-P8: class D;
-P9: class E or class D;
-P10: class D;
-P11: class E or class D and
-P12: class C or E or class D or class F;
-it may also be the D-isomer at P6 and P7;
-if n is 13, then the amino acid residues at positions 1-13 are:
-P1: class C or class D or class E;
-P2: class E or class D;
-P3: class C or class D;
-P4: class E or class C;
-P5: class E or class D;
-P6: class E or class F, or the residue is Pro;
-P7: class E, or the residue is Pro;
-P8: class D, or the residue is Pro;
-P9: class D;
-P10: class E or class C;
-P11: class C or class D;
-P12: class E or class D and
-P13: class C or class D or class E;
-it may also be the D-isomer at P6, P7 and P8;
-if n is 14, then the amino acid residues at positions 1-14 are:
-P1: class C or class D or class E;
-P2: class E or class D;
-P3: class C or class D;
-P4: class D;
-P5: class E;
-P6: class E;
-P7: class E or class F or of formula-A1-A69-CO-;
-P8: e or formula-B-CO-;
-P9: class D;
-P10: class C;
-P11: class E or class D;
-P12: class D or class C;
-P13: class E or class D and
-P14: class C or class D or class E;
-it may also be the D-isomer at P7 and P8;
-if n is 15, then the amino acid residues at positions 1-15 are:
-P1: class C and class D or class E;
-P2: class E or class D;
-P3: class C and class D;
-P4: class E or class C;
-P5: class C;
-P6: class E or class D;
-P7: class C, or the residue is Pro;
-P8: class E or class F, or the residue is Pro;
-P9: class E or class F, or the residue is Pro;
-P10: class E;
-P11: class C;
-P12: class E or class C;
-P13: class D or class C;
-P14: class E or class D and
-P15: class C and class D or class E;
-it may also be the D-isomer at P7, P8 and P9; and
-if n is 16, then the amino acid residues at positions 1-16 are:
-P1: class D or class E;
-P2: class E or class D;
-P3: class C or class D;
-P4: class E or class D;
-P5: class D;
-P6: class E;
-P7: class E or class F;
-P8: class E or class F or of formula-A1-A69-CO-;
-P9: e or formula-B-CO-;
-P10: class D;
-P11: class E;
-P12: class D;
-P13: class E or class C;
-P14: class C or class D;
-P15: class E or class D and
-P16: class C or class D or class E;
d-isomers are also possible at P8 and P9.
18. The compound of claim 17, wherein n is 12 and the amino acid residues at positions 1-12 are:
-P1: leu; arg; lys; tyr; trp; val; gln or 4-AmPhe;
-P2: arg; trp or Gln;
-P3: leu; val; ile or Phe;
-P4: lys; arg; gln or Orn;
-P5: lys or Arg;
-P6: arg; y (Bzl) orDY(Bzl)；
-P7：Arg；
-P8: trp; bip; 1-Nal; y (Bzl) or Val;
-P9: lys; arg or n; tyr; trp or Gln;
-P10: tyr; t (Bzl) or Y (Bzl);
-P11: arg or Tyr; and
-P12: val; arg; 1-Nal or 4-AmPhe.
19. A compound of formula Ia according to claim 1, where the template isDPro-LPro; n is
12; and the amino acid residues at positions 1-12 are:
-P1：Leu；
-P2：Arg；
-P3：Leu；
-P4：Lys；
-P5：Lys；
-P6：Arg；
-P7：Arg；
-P8：Trp；
-P9：Lys；
-P10：Tyr；
-P11: arg; and
-P12：Val。
20. a compound of formula Ia according to claim 1, where the template isDPro-LPro; n is 12; and the amino acid residues at positions 1-12 are:
-P1：Leu；
-P2：Arg；
-P3：Leu；
-P4：Lys；
-P5：Lys；
-P6：Arg；
-P7：Arg；
-P8：Y(Bzl)；
-P9：Lys；
-P10：Tyr；
-P11: arg; and
-P12：Val。
21. a compound of formula Ia according to claim 1, where the template isDPro-LPro; n is 12; and the amino acid residues at positions 1-12 are:
-P1：Leu；
-P2：Arg；
-P3：Leu；
-P4：Lys；
-P5：Lys；
-P6：Arg；
-P7：Arg；
-P8：Trp；
-P9：Lys；
-P10：Tyr；
-P11: arg; and
-P12：1-Nal。
22. a compound of formula Ia according to claim 1, where the template isDPro-LPro; n is 12; and the amino acid residues at positions 1-12 are:
-P1：Leu；
-P2：Arg；
-P3：Leu；
-P4：Lys；
-P5：Lys；
-P6：Arg；
-P7：Arg；
-P8：Bip；
-P9：Lys；
-P10：Tyr；
-P11: arg; and
-P12：Val。
23. a compound of formula Ia according to claim 1, where the template is DPro-LPro; n is 12; and the amino acid residues at positions 1-12 are:
-P1：Leu；
-P2：Arg；
-P3：Leu；
-P4：Lys；
-P5：Lys；
-P6：Arg；
-P7：Arg；
-P8：Trp；
-P9：Lys；
-P10：T(Bzl)；
-P11: arg; and
-P12：Val。
24. a process for preparing compounds of the formula Ia according to claim 1A compound wherein the template isDPro-LPro; n is 12; and the amino acid residues at positions 1-12 are:
-P1：Leu；
-P2：Arg；
-P3：Leu；
-P4：Lys；
-P5：Lys；
-P6：Arg；
-P7：Arg；
-P8：Trp；
-P9：Arg；
-P10：Tyr；
-P11: arg; and
-P12：Val。
25. a compound of formula Ia according to claim 1, where the template isDPro-LPro; n is 12; and the amino acid residues at positions 1-12 are:
-P1：Leu；
-P2：Trp；
-P3：Leu；
-P4：Lys；
-P5：Lys；
-P6：Arg；
-P7：Arg；
-P8：Bip；
-P9：Lys；
-P10：Tyr；
-P11: arg; and
-P12：Val。
26. a compound of formula Ia according to claim 1, where the template isDPro-Phe; n is 12; and the amino acid residues at positions 1-12 are:
-P1：Leu；
-P2：Arg；
-P3：Leu；
-P4：Lys；
-P5：Lys；
-P6：Arg；
-P7：Arg；
-P8：Trp；
-P9：Lys；
-P10：Tyr；
-P11: arg; and
-P12：Val。
27. a compound of formula Ia according to claim 1, where the template isDPro- (2R, 4S) -4- [ n-hexylcarbonylamino]-LPro; n is 12; and the amino acid residues at positions 1-12 are:
-P1：Leu；
-P2：Arg；
-P3：Leu；
-P4：Lys；
-P5：Lys；
-P6：Arg；
-P7：Arg；
-P8：Trp；
-P9：Lys；
-P10：Tyr；
-P11: arg; and
-P12：Val。
28. a compound of formula Ia according to claim 1, where the template isDPro- (2R, 4S) -4- [ cyclohexylcarbonylamino]-LPro; n is 12; and the amino acid residues at positions 1-12 are:
-P1：Leu；
-P2：Arg；
-P3：Leu；
-P4：Lys；
-P5：Lys；
-P6：Arg；
-P7：Arg；
-P8：Trp；
-P9：Lys；
-P10：Tyr；
-P11: arg; and
-P12：Val。
29. the compound of claim 1, wherein the template is of formula (c1), wherein R20Is H; r35Is methyl; r36Is a methoxy group; r37Is H and R38Is H; n is12; and the amino acid residues at positions 1-12 are:
-P1：Leu；
-P2：Arg；
-P3：Leu；
-P4：Lys；
-P5：Lys；
-P6：Arg；
-P7：Arg；
-P8：Trp；
-P9：Lys；
-P10：Tyr；
-P11: arg; and
-P12：Val。
30. A compound of formula Ia according to claim 1, where the template isDPro-LPro; n is 12; and the amino acid residues at positions 1-12 are:
-P1：Arg；
-P2：Trp；
-P3：Leu；
-P4：Lys；
-P5：Lys；
-P6：Arg；
-P7：Arg；
-P8：Trp；
-P9：Lys；
-P10：Tyr；
-P11: tyr; and
-P12：Val。
31. a compound of formula Ia according to claim 1, where the template isDPro-LPro; n is 12; and the amino acid residues at positions 1-12 are:
-P1：Leu；
-P2：Trp；
-P3：Leu；
-P4：Lys；
-P5：Lys；
-P6：Arg；
-P7：Arg；
-P8：Trp；
-P9：Lys；
-P10：Tyr；
-P11: tyr; and
-P12：Arg。
32. a compound of formula Ia according to claim 1, where the template isDPro-LPro; n is 12; and the amino acid residues at positions 1-12 are:
-P1：Arg；
-P2：Trp；
-P3：Leu；
-P4：Lys；
-P5：Lys；
-P6：Arg；
-P7：Arg；
-P8：Trp；
-P9：Lys；
-P10：Tyr；
-P11: tyr; and
-P12：Arg。
33. a compound of formula Ia according to claim 1, where the template isDPro-LPro; n is 12; and the amino acid residues at positions 1-12 are:
-P1：Leu；
-P2：Arg；
-P3：Leu；
-P4：Lys；
-P5：Lys；
-P6：DY(Bzl)；
-P7：Arg；
-P8：Trp；
-P9：Lys；
-P10：Tyr；
-P11: arg; and
-P12：Val。
34. a compound of formula Ia according to claim 1, where the template isDPro-LPro; n is 12; and the amino acid residues at positions 1-12 are:
-P1：Arg；
-P2：Bip；
-P3：Leu；
-P4：Lys；
-P5：Lys；
-P6：Arg；
-P7：Arg；
-P8：Trp；
-P9：Lys；
-P10：Tyr；
-P11: tyr; and
-P12：Arg。
35. a compound of formula Ia according to claim 1, where the template isDPro-LPro; n is 12; and the amino acid residues at positions 1-12 are:
-P1：Lys；
-P2：Trp；
-P3：Leu；
-P4：Lys；
-P5：Lys；
-P6：Arg；
-P7：Arg；
-P8：Trp；
-P9：Lys；
-P10：Tyr；
-P11: tyr; and
-P12：Arg。
36. a compound of formula Ia according to claim 1, where the template isDPro-LPro; n is 12; and the amino acid residues at positions 1-12 are:
-P1：Tyr；
-P2：Trp；
-P3：Leu；
-P4：Lys；
-P5：Lys；
-P6：Arg；
-P7：Arg；
-P8：Trp；
-P9：Lys；
-P10：Tyr；
-P11: tyr; and
-P12：Arg。
37. as in claimA compound of formula Ia according to claim 1, wherein the template isDPro-LPro; n is 12; and the amino acid residues at positions 1-12 are:
-P1：Trp；
-P2：Trp；
-P3：Leu；
-P4：Lys；
-P5：Lys；
-P6：Arg；
-P7：Arg；
-P8：Trp；
-P9：Lys；
-P10：Tyr；
-P11: tyr; and
-P12：Arg。
38. a compound of formula Ia according to claim 1, where the template isDPro-LPro; n is 12; and the amino acid residues at positions 1-12 are:
-P1：Val；
-P2：Trp；
-P3：Leu；
-P4：Lys；
-P5：Lys；
-P6：Arg；
-P7：Arg；
-P8：Trp；
-P9：Lys；
-P10：Tyr；
-P11: tyr; and
-P12：Arg。
39. a compound of formula Ia according to claim 1, where the template isDPro-LPro; n is 12; and the amino acid residues at positions 1-12 are:
-P1：Gln；
-P2：Trp；
-P3：Leu；
-P4：Lys；
-P5：Lys；
-P6：Arg；
-P7：Arg；
-P8：Trp；
-P9：Lys；
-P10：Tyr；
-P11: tyr; and
-P12：Arg。
40. a compound of formula Ia according to claim 1, where the template isDPro-LPro; n is 12; and the amino acid residues at positions 1-12 are:
-P1：Leu；
-P2：Arg；
-P3：Leu；
-P4：Lys；
-P5：Lys；
-P6：Y(Bzl)；
-P7：Arg；
-P8：Trp；
-P9：Lys；
-P10：Tyr；
-P11: arg; and
-P12：Val。
enantiomers of compounds of formula Ia and Ib according to claim 1.
42. The use of a compound according to any one of claims 1 to 41 as therapeutically active substance for the manufacture of a medicament.
43. A pharmaceutical composition comprising a compound according to any one of claims 1 to 41 and a pharmaceutically inert carrier.
44. A composition according to claim 43, in a form suitable for oral, topical, transdermal, injection, buccal, transmucosal, pulmonary or inhalation administration.
45. A composition as claimed in claim 43 or 44 in the form of a tablet, dragee, capsule, solution, liquid, gel, plaster, cream, ointment, syrup, slurry, suspension, mist, nebuliser or suppository.
46 use of a compound according to any one of claims 1 to 41 for the manufacture of a medicament for the treatment or prophylaxis of infection or a disease associated with infection, or for the manufacture of a medicament useful against malignant cells for the treatment of cancer.
The use of claim 46, wherein the infection is cystic fibrosis lung infection.
48. Use of a compound according to any one of claims 1 to 41 as a disinfectant or preservative for food, cosmetics, pharmaceuticals and other nutrient-containing goods.
49. Use of a compound according to claims 1-41 to prevent the growth of surface microorganisms.
50. A process for the production of a compound as claimed in any one of claims 1 to 40, which process comprises:
(a) coupling a suitably functionalized solid support with a suitably N-protected derivative of an amino acid which is in position N/2, N/2+1 or N/2-1 in the desired end product if N is an even number and in position N/2+1/2 or N/2-1/2, respectively, if N is an odd number, any functional groups which may be present in said N-protected amino acid derivative being likewise suitably protected;
(b) removing the N-protecting group from the product thus obtained;
(c) coupling the product thus obtained with a suitably N-protected derivative of an amino acid which is suitably protected at a position in the desired end product close to the N-terminal amino acid residue, any functional groups which may be present in said N-protected amino acid derivative being likewise suitably protected;
(d) Removing the N-protecting group from the product thus obtained;
(e) repeating steps (c) and (d) as often as necessary until the N-terminal amino acid residue has been introduced;
(f) coupling the product thus obtained with a compound of the general formula;
wherein
As defined above, and X is an N-protecting group, or if
The above group (a1) or (a2), alternatively
(fa) coupling the product obtained in step (d) or (e) with a suitably N-protected derivative of an amino acid of formula III
HOOC-B-H III or HOOC-A-H IV
Wherein B and A are as defined above, any functional groups which may be present in the N-protected amino acid derivative are likewise suitably protected;
(fb) removing the N-protecting group from the product thus obtained; and
(fc) coupling of the product thus obtained with a suitable N-protected derivative of an amino acid having the above general formulae IV and III, respectively, any functional groups which may be present in said N-protected amino acid derivative being likewise suitably protected;
(g) removing the N-protecting group from the product obtained in step (f) or (fc);
(h) coupling the product thus obtained with a suitably N-protected derivative of an amino acid which is in the N-position in the desired end product, any functional groups which may be present in said N-protected amino acid derivative being likewise suitably protected;
(i) Removing the N-protecting group from the product thus obtained;
(j) coupling the product thus obtained with a suitably N-protected derivative of an amino acid which is suitably protected at a position remote from the N-position in the desired end product, any functional groups which may be present in said N-protected amino acid derivative being likewise suitably protected;
(k) removing the N-protecting group from the product thus obtained;
(l) Repeating steps (j) and (k) as often as necessary until all amino acid residues have been introduced;
(m) if desired, selectively deprotecting one or more of the protected functional groups present in the molecule and suitably replacing the reactive groups so released;
(o) detaching the product thus obtained from the solid support;
(p) cyclizing the product isolated from the solid support;
(q) if necessary, subjecting the mixture to a thermal treatment,
(qa) forming one or more interchain bonds between suitable amino acid residues at the relative position of the β -chain region; and/or
(qb) linking the two structural units of class Ia via a bridge-G1-L-G2-;
(r) removing any protecting groups present on the functional groups of any members of the chain of amino acid residues and, if desired, any protecting groups that may also be present in the molecule; and
(s) if desired, converting the product thus obtained into a pharmaceutically acceptable salt or converting the pharmaceutically acceptable or unacceptable salt thus obtained into the corresponding free compound of formula I or into a different pharmaceutically acceptable salt.
51. An improvement of the process of claim 50 for the production of the compound of claim 41, wherein all enantiomers of chiral starting material are used.
HK04107145.5A 2001-02-23 2002-02-18 Template-fixed peptidomimetics with antimicrobial activity HK1064391B (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
EPPCT/EP01/02072 2001-02-23
EP0102072 2001-02-23
PCT/EP2002/001711 WO2002070547A1 (en) 2001-02-23 2002-02-18 Template-fixed peptidomimetics with antimicrobial activity

Publications (2)

Publication Number Publication Date
HK1064391A1 HK1064391A1 (en) 2005-01-28
HK1064391B true HK1064391B (en) 2006-12-01

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