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HK1081561B - Template-fixed peptidomimetics with antibacterial activity - Google Patents

Template-fixed peptidomimetics with antibacterial activity Download PDF

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Publication number
HK1081561B
HK1081561B HK06101924.3A HK06101924A HK1081561B HK 1081561 B HK1081561 B HK 1081561B HK 06101924 A HK06101924 A HK 06101924A HK 1081561 B HK1081561 B HK 1081561B
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HK
Hong Kong
Prior art keywords
lower alkyl
chr
group
carbon atoms
amino acid
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HK06101924.3A
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Chinese (zh)
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HK1081561A1 (en
Inventor
J．W．弗里吉布洛德
D．奥布雷希特
J．A．罗宾逊
O．塞利耶
M.凯斯勒
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波利弗尔有限公司
苏黎世大学
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Priority claimed from PCT/EP2002/009278 external-priority patent/WO2004018503A1/en
Publication of HK1081561A1 publication Critical patent/HK1081561A1/en
Publication of HK1081561B publication Critical patent/HK1081561B/en

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Template-fixed peptidomimetics with antibacterial activity
The present invention provides template-fixed β -hairpin peptidomimetics (peptidomimetics) defined below incorporating a template-fixed chain of 12 α -amino acid residues which are Gly, or Pro, or some species, depending on their position in the chain. These template-immobilized beta-hairpin mimetics have selective antimicrobial activity. In addition, the present invention provides an efficient synthetic method by which these compounds can be made into parallel library formats as desired. These β -hairpin peptidomimetics have improved potency, bioavailability, half-life and, most importantly, a significantly increased ratio of antibacterial activity (on the one hand) and hemolysis of erythrocytes (on the other hand).
The increasing problem of microbial resistance to conventional antibiotics has contributed to a strong interest in developing novel antimicrobial agents with new modes of action (h.breithaupt, nat. biotechnol.1999, 17, 1165-. One emerging 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. cake 236], tachyplesis [ T.Nakamura, H.Furunaka, T.Miyata, F.Tokunaga, T.Muta, S.Iwanaga, M.Niwa, T.Takao, Y.Shimonishi, Y.J.biol.Chem.1988, 263, 16709. quick 16713], and defenseins [ R.I.Lehreger, A.K.Lichstein, T.ganz, Annu.Rev.128. 1993, 11, 105. helic peptides [ e.I.Lechener, A.K.Lichstein, T.Gannz, Annu.Rev.128. 1993, 11, 105. helic peptides [ e.I.L.L.L.L.S.S.I.Lehre., FEBS Lett.1993, 327, 231. Bufonis.S.231. beta.236. peptide, and, S.S.S.S.I.I.I.S.S. Wagnerischen, S.S.S.S.S.A.S.I.I.S.I.S.S.A, S.S.S.I.I.S.S.S.S.A.I. niwa, T.S.S.S.S.S.S.A.S.S.A.A.S.S.A.S.A.A.A.S.S.S.S.A.S.S.S.S.S.A.A., e.maier, R.Benz, R.E.Hancock, Biochemistry 1999, 38, 7235-.
The antimicrobial activity of many of these cationic peptides is often associated with their preferred secondary structure observed in aqueous solutions or in membranous environments (n.sitaram, r.nagaraj, biochim.biophysis.acta 1999, 1462, 29-54). Structural studies using Nuclear Magnetic Resonance (NMR) spectroscopy showed 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-. In protegrin analogs lacking one or both of these disulfide bonds, the stability of the β -hairpin conformation 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, Biopolymers 2000, 55, 88-98; S.L.Harwing, A.Waring, H.J.Yang, Y.Cho, L.Tan, R.I.Lehrer, R.J.Eur.J.Biochem.1996, 240, 352-357; M.E.GogoniMan, A.Memelas, P.Aurnest, C.J.Bucko.J.Biochem.1996, 240, 352-357, M.E.Gogoniman, A.E.Googlandla, A.P.Aurentz, C.Chakusey, C.J.Chakura, C.J.J.J.J.J.J.J.Biochem.1996, U.E.Tokayak.43, Tagru.K.19, S.K.K.2, Takai.K.K.K.K.2, U.K.No. No. 2, U.K.K.K.K.K.K. No. 2, U.K. K. No. 3, U.K. K. No. 2, U.K. K.. Similar observations were made for analogues of tachplesinum (h.tamamamura, r.ikoma, m.niwa, s.funakoshi, t.murakami, n.fujii, chem.pharm.bull.1993, 41, 978-. These results indicate 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 that favor the α -helical structure, the amphipathic structure of the helix appears to play a key role in determining antimicrobial activity (a.tossi, l.sandri, a.gianga sporo, a.biopolymers 2000, 55, 4-30). Gramicidin S is a backbone-cyclic peptide with a well-defined β -hairpin structure (s.e. hull, r.karlsson, p.main, m.m.wood fson, e.j.dodson, Nature 1978, 275, 206-. However, the high hemolytic activity of gramicidin S prevents its widespread use as an antibiotic. Recent structural studies of NMR have shown that high hemolytic activity is clearly related to the highly amphipathic nature of the cyclic β -hairpin molecule, but antimicrobial activity and hemolytic activity can be separated by adjusting conformation and amphiphilicity (l.h.kondejewski, m.jelokhani-Niaraki, s.w.farmer, b.lix, m.kay, b.d.sykes, r.e.hancock, r.s.hodges, j.biol.chem.1999, 274, 13181-jar 13192; c.mcinnes l.h.kondejewski, r.s.hodges, b.d.chekes, j.biol.m.2000, 275, 14287-jar 14294).
A new cyclic antimicrobial peptide RTD-1 was recently reported to be from primate white blood cells (y. -q. tang, j. yuan, G.K.Tran, c.j.miller, a.j.oelette, m.e.selsted, Science 1999, 286, 498-. The peptide contains three disulfide bridges, which serve to constrain the cyclic peptide backbone into a hairpin geometry. The cleavage of these three 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, all cystine-limited removal did not always result in a large loss of antimicrobial activity, but modulated membralytic selectivity (J.P.Tam, C.Wu, J. -L.Yang, Eur.J.biochem.2000, 267, 3289-.
One of the key issues in designing new selective cationic antimicrobial peptides is bioavailability, stability and reduced hemolytic activity. 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.Fiddes, Biopolymers 2000, 55, 88-98; C.Chang, L.Gu, J.Chen, US-Pat: 5, 916, 872, 1999). This high hemolytic activity substantially excludes its use in vivo and represents a serious drawback in clinical applications. In addition, the antibiotic activity of the analogs generally decreases significantly with increasing salt concentration, such that antimicrobial activity can be significantly reduced under in vivo conditions (about 100-.
Protegrin 1 has potent and similar activity in low and high salt assays against gram positive and gram negative bacteria and fungi. This broad antimicrobial activity, coupled with a rapid mode of action, and its ability to kill bacteria resistant to other classes of antibiotics, makes them an attractive target for the development of clinically useful antibiotics. The activity against gram-positive bacteria is generally higher than that against gram-negative bacteria. However, protegrin 1 also has a high hemolytic activity against erythrocytes and thus a low selectivity for microbial cells. Targeted CD experiments (W.T.Heller, A.J.Waring, R.I.Lehrer, H.W.Huang, Biochemistry1998, 37, 17331-. Studies on cyclic protegrin analogues (j. -p.tam, c.wu, j. -l.yang, eur.j.biochem.2000, 267, 3289-3300) have shown that the increase in conformational rigidity brought about by backbone cyclisation and multiple disulphide bridges can lead to a membrolytic selectivity to separate the antimicrobial activity from the haemolytic activity, at least for those series of compounds studied.
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 three disulfide bridges (J.P.Tam, C.Wu, J.L.Yang, Eur.J.biochem.2000, 267, 3289-.
Cathelicidin, a 37-residue linear helical cationic peptide, and analogs are currently being investigated as inhalation therapeutics 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, Antimicro.Agent and Chemother.2001, 45, 2838-2844; R.E.W.Hancock, R.Lehrer, trends Biotechnol.1998, 16, 82-88). Over 80% of CF patients suffer chronic infection with P.aeruginosa (C.A.Demko, P.J.Biard, P.B.Davies, J.Clin.epidemiol.1995, 48, 1041-. Other antimicrobial peptides directed against pseudomonas (y.h. yau, b.ho, n.s.tan, m.l.ng, j.l.ding, antimicro.agent and chemither.2001, 45, 2820-2825 and references cited therein), such as FALL-39, SMAP-29, and lepidopteran insecticidal peptides, have less desirable properties such as strong antimicrobial activity over a wide range of pH, rapid kill rates, and low hemolytic activity.
Among the compounds described below, a novel approach was introduced for stabilizing the β -hairpin conformation in backbone-cyclic cationic peptidomimetics with selective antimicrobial activity. This involves grafting cationic and hydrophobic hairpin sequences onto a template, the function of which is to constrain the peptide loop backbone to a hairpin geometry.
Template-bound hairpin mimetic peptides have been described in the literature (D, Obrecht, M.Altorfer, J.A.Robinson, adv.Med.Chem.1999, 4, 1-68; J.A.Robinson, Syn.Lett.2000, 4, 429-441), but these molecules have not previously been evaluated for the development of selective antimicrobial peptides. However, the ability to generate β -hairpin peptidomimetics using combinatorial and parallel synthetic methods has been established (L.Jiang, K.Moehle, B.Dhanapaal, D.Obrecht, J.A.Robinson, Helv.Chim.acta.2000, 83, 3097-. These methods enable the synthesis and screening of large hairpin mimetic libraries, which in turn significantly facilitates structure-activity studies and thus the discovery of new molecules with potent selective antimicrobial activity and very low hemolytic activity against human erythrocytes. The method enables the synthesis of beta-hairpin peptidomimetics with novel selectivity for various multidrug resistant Pseudomonas or Acinetobacter strains.
The beta-hairpin peptidomimetics of the invention are compounds having the general formula
Wherein
Is a radical of one of the formulae
Wherein
Is a residue of an L-alpha-amino acid and B is of the formula-NR20CH(R71) -or an enantiomer of one of the groups a1-a69 as defined below;
is a radical of one of the formulae
R1Is H; a lower alkyl group; 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)sSO2R62(ii) a Or- (CH)2)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)sSO2R62(ii) a Or- (CH)2)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)sSO2R62(ii) a Or- (CH)2)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)sSO2R62(ii) a Or- (CH)2)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)sSO2R62(ii) a Or- (CH)2)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)sSO2R62(ii) a Or- (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)sSO2R62(ii) a Or- (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)sSO2R62(ii) a Or- (CH)2)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)sSO2R62(ii) a Or- (CH)2)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)sSO2R62(ii) a Or- (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)sSO2R62(ii) a Or- (CH)2)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)sSO2R62(ii) a Or- (CH)2)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)sSOR62(ii) a Or- (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)sSO2R62(ii) a Or- (CH)2)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)sSO2R62(ii) a Or- (CH)2)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)sSO2R62(ii) a Or- (CH)2)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)sSO2R62(ii) a Or- (CH)2)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(CR61)sNR20CONR33R82；
-(CH2)p(CHR61)sCOOR57；-(CH2)p(CHR61)sCONR58R59；-(CH2)p(CHR61)sPO(OR60)2；
-(CH2)p(CHR61)sSO2R62(ii) a Or- (CH)2)o(CHR61)sC6H4R8(ii) a Or
R18And R19Together may form: - (CH)2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-; or
-(CH2)2NR57(CH2)2-；
R20Is H; an alkyl group; an alkenyl group; 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)sSO2R62(ii) a Or- (CH)2)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)sSO2R62(ii) a Or- (CH)2)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)sSO2R62(ii) a Or- (CH)2)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)sSO2R62(ii) a Or- (CH)2)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)sSO2R62(ii) a Or- (CH)2)o(CHR61)sC6H4R8；
R26Is H; alkane (I) and its preparation methodA 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)sSO2R62(ii) a Or- (CH)2)o(CHR61)sC6H4R8(ii) a Or
R25And R26Together may form: - (CH)2)2-6-；-(CH2)rO(CH2)r-；-(CH2)rS(CH2)r-; or
-(CH2)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)sSO2R62(ii) a Or- (CH)2)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)sSO2R62(ii) a Or- (CH)2)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)sSO2R62(ii) a Or- (CH)2)o(CHR61)sC6H4R8；
R30Is H; an alkyl group; an alkenyl group; 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)sSO2R62(ii) a Or- (CH)2)o(CHR61)sC6H4R8；
R32Is H; a lower alkyl group; 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)sSO2R62(ii) a Or- (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
-(CH2)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)sSO2R62(ii) a Or- (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)sSO2R62(ii) a Or- (CH)2)o(CHR61)sC6H4R8；
R37Is H; f; br; cl; NO2；CF3(ii) a A lower alkyl 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)sSO2R62(ii) a Or- (CH)2)o(CHR61)sC6H4R8；
R38Is H; f; br; cl; NO2；CF3(ii) a 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)sSO2R62(ii) a Or- (CH)2)o(CHR61)sC6H4R8；
R39Is H; an alkyl group; an alkenyl group; or aryl-lower alkyl;
R40is H; an alkyl group; an alkenyl group; or aryl-lower alkyl;
R41is H; f; br; cl; NO2；CF3(ii) a 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)sSO2R62(ii) a Or- (CH)2)o(CHR61)sC6H4R8；
R42Is H; f; br; cl; NO2；CF3(ii) a 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)sSO2R62(ii) a Or- (CH)2)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)sSO2R62(ii) a Or- (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)sSO2R62(ii) a Or- (CH)2)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)sSO2R62(ii) a Or- (CH)2)s(CHR61)sC6H4R8；
R46Is H; an alkyl group; an alkenyl group; or- (CH)2)o(CHR61)pC6H4R8；
R47Is H; an alkyl group; an alkenyl group; or- (CH)2)o(CHR61)sOR55；
R48Is H; a lower alkyl group; a lower alkenyl group; or aryl-lower alkyl;
R49is H; an alkyl group; an alkenyl group; - (CHR)61)sCOOR57；(CHR61)sCONR58R59；(CHR61)sPO(OR60)2；
-(CHR61)sSOR62(ii) a Or- (CHR)61)sC6H4R8；
R50Is H; a lower alkyl group; 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)sSO2R62(ii) a Or- (CH)2)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)sSO2R62(ii) a Or- (CH)2)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)sSO2R62(ii) a Or- (CH)2)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)sCONR58R59(ii) a Or- (CH)2)o(CHR61)sC6H4R8；
R55Is H; a lower alkyl group; a lower alkenyl group; aryl-lower alkyl; - (CH)2)m(CHR61)sOR57；
-(CH2)m(CHR61)sNR34R63；-(CH2)m(CHR61)sOCONR75R82；
-(CH2)m(CHR61)sNR20CONR78R82；-(CH2)o(CHR61)s-COR64；-(CH2)o(CHR61)COOR57(ii) a Or
-(CH2)o(CHR61)sCONR58R59；
R56Is H; a lower alkyl group; a lower alkenyl group; aryl-lower alkyl; - (CH)2)m(CHR61)sOR57；
-(CH2)m(CHR61)sNR34R63；-(CH2)m(CHR61)sOCONR75R82；
-(CH2)m(CHR61)sNR20CONR78R82；-(CH2)o(CHR61)s-COR64(ii) a Or
-(CH2)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
-(CH2)2NR57(CH2)2-；
R60Is H; a lower alkyl group; a lower alkenyl group; an aryl group; 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)oNR58R59(ii) a Or- (CH)2)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；-SO2R62(ii) a OR-PO (OR)60)2；
R34And R63Together may form: - (CH)2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-; or
-(CH2)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;
-(CH2)p(CHR61)sOR65；-(CH2)p(CHR61)sSR66(ii) a Or- (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；
-COOR57(ii) a or-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;
z is a chain of 12 alpha-amino acid residues, the positions of said amino acid residues in said chain being counted starting from the N-terminal amino acid, such that these amino acid residues are Gly or Pro, or of the formula-A-CO-, or of the formula-B-CO-, or of one of the following types, depending on their position in the chain
C：NR20CH(R72)CO-；
D：-NR20CH(R73)CO-；
E：-NR20CH(R74)CO-；
F：-NR20CH(R84)CO-；
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)pSO2R62(ii) a Or
-(CH2)o-C6R67R68R69R70R76；
R72Is H; a lower alkyl group; a lower alkenyl group; - (CH)2)p(CHR61)sOR85(ii) a Or- (CH)2)p(CHR61)sSR85；
R73Is- (CH)2)oR77；-(CH2)rO(CH2)oR77；-(CH2)rS(CH2)oR77(ii) a Or- (CH)2)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)pNR80CONR78R79(ii) a Or- (CH)2)pC6H4N80CONR78R79；
R75Is a lower alkyl group; a lower alkenyl group; or aryl-lower alkyl;
R33and R75Together may form: - (CH)2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-; or
-(CH2)2NR57(CH2)2-；
R75And R82Together may form: - (CH)2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-; or
-(CH2)2NR57(CH2)2-；
R76Is H; a lower alkyl group; a lower alkenyl group; aryl-lower alkyl; - (CH)2)oOR72；-(CH2)oSR72；
-(CH2)oNR33R34；-(CH2)oOCONR33R75；-(CH2)oNR20CONR33R82；
-(CH2)oCOOR75；-(CH2)oCONR58R59；-(CH2)oPO(OR60)2；-(CH2)pSO2R62(ii) a Or
-(CH2)oCOR64；
R77is-C6R67R68R69R70R76(ii) a Or a heteroaryl group having one of the following structural formulae
R78Is H; a lower alkyl group; an aryl group; or aryl-lower alkyl;
R78and R82Together may form: - (CH)2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-; or
-(CH2)2NR57(CH2)2-；
R79Is H; a lower alkyl group; an aryl group; or aryl-lower alkyl; or
R78And R79Taken together, may be- (CH)2)2-7-；-(CH2)2O(CH2)2-; or- (CH)2)2NR57(CH2)2-；
R80Is H; or lower alkyl;
R81is H; a lower alkyl group; or aryl-lower alkyl;
R82is H; a lower alkyl group; an aryl group; a heteroaryl group; or aryl-lower alkyl;
R33and R82Together may form: - (CH)2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-; or
-(CH2)2NR57(CH2)2-；
R83Is H; a lower alkyl group; an aryl group; or-NR78R79；
R84Is- (CH)2)m(CHR61)sOH；-(CH2)pCONR78R79；-(CH2)pNR80CONR78R79；-(CH2)pC6H4CONR78R79(ii) a Or- (CH)2)pC6H4NR80CONR78R79；
R85Is a lower alkyl group; or lower alkenyl;
with the proviso that in the chain Z of 12 α -amino acid residues the amino acid residues in positions 1 to 12 are:
-P1: class C or class D or class E or class F, or the residue is Pro;
-P2: a species D;
-P3: class C, or class D, or the residue is Pro;
-P4: class C, or class D, or class E;
-P5: species E, or species D, or species C, or species F, or the residue is Gly or Pro;
-P6: class E, or class F or having the formula-A-CO-, or the residue is Gly;
-P7: class C, or class E, or class F, or having the formula-B-CO-;
-P8: class D, or class C, or class F, or the residue is Pro;
-P9: class C, or class E, or class D, or class F;
-P10: class F, or class D or class C, or the residue is Pro;
-P11: class E or class D or class C or class F; and
-P12: class C or class D or class E or class F, or the residue is Pro; or
-P4 and P9 and/or P2 and P11 together may form a H-like group; and at P6 and P7, the D-isomer is also possible;
a further prerequisite is that
-the amino acid residue in P4 is of the type C; and/or
-the amino acid residue in P5 is of the species F; and/or
-the amino acid residue in P7 is of the type C; and/or
-the amino acid residue in P8 is of the species F; and/or
-the amino acid residue in P9 is of the type C; and/or
-the amino acid residue in P10 is of the species F; and/or
-the amino acid residue in P11 is of the type C or of the type F;
and pharmaceutically acceptable salts thereof.
According to the invention, these β -hairpin peptidomimetics can be made by a method comprising:
(a) coupling a suitably functionalized solid support (support) with a suitable N-protected derivative of an amino acid at position 5, 6 or 7 in the desired end product, any functional groups that may be present in said N-protected amino acid derivative also being suitably protected;
(b) removing the N-protecting group from the product thus obtained;
(c) coupling the product thus obtained with a suitable N-protected derivative of an amino acid at a position closer to the N-terminal amino acid residue in the desired end product, any functional groups which may be present in said N-protected amino acid derivative also being suitably protected;
(d) removing the N-protecting group from the product thus obtained;
(e) repeating steps (c) and (d) 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), as an alternative,
(fa) coupling the product obtained in step (e) with a suitable N-protected derivative of an amino acid of the general formula
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 also suitably protected;
(fb) removing the N-protecting group from the product thus obtained; and
(fc) coupling of the product thus obtained with suitable N-protected derivatives of amino acids having the general formulae IV and III above, respectively, any functional groups which may be present in said N-protected amino acid derivatives also being 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 suitable N-protected derivative of the amino acid at position 12 in the desired end product, any functional groups which may be present in said N-protected amino acid derivative also being suitably protected;
(i) removing the N-protecting group from the product thus obtained;
(j) coupling the product thus obtained with a suitable N-protected derivative of an amino acid at a position further away from position 12 in the desired end product, any functional groups which may be present in said N-protected amino acid derivative also being suitably protected;
(k) removing the N-protecting group from the product thus obtained;
(l) Repeating steps (j) and (k) until all amino acid residues have been introduced;
(m) if desired, selectively deprotecting one or several protected functional groups present in the molecule and appropriately substituting the reactive groups thus released;
(o) separating the product thus obtained from the solid support;
(p) cyclizing the cleaved product from the solid support;
(q) if desired, forming one or two interchain bonds between the side chains of suitable amino acid residues at opposite positions in the β -chain region;
(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 additionally 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 structural formula I or into a different pharmaceutically acceptable salt.
Alternatively, peptidomimetics of the invention can be prepared as follows
(a') coupling a suitably functionalized solid support 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), as an alternative
(a' a) coupling of said suitably functionalized solid support with a suitable N-protected derivative of an amino acid having the general formula
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;
(a' b) removing the N-protecting group from the product thus obtained; and
(a' c) coupling the product thus obtained with suitable N-protected derivatives of amino acids having the general formulae IV and III above, respectively, any functional groups which may be present in said N-protected amino acid derivatives being likewise suitably protected;
(b ') removing the N-protecting group from the product obtained in step (a ') or (a ' c);
(c') coupling the product thus obtained with a suitable N-protected derivative of the amino acid at position 12 in the desired end product, any functional groups which may be present in said N-protected amino acid derivative likewise being suitably protected;
(d') removing the N-protecting group from the product thus obtained;
(e') coupling the product thus obtained with a suitable N-protected derivative of an amino acid at a position further away from position 12 in the desired end product, any functional groups which may be present in said N-protected amino acid derivative likewise being suitably protected;
(f') removing the N-protecting group from the product thus obtained;
(g ') repeating steps (e ') and (f ') until all amino acid residues have been introduced;
(h') if desired, selectively deprotecting one or several of the protected functional groups present in the molecule and appropriately substituting the reactive groups thus released;
(i') separating the product thus obtained from the solid support;
(j') cyclizing the product cleaved from the solid support;
(k') if desired, forming one or two interchain bonds between the side chains of the appropriate amino acid residues at opposite positions in the β -chain region;
(l') 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 which may additionally be present in the molecule; and
(m') 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 formula I. These enantiomers can be made by varying the above process, wherein all enantiomers of chiral starting materials are used.
The term "alkyl" as used in the present specification, alone or in combination, denotes a saturated, straight-chain or branched hydrocarbon radical having up to 24, preferably up to 12, carbon atoms. Similarly, the term "alkenyl" denotes straight-chain or branched hydrocarbon radicals having up to 24, preferably up to 12, carbon atoms and containing at least one or, depending on the chain length, up to four olefinic double bonds. The term "lower" denotes groups and compounds having up to 6 carbon atoms. Thus, for example, the term "lower alkyl" denotes a saturated, straight-chain or branched 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" denotes an aromatic carbocyclic hydrocarbon radical comprising one or two six-membered rings, such as phenyl or naphthyl, which may be substituted by up to three substituents such as Br, Cl, F, CF3，NO2Lower alkyl or lower alkenyl. The term "heteroaryl" denotes an aromatic heterocyclic group comprising one or two five-and/or six-membered rings, wherein at least one ring comprises up to three heteroatoms selected from O, S and N and the ring is optionally substituted; representative examples of such optionally substituted heteroaryl groups are as defined above for R77Is given in the following.
The structural component-A-CO-represents an amino acid structural unit, which together with the structural component-B-CO-forms the templates (a1) and (a 2). Templates (a) - (p) constitute building blocks having an N-terminus and a C-terminus, which are spatially oriented such that the distance between these two groups may be 4.0-5.5A. Peptide chain Z is linked to the C-terminus and N-terminus of templates (a) - (p) via the respective N-and C-termini, such that the templates and chain form a cyclic structure, such as the one depicted in structural formula I. If the distance between the N-and C-termini of the template is 4.0-5.5A, as is the case here, the template will induce the H-bond network required for the formation of the beta-hairpin conformation in the peptide chain Z. The template and peptide chain thus form a β -hairpin mimetic (mimetic).
The beta-hairpin conformation is highly relevant for the antibiotic activity of the beta-hairpin mimetics of the invention. The β -hairpin stabilized conformational properties of the templates (a) - (p) play a key role not only for selective antimicrobial activity but also for the synthetic process as defined above, since the introduction of the template at the beginning of the linearly protected peptide precursor significantly increases the cyclization reaction yield.
The structural units A1-A69 belong to the class of amino acids, the N-terminus of which is a secondary amine forming part of a ring. Among the amino acids encoded by the gene, only proline falls into this class. The structural units A1-A69 are in configuration (D) and they are bound together with the structural unit-B-CO-in configuration (L). The preferred combination of templates (a1) is-DA1-CO-LB-CO-toDA69-CO-LB-CO-. Thus, for example,DPro-Lpro constitutes a prototype (prototype) of template (a 1). Less preferred, but possible wherein the template (a2) isLA1-CO-DB-CO-toLA69-CO-DA combination of B-CO-. Thus, for example,LPro-Dpro constitutes a less preferred prototype of template (a 2).
It is understood that the structural unit in which A has the (D) -configuration-A1-CO-to-A69-CO-carries the group R in the alpha-position relative to the N-terminus1。R1Are H and lower alkyl, most preferred R1The values are H and methyl. It will be understood by those skilled in the art that A1-A69 is shown in the (D) -configuration if R is1H and methyl correspond to the (R) -configuration. Depending on the rule R according to Cahn, Ingold and Prelog1This configuration may also have to be denoted (S) by priority of other values of (a).
Except that R1The structural units-A1-CO-to-A69-CO-may be carriedOthers being referred to as R2-R17A substituent of (1). The other substituent may be H, and if it is not H, it is preferably an aliphatic or aromatic group of small to medium size. R2-R17Examples of preferred values of (c) are:
-R2: h; a lower alkyl group; a lower alkenyl group; (CH)2)mOR55(wherein R is55: a lower alkyl group; or lower alkenyl); (CH)2)mSR56(wherein R is56: a lower alkyl group; or lower alkenyl); (CH)2)mNR33R34(wherein R is33: a lower alkyl group; or lower alkenyl; r34: h; or lower alkyl; r33And R34Together form:
-(CH2)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: a lower alkyl group; or R33And R75Together form: - (CH)2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-; or
-(CH2)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 R82Together form: - (CH)2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-; or
-(CH2)2NR57(CH2)2-; wherein R is57: h; or lower alkyl); - (CH)2)oN(R20)COR64(wherein: R20: h; or lower alkyl; r64: a lower alkyl group; or lower alkenyl); - (CH)2)oCOOR57(wherein R is57: a lower alkyl group; or lower alkenyl); - (CH)2)oCONR58R59(wherein R is58: a lower alkyl group; 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 is60: a lower alkyl group; or lower alkenyl); - (CH)2)oSO2R62(wherein R is62: a lower alkyl group; or lower alkenyl); or
-(CH2)qC6H4R8(wherein R is8：H；F；Cl；CF3(ii) a A lower alkyl group; a lower alkenyl group; or lower alkoxy).
-R3: h; a lower alkyl group; a lower alkenyl group; - (CH)2)mOR55(wherein R is55: a lower alkyl group; or lower alkenyl); - (CH)2)mSR56(wherein R is56: a lower alkyl group; or lower alkenyl); - (CH)2)mNR33R34(wherein R is33: a lower alkyl group; 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: a lower alkyl group; or R33And R75Together form: - (CH)2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-; or
-(CH2)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 R82Together form: - (CH)2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-; or
-(CH2)2NR57(CH2)2-; wherein R is57: h; or lower alkyl); - (CH)2)oN(R20)COR64(wherein: R20: h; or lower alkyl; r64: a lower alkyl group; or lower alkenyl); - (CH)2)oCOOR57(wherein R is57: a lower alkyl group; or lower alkenyl); - (CH)2)oCONR58R59(wherein R is58: a lower alkyl group; or lower alkenyl; and R59: h; a lower alkyl group; 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: a lower alkyl group; or lower alkenyl); - (CH)2)oSO2R62(wherein R is62: a lower alkyl group; or lower alkenyl); or- (CH)2)qC6H4R8(wherein R is8：H；F；Cl；CF3(ii) a A lower alkyl group; a lower alkenyl group; or lower alkoxy).
-R4: h; a lower alkyl group; a lower alkenyl group; - (CH)2)mOR55(wherein R is55: a lower alkyl group; or lower alkenyl); - (CH)2)mSR56(wherein R is56: a lower alkyl group; or lower alkenyl); - (CH)2)mNR33R34(wherein R is33: a lower alkyl group; 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)mOCONR33R57(wherein R is33: h; or lower alkyl; or lower alkenyl; r75: a lower alkyl group; or R33And R75Together form: - (CH)2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-; or
-(CH2)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 R82Together form: - (CH)2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-; or
-(CH2)2NR57(CH2)2-; wherein R is57: h; or lower alkyl); - (CH)2)mN(R20)COR64(wherein: R20: h; or lower alkyl; r64: a lower alkyl group; or lower alkenyl); - (CH)2)oCOOR57(wherein R is57: a lower alkyl group; or lower alkenyl); - (CH)2)oCONR58R59(wherein R is58: a lower alkyl group; 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 is60: a lower alkyl group; or lower alkenyl); - (CH)2)oSO2R62(wherein R is62: a lower alkyl group; or lower alkenyl); or- (CH)2)qC6H4R8(wherein R is8：H；F；Cl；CF3(ii) a A lower alkyl group; a lower alkenyl group; or lower alkoxy).
-R5: a lower alkyl group; a lower alkenyl group; - (CH)2)oOR55(wherein R is55: a lower alkyl group; or lower alkenyl); - (CH)2)oSR56(wherein R is56: a lower alkyl group; or lower alkenyl); - (CH)2)oNR33R34(wherein R is33: a lower alkyl group; or lower alkenyl; r34: h; or lower alkyl; or R33And R34Together 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)oOCONR33R75(wherein R is33: h; or lower alkyl; or lower alkenyl; r75: a lower alkyl group; or R33And R75Together form: - (CH)2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-; or
-(CH2)2NR57(CH2)2-；R57: wherein 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
-(CH2)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);
-(CH2)oCOOR57(wherein R is57: a lower alkyl group; or lower alkenyl); - (CH)2)oCONR58R59(wherein R is58: a lower alkyl group; 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 is60: a lower alkyl group; or lower alkenyl); - (CH)2)oSO2R62(wherein R is62: a lower alkyl group; or lower alkenyl); or- (CH)2)qC6H4R8(wherein R is8：H；F；Cl；CF3(ii) a A lower alkyl group; a lower alkenyl group; or lower alkoxy).
-R6: h; a lower alkyl group; a lower alkenyl group; - (CH)2)oOR55(wherein R is55: a lower alkyl group; or lower alkenyl); - (CH)2)oSR56(wherein R is56: a lower alkyl group; or lower alkenyl); - (CH)2)oNR33R34(wherein R is33: a lower alkyl group; or lower alkenyl; r34: h; or lower alkyl; or R33And R34Together 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)oOCONR33R75(wherein R is33: h; or lower alkyl; or lower alkenyl; r75: a lower alkyl group; or R33And R75Together form: - (CH)2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-; or
-(CH2)2NR57(CH2)2-; wherein R is57: h; or lower alkyl); - (CH)2)oNR20CONR33R82 (wherein R20: 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
-(CH2)2NR57(CH2)2-; wherein R is57: h; or lower alkyl); - (CH)2)oN(R20)COR64(wherein: R20: h; or lower alkyl; r64: a lower alkyl group; or lower alkenyl); - (CH)2)oCOOR57(wherein R is57: a lower alkyl group; or lower alkenyl); - (CH)2)oCONR58R59(wherein R is58: a lower alkyl group; 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 is60: a lower alkyl group; or lower alkenyl); - (CH)2)oSO2R62(wherein R is62: is low inA lower alkyl group; or lower alkenyl); or- (CH)2)qC6H4R8(wherein R is8：H；F；Cl；CF3(ii) a A lower alkyl group; a lower alkenyl group; or lower alkoxy).
-R7: a lower alkyl group; a lower alkenyl group; - (CH)2)qOR55(wherein R is55: a lower alkyl group; or lower alkenyl); - (CH)2)qSR56(wherein R is56: a lower alkyl group; or lower alkenyl); - (CH)2)qNR33R34(wherein R is33: a lower alkyl group; or lower alkenyl; r34: h; or lower alkyl; or R33And R34Together 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)qOCONR33R75(wherein R is33: h; or lower alkyl; or lower alkenyl; r75: a lower alkyl group; or33And R75Together form: - (CH)2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-; or
-(CH2)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
-(CH2)2NR57(CH2)2-; wherein R is57: h; or lower alkyl); - (CH)2)qN(R20)COR64(wherein: R20: h; or lower alkyl; r64: a lower alkyl group; or lower alkenyl); - (CH)2)rCOOR57(wherein R is57: a lower alkyl group; or lower alkenyl); - (CH)2)qCONR58R59(wherein R is58: a lower alkyl group; 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)rPO(OR60)2(wherein R is60: a lower alkyl group; or lower alkenyl); (CH)2)rSO2R62(wherein R is62: a lower alkyl group; or lower alkenyl); or- (CH)2)qC6H4R8(wherein R is8：H；F；Cl；CF3(ii) a A lower alkyl group; a lower alkenyl group; or lower alkoxy).
-R8：H；F；Cl；CF3(ii) a A lower alkyl group; a lower alkenyl group; - (CH)2)oOR55(wherein R is55: a lower alkyl group; or lower alkenyl); (CH)2)oSR56(wherein R is56: a lower alkyl group; or lower alkenyl); - (CH)2)oNR33R34(wherein R is33: a lower alkyl group; 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: a lower alkyl group; 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);
-(CH2)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);
-(CH2)oN(R20)COR64(wherein: R20: h; or lower alkyl; r64: a lower alkyl group; or lower alkenyl);
-(CH2)oCOOR57(wherein R is57: a lower alkyl group; or lower alkenyl); - (CH)2)oCONR58R59(wherein R is58: a lower alkyl group; or lower alkenyl; and R59: h; or lower alkyl; or R58And R59Together formThe composition is as follows:
-(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: a lower alkyl group; or lower alkenyl); - (CH)2)oSO2R62(wherein R is62: a lower alkyl group; or lower alkenyl); or- (CH)2)qC6H4R8(wherein R is8：H；F；Cl；CF3(ii) a A lower alkyl group; a lower alkenyl group; or lower alkoxy).
-R9: a lower alkyl group; a lower alkenyl group; - (CH)2)oOR55(wherein R is55: a lower alkyl group; or lower alkenyl); - (CH)2)oSR56(wherein R is56: a lower alkyl group; or lower alkenyl); - (CH)2)oNR33R34(wherein R is33: a lower alkyl group; or lower alkenyl; r34: h; or lower alkyl; or R33And R34Together 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)oOCONR33R75(wherein R is33: h; or lower alkyl; or lower alkenyl; r75: a lower alkyl group; or R33And R75Together form: - (CH)2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-; or
-(CH2)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 R82Together form: - (CH)2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-; or
-(CH2)2NR57(CH2)2-; wherein R is57: h; or lower alkyl); - (CH)2)oN(R20)COR64(wherein: R20: h; or lower alkyl; r64: a lower alkyl group; or lower alkenyl); - (CH)2)oCOOR57(wherein R is57: a lower alkyl group; or lower alkenyl); - (CH)2)oCONR58R59(wherein R is58: a lower alkyl group; 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 is60: a lower alkyl group; or lower alkenyl); - (CH)2)oSO2R62(wherein R is62: a lower alkyl group; or lower alkenyl); or- (CH)2)qC6H4R8(wherein R is8：H；F；Cl；CF3(ii) a A lower alkyl group; a lower alkenyl group; or lower alkoxy).
-R10: a lower alkyl group; a lower alkenyl group; - (CH)2)oOR55(wherein R is55: a lower alkyl group; or lower alkenyl); - (CH)2)oSR56(wherein R is56: a lower alkyl group; or lower alkenyl); - (CH)2)oNR33R34(wherein R is33: a lower alkyl group; or lower alkenyl; r34: h; or lower alkyl; or R33And R34Together 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)oOCONR33R75(wherein R is33: h; or lower alkyl; or lower alkenyl; r75: a lower alkyl group; or R33And R75Together form: - (CH)2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-; or
-(CH2)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
-(CH2)2NR57(CH2)2-; wherein R is57: h; or lower alkyl); - (CH)2)oN(R20)COR64(wherein：R20: h; or lower alkyl; r64: a lower alkyl group; or lower alkenyl); - (CH)2)oCOOR57(wherein R is57: a lower alkyl group; or lower alkenyl); - (CH)2)oCONR58R59(wherein R is58: a lower alkyl group; or lower alkenyl; and R59: h; a lower alkyl group; 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: a lower alkyl group; or lower alkenyl); - (CH)2)oSO2R62(wherein R is62: a lower alkyl group; or lower alkenyl); or- (CH)2)qC6H4R8(wherein R is8：H；F；Cl；CF3(ii) a A lower alkyl group; a lower alkenyl group; or lower alkoxy).
-R11: h; a lower alkyl group; a lower alkenyl group; - (CH)2)mOR55(wherein R is55: a lower alkyl group; or lower alkenyl); - (CH)2)mSR56(wherein R is56: a lower alkyl group; or lower alkenyl); - (CH)2)mNR33R34(wherein R is33: a lower alkyl group; 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: a lower alkyl group; or R33And R75Together form: - (CH)2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-; or
-(CH2)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 R82Together form: - (CH)2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-; or
-(CH2)2NR57(CH2)2-; wherein R is57: h; or lower alkyl); - (CH)2)mN(R20)COR64(wherein: R20: h; or lower alkyl; r64: a lower alkyl group; or lower alkenyl); - (CH)2)oCOOR57(wherein R is57: a lower alkyl group; or lower alkenyl); - (CH)2)oCONR58R59(wherein R is58: a lower alkyl group; or lower alkenyl; and R59: h; a lower alkyl group; 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: a lower alkyl group; or lower alkenyl)；-(CH2)oSO2R62(wherein R is62: a lower alkyl group; or lower alkenyl); or- (CH)2)qC6H4R8(wherein R is8：H；F；Cl；CF3(ii) a A lower alkyl group; a lower alkenyl group; or lower alkoxy).
-R12: h; a lower alkyl group; a lower alkenyl group; - (CH)2)mOR55(wherein R is55: a lower alkyl group; or lower alkenyl); - (CH)2)mSR56(wherein R is56: a lower alkyl group; or lower alkenyl); - (CH)2)mNR33R34(wherein R is33: a lower alkyl group; 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: a lower alkyl group; or R33And R75Together form: - (CH)2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-; or
-(CH2)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 R82Together form: - (CH)2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-; or
-(CH2)2NR57(CH2)2-; wherein R is57: h; or lower alkyl); - (CH)2)mN(R20)COR64(wherein: R20: h; or lower alkyl; r64: a lower alkyl group; or lower alkenyl); - (CH)2)rCOOR57(wherein R is57: a lower alkyl group; or lower alkenyl); - (CH)2)rCONR58R59(wherein R is58: a lower alkyl group; 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)rPO(OR60)2(wherein R is60: a lower alkyl group; or lower alkenyl); - (CH)2)oSO2R62(wherein R is62: a lower alkyl group; or lower alkenyl); or- (CH)2)qC6H4R8(wherein R is8：H；F；Cl；CF3(ii) a A lower alkyl group; a lower alkenyl group; or lower alkoxy).
-R13: a lower alkyl group; a lower alkenyl group; - (CH)2)qOR55(wherein R is55: a lower alkyl group; or lower alkenyl); - (CH)2)qSR56(wherein R is56: a lower alkyl group; or lower alkenyl); - (CH)2)qNR33R34(wherein R is33: a lower alkyl group; or lower alkenyl; r34: h; or lower alkyl; or R33And R34Together 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)qOCONR33R75(wherein R is33: h; or lower alkyl; or lower alkenyl; r75: a lower alkyl group; or R33And R75Together form: - (CH)2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-; or
-(CH2)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
-(CH2)2NR57(CH2)2-; wherein R is57: h; or lower alkyl); - (CH)2)qN(R20)COR64(wherein: R20: h; or lower alkyl; r64: a lower alkyl group; or lower alkenyl); - (CH)2)rCOO57(wherein R is57: a lower alkyl group; or lower alkenyl); - (CH)2)qCONR58R59(wherein R is58: a lower alkyl group; 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)rPO(OR60)2(wherein R is60: a lower alkyl group; or lower alkenyl); - (CH)2)rSO2R62(wherein R is62: a lower alkyl group; or lower alkenyl); or
-(CH2)qC6H4R8(wherein R is8：H；F；Cl；CF3(ii) a A lower alkyl group; a lower alkenyl group; or lower alkoxy).
-R14: h; a lower alkyl group; a lower alkenyl group; - (CH)2)mOR55(wherein R is55: a lower alkyl group; or lower alkenyl); - (CH)2)mSR56(wherein R is56: a lower alkyl group; or lower alkenyl); - (CH)2)mNR33R34(wherein R is33: a lower alkyl group; 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: a lower alkyl group; or R33And R75Together form: - (CH)2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-; or
-(CH2)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 R82Together form: - (CH)2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-; or
-(CH2)2NR57(CH2)2-; wherein R is57: h; or lower alkyl); - (CH)2)mN(R20)COR64(wherein: R20: h; a lower alkyl group; r64: a lower alkyl group; or lower alkenyl); - (CH)2)oCOOR57(wherein R is57: a lower alkyl group; or lower alkenyl); - (CH)2)oCONR58R59(wherein R is58: a lower alkyl group; 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 is60: a lower alkyl group; or lower alkenyl); - (CH)2)oSO2R62(wherein R is62: a lower alkyl group; or lower alkenyl); - (CH)2)qC6H4R8(wherein R is8：H；F；Cl；CF3(ii) a A lower alkyl group; a lower alkenyl group; or lower alkoxy).
-R15: a lower alkyl group; a lower alkenyl group; - (CH)2)oOR55(wherein R is55: a lower alkyl group; or lower alkenyl); -(CH2)oSR56(wherein R is56: a lower alkyl group; or lower alkenyl); - (CH)2)oNR33R34(wherein R is33: a lower alkyl group; or lower alkenyl; r34: h; or lower alkyl; or R33And R34Together 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)oOCONR33R75(wherein R is33: h; or lower alkyl; or lower alkenyl; r75: a lower alkyl group; or R33And R75Together form: - (CH)2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-; or
-(CH2)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
-(CH2)2NR57(CH2)2-; wherein R is57: h; or lower alkyl); (CH)2)oN(R20)COR64(wherein: R20: h; or lower alkyl; r64: a lower alkyl group; or lower alkenyl); of particular interest are NR20CO lower alkyl (R)20H; or lower alkyl); - (CH)2)oCOOR57(wherein R is57: a lower alkyl group; or lower alkenyl);
-(CH2)oCONR58R59(wherein R is58: lower alkyl, or lower alkenyl; and R59: h; a lower alkyl group; or R58And R59Together form: - (CH)2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-; or
-(CH2)2NR57(CH2)2-; wherein R is57: h; or lower alkyl); - (CH)2)oPO(OR60)2(wherein R is60: a lower alkyl group; or lower alkenyl); - (CH)2)oSO2R62(wherein R is62: a lower alkyl group; or lower alkenyl); or
-(CH2)qC6H4R8(wherein R is8：H；F；Cl；CF3(ii) a A lower alkyl group; a lower alkenyl group; or lower alkoxy).
-R16: a lower alkyl group; a lower alkenyl group; - (CH)2)oOR55(wherein R is55: a lower alkyl group; or lower alkenyl); - (CH)2)oSR56(wherein R is56: a lower alkyl group; or lower alkenyl); - (CH)2)oNR35R34(wherein R is33: a lower alkyl group; or lower alkenyl; r34: h; or lower alkyl; or R33And R34Together 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)oOCONR33R75(wherein R is33: h; or lower alkyl; or lower alkenyl; r75: a lower alkyl group; or R33And R75Together form: - (CH)2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-; or
-(CH2)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
-(CH2)2NR57(CH2)2-; wherein R is57: h; or lower alkyl); - (CH)2)oN(R20)COR64(wherein: R20: h; or lower alkyl; r64: a lower alkyl group; or lower alkenyl); - (CH)2)oCOOR57(wherein R is57: a lower alkyl group; or lower alkenyl); - (CH)2)oCONR58R59(wherein R is58: a lower alkyl group; 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 is60: a lower alkyl group; or lower alkenyl); - (CH)2)oSO2R62(wherein R is62: a lower alkyl group; or lower alkenyl); or- (CH)2)qC6H4R8(wherein R is8：H；F；Cl；CF3(ii) a A lower alkyl group; a lower alkenyl group; or lower alkoxy).
-R17: a lower alkyl group; a lower alkenyl group; - (CH)2)qOR55(wherein R is55: a lower alkyl group; or lower alkenyl); - (CH)2)qSR56(wherein R is56: a lower alkyl group; or lower alkenyl); - (CH)2)qNR33R34(wherein R is33: a lower alkyl group; or lower alkenyl; r34: h; or lower alkyl; or R33And R34Together 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)qOCONR33R75(wherein R is33: h; or lower alkyl; or lower alkenyl; r75: a lower alkyl group; or R33And R75Together form: - (CH)2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-; or
-(CH2)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
-(CH2)2NR57(CH2)2-; wherein R is57: h; or lower alkyl); - (CH)2)qN(R20)COR64(wherein: R20: h; or lower alkyl; r64: a lower alkyl group; or lower alkenyl); - (CH)2)rCOOR57(wherein R is57: a lower alkyl group; or lower alkenyl); - (CH)2)qCONR58R59(wherein R is58: a lower alkyl group; or lower alkenyl; and R59: h; a lower alkyl group; 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)rPO(OR60)2(wherein R is60: a lower alkyl group; or lower alkenyl); - (CH)2)rSO2R62(wherein R is62: a lower alkyl group; or lower alkenyl); or- (CH)2)qC6H4R8(wherein R is8：H；F；Cl；CF3(ii) a A lower alkyl group; a lower alkenyl group; or lower alkoxy).
Among the structural units a1 to a69, the following are preferred: a5 (R)2Is H), A8, A22, A25, A38 (R)2Is H), a42, a47, and a 50. Most preferred are building blocks of the 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; especially wherein R64Is 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 class of open-chain alpha-substituted alpha-amino acids, the structural units A71 and A72 to the corresponding beta-amino acid analogs and the structural units A73-A104 to the cyclic analogs of A70. These amino acid derivatives have been shown to confine small peptides in a well-defined reverse-turn or U-shaped conformation (C.M. Venkatachalam, biopolymer, 1968, 6, 1425-1434; W.Kabsch, Cscand, biopolymer, 1983, 22, 2577). These building blocks or templates are ideally suited for stabilizing the beta-hairpin conformation in the peptide loop (D.Obrecht, M.Altorfer, J.A.Robinson, "novel peptide mimetic building blocks and strategies for efficient targeting", adv.Med Chem.1999, Vol.4, 1-68; P.Balaram, "non-canonical amino acids in peptide design and protein engineering", curr.Opin.struct.biol.1992, 2, 845-.
It has been found that two enantiomers of the structural units-a 70-CO-to a 104-CO-together with the structural unit-B-CO-in the L-configuration effectively stabilize and induce the beta-hairpin conformation (d.obrecht,alterfer, j.a.robinson, "novel peptide mimetic building blocks and strategies for efficient guided search", adv.med chem.1999, vol.4, 1-68; obrecht, c.，K.Müller，H.Heimgartner，F.Stierli，Helv.Chim.Acta 1992，75，1666-1696；D.Obrecht，U.Bohdal，J.Daly，C.Lehmann，P.K.M uller, tetrahedron, 1995, 51, 10883-; obrecht, c.lehmann, c.ruffieux, P.K.Müller，Helv.Chim.Acta 1995，78，1567-1587；D.Obrecht，U.Bohdal，C.Broger，D.Bur，C.Lehmann，R.Ruffieux，P.C.Spiegler，Helv.Chim.Acta 1995，78，563-580；D.Obrecht，H.Karajiannis，C.Lehmann，P.，C.Spiegler，Helv.Chim.Acta 1995，78，703-714)。
Thus, for the purposes of the present invention, templates (A1) may also consist of the structural units-A70-CO-to A104-CO-in which the structural units A70 to A104 are in the (D) -or (L) -configuration, and of the structural units-B-CO-in the (L) -configuration.
R in A70-A10420Preferred values of (b) are H or lower alkyl, with methyl being most preferred. R in the structural units A70 to 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: a lower alkyl group; or lower alkenyl); - (CH)2)pSR56(wherein R is56: a lower alkyl group; or lower alkenyl); - (CH)2)pNR33R34(wherein R is33: a lower alkyl group; or lower alkenyl; r34: h; or lower alkyl; or R33And R34Together 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)pOCONR33R75(wherein R is33: h; or lower alkyl; or lower alkenyl; r75: a lower alkyl group; or R33And R75Together form: - (CH)2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-; or
-(CH2)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 R82Together form: - (CH)2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-; or
-(CH2)2NR57(CH2)2-; wherein R is57: h; or lower alkyl); - (CH)2)pN(R20)COR64(wherein: R20: h; or lower alkyl; r64: lower alkyl(ii) a Or lower alkenyl); - (CH)2)pCOOR57(wherein R is57: a lower alkyl group; or lower alkenyl); - (CH)2)pCONR58R59(wherein R is58: a lower alkyl group; 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 is60: a lower alkyl group; or lower alkenyl); - (CH)2)pSO2R62(wherein R is62: a lower alkyl group; or lower alkenyl); or- (CH)2)oC6H4R8(wherein R is8：H；F；Cl；CF3(ii) a A lower alkyl group; a lower alkenyl group; or lower alkoxy).
-R21: h; a lower alkyl group; a lower alkenyl group; - (CH)2)oOR55(wherein R is55: a lower alkyl group; or lower alkenyl); - (CH)2)oSR56(wherein R is56: a lower alkyl group; or lower alkenyl); - (CH)2)oNR33R34(wherein R is33: a lower alkyl group; or lower alkenyl; r34: h; or lower alkyl; or R33And R34Together 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)oOCONR33R75(wherein R is33: h; or lower alkyl; or lower alkenyl; r75: a lower alkyl group; or R33And R75Together form: - (CH)2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-; or
-(CH2)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
-(CH2)2NR57(CH2)2-; wherein R is57: h; or lower alkyl); - (CH)2)oN(R20)COR64(wherein: R20: h; or lower alkyl; r64: a lower alkyl group; or lower alkenyl); - (CH)2)oCOOR57(wherein R is57: a lower alkyl group; or lower alkenyl); - (CH)2)oCONR58R59(wherein R is58: lower alkyl, or lower alkenyl; and R59: h; a lower alkyl group; 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: a lower alkyl group; or lower alkenyl); (CH)2)oSO2R62(wherein R is62: a lower alkyl group; or lower alkenyl); or (CH)2)qC6H4R8(wherein R is8：H；F；Cl；CF3(ii) a A lower alkyl group; a lower alkenyl group; or lower alkoxy).
-R22: a lower alkyl group; a lower alkenyl group; - (CH)2)oOR55(wherein R is55: a lower alkyl group; or lower alkenyl); - (CH)2)oSR56(wherein R is56: a lower alkyl group; or lower alkenyl); - (CH)2)oNR33R34(wherein R is33: a lower alkyl group; or lower alkenyl; r34: h; or lower alkyl; or R33And R34Together 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)oOCONR33R75(wherein R is33: h; or lower alkyl; or lower alkenyl; r75: a lower alkyl group; or R33And R75Together form: - (CH)2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-; or
-(CH2)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
-(CH2)2NR57(CH2)2-; wherein R is57: h; or lower alkyl); - (CH)2)oN(R20)COR64(wherein: R20: h; or lower alkyl; r64: a lower alkyl group; or lower alkenyl); - (CH)2)oCOOR57(wherein R is57: a lower alkyl group; or lower alkenyl); - (CH)2)oCONR58R59(wherein R is58: lower alkyl, or lower alkenyl; and R59: h; a lower alkyl group; 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: a lower alkyl group; or lower alkenyl); - (CH)2)oSO2R62(wherein R is62: a lower alkyl group; or lower alkenyl); or- (CH)2)qC6H4R8(wherein R is8: h; f; cl; CF; a lower alkyl group; a lower alkenyl group; or lower alkoxy).
-R23: h; a lower alkyl group; a lower alkenyl group; - (CH)2)oOR55(wherein R is55: a lower alkyl group; or lower alkenyl); - (CH)2)oSR56(wherein R is56: a lower alkyl group; or lower alkenyl); - (CH)2)oNR33R34(wherein R is33: a lower alkyl group; or lower alkenyl; r34: h; or lower alkyl; or R33And R34Together 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)oOCONR33R75(wherein R is33: h; or lower alkyl; or lower alkenyl; r75: a lower alkyl group; or R33And R75Together form: - (CH)2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-; or
-(CH2)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
-(CH2)2NR57(CH2)2-; wherein R is57: h; or lower alkyl); - (CH)2)oN(R20)COR64(wherein: R20: h; or lower alkyl; r64: a lower alkyl group; or lower alkenyl); of particular interest are NR20CO lower alkyl (R)20H; or lower alkyl); - (CH)2)oCOOR57(wherein R is57: a lower alkyl group; or lower alkenyl);
-(CH2)oCONR58R59(wherein R is58: lower alkyl, or lower alkenyl; and R59: h; a lower alkyl group; or R58And R59Together form: - (CH)2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-; or
-(CH2)2NR57(CH2)2-; wherein R is57: h; or lower alkyl); - (CH)2)oPO(OR60)2(wherein R is60: a lower alkyl group; or lower alkenyl); - (CH)2)oSO2R62(wherein R is62: a lower alkyl group; or lower alkenyl); or
-(CH2)qC6H4R8(wherein R is8：H；F；Cl；CF3(ii) a A lower alkyl group; a lower alkenyl group; or lower alkoxy);
-R24: a lower alkyl group; a lower alkenyl group; - (CH)2)oOR55(wherein R is55: a lower alkyl group; or lower alkenyl); - (CH)2)oSR56(wherein R is56: a lower alkyl group; or lower alkenyl); - (CH)2)oNR33R34(wherein R is33: a lower alkyl group; or lower alkenyl; r34: h; or lower alkyl; or R33And R34Together 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)oOCONR33R75(wherein R is33: h; or lower alkyl; or lower alkenyl; r75: a lower alkyl group; or R33And R75Together form: - (CH)2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-; or
-(CH2)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
-(CH2)2NR57(CH2)2-; wherein R is57: h; or lower alkyl); - (CH)2)oN(R20)COR64(wherein: R20: h; or lower alkyl; r64: a lower alkyl group; or lower alkenyl); of particular interest are NR20CO lower alkyl (R)20H; or lower alkyl); - (CH)2)oCOOR57(wherein R is57: a lower alkyl group; or lower alkenyl);
-(CH2)oCONR58R59(wherein R is58: lower alkyl, or lower alkenyl; and R59: h; a lower alkyl group; or R58And R59Together form: - (CH)2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-; or
-(CH2)2NR57(CH2)2-; wherein R is57: h; or lower alkyl); - (CH)2)oPO(OR60)2(wherein R is60: a lower alkyl group; or lower alkenyl); - (CH)2)oSO2R62(wherein R is62: a lower alkyl group; or lower alkenyl); or
-(CH2)qC6H4R8(wherein R is8：H；F；Cl；CF3(ii) a A lower alkyl group; a lower alkenyl group; or lower alkoxy);
-R25: h; a lower alkyl group; a lower alkenyl group; - (CH)2)mOR55(wherein R is55: a lower alkyl group; or lower alkenyl); - (CH)2)mNR33R34(wherein R is33: a lower alkyl group; 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
-(CH2)2NR57(CH2)2-; wherein R is57: h; or lower alkyl); - (CH)2)mOCONR33R75(wherein R is33: h; or lower alkyl; or lower alkenyl; r75: a lower alkyl group; 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);
-(CH2)mNR20CONR33R82(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);
-(CH2)mN(R20)COR64(wherein: R20: h; or lower alkyl; r64: a lower alkyl group; or lower alkenyl);
-(CH2)oCOOR57(wherein R is57: a lower alkyl group; or lower alkenyl); - (CH)2)oCONR58R59(wherein R is58: a lower alkyl group; or lower alkenyl; and R59: h; a lower alkyl group; or R58And R59Together 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: a lower alkyl group; or lower alkenyl); - (CH)2)oSO2R62(wherein R is62: a lower alkyl group; or lower alkenyl); or- (CH)2)qC6H4R8(wherein R is8：H；F；Cl；CF3(ii) a A lower alkyl group; a lower alkenyl group; or lower alkoxy).
-R26: h; a lower alkyl group; a lower alkenyl group; - (CH)2)mOR55(wherein R is55: a lower alkyl group; or lower alkenyl); - (CH)2)mNR33R34(wherein R is33: a lower alkyl group; 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
-(CH2)2NR57(CH2)2-; wherein R is57: h; or lower alkyl); - (CH)2)mOCONR33R75(wherein R is33: h; or lower alkyl; or lower alkenyl; r75: a lower alkyl group; 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);
-(CH2)mNR20CONR33R82(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);
-(CH2)mN(R20)COR64(wherein: R20: h; or lower alkyl; r64: a lower alkyl group; or lower alkenyl);
-(CH2)oCOOR57(wherein R is57: a lower alkyl group; or lower alkenyl); - (CH)2)oCONR58R59(wherein R is58: a lower alkyl group; or lower alkenyl; and R59: h; a lower alkyl group; or R58And R59Together 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: a lower alkyl group; or lower alkenyl); - (CH)2)oSO2R62(wherein R is62: a lower alkyl group; or lower alkenyl); or- (CH)2)qC6H4R8(wherein R is8：H；F；Cl；CF3(ii) a A lower alkyl group; a lower alkenyl group; or lower alkoxy).
-or, 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: a lower alkyl group; or lower alkenyl); - (CH)2)oSR56(wherein R is56: a lower alkyl group; or lower alkenyl); - (CH)2)oNR33R34(wherein R is33: a lower alkyl group; or lower alkenyl; r34: h; or lower alkyl; or R33And R34Together 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)oOCONR33R75(wherein R is33: h; or lower alkyl; or lower alkenyl; r75: a lower alkyl group; or R33And R75Together form: - (CH)2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-; or
-(CH2)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
-(CH2)2NR57(CH2)2-; wherein R is57: h; or lower alkyl); - (CH)2)oN(R20)COR64(wherein: R20: h; or lower alkyl; r64: a lower alkyl group; or lower alkenyl); - (CH)2)oCOOR57(wherein R is57: a lower alkyl group; or lower alkenyl); - (CH)2)oCONR58R59(wherein R is58: lower alkyl, or lower alkenyl; and R59: h; a lower alkyl group; 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); -(CH2)oPO(OR60)2(wherein R is60: a lower alkyl group; or lower alkenyl); - (CH)2)oSO2R62(wherein R is62: a lower alkyl group; or lower alkenyl); or- (CH)2)qC6H4R8(wherein R is8：H；F；Cl；CF3(ii) a A lower alkyl group; a lower alkenyl group; or lower alkoxy).
-R28: a lower alkyl group; a lower alkenyl group; - (CH)2)oOR55(wherein R is55: a lower alkyl group; or lower alkenyl); - (CH)2)oSR56(wherein R is56: a lower alkyl group; or lower alkenyl); - (CH)2)oNR33R34(wherein R is33: a lower alkyl group; or lower alkenyl; r34: h; or lower alkyl; or R33And R34Together 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)oOCONR33R75(wherein R is33: h; or lower alkyl; or lower alkenyl; r75: a lower alkyl group; or R33And R75Together form: - (CH)2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-; or
-(CH2)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 is low inAn alkyl group; or R33And R82Together form: - (CH)2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-; or
-(CH2)2NR57(CH2)2-; wherein R is57: h; or lower alkyl); - (CH)2)oN(R20)COR64(wherein: R20: h; or lower alkyl; r64: a lower alkyl group; or lower alkenyl); - (CH)2)oCOOR57(wherein R is57: a lower alkyl group; or lower alkenyl); - (CH)2)oCONR58R59(wherein R is58: lower alkyl, or lower alkenyl; and R59: h; a lower alkyl group; 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: a lower alkyl group; or lower alkenyl); - (CH)2)oSO2R62(wherein R is62: a lower alkyl group; or lower alkenyl); or- (CH)2)qC6H4R8(wherein R is8：H；F；Cl；CF3(ii) a A lower alkyl group; a lower alkenyl group; or lower alkoxy).
-R29: a lower alkyl group; a lower alkenyl group; - (CH)2)oOR55(wherein R is55: a lower alkyl group; or lower alkenyl); - (CH)2)oSR56(wherein R is56: a lower alkyl group; or lower alkenyl); - (CH)2)oNR33R34(wherein R is33: low gradeAn alkyl group; or lower alkenyl; r34: h; or lower alkyl; or R33And R34Together 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)oOCONR33R75(wherein R is33: h; or lower alkyl; or lower alkenyl; r75: a lower alkyl group; or R33And R75Together form: - (CH)2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-; or
-(CH2)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
-(CH2)2NR57(CH2)2-; wherein R is57: h; or lower alkyl); - (CH)2)oN(R20)COR64(wherein: R20: h; or lower alkyl; r64: a lower alkyl group; or lower alkenyl); of particular interest are NR20CO lower alkyl (R)20H; or lower alkyl); - (CH)2)oCOOR57(wherein R is57: a lower alkyl group; or lower alkenyl);
-(CH2)oCONR58R59(wherein R is58: lower alkyl, or lower alkenyl; and R59: h; a lower alkyl group; or R58And R59Together form: - (CH)2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-; or
-(CH2)2NR57(CH2)2-; wherein R is57: h; or lower alkyl); - (CH)2)oPO(OR60)2(wherein R is60: a lower alkyl group; or lower alkenyl); - (CH)2)oSO2R62(wherein R is62: a lower alkyl group; or lower alkenyl); or
-(CH2)qC6H4R8(wherein R is8：H；F；Cl；CF3(ii) a A lower alkyl group; a lower alkenyl group; or lower alkoxy).
For templates (b) through (p), such as (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: a lower alkyl group; or lower alkenyl); - (CH)2)oSR56(wherein R is56: a lower alkyl group; or lower alkenyl); - (CH)2)oNR33R34(wherein R is33: a lower alkyl group; 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: a lower alkyl group; 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);
-(CH2)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);
-(CH2)oN(R20)COR64(wherein: R20: h; or lower alkyl; r64: a lower alkyl group; or lower alkenyl);
-(CH2)oCOOR57(wherein R is57: a lower alkyl group; or lower alkenyl); - (CH)2)oCONR58R59(wherein R is58: a lower alkyl group; or lower alkenyl; and R59: h; or lower alkyl; or R58And R59Together 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: a lower alkyl group; or lower alkenyl); - (CH)2)oSO2R62(wherein R is62: a lower alkyl group; or lower alkenyl); or- (CH)2)qC6H4R8(wherein R is8：H；F；Cl；CF3(ii) a A lower alkyl group; a lower alkenyl group; or lower alkoxy).
-R20: h; or a lower alkyl group.
-R30: h, methyl.
-R33: h; a lower alkyl group; a lower alkenyl group; - (CH)2)pOR55(wherein R is55: a lower alkyl group; or lower alkenyl); - (CH)2)pNR33R34(wherein R is33: a lower alkyl group; 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
-(CH2)2NR57(CH2)2-; wherein R is57: h; or lower alkyl); - (CH)2)pOCONR33R75(wherein R is33: h; or lower alkyl; or lower alkenyl; r75: a lower alkyl group; 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);
-(CH2)pNR20CONR33R82(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);
-(CH2)pN(R20)COR64(wherein: R20: h; or lower alkyl; r64: a lower alkyl group; or lower alkenyl);
-(CH2)oCOOR57(wherein R is57: a lower alkyl group; or lower alkenyl); (-CH)2)oCONR58R59(wherein R is58: lower alkyl, or lower alkenyl; and R59: h; a lower alkyl group; or R58And R59Together 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: a lower alkyl group; or lower alkenyl); - (CH)2)oSO2R62(wherein R is62: a lower alkyl group; or lower alkenyl); or- (CH)2)rC6H4R8(wherein R is8：H；F；Cl；CF3(ii) a A lower alkyl group; a lower alkenyl group; or lower alkoxy); most preferred is-CH2CONR58R59(R58: h; or lower alkyl; r59: a lower alkyl group; or is low inAlkenyl).
-R32: h, methyl.
-R33: a lower alkyl group; a lower alkenyl group; - (CH)2)mOR55(wherein R is55: a lower alkyl group; or lower alkenyl); - (CH)2)mNR34R63(wherein R is34: a lower alkyl group; or lower alkenyl; r63: h; or lower alkyl; or R34And R63Together form: - (CH)2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-; or
-(CH2)2NR57(CH2)2-; wherein R is57: h; or lower alkyl); (CH)2)mOCONR75R82(wherein R is75: a lower alkyl group; or lower alkenyl; r82: h; or lower alkyl; or R75And 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);
-(CH2)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);
-(CH2)mN(R20)COR64(wherein: R20: h; or lower alkyl; r64: a lower alkyl group; or lower alkenyl);
-(CH2)oCOOR57(wherein R is57: a lower alkyl group; or lower alkenyl); - (CH)2)oCONR58R59(wherein R is58: a lower alkyl group; or lower alkenyl; and R59: h; a lower alkyl group; or R58And R59Together 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).
-R34: h; or a lower alkyl group.
-R35: h; a lower alkyl group; a lower alkenyl group; - (CH)2)mOR55(wherein R is55: a lower alkyl group; or lower alkenyl); - (CH)2)mNR33R34(wherein R is33: a lower alkyl group; 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
-(CH2)2NR57(CH2)2-; wherein R is57: h; or lower alkyl); - (CH)2)mOCONR33R75(wherein R is33: h; or lower alkyl; or lower alkenyl; r75: a lower alkyl group; or R33And R75Are formed together：-(CH2)2-6-；
-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-; or- (CH)2)2NR57(CH2)2-; wherein R is57: h; or lower alkyl);
-(CH2)mNR20CONR33R82(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);
-(CH2)mN(R20)COR64(wherein: R20: h; or lower alkyl; r64: a lower alkyl group; or lower alkenyl);
-(CH2)oCOOR57(wherein R is57: a lower alkyl group; or lower alkenyl); - (CH)2)oCONR58R59(wherein R is58: a lower alkyl group; or lower alkenyl; and R59: h; a lower alkyl group; or R58And R59Together 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).
-R36: a lower alkyl group; low gradeAn alkenyl group; or aryl-lower alkyl.
-R37: h; a lower alkyl group; a lower alkenyl group; - (CH)2)pOR55(wherein R is55: a lower alkyl group; or lower alkenyl); - (CH)2)pNR33R34(wherein R is33: a lower alkyl group; 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
-(CH2)2NR57(CH2)2-; wherein R is57: h; or lower alkyl); - (CH)2)pOCONR33R75(wherein R is33: h; or lower alkyl; or lower alkenyl; r75: a lower alkyl group; 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);
-(CH2)pNR20CONR33R82(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);
-(CH2)pN(R20)COR64(wherein: R20: h; or lower alkyl; r64: a lower alkyl group; or lower alkenyl);
-(CH2)oCOOR57(wherein R is57: a lower alkyl group; or lower alkenyl); - (CH)2)oCONR58R59(wherein R is58: lower alkyl, or lower alkenyl; and R59: h; a lower alkyl group; or R58And R59Together 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: a lower alkyl group; or lower alkenyl); - (CH)2)oSO2R62(wherein R is62: a lower alkyl group; or lower alkenyl); or- (CH)2)qC6H4R8(wherein R is8：H；F；Cl；CF3(ii) a A lower alkyl group; a lower alkenyl group; or lower alkoxy).
-R38: h; a lower alkyl group; a lower alkenyl group; - (CH)2)pOR55(wherein R is55: a lower alkyl group; or lower alkenyl); - (CH)2)pNR33R34(wherein R is33: a lower alkyl group; 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
-(CH2)2NR57(CH2)2-; wherein R is57: h; or lower alkyl);-(CH2)pOCONR33R75(wherein R is33: h; or lower alkyl; or lower alkenyl; r75: a lower alkyl group; or R33And R78Together 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)pNR20CONR33R82(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);
-(CH2)pN(R20)COR64(wherein: R20: h; or lower alkyl; r64: a lower alkyl group; or lower alkenyl);
-(CH2)oCOOR57(wherein R is57: a lower alkyl group; or lower alkenyl); - (CH)2)oCONR58R59(wherein R is58: lower alkyl, or lower alkenyl; and R59: h; a lower alkyl group; or R58And R59Together 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: a lower alkyl group; or lower alkenyl); - (CH)2)oSO2R62(wherein R is62: a lower alkyl group; or lower alkenyl); or- (CH)2)qC6H4R8(wherein R is8：H；F；Cl；CF3(ii) a A lower alkyl group; a lower alkenyl group; or lower alkoxy).
-R39: h; a lower alkyl group; a lower alkenyl group; - (CH)2)mOR55(wherein R is55: a lower alkyl group; or lower alkenyl); - (CH)2)mN(R20)COR64(wherein: R20: h; or lower alkyl; r64: a lower alkyl group; or lower alkenyl); - (CH)2)oCOOR57(wherein R is57: a lower alkyl group; or lower alkenyl); - (CH)2)oCONR58R59(wherein R is58: a lower alkyl group; or lower alkenyl; and R59: h; a lower alkyl group; 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).
-R40: a lower alkyl group; a lower alkenyl group; or aryl-lower alkyl.
-R41: h; a lower alkyl group; a lower alkenyl group; - (CH)2)pOR55(wherein R is55: a lower alkyl group; or lower alkenyl); - (CH)2)pNR33R34(wherein R is33: a lower alkyl group; 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
-(CH2)2NR57(CH2)2-; wherein R is57: h; or lower alkyl); - (CH)2)pOCONR33R75(wherein R is33: h; or lower alkyl; or lower alkenyl; r75: a lower alkyl group; 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);
-(CH2)pNR20CONR33R82(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);
-(CH2)pN(R20)COR64(wherein: R20: h; or lower alkyl; r64: a lower alkyl group; or lower alkenyl);
-(CH2)oCOOR57(wherein R is57: a lower alkyl group; or lower alkenyl); - (CH)2)oCONR58R59(wherein R is58: lower alkyl, or lower alkenyl; and R59: h; a lower alkyl group; or R58And R59Together 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: a lower alkyl group; or lower alkenyl); - (CH)2)oSO2R62(wherein R is62: a lower alkyl group; or lower alkenyl); or- (CH)2)qC6H4R8(wherein R is8：H；F；Cl；CF3(ii) a A lower alkyl group; a lower alkenyl group; or lower alkoxy).
-R42: h; a lower alkyl group; a lower alkenyl group; - (CH)2)pOR55(wherein R is55: a lower alkyl group; or lower alkenyl); - (CH)2)pNR33R34(wherein R is33: a lower alkyl group; 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
-(CH2)2NR57(CH2)2-; wherein R is57: h; or lower alkyl); - (CH)2)pOCONR33R75(wherein R is33: h; or lower alkyl; or lower alkenyl; r75: a lower alkyl group; 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);
-(CH2)pNR20CONR33R82(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);
-(CH2)pN(R20)COR64(wherein: R20: h; or lower alkyl; r64: a lower alkyl group; or lower alkenyl);
-(CH2)oCOOR57(wherein R is57: a lower alkyl group; or lower alkenyl); - (CH)2)oCONR58R59(wherein R is58: lower alkyl, or lower alkenyl; and R59: h; a lower alkyl group; or R58And R59Together 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: a lower alkyl group; or lower alkenyl); - (CH)2)oSO2R62(wherein R is62: a lower alkyl group; or lower alkenyl); or- (CH)2)qC6H4R8(wherein R is8：H；F；Cl；CF3(ii) a A lower alkyl group; a lower alkenyl group; or lower alkoxy).
-R43: h; a lower alkyl group; a lower alkenyl group; - (CH)2)mOR55(wherein R is55: a lower alkyl group; or lower alkenyl); - (CH)2)mSR56(wherein R is56: a lower alkyl group; or lower alkenyl); - (CH)2)mNR33R34(wherein R is33: a lower alkyl group; or lower alkenyl; r34: h; or lower alkyl; or R33And R34Together 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)mOCONR33R75(wherein R is33: h; or lower alkyl; or lower alkenyl; r75: a lower alkyl group; or R33And R75Together form: - (CH)2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-; or
-(CH2)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 R82Together form: - (CH)2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-; or
-(CH2)2NR57(CH2)2-; wherein R is57: h; or lower alkyl); - (CH)2)mN(R20)COR64(wherein: R20: h; or lower alkyl; r64: a lower alkyl group; or lower alkenyl); - (CH)2)oCOOR57(wherein R is57: a lower alkyl group; or lower alkenyl); - (CH)2)oCONR58R59(wherein R is58: a lower alkyl group; or lower alkenyl; and R59: h; a lower alkyl group; 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: a lower alkyl group; or lower alkenyl); - (CH)2)oSO2R62(wherein R is62: a lower alkyl group; or lower alkenyl); or- (CH)2)qC6H4R8(wherein R is8：H；F；Cl；CF3(ii) a A lower alkyl group; a lower alkenyl group; or lower alkoxy).
-R44: a lower alkyl group; a lower alkenyl group; - (CH)2)pOR55(wherein R is55: a lower alkyl group; or lower alkenyl); - (CH)2)pSR56(wherein R is56: a lower alkyl group; or lower alkenyl); - (CH)2)pNR33R34(wherein R is33: a lower alkyl group; or lower alkenyl; r34: h; or lower alkyl; or R33And R34Together 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)pOCONR33R75(wherein R is33: h; or lower alkyl; or lower alkenyl; r75: a lower alkyl group; or R33And R78Together form: - (CH)2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-; or
-(CH2)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 R82Together form: - (CH)2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-; or
-(CH2)2NR57(CH2)2-; wherein R is57: h; or lower alkyl); - (CH)2)pN(R20)COR64(wherein: R20: h; or lower alkyl; r64: a lower alkyl group; or lower alkenyl); - (CH)2)pCOOR57(wherein R is57: a lower alkyl group; or lower alkenyl); - (CH)2)pCONR58R59(wherein R is58: a lower alkyl group; or lower alkenyl; and R59: h; a lower alkyl group; 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); or- (CH)2)oC6H4R8(wherein R is8：H；F；Cl；CF3(ii) a A lower alkyl group; a lower alkenyl group; or lower alkoxy).
-R45: h; a lower alkyl group; a lower alkenyl group; - (CH)2)oOR55(wherein R is55: a lower alkyl group; or lower alkenyl); - (CH)2)oSR56(wherein R is56: a lower alkyl group; or lower alkenyl); - (CH)2)oNR33R34(wherein R is33: a lower alkyl group; or lower alkenyl; r34: h; or lower alkyl; or R33And R34Together 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)sOCONR33R75(wherein R is33: h; or lower alkyl; or lower alkenyl; r75: a lower alkyl group; or R33And R75Together form: - (CH)2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-; or
-(CH2)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
-(CH2)2NR57(CH2)2-; wherein R is57: h; or lower alkyl); - (CH)2)oN(R20)COR64(wherein: R20: h; or lower alkyl; r64: a lower alkyl group; or lower alkenyl); - (CH)2)oCOOR57(wherein R is57: a lower alkyl group; or lower alkenyl); - (CH)2)oCONR58R59(wherein R is58: a lower alkyl group; or lower alkenyl; and R59: h; a lower alkyl group; 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); or- (CH)2)sC6H4R8(wherein R is8：H；F；Cl；CF3(ii) a A lower alkyl group; a lower alkenyl group; or lower alkoxy).
-R46: h; a lower alkyl group; a lower alkenyl group; - (CH)2)sOR55(wherein R is55: a lower alkyl group; or lower alkenyl); - (CH)2)sSR56(wherein R is56: a lower alkyl group; or lower alkenyl); - (CH)2)sNR33R34(wherein R is33: a lower alkyl group; or lower alkenyl; r34: h; or lower alkyl; or R33And R34Together 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)sOCONR33R75(wherein R is33: h; or lower alkyl; or lower alkenyl; r75: a lower alkyl group; or R33And R75Together form: - (CH)2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-; or
-(CH2)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
-(CH2)2NR57(CH2)2-; wherein R is57: h; or lower alkyl); - (CH)2)sN(R20)COR64(wherein: R20: h; or lower alkyl; r64: a lower alkyl group; or lower alkenyl); - (CH)2)oCOOR57(wherein R is57: a lower alkyl group; or lower alkenyl); - (CH)2)oCONR58R59(wherein R is58: a lower alkyl group; or lower alkenyl; and R59: h; a lower alkyl group; 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); or- (CH)2)sC6H4R8(wherein R is8：H；F；Cl；CF3(ii) a A lower alkyl group; a lower alkenyl group; or lower alkoxy).
-R47: h; OR OR55(wherein R is55: a lower alkyl group; or lower alkenyl).
-R48: h; or a lower alkyl group.
-R49: h; a lower alkyl group; - (CH)2)oCOOR57(wherein R is57: a lower alkyl group; or lower alkenyl);
-(CH2)oCONR58R59(wherein R is58: a lower alkyl group; or lower alkenyl; and R59: h; a lower alkyl group; or R58And R59Together form: - (CH)2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-; or
-(CH2)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; a lower alkenyl group; or lower alkoxy).
-R50: h; a methyl group.
-R51: h; a lower alkyl group; a lower alkenyl group; - (CH)2)mOR55(wherein R is55: a lower alkyl group; or lower alkenyl); - (CH)2)mNR33R34(wherein R is33: a lower alkyl group; 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
-(CH2)2NR57(CH2)2-; wherein R is57: h; or lower alkyl); (CH)2)mOCONR33R75(wherein R is33: h; or lower alkyl; or lower alkenyl; r75: a lower alkyl group; 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);
-(CH2)mNR20CONR33R82(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);
-(CH2)mN(R20)COR64(wherein: R20: h; or lower alkyl; r64: a lower alkyl group; or lower alkenyl);
-(CH2)pCOOR57(wherein R is57: a lower alkyl group; or lower alkenyl); - (CH)2)pCONR58R59(wherein R is58: a lower alkyl group; or lower alkenyl; and R59: h; a lower alkyl group; or R58And R59Together 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); or- (CH)2)rC6H4R8(wherein R is8：H；F；Cl；CF3(ii) a A lower alkyl group; a lower alkenyl group; or lower alkoxy).
-R52: h; a lower alkyl group; a lower alkenyl group; - (CH)2)mOR55(wherein R is55: a lower alkyl group; or lower alkenyl); - (CH)2)mNR33R34(wherein R is33: a lower alkyl group; 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
-(CH2)2NR57(CH2)2-; wherein R is57: h; or lower alkyl); - (CH)2)mOCONR33R75(wherein R is33: h; or lower alkyl; or lower alkenyl; r75: a lower alkyl group; 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);
-(CH2)mNR20CONR33R82(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-；R57: h; or lower alkyl);
-(CH2)mN(R20)COR64(wherein: R20: h; or lower alkyl; r64: a lower alkyl group; or lower alkenyl);
-(CH2)pCOOR57(wherein R is57: a lower alkyl group; or lower alkenyl); - (CH)2)pCONR58R59(wherein R is58: a lower alkyl group; or lower alkenyl; and R59: h; a lower alkyl group; or R58And R59Together 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); or- (CH)2)rC6H4R8(wherein R is8：H：F；Cl；CF3(ii) a A lower alkyl group; a lower alkenyl group; or lower alkoxy).
-R53: h; a lower alkyl group; a lower alkenyl group; - (CH)2)mOR55(wherein R is55: a lower alkyl group; or lower alkenyl); - (CH)2)mNR33R34(wherein R is33: a lower alkyl group; 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
-(CH2)2NR57(CH2)2-; wherein R is57: h; or lower alkyl); - (CH)2)mOCONR33R75(wherein R is33: h; or lower alkyl; or lower alkenyl; r75: a lower alkyl group; 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);
-(CH2)mNR20CONR33R82(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);
-(CH2)mN(R20)COR64(wherein: R20: h; or lower alkyl; r64: a lower alkyl group; or lower alkenyl);
-(CH2)pCOOR57(wherein R is57: a lower alkyl group; or lower alkenyl); - (CH)2)pCONR58R59(wherein R is58: a lower alkyl group; or lower alkenesA group; and R59: h; a lower alkyl group; or R58And R59Together 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); or- (CH)2)rC6H4R8(wherein R is8：H；F；Cl；CF3(ii) a A lower alkyl group; a lower alkenyl group; or lower alkoxy).
-R54: a lower alkyl group; a lower alkenyl group; or aryl-lower alkyl.
Among the structural units a70 to a104, the following are preferred: a74 (R)22Is H), A75, A76, A77 (R)22Is H), a78 and a 79.
The structural units-B-CO-in templates (a1) and (a2) represent L-amino acid residues. Preferred values for B are: -NR20CH(R71) And a radical A5 (R)2Is H), A8, A22, A25, A38 (R)2Is H), the enantiomers of a42, a47, and a 50. Most preferred 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
Ala L-alanine
Ser L-serine
Thr L-threonine
Trp L-tryptophan
Tyr L-tyrosine
Val L-valine
Cit L-citrulline
Orn L-ornithine
tBuA L-t-butylalanine
Sar Sarcosine
t-BuG L-tert-butylglycine
4AmPhe L-p-aminophenylalanine
3AmPhe L-m-aminophenylalanine
2AmPhe L-o-aminophenylalanine
Phe(mC(NH)＝NH) L-m-amidinophenylalanine
Phe(pC(NH)＝NH) L-p-amidinophenylalanine
Phe(mNHC(NH)＝NH) L-meta-guanidinophenylalanine
Phe(pNHC(NH)＝NH) L-p-guanidinophenylalanine
Phg L-phenylglycine
Cha L-Cyclohexylalanine
Cal L-3-Cyclobutylalanine
Ala L-alanine
Cal 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
3，4Cl-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
ABu L-2, 4-diaminobutyric acid
Dbu (S) -2, 3-diaminobutyric acid
Abu Gamma-aminobutyric acid (GABA)
Ala L-alanine
Aha Epsilon-aminocaproic acid
Aib Alpha-aminoisobutyric acid
Y(Bzl) L-O-benzyltyrosine
Bip L-Biphenylalanine (L-Biphenylalanine)
S(Bzl) L-O-benzylserine
T(Bzl) L-O-benzylthreonine
hCha 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-2-piperidinoic 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
Ala L-alanine
MeLeu L-N-methylleucine
In addition, the most preferred values of B also include groups of the kind 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; especially those radicals in which 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).
The peptide chain Z of the β -hairpin mimetics described herein is generally defined in terms of amino acid residues belonging to one of the following classes:
the class C-NR20CH(R72) CO-; "hydrophobic: small to medium size
The species D-NR20CH(R73) CO-; "hydrophobic: macro-or hetero-aromatic
The species E-NR20CH(R74) CO-; "polar-cationic" and "urea-derived
Class F-NR20CH(R84) CO-; "polar-uncharged
The species H-NR20-CH(CO-)-(CH2)4-7-CH(CO-)-NR20-；
-NR20-CH(CO-)-(CH2)pS(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
In addition, the amino acid residues in the chain Z can also have the formula-A-CO-or have the formula-B-CO-, in which A and B are as defined above. Finally, Gly may also be an amino acid residue in chain Z, and Pro may also be an amino acid residue in chain Z, except for positions where an interchain linkage (H) may be present.
Class C includes those according to the para-substituent R72Has a small to medium size hydrophobic side chain group. Hydrophobic residues refer to amino acid side chains that are uncharged at physiological pH and are repelled by aqueous solutions. In addition, these side chains generally do not contain hydrogen bondsDonor 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. They may contain hydrogen bond acceptor groups such as ethers, thioethers, esters, tertiary amides, alkyl-or arylphosphonates and phosphates or tertiary amines. Genes encode small to medium size amino acids including alanine, isoleucine, leucine, methionine and valine.
Class D includes those according to the substituent R73Have aromatic and heteroaromatic side chain groups. An aromatic amino acid residue refers to a hydrophobic amino acid having a side chain comprising at least one ring with a conjugated pi-electron system (aromatic group). They may additionally 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 arylphosphonate-and phosphates or tertiary amines. Aromatic amino acids encoded by the gene include phenylalanine and tyrosine.
Heteroaromatic amino acid residues are referred to in terms of the para-substituent R77Has a side chain comprising at least one ring having a conjugated pi-system into which at least one heteroatom such as, but not limited to, O, S and N is introduced. In addition, such 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, phosphates, 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. The gene encodes heteroaromatic amino acids including tryptophan and histidine.
Class E includes those according to the para-substituent R74Contains amino acids with side chains of polar-cationic, amido-and urea-derived residues. Polar-cationic refers to a basic side chain that is protonated at physiological pH. Gene-encoded polar-cationic amino groupsAcids include arginine, lysine and histidine. Citrulline is an example of a urea-derived amino acid residue.
Class F includes the substituents R84The general definition of (a) includes amino acids having side chains of polar-uncharged residues. Polar-uncharged residues refer to hydrophilic side chains that are uncharged at physiological pH, but are 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 arylphosphonate-and phosphate esters or tertiary amines. The polar-uncharged amino acids encoded by the gene include asparagine, cysteine, glutamine, serine and threonine.
Class H comprises the side chains of preferred (L) -amino acids at opposite positions of the β -strand region where interchain bonds can be formed. The most common bond is a disulfide bridge formed by cysteine and homocysteine located in opposite positions of the beta-strand. Various methods are known for forming disulfide bonds, including those described below: tam et al, Synthesis, 1979, 955-957; 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, peptide, pages 164-. Most advantageously, for the purposes of the present invention, disulfide bonds can be made using an acetamidomethyl (Acm) -protecting group (for cysteine). One well-defined interchain linkage is the formation of amide bonds linking ornithine and lysine, respectively, at opposite β -strand positions to glutamic and aspartic acid residues. Preferred protecting groups for the side chain amino-groups of ornithine and lysine are allyloxycarbonyl (Alloc) and allyl esters for aspartic acid and glutamic acid. Finally, interchain linkages may also be established by linking the amino groups of lysine and ornithine located at opposite β -strand positions with a reagent such as N, N-carbonyl imidazole to form a cyclic urea.
As previously mentioned, the positions of the interchain bonds are the P4 and P9 positions together; and/or P2 and P11. These interchain linkages are known to stabilize the β -hairpin conformation and thus constitute an important structural component for the design of β -hairpin mimetics.
The most preferred amino acid residues in the chain Z are those derived from natural alpha-amino acids. The following list of amino acids which are suitable for use in the invention per se or residues thereof, where the abbreviations correspond to the commonly used convention:
other α -amino acids which are suitable for use in the present invention by themselves or in their residues include:
particularly preferred residues of class C are:
ala L-alanine Ile L-isoleucine Leu L-leucine Met L-methionine Val L-valine tBuA L-t-butylalanine t-BuG L-tert-butylglycine Cha L-cyclohexylalanine Cal L-3-Cyclobutylalanine Cal L-3-Cyclopentylalanine Nle L-norleucine hRha L-homocyclohexylAlanine OctG L-octylglycine MePhe L-N-methylphenylalanine MeNle L-N-methylnorleucine MeAla L-N-methylalanine MeIle L-N-methylisoleucine MeVal L-N-methylvaline MeLeu L-N-methylleucine
Particularly preferred residues of class D 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, 4Cl-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-homophenylalanine Bpa L-4-benzoylphenylalanine
Particularly preferred residues of class E are
Arg L-arginine Lys L-lysine Orn L-ornithine Dpr L-2, 3-diaminopropionic acid ABu L-2, 4-diaminobutyric acid Dbu (S) -2, 3-diaminobutyric acid Phe (pNH)) L-p-aminophenylalanine Phe (mNH)) L-m-aminophenylalanine, Phe (oNH)) L-o-aminophenylalanine hArg L-homoarginine Phe (mC (NH)) Phe (pC (NH) L-m-amidinophenylalanine) Phe (mnch (NH) L-p-amidinophenylalanine) Phe (pnch (NH) L-m-guanidinophenylalanine) (NH) L-p-guanidinophenylalanine Cit L-citrulline
Particularly preferred residues of class F are
Asn L-asparagine Cys L-cysteine Gln L-glutamine Ser L-serine Thr L-threonine Cit L-citrulline Pen L-penicillamine AcLys L-N-acetyl lysine hCys L-homocysteine hSer L-homoserine
Typically, the peptide chain Z within the β -hairpin mimetic of the invention comprises 12 amino acid residues. The positions P1-P12 of each amino acid residue in the chain Z are clearly defined as follows: p1 represents the first amino acid in chain Z coupled with its N-terminus to the C-terminus of template (B) - (P) or of a group-B-CO-in template (a1), or of a group-A-CO-in template a2, and P12 represents the last amino acid in chain Z coupled with its C-terminus to the N-terminus of a group-A-CO-in template (B) - (P) or of a group-B-CO-in template (a1), or of a group-B-CO-in template (a 2). The positions P1-P12 preferably contain an amino acid residue belonging to one of the above classes C-F, or of the formula-A-CO-or of the formula-B-CO-, respectively, as follows:
p1: class C or class D or class E or class F;
p2: a species D;
p3: class C;
p4: class E, or class C;
p5: class E, or class F;
p6: class E, or class F, or having the formula-A-CO-;
p7: class E, or class F, or having the formula-B-CO-;
p8: class D, or class C, or class F;
p9: class C, or class E;
p10: class F, or class D, or class C;
p11: class D, or class C, or class F;
p12: class C or class D or class E or class F;
at P6 and P7, the D-isomer is also possible;
provided that
The amino acid residue in position-P4 is of the type C; and/or
The amino acid residue in position-P5 is of the type F; and/or
The amino acid residue in position-P8 is of the type F; and/or
The amino acid residue in position-P9 is of the type C; and/or
The amino acid residue in position-P10 is of the type F; and/or
The amino acid residue in position-P11 is of the type C or F.
Most preferably, the amino acid residues in positions P1 to P12 are:
·P1：Arg；
·P2：Trp；
·P3：Leu；
p4: lys or Val;
·P5：Lys；
·P6：Arg；
·P7：Arg；
·P8：Trp；
p9: leu, Val or Lys;
p10: tyr, Thr, or Gln;
p11: val, Leu, Tyr or Gln; and
·P12：Arg；
provided that
-the amino acid residue in position P4 is Val; and/or
-the amino acid residue in position P9 is Leu or Val; and/or
-the amino acid residue in position P10 is Thr or Gln; and/or
The amino acid residue in position-P11 is Val or Leu or Gln.
Particularly preferred β -peptide mimetics of the present invention include those described in examples 1 to 8.
The methods of the invention may advantageously be carried out as parallel array syntheses (parallel array syntheses) resulting in a library of template-fixed β -hairpin peptidomimetics having the general formula I above. These parallel syntheses yield arrays of many (usually 24-192, typically 96) compounds of formula I in high yields and defined purities, with minimal formation of dimer and polymer by-products. For functionalized solid supports (i.e., solid support plus linker molecule), proper selection of template and cyclization reaction sites therefore plays an important role.
The functionalized solid support is suitably derived from polystyrene crosslinked using preferably 1-5% divinylbenzene; polystyrene coated with polyethylene glycol spacers (Tentagel)R) (ii) a And polyacrylamide resins (see also Obrecht, d.; Villalgordo, j. -M, "solid-supported combinations and parallel syntheses of libraries of small molecular weight compounds", series of tetrahedron organic systems, vol.17, Pergamon, Elsevier Science, 1998).
The solid support is functionalized with a linker, i.e. a bifunctional spacer molecule comprising an anchoring group at one end for attachment to the solid support and a selectively cleavable functional group at the other end 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) butyric acid (HMPB linker), trityl and 2-chlorotrityl.
Preferably, the support is derived from polystyrene cross-linked with (most preferably 1-5%) divinylbenzene and functionalized with 2-chlorotrityl linkers.
If carried out as a parallel array synthesis, the process of the invention may advantageously be carried out as described below, but it will be immediately apparent to the skilled person how these processes may be adjusted as necessary when the synthesis of a single compound of formula I above is required.
The number of reaction vessels (generally 24-192, typically 96) is equal to the total number of compounds to be synthesized by the parallel process, to which 25-1000mg, preferably 100mg, of a suitable functionalized solid support, preferably 1-3% crosslinked polystyrene or tentagel resin, are loaded.
The solvent to be 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), isopropyl alcohol 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 fragments with the development of various linking agents that release the 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 linkers (Sasrin)RLinker, Mergler et al, tetrahedron letters, 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, where the Boc/tBu-group attachment of a protecting group is compatible with the protection scheme. Other linkers suitable for use in the process of the invention include superacid labile 4- (2, 4-dimethoxyphenyl-hydroxymethyl) -phenoxy linker (Rink linker, Rink, h. tetrahedron communication, 1987, 28, 3787-; 4- (4-hydroxymethyl-3-methoxybenzene)Oxy) butyric acid derived linkers (HMPB-linkers,&riniker, peptide, 1991, 1990131), which is also cleaved with 1% TFA/DCM to give peptide fragments containing all acid labile side chain protecting groups; and, in addition, 2-chlorotrityl chloride linker (Barlos et al, tetrahedron letters, 1989, 30, 3943-.
Suitable protecting groups for amino acids and correspondingly for their residues are, for example,
for amino groups (e.g. also present in the side chain of lysine)
Cbz Benzyloxycarbonyl group
Boc Tert-butyloxycarbonyl radical
Fmoc 9-fluorenylmethoxycarbonyl
Alloc Allyloxycarbonyl radical
Teoc Trimethylsilyl ethoxycarbonyl group
Tcc Trichloroethoxycarbonyl
Nps o-nitrophenylsulfonyl;
Trt triphenylmethyl or trityl
For carboxyl groups (as also present in the side chains of aspartic and glutamic acids), where reaction with the alcohol component converts to esters
tBu Tert-butyl radical
Bn Benzyl radical
Me Methyl radical
Ph Phenyl radical
Pac Phenacyl radical
Allyl radical
Tse Trimethylsilylethyl group
Tce Trichloroethyl;
for guanidino groups (as present in the side chain of arginine)
Pmc 2, 2, 5, 7, 8-pentamethylchroman-6-sulfonyl
Ts P-toluenesulfonyl (i.e., p-toluenesulfonyl)
Cbz Benzyloxycarbonyl group
Pbf Pentamethyldihydrobenzofuran-5-sulfonyl
For hydroxyl groups (as present in the side chains of threonine and serine)
tBu Tert-butyl radical
Bn Benzyl radical
Trt Trityl radical
And for thiol groups (as present in the side chain of cysteine)
Acm Acetaminomethyl group
tBu Tert-butyl radical
Bn Benzyl radical
Trt Trityl radical
Mtr 4-methoxytrityl.
The 9-fluorenylmethoxycarbonyl- (Fmoc) -protected amino acid derivative is preferably used as a building block to construct template-fixed beta-hairpin loop mimetics of formula I. For deprotection, i.e. cleavage of the Fmoc group, 20% piperidine (in DMF) or 2% DBU/2% piperidine (in DMF) may be used.
The amount of reactants, i.e. amino acid derivatives, is usually 1-20 equivalents based on the milliequivalents/gram (meq/g) loading of the functionalized solid support initially weighed into the reaction tube (typically 0.1-2.85meq/g for polystyrene resins). Additional equivalents of reactants may be used if necessary to drive the reaction to completion within a reasonable time. The reaction tubes, as well as the holder block and manifold (maniffold) were reinserted into the reservoir block and the device was secured together. A gas flow is initiated through the manifold to provide a controlled environment, such as nitrogen, argon, air, and the like. The gas flow may also be heated or cooled before flowing through the manifold. Heating or cooling of the reaction well is achieved by heating the reaction zone or external cooling with isopropanol/dry ice and the like to achieve the desired synthesis reaction. Agitation is achieved by shaking or magnetic stirring (within the reaction tube). Preferred workstations, but not limited to, are Labsource's Combi-chemstation and MultiSyn Tech's-Syro synthesizers.
Amide bond formation requires activation of the alpha-carboxyl group for the acylation step. If the activation is carried out using a customary carbodiimide such as dicyclohexylcarbodiimide (DCC, Sheehan)&Hess, j.am.chem.soc.1955, 77, 1067-1068) or diisopropylcarbodiimide (DIC, saratakis et al, biochem.biophysis.res.commun.1976, 73, 336-342), the dicyclohexylurea obtained being insoluble and diisopropylurea being soluble in the solvents generally used. In one variant of the carbodiimide process, a 1-hydroxybenzotriazole (HOBt,&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 letters, 1975, 14, 1219-; these phosphonium reagents are also suitable for in situ formation of HOBt esters 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 letters, 1994, 35, 2279-.
Since near quantitative coupling reactions are necessary, it is desirable to have experimental evidence of reaction completion. The ninhydrin test (Kaiser et al, analytical biochemistry, 1970, 34, 595) can be performed easily and quickly after each coupling step, where a positive colorimetric response to an aliquot of the resin-bonded peptide qualitatively indicates the presence of a primary amine. Fmoc chemistry enables spectrophotometric detection of Fmoc chromophores upon their release with base (Meienhofer et al, int.J. peptide Protein Res.1979, 13, 35-42).
The resin bonded intermediate within each reaction tube is washed free of excess retained reagent, solvent, and by-products by repeated exposure to pure solvent by one of two methods:
1) the reaction well was filled with solvent (preferably 5ml), the reaction tube and the set of clamps and manifold were immersed and stirred for 5-300 minutes, preferably 15 minutes, and then drained by gravity, followed by removal of the solvent by applying air pressure through the manifold inlet (while closing the outlet);
2) the manifold is removed from the clamp set and an aliquot (preferably 5ml) of the solvent is dispensed through the top of the reaction tube and discharged by gravity through a filter into a receiving container such as a test tube or vial.
The above washing steps are repeated up to about 50 times (preferably about 10 times), wherein the efficiency of removal of the reagents, solvents, and by-products is determined by TLC, GC, or by examining the washings and the like.
The above procedure of reacting the resin-bonded compound with the reagent in the reaction well and then removing excess reagent, byproducts and solvent is repeated for each successive conversion process until the final resin-bonded fully protected linear peptide is obtained.
Before the fully protected linear peptide is detached from the solid support, one or more of the protected functional groups present in the molecule may be optionally deprotected and the reactive groups so liberated suitably substituted, if desired. To this end, the functional group must initially be protected by a protecting group which can be selectively removed without affecting the remaining protecting groups present. Alloc (allyloxycarbonyl) is an example of such a protecting group for an amino group, which can for example make use of Pd0And phenylsilane at CH2Cl2Is selectively removed without affecting the remaining protecting groups present in the molecule, such as Fmoc. The reactive groups so released may then be treated with a reagent suitable for introducing the desired substituent. Thus, for example, an amino group can be acylated with an acylating agent corresponding to the acyl substituent to be introduced.
The separation of the fully protected linear peptide from the solid support is achieved by dipping the reaction tube, as well as the set of clamps and manifold into a reaction well containing a solution of the cleaving reagent (preferably 3-5 ml). Gas flow, temperature control, agitation, and reaction monitoring are as described above and performed as needed to effect the isolation reaction. The reaction tubes, as well as the clamp set and manifold, are disconnected from the reservoir set and raised above the solution level but below the upper lip of the reaction wells, and then air pressure is applied through the manifold inlet (while the outlet is closed) to effectively drain the final product solution into the reservoir wells. The resin remaining in the reaction tube is then washed 2-5 times as above with 3-5ml of a suitable solvent to extract (wash out) as much of the isolated product as possible. The product solutions thus obtained were combined, taking care to avoid cross-mixing. Each solution/extract is then treated 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 reactions in solution.
The solution containing the fully protected linear peptide derivative which has been cleaved from the solid support and neutralized with a base is evaporated. The cyclization reaction is then carried out in solution using solvents such as DCM, DMF, dioxane, THF and the like. Various coupling reagents mentioned earlier may be used for the cyclization reaction. The duration of the cyclization reaction is about 6 to 48 hours, preferably about 24 hours. The progress of the reaction is monitored, for example, by RP-HPLC (reverse phase high performance liquid chromatography). The solvent is then removed by evaporation, the fully protected cyclic peptide derivative is dissolved in a water-immiscible solvent, such as DCM, and the solution is extracted with water or a mixture of water-miscible solvents to remove any excess coupling reagent.
Before the protective group is removed from the fully protected cyclic peptide, interchain bonds between the side chains of suitable amino acid residues can be formed, if desired, at opposite positions in the β -chain region.
Interchain bonds and their formation have been discussed above in explaining groups of class H, for example, may be disulfide bridges formed by cysteine and homocysteine in opposite positions of the B-chain, or glutamic and aspartic acid residues which are linked to ornithine and lysine, respectively, in opposite β -chain positions by amide bond formation. The formation of these interchain bonds can be carried out by methods well known in the art.
Finally, fully protected peptide derivatives of class I were treated with 95% TFA, 2.5% H2O, 2.5% TIS or another combination of scavengers was treated to effect cleavage of the protecting group. The cleavage reaction time is usually 30 minutes to 12 hours, preferably about 2 hours. Most of the TFA was then evaporated and the product was precipitated with ether/hexane (1: 1) or other solvent suitable for this purpose. 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 in the biological analysis, or it must be further purified, for example by preparative HPLC.
The fully deprotected 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 compound of formula I or into a different pharmaceutically acceptable salt, as described above, if desired. Any of these manipulations can be performed by methods well known in the art.
The starting materials for the process of the present invention, the pre-starting materials used therein, and the preparation of these starting and pre-starting materials will now be discussed in detail.
Building blocks of class A can be synthesized according to literature procedures described below. The corresponding amino acids have been described as unprotected or as Boc-or Fmoc-protected racemates, (D) -or (L) -isomers. It will be appreciated that the unprotected amino acid building blocks can be readily converted into the corresponding Fmoc-protected amino acid building blocks required for the present invention by standard protecting group treatment. An overview describing the general process for synthesizing alpha-amino acids includes: r. Duthaler, tetrahedron (reported) 1994, 349, 1540-1650; r.m. williams, "synthesis of optically active α -amino acids", tetrahedral organic chemistry Series (Tetrahedron ovorganic chemistry Series), vol.7, j.e. baldwin, p.d. magnus (Eds.), Pergamon press, Oxford 1989. One method that is particularly useful for the synthesis of optically active alpha-amino acids relevant to the present invention involves kinetic resolution using hydrolases (M.A. Verhovskaya, I.A. Yamskov, Russian chem.Rev.1991, 60, 1163-Across 1179; R.M.Williams, "Synthesis of optically active alpha-amino acids", tetrahedron organic chemistry series, Vol.7, J.E.Baldwin, P.D.Magnus (Eds.), Pergamon Press, Oxford 1989, Chapter 7, p.257-279). Hydrolytic enzymes include amide and nitrile hydrolysis by aminopeptidases or nitrilases, cleavage of N-acyl groups by acyltransferases, and ester hydrolysis by lipases or proteases. It is fully established that certain enzymes specifically lead to the pure (L) -enantiomer, whereas other enzymes give the corresponding (D) -enantiomer (e.g.: R.Duthaler, Tetrahedron Report (Tetrahedron Report)1994, 349, 1540-.
A1: see D.BeN-Ishai, Tetrahedron (Tetrahedron), 1977, 33, 881-; sato, A.P.Kozikowski, tetrahedron letters (tetrahedron Lett.), 1989, 30, 4073-; baldwin, c.n.farthing, a.t.russell, c.j.schofield, a.c.spirey, tetrahedron communication, 1996, 37, 3761-; baldwin, r.m.adlington, n.g.robinson, j.chem.soc.chem.commun.1987, 153-; p.wipf, y.uto, tetrahedral communication, 1999, 40, 5165-; baldwin, R.M.Adlington, A.O 'Neil, A.C.Spirey, J.B.Sweeney, J.chem.Soc.chem.Commun.1989, 1852-E.Baldwin, R.M.Adlington, A.O' Neil, J.C.Spirey, for R.B.Sweeney, J.chem.Soc.chem.Commun.19891＝H，R2＝H)；T.Hiyama，Bull.Chem.Soc.Jpn.1974，47，2909-2910；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.Thijs，B.Zwannenburg，Recl.Trav.Chim.Pays-Bas 1992，111，59-68(R1＝H，R2Hexyl); legtes, l.thijs, b.zwannenburg, recl.trav.chim.pays-Bas 1992, 111, 16-21; G.A. Molander, P.J.Stengel, J.org.chem.1995, 21, 6660-1＝H，R2Ph); funaki, L.Thijs, B.Zwannenburg, tetrahedron, 1996, 52, 9909-1＝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.Acta 1986，69，1442-1460(R2＝CH(OH)CH2OH); m.carduccu, s.fioravanti, m.a.loreto, l.pellacani, p.a.tardella, tetrahedron communication, 1996, 37, 3777-; lakner, l.p.hager, tetrahedron: asymmetry 1997, 21, 3547-3550 (R)1＝Me，R2H, Me); g.a. molander, p.j.stenel, tetrahedron, 1997, 26, 8887-; loreto, F.Pompei, P.A.Tardella, D.Tofani, tetrahedron, 1997, 53, 15853-one 15858 (R.A.Loreto, F.Pompei, P.A.Tardella, D.Tofani, tetrahedron, 1997, 53, 15853-one)1＝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.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，R2H); 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, 4879-1＝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.Vettiger，H.-M.Müller，D.Plattner，W.Petter，Liebigs Ann.Chem.1990，687-695(R1Aryl CH (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.Bly thin，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.bisland, c.weber, j.inglis, c.a.schiffer, w.f.van Gunsteren, j.a.robinson j.am.chem.soc.1995, 117, 7904 (r.bsland, c.weber, j.inglis, c.a.schiffer, w.f.van Gunsteren, j.a.robinson j.am.chem.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.Mesh ulam，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；R23-pyridyl); e.m.khalil, w.j.ojala, a.pradham, v.d.nair, w.b.gleason, j.med.chem.1999, 42, 628 637; khalil, N.L. Subasinge, R.L. Johnson, Tetrahedron Lett.1996, 37, 3441-1Allyl; 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.1987，30，536-541；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.Lewiz，J.Wilkie，T.J.Rutherford，D.Gani，J.Chem.Soc.PerkinTrans.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；R3H); floris, n.terhiuis, h.hiemstra, n.w.speckamp, tetrahedron, 1993, 49, 8605-; 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-; c.e.o' Connell, k.ackermann, c.a.rowell, a.garcia, m.d.lewis, c.e.schwartz, bioorg.med.chem.lett.1999, 9, 2095-; lowe, T.Vilaivan, J.chem.Soc.PerkinTrans.1997, 547-554; bellier, I.McCort-Trancepain, B.Ducos, S.Danascimenta, H.Mundal, J.Med.Chem.1997, 40, 3947-; m.peterson, r.vince j.med.chem.1991, 34, 2787-; e.m. smith, g.f. swiss, b.r. neutadt, e.h. gold, j.a. sommer, j.med.chem.1988, 31, 875-; E.Rubibi, C.Gilon, Z.Selinger, M.Chorev, Tetrahedron 1986, 42, 6039-1＝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，Heterocycles 1996，42，489-492(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；R6Allyl); ohki, chem.pharm.Bull.1976, 24, 1362-1＝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.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，TetrahedronLett.1997，38，3687-3690(R1＝H；R7＝CONH2)；P.P.Waid，G.A.Flynn，E.W.Huber，J.S.Sabol，Tetrahedron Lett.1996，37，4091-4094(R1＝H；R7＝(4-BnO)C6H4)；N.A.Sasaki，R.Pauli，P.Potier，Tetrahedron Lett.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.Angew.Chem.1981，93，272-273(R1＝H；R7Aryl ═ O); H.Mosberg, A.L.Lomi ze, C.Wang, H.Kroona, D.L.Heyl, J.Med.chem.1994, 37, 4371-4383 (R.1＝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.powell, j.m.deftreset, 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；R6Allyl); barralough, P.Hudhomme, C.A.Spray, D.W.Young, Tetrahedron 1995, 51, 4195-1＝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(ii) a Bn; an allyl group; CH (CH)2COOMe)；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.yevich, j.heterocyclic.chem.1984, 21, 1355-; 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.heaton, b.j.chapman, m.guzel, tetrahedron: asymmetry 1997, 8, 3625-3636; 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.Marwa.h，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 made 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 resolution (e.g., lipase); vi: NaOH, MeOH, H2O, heating;
vii：FmocOSu，Na2CO3aq. dioxane, 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.commu.1993, 1434-; Y.Matsumura, Y.Takeshima, H.Ohita, Bull.chem.Soc.Jpn.1994, 67, 304-306 (R)1＝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.dayies, j.chem.soc.perkin Trans 1, 1976, 2390-; bevan, j.chem.soc.c, 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, registration number 648833 (R)1＝R4＝R8H). Such compounds can be prepared according to scheme 2.
Scheme 2
i：NaH，CH2(COOMe)2，DMSO；ii：NaH，R1-X，DMSO；iii：NaOHaq.，MeOH，75°；iv：DBU，Mel，DMF；v：LDA，BocN＝NBoc；vi：TFA，CH2Cl2；vii：CbzCl，Na2CO3aq., dioxane; viii: enzymatic resolution (e.g., lipase); then DBu, Mel, DMF; ix: NaH, R4-X，THF；x：Pd/C，H2，EtOH；xi：LiOHx1H2O，MeOH，H2O；xii：FmocOSu，Na2CO3aq. dioxane, 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.Bull.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.Chem.Commun.1990，1578-1580；D.I.C.Range，N.F.Hayes，D.E.Bays，D.Belton，J.Brain，J.Med.Chem.1992，35，490-501；H.Kessler，M.Kuehn，T.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.D.Leeson, B.J.Williams, R.Baker, T.Ladduwahetty, K.W.Moore, M.Rowley, J.chem.Soc.chem.Comm1＝H；R10＝NHOBn)。
A23: see Beyerman, Boekee, Recl.Trav.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 also the description of the Plieninger,Chem.Ber.1959，92，1579-1584；D.W.Knight，N.Lewis，A.C.Share，D.Haigh，J.Chem.Soc.Perkin Trans.1 1998，22，3673-3684；J.Drummond，G.Johnson，D.G.Nicklel，D.F.Ortwine，R.F.Bruns，B.Welbaum，J.Med.Chem.1989，32，2116-2128；M.P.Moyer，P.L.Feldman，H.Rapoport，J.Org.Chem.1985，50，5223-5230(R1＝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-; 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, 5254-1＝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: NaBH4 or NaCNBH3，MeOH；iv：Boc2O，THF；v：LiOHx1H2O，MeOH，H2O；vi：Pd/C.H2，EtOH；vii：FmocOSu，Na2CO3aq. dioxane, 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-; patel, a. banerjee, r.l.hanson, d.b.brzozowski, l.w.parker, l.j.szarka, tetrahedron: asymmetry 1999, 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.s human, 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 (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.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.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, N-benzoylglycine tert-butyl ester, DMF; ii: NaH, Pd (0), toluene; iii: TFA, CH2Cl2(ii) a iv: polyphosphoric acid; v: naohaq., MeOH, 75 °; then hclaq.; vi: DBU, Mel, DMF; vii: lithium hexamethyl-dililazide, THF, trimethylchlorosilane, -78 °; after R1-x; viii: enzymatic resolution (e.g., lipase); after this time, the product was isolated as the methyl ester: DBU, Mel, DMF; ix: naohaq., MeOH, heat; x: fmocosu, Na2CO3aq. dioxane, dioxane
Scheme 5
i：Boc2O，Na2CO3aq. dioxane, dioxane(ii) a ii: DBU, Mel, DMF; iii: lithium hexamethylisidazide, THF, trimethylchlorosilane, -78 °; after R2-x；iv：LiOHx1H2O，MeOH，H2O；v：TFA，CH2Cl2；vi：FmocOSu，Na2CO3aq. dioxane, dioxane
A32 can be prepared according to the following: 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.vanBinst，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.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.Perkin Trans.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 registration 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-; nicolaou, G. -Q.Shi, K.Namoto, F.Bernal, J.Chem.Soc.Chem.Commun.1998, 1757-1＝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 can be prepared according to scheme 6.
Scheme 6
i：BocNHNH2，NaCNBH3，MeOH，AcOH；ii：CbzCl，Et3N，CH2Cl2；iii：TFA，CH2Cl2(ii) a Then piperidine, DMAP, heat; iv: resolution (e.g., lipase); v: DBU, Mel, DMF; vi: lawesson reagent, toluene, 75 °; vii: DBU, Mel, DMF; viii: NaBH4 or NaCNBH3MeOH; ix: r3 is introduced by reductive amination, alkylation or acylation; x: liohx1H2O，MeOH，H2O；xi：Pd/C，H2，EtOH；xii：FmocOSu，Na2CO3aq. dioxane, dioxane
A41: such compounds may be prepared according to the scheme.
Scheme 7
i: resolution (e.g., lipase); then isolated as methyl ester: DBU, Mel, DMF; ii: NaH, R4-X，THF；iii：LiOHx1H2O，MeOH，H2O；iv：Pd/C，H2，EtOH；v：FmocOSu，Na2CO3aq. dioxane, dioxane
A42-A46: such compounds may be prepared according to schemes 8 to 12. Important 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-.
Scheme 8
i: lithium hexamethylisidazide, THF, trimethylchlorosilane, -78 °; after R5-X; ii: HBr; iii: DBU, Mel, DMF; iv: DIBAL-H, THF; v: EtOH, pyridinium p-toluenesulfonate, molecular sieve 4A; vi: lithium hexamethylisilazide, 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，Na2CO3aq. dioxane
Scheme 9
i: lithium hexamethylisidazide, THF, trimethylchlorosilane, -78 °; after R6-X; ii: HBr; iii: DBU, Mel, DMF; iv: DIBAL-H, THF; v: EtOH, pyridinium p-toluenesulfonate, molecular sieve 4A; vi: lithiumhexamethylisilazide, THF, -78 °, 39; vii: Pd/C, H2EtOH; then DBU, Mel, DMF; then TFA, CH2Cl2: viii: hclaq., THF; then Na (OAc)3BH, AcOH, dichloroethane; viii: boc2O，Et3N，CH2Cl2；ix：Bu4NFx10H2O, THF; ix: pyridinium chlorochromate; x: liohx1H2O，MeOH，H2O；xi：TFA，CH2Cl2；xii：FmocOSu，Na2CO3aq. dioxane, dioxane
Scheme 10
i: HBr; ii: DBU, Mel, DMF; iii: DIBAL-H, THF; iv: EtOH, pyridinium p-toluenesulfonate, molecular sieve 4A; v: lithium hexamethylisidazide, THF, -78 °, 43; vi: Pd/C, H2EtOH; then DBU, Mel, DMF; then TFA, CH2Cl2(ii) a vii: hclaq., THF; then Na (OAc)3BH, AcOH, dichloroethane; viii: liohx1H2O，MeOH，H2O；ix：FmocOSu，Na2CO3aq. dioxane, dioxane
Scheme 11
i: HBr; ii: DBU, Mel, DMF; iii: DIBAL-H, THF; iv: EtOH, pyridinium p-toluenesulfonate, molecular sieve 4A; v: lithium hexamethylisidazide, 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: liohx1H2O，MeOH，H2O；xii：TFA，CH2Cl2；xiii：FmocOSu，Na2CO3aq. dioxane, dioxane
Scheme 12
i: HBr; ii: DBU, Mel, DMF; iii: DIBAL-H, THF; iv: EtOH, pyridinium p-toluenesulfonate, molecular sieve 4A; v: lithium hexamethylisidazide, THF, -78 °, 51; 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: liohx1H2O，MeO H，H2O；xii：TFA，CH2Cl2；xiii：FmocOSu，Na2CO3aq. dioxane, 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 the type A49 may also be present according to the formulaExample 13 is prepared.
Scheme 13
i：NaH，CbzNH(CH2)2Br，THF；ii：Pd/C，H2，EtOH；iii：EDCI，CH2Cl2Diisopropylethylamine; iv: NaH, R12-X，THF；v：LiOHx1H2O，MeOH，H2O；vi：TFA，CH2Cl2：vii：FmocOSu，Na2CO3aq. dioxane, dioxane
A50 and a 51: these classes 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 hexamethylisidazide, THF, -78 °, 59; vi: Pd/C, H2EtOH; then DBU, Mel, DMF; then TFA, CH2Cl2(ii) a vii: hclaq., THF; then Na (OAc)3BH, AcOH, dichloroethane; viii: liohx1H2O，MeOH，H2O；ix：FmocOSu，Na2CO3aq. dioxane, dioxane
Scheme 15
i：HBr；ii：DBU，Mel，DMF；iii：DIBAH，THF；iv：Etioh, pyridinium p-toluenesulfonate, molecular sieve 4A; v: lithium hexamethylisilazide, THF, -78 °, 63 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: liohx1H2O，MeOH，H2O；xii：TFA，CH2Cl2：xiii：FmocOSu，Na2CO3aq. dioxane, 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 hexamethyidisilizide, THF, trimethylchlorosilane, -78 °; after R6-X; iv: naohaq., MeOH, 75 °; then hclaq.; v: DBU, Mel, DMF; vi: lithium hexamethyl-dililazide, THF, trimethylchlorosilane, -78 °; after R7-X; vii: resolution (e.g., lipase); then DBU, Mel, DMF; viii: liohx1H2O，MeOH，H2O；ix：TFA，CH2Cl2；x：FmocOSu，Na2CO3aq. dioxane, 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，Na2CO3aq. dioxane, 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 is heated; iii: resolution (e.g., lipase); iv: DBU, Mel, DMF; v: NaH, R12-X，THF；vi：LiOHx1H2O，MeOH，H2O；vii：TFA，CH2Cl2；viii：FmocOSu，Na2CO3aq. dioxane, dioxane
Scheme 19
i: HBr; ii: DBU, Mel, DMF; iii: DIBAL-H, THF; iv: EtOH, pyridinium p-toluenesulfonate, molecular sieve 4A; v: lithium hexamethyidisilazide，THF，-78°，86；vi：Pd/C，H2EtOH; then DBU, Mel, DMF; then TFA, CH2Cl2(ii) a vii: hclaq., THF; then Na (OAc)3BH, AcOH, dichloroethane; viii: liohx1H2O，MeOH，H2O；ix：FmocOSu，Na2CO3aq. dioxane, dioxane
A57: such compounds may be prepared according to scheme 20.
Scheme 20
i: NaOMe, MeOH; ii: NaH, THF; iii: naohaq., MeOH, 75 °; then hclaq.; iv: DBU, Mel, DMF; v: lithium hexamethylisidazide, THF, trimethylchlorosilane, -78 °; after R1-X; vi: resolution (e.g., lipase); the methyl ester was then isolated: DBU, Mel, DMF; vii: liohx1H2O，MeOH，H2O；viii：TFA，CH2Cl2；ix：FmocOSu，Na2CO3aq. dioxane, 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: naohaq., MeOH, 75 °; then hclaq.; iv: DBU, Mel, DMF; v: lithium hexamethylisidazide, THF, trimethylchlorosilane, -78 °; then R1-X; vi: resolution (e.g., lipase); the methyl ester was then isolated: the number of the DBU is greater than the maximum number of the DBU,Mel，DMF；vii：LiOHx1H2O，MeOH，H2O；viii：TFA，CH2Cl2；ix：FmocOSu，Na2CO3aq. dioxane, 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 (2.2equiv.), R1-X；v：Raney-Ni，H2，EtOH；vi：CbzCl，Et3N，CH2Cl2；vii：NaH，Br(CH2)2Br, THF; viii: resolution (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，Na2CO3aq. dioxane, 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: resolution (e.g., lipase); then DBU, Mel, DMF; ii: lithium hexamethylisidazide, THF, trimethylchlorosilane, -78 °; after R6-X；iii：LiOHx1H2O，MeOH，H2O；iv：TFA，CH2Cl2；v：FmocOSu，Na2CO3aq. dioxane, 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；R8H); beilstein registration number: 459155 (R)1＝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 diazomethane; iv: HBr, CH2Cl2(ii) a v: NaH, THF; vi: naohaq., MeOH, 75 °; then hclaq.; vii: DBU, Mel, DMF; viii: diisopropylamino aluminium, THF, trimethylchlorosilane, -78 °; then R1-X; ix: resolution (e.g., lipase); the methyl ester was then isolated: DBU, Mel, DMF; x: liohx1H2O，MeOH，H2O；xi：TFA，CH2Cl2；xii：FmocOSu，Na2CO3aq. dioxane, dioxane
A65 and a 67: these classes 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, ClCOOMe, THF; v: resolution (e.g., lipase); after this time, the product was isolated as the methyl ester: DBU, Mel, DMF; vi: liohx1H2O，MeOH，H2O；vii：TFA，CH2Cl2；viii：FmocOSu，Na2CO3aq. dioxane, 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, Mel, DMF; vii: lithiumhexamethylisilazide, THF, trimethylchlorosilane, -78 °; after R1-X；viii：Pd/C，H2，EtOH；ix：NaH，THF，R14-X; x: resolution (e.g., lipase); the methyl ester was then isolated: DBU, Mel, DMF; xi: liohx1H2O，MeOH，H2O；xii：TFA，CH2Cl2；xiii：FmocOSu，Na2CO3aq., dioxane a 66: see G.L.Grunewa ld, L.H.Dahanukar, J.heterocyclic.chem.1994, 31, 1609-1＝H；R8＝H，8-NO2；C(1)＝O)。
A68: see Griesbeck, H.Mauder, I.Muller, 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 mentioned above, the structural unit A70 belongs to the open-chain alpha-substituted alpha-amino acids, A71 and A72 to the corresponding beta-amino acid analogs and A73-A104 to the cyclic analogs of A70.
Building blocks of the species A70 and A73-A104 have been synthesized by several different general methods: by [2+2 ] of alkenones with imines]Cycloaddition (I.Ojima, H.J.C.Chen, X.Quin, tetrahedron letters, 1988, 44, 5307-; synthesis of chiral aldol condensation reaction (Y.Ito, M.Sawamura, E.Shirakawa, K.Hayashikazi, T.Hayashi, tetrahedron letters, 1988, 29, 235-152), synthesis of chiral aldol condensation reaction (J.S.Amato, L.M.Weinstock, S.Karady, US 4508921A; M.Gander-Coqoz, D.Seebach, Helv.Chim.acta 1988, 71, 224-236; A.K.Beck, D.Seebach, Chimia 1988, 42, 142-144; Vitd.Seebach, J.D.Aebi, M.124gander-Coqoz, R.Nakaef, Helv.chim. acta 1987, 70, 4-1987; D.Seebach, A.Aca, Fander-Coqoz, R.Nakah, Helv.29-02-68, Schizok.K.68, Schizoff # K.S.S.S.S.K.V.68, S.S.K.D.1988, X.S.S.K.8, S.K.S.8, S.E.S.7, S.K.7, S.E.K.S.S.A.A.S.A.A.S.A.A.A.S.A.A.A.S.A.A.A.A.A.A.A.A.A.A.A.A.A.A.A.A.A.A.A.A.A.A.A.A.A.A.A.A.A.A.A.A.A.A.A.A.A.A.A.A.A.A.A.A.A.A.A.A.A.A.A.A.A.A.A.A.A.A.A.A.A.A.A.A.A.A.A, V.M.Belikov, J.chem.Soc.Perkin Trans.1, 1988, 305-; M.Kolb, J.Barth, Liebigs Ann.Chem.1983, 1668-1688); (U) was synthesized by di-lactonamide ether.Hinrichs, R.Lonsky, Angew.chem.1987, 99, 137-138); the resolution of racemic amino acids by microbial resolution (k.sakashita, i.watanabe, JP 62/253397a2) and by the hydantoin process, in combination with a chiral auxiliary derived from L-phenylalanine amide (d.obrecht, c.spiegler, P.K.Müller，H.Heimgartner，F.Stierli，Helv.Chim.Acta 1992，75，1666-1696；D.Obrecht，U.Bohdal，J.Daly，C.Lehmann，P.K.M uller, tetrahedron, 1995, 51, 10883-; obrecht, c.lehmann, c.ruffieux, P.K.Müller，Helv.Chim.Acta 1995，78，1567-1587；D.Obrecht，U.Bohdal，C.Broger，D.Bur，C.Lehmann，R.Ruffieux，P.C.Spiegler，Helv.Chim.Acta 1995，78，563-580；D.Obrecht，H.Karajiannis，C.Lehmann，P.C.Spiegler，Helv.Chim.Acta 1995，78，703-714；D.Obrecht，M.Altorfer，C.Lehmann，P.K.M muller, J.org.chem.1996, 61, 4080-; obrecht, c.abrecht, m.altorfer, u.bohdal, a.grieder, p.pfyffer, k.muller, helv.chim.acta1996, 79, 1315-. The latter process is particularly useful for preparing enantiomers in pure form of the building blocks of the classes A70 (see scheme 27) and A73-A104 (see scheme 28).
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 cyclohexylamide, N-methylpyrrolidone, 70 °; vi: CH (CH)3SO3H，MeOH，80°；vii：6N HClaq., dioxane, 100 °; viii: me3SiCl，DIEA，CH2Cl2(ii) a Then FmocCl
The method depicted in scheme 27 comprises reacting the appropriate ketone 126 with KCN, (NH)4)2CO3Treatment in an ethanol/water mixture (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.chem.1971, 1175) gives the corresponding hydantoin 127 which is then treated with Ba (OH)2Hydrolysis in water at 120-. Schotten-Baumann acylation (HoubeN-Weyl, 'methodder Organischen Chemie', volume XI/2, sticktoff-verbindngen IIund III ', Georg Tieme Verlag, Stuttgart, pp 339), followed by cyclization with N, N' -dicyclohexylcarbodiimide to give azlactone 129(d.obrecht, u.bohdal, c.broger, d.bur, c.lehmann, r.ruffiex, P).C.Spiegler，Helv.Chim.Acta 1995，78，563-580；D.Obrecht，C.Spiegler，P.K.M muller, H.Heimgartner, F.Stierli, Helv.Chim.acta 1992, 75, 1666-. Alternatively, azlactone 129 can also be prepared starting from amino acids 130 and 131, by Schotten-Baumann acylation and cyclization with N, N' -dicyclohexylcarbodiimide to azlactone 132 and 133 and alkylation to 129(d.obrecht, u.bohdal, c.broger, d.bur, c.lehmann, r.ruffieux, P).C.Spiegler，Helv.Chim.Acta 1995，78，563-580；D.Obrecht，C.Spiegler，P.K.M muller, H.Heimgartner, F.Stierli, Helv.Chim.acta 1992, 75, 1666-. 129 were treated with L-phenylalanine cyclohexylamide (d.obrecht, u.bohdal, c.broger, d.bur, c.lehmann, r.ruffieux, P.Spiegler, helv, chim. acta 1995, 78, 563-. 134 and 135 were treated with methanesulfonic acid in methanol at 80 deg. to give esters 136a and 136b, which were then converted to the corresponding Fmoc-protected final building blocks 137a and 137 b.
Scheme 28
i：KCN，(NH4)2CO3，EtOH/H2O；ii：Ba(OH)2，H2O; iii: naoh, PhCOCl, dioxane; then DCC, CH2Cl2(ii) a iv: l-phenylalanine cyclohexylamide, N-methylpyrrolidone, 70 °; v: CH (CH)3SO3H, MeOH, 80 °; vi: 6N hclaq., dioxane, 100 °; vii: me3SiCl，DtEA，CH2Cl2；the FmocCl
According to the general procedure described in scheme 28 (d.obrecht, u.bohdal, c.broger, d.bur, c.lehmann, r.ruffieux, P.C.Spiegler，Helv.Chim.Acta 1995，78，563-580；D.Obrecht，C.Spiegler，P.K.M muller, H.Heimgartner, F.Stierli, Helv.Chim.acta 1992, 75, 1666-The corresponding ketone 138 was prepared starting with hydantoin formation (139) (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.chem.1971, 1175; d.obrecht, u.bohdal, c.broger, d.bur, c.lehmann, r.ruffieux, P.Spiegler, Helv, Chim, acta 1995, 78, 563-2) Racemic amino acid 140 is obtained, which is then cyclized with N, N' -dicyclohexylcarbodiimide by Schotten-Baumann-acylation to give azlactone 141. Reacted with L-phenylalanine cyclohexylamide (d.obrecht, u.bohdal, c.broger, d.bur, c.lehmann, r.ruffieux, P.Spiegler, Helv. Chim. acta 1995, 78, 563-. Treatment of 142 and 143 with methanesulfonic acid in methanol at 80 ° gives esters 144a and 144b, which are then converted to the corresponding appropriately protected amino acid precursors 145a and 145b, ready for peptide synthesis.
A71: such amino acid building blocks (see formula 147) can be conveniently 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, 2218-19Forming: - (CH)2)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 R19Forming: - (CH)2)5-；R20＝Me)。
The amino acid building blocks of class a72 may suitably be prepared according to scheme 30 by Arndt-eisert C1-homologation of compounds of class a 70.
Scheme 30
i: iBuOCOCl, Dinopropylethylamine, CH2Cl2: then diazomethane, hv or Cu (I)
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 may be prepared according to the following: 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，Phytochemistry1987，26，2695(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 T.Wakamiya, Y.Oda, H.Fujita, T.Shiba, tetrahedron letters, 1986, 27, 2143-; and U is adopted.Hupfeld, R.Gull, Angew.chem.1986, 98, 755-activated 756; baldwin, r.m.adlington, b.j.rawlings, tetrahedral communication, 1985, 26, 481-; D.Kalvin, K.Ramalinggram, R.Woodard, Synth.Comm.1985, 15, 267-272 and L.M.Izquierdo, I.Arenal, M.Bernabe, E.Alvarez, tetrahedron letters, 1985, 41, 215-220.
A74: such compounds can be prepared according to the general procedure described in scheme 28 starting from the corresponding cyclobutanone.
A75 and A76: 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 can be prepared according to J.H.Burckhalter, G.Schmied, J.Pharm.Sci.1966, 55, 443-23Aryl).
A78: such compounds may be prepared according to 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 the general procedure described in scheme 28 starting from the corresponding pyrrolidin-3-one.
A80-A82: such compounds can 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.Yoshimura, S.Kondo, M.Ihara, H.Hashimoto, Carbohydrate Res.1982, 99, 129-142.
A83: such compounds can be prepared according to the general procedure described in scheme 28, starting from the corresponding pyrazolin-4-ones.
A84: such compounds may be prepared according to R.M. Pinder, B.H.Butcher, D.H.Buxton, D.J.Howells, J.Med.chem.1971, 14, 892-893; obrecht, u.bohdal, c.broger, d.bur, c.lehmann, r.ruffieux, P.Spiegler, Helv, Chim.acta 1995, 78, 563-.
A85: such compounds can be prepared according to the general procedure described in scheme 28, starting from the corresponding indan-1, 3-dione.
A86: such compounds can be prepared according to the general procedure described in scheme 28, starting from the corresponding indan-2-one.
A87: such compounds and analogues thereof may be prepared according to c.cativiela, m.d.diaz deVillegas, 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 the general procedure described in scheme 28 starting from the corresponding piperidin-3-ones.
A90: such compounds can be prepared according to the general procedure described in scheme 28, starting from the corresponding tetrahydrothiopyran-3-one.
A91: such compounds can be prepared according to the general procedure described in scheme 28, starting from the corresponding tetrahydropyran-3-one.
A92: such compounds can be prepared according to the general procedure described in scheme 28, starting from the corresponding piperidine-2, 5-dione.
A93: such compounds can be prepared according to the general procedure 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 can 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 the general procedure described in scheme 28, starting from the corresponding tetrahydropyran-4-one.
A97: such compounds can be prepared according to the general procedure 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.K.Müller，H.Heimgartner，F.Stierli，Helv.Chim.Acta 1992，75，1666-1696)。
A99: such compounds can be prepared according to the general procedure described in scheme 28 starting from the corresponding tetrahydronaphthalene-1, 4-dione mono-diethyl acetal.
A100: such compounds can be prepared according to the general procedure described in scheme 28, starting from the corresponding tetrahydroquinolin-4-one.
A101: such compounds can be prepared according to the general procedure described in scheme 28, starting from the corresponding tetrahydroquinoline-2, 4-dione.
A102: such compounds can be prepared according to the following: ishizumi, N.Ohashi, N.Tanno, J.org.chem.1987, 52, 4477-; obrecht, u.bohdal, c.broger, d.bur, c.lehmann, r.ruffieux, P.C.Spiegler，Helv.Chim.Acta 1995，78，563-580；D.Obrecht，C.Spiegler，P.K.Müller，H.Heimgartner，F.Stierli，Helv.Chim.Acta 1992，75，1666-1696；D.R.Haines，R.W.Fuller，S.Ahmad，D.T.Vistica，V.E.Marquez，J.Med.Chem.1987，30，542-547；T.Decks，P.A.Crooks，R.D.Waigh，J.Pharm.Sci 1984，73，457-460；I.A.Blair，L.N.Mander，Austr.J.Chem.1979，32，1055-1065。
The general description of the structural units of species (b) to (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 building blocks and strategies for efficient guided search", adv.Med.chem.1999, Vol.4, 1-68
Templates of species (b1) may be prepared according to schemes 31 and 32.
Scheme 31
i: 150 is treated with a dehydrating reagent such as thionyl chloride in methanol at elevated temperature, suitably under reflux.
ii: boc is introduced, for example, using di-tert-butyl dicarbonate (di-tert. -butyl dicarbanate) and triethylamine in a suitable solvent such as dichloromethane; any other suitable N-protecting group (not shown in reaction scheme 31) can be introduced in a similar manner.
iii: the product formed is reacted with phthalimide, diethyl diazodicarboxylate and triphenylphosphine under standard Mitsunobu conditions (Mitsunobu, O.; Wada, M.; Sano, T.J.J.Am.chem.Soc.1972, 94, 672) to give 151, conveniently.
iv: 151 was treated with trifluoroacetic acid in dichloromethane.
v: 152 was coupled with Cbz-Asp (tBu) OH in DMF using reagents such as HBTU and 1-hydroxybenzotriazole (HOBt) using bases such as diisopropylethylamine under standard peptide coupling conditions to afford 153.
vi: suitably by using H2And a catalyst such as palladium on charcoal in a solventSuch as ethanol, DMF and ethyl acetate, to remove the Cbz-group.
vii: the phthalimide group is suitably prepared by treatment with hydrazine in a suitable solvent such as ethanol at elevated temperature, suitably at about 80 ℃ and subjecting the product formed to treatment with trifluoroacetic acid in CH2Cl2And 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 mixture of solvents such as dioxane and water, or dichloromethane using a base such as sodium carbonate or triethylamine to give 154, e.g. Bislang, c.; weber, c.; robinson, J.A.Helv.Chim.acta 1996, 79, 1825-.
Scheme 32
i: 150 is treated with a dehydrating reagent such as thionyl chloride in a suitable solvent such as methanol at elevated temperature, suitably under reflux.
ii: the resulting amino acid ester is N-protected under standard conditions for the introduction of the Cbz-group, such as using benzyloxycarbonyl chloride and triethylamine in a suitable solvent such as dichloromethane.
iii: the Cbz-protected amino acid methyl ester is treated with trimethylsilyl chloride and a base such as triethylamine in a solvent such as tetrahydrofuran, cooled suitably to about-78 ℃, and then reacted with a strong base such as lithium diisopropylamide or lithium hexamethyldisilylazide and tert-butyl bromoacetate to give 155 as a mixture of diastereomers, e.g., Bislang, 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.; bislang, c.; favre, m.; jiang, l.; robinson, J.A.J.chem.Soc.chem.Commun.1996, 2155-2156.
iv: 155 with phthalimide, diethyl diazodicarboxylate and triphenylphosphine under standard Mitsunobu conditions (Mitsunobu, O.; Wada, M.; Sano, T.J.J.J.am.chem.Soc.1972, 94, 672).
v: the resulting product used H2And a suitable catalyst such as palladium on charcoal, in a solvent such as ethyl acetate, DMF or ethanol; the diastereomer was subsequently separated and 156 was obtained.
vi: 156 is coupled with Fmoc-Asp (allyl) OH under standard peptide coupling conditions using reagents such as HATU, HOAt and bases such as diisopropylethylamine in a suitable solvent such as DMF.
vii: cyclization with DBU in DMF suitably gives 157.
viii: the phthalimide group is suitably cleaved from the resulting product by hydrazinolysis, e.g. treatment with methylhydrazine in a suitable solvent such as 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 mixture of solvents such as dioxane and water, or dichloromethane using a base such as sodium carbonate or triethylamine to give 158.
x: standard removal of allyl ester groups using, for example, palladium (0) as a catalyst gives 159.
(b2) Type templates can be prepared according to scheme 33.
Scheme 33
i: 160 (available from vitamin C, e.g. as described in Hubschwerlen, C. (Synthesis, 1986, 962)) was treated with phthalimide, diethyl diazodicarboxylate 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: amino groups by reaction with benzoylating agents, e.g. benzoic anhydride or benzoyl chloride, and bases, e.g. triethylamine or
The 4-dimethylaminopyridine is protected by treatment 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, e.g. at about 80 ℃.
v: the tert-butoxycarbonyl group is introduced in a suitable solvent such as dichloromethane using, for example, di-tert-butyloxycarbonyl dicarbonate (di-tert. -butyloxycarbonyl dicarbonate), triethylamine and a catalytic amount of 4-dimethylaminopyridine.
vi: with aqueous sodium carbonate in tetrahydrofuran, followed by acidification.
vii: the carboxylic acid group is conveniently esterified with diazomethane in a suitable solvent such as diethyl ether to give 161.
viii by reaction with H as appropriate2Hydrogenation in the presence of a catalyst such as palladium on charcoal in a solvent such as DMF to remove the Cbz-group gives 161 as Pfeifer, m.; robinson, j.a.j.chem.soc.chem.commun.1998, 1977.
ix: 161 is coupled with Cbz-asp (tbu) OH under standard peptide coupling conditions in DMF using reagents such as HBTU and 1-hydroxybenzotriazole using bases such as diisopropylethylamine to give 162, such as Pfeifer, m.; robinson, j.a.j.chem.soc.chem.commun.1998, 1977.
x: such as by using H2And a catalystRemoval of the Cbz-group, e.g., by hydrogenation of palladium on charcoal under standard conditions, gives 163, e.g., Pfeifer, m.; robinson, j.a.j.chem.soc.chem.commun.1998, 1977.
xi: the tert-butyl ester and tert-butyloxycarbonyl groups are suitably cleaved off using trifluoroacetic acid in dichloromethane or 4N hydrochloric acid in dioxane.
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 mixture of solvents such as dioxane and water, or dichloromethane using a base such as sodium carbonate or triethylamine to give 164, e.g. Pfeifer, m.; robinson, j.a.j.chem.soc.chem.commun.1998, 1977.
(c1) Type templates can be prepared according to schemes 34-37.
Scheme 34
i: 166 was synthesized from 165 according to p.waldmeier, "solid-supported synthesis of highly substituted xanthene-derived templates for the synthesis of β -turn stabilized cyclic peptide libraries" (bosch paper, university of zurich, 1996). To cleave the phthalimide group, 166 is suitably subjected to hydrazinolysis, such as treatment with hydrazine hydrate in a suitable solvent such as ethanol at elevated temperature, such as at about 80 ℃.
ii: the intermediate aminonitrile is suitably saponified under basic conditions, e.g. using aqueous sodium hydroxide in a suitable solvent, e.g. ethanol, at elevated temperature, suitably under reflux, to give 167.
iii: 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 mixture of solvents such as dioxane and water, or dichloromethane using a base such as sodium carbonate or triethylamine 168 as described in p.waldmeier, "solid-supported synthesis of highly substituted xanthene derived templates for the synthesis of β -turn stabilized cyclic peptide libraries" (bosch article, university of zurich, 1996).
iv: the regioselective bromination of 167 is preferably carried out using bromine in acetic acid and dichloromethane. In a similar manner, R37＝NO2Can be prepared by using HNO3Treated in acetic acid to introduce and R37＝CH2NPht by treatment with hydroxymethylphthalimide in H2SO4Is introduced by middle treatment.
v: the amino group is suitably Cbz-protected with a reagent such as benzyloxycarbonyl chloride or succinimide in a suitable solvent such as dioxane in the presence of a base such as aqueous sodium hydroxide.
vi: the carboxylic acid groups are preferably esterified using DBU and methyl iodide in DMF to afford 169.
vii: lower alkyl, substituted lower alkyl and aryl substituents (R.sub.H.CHEM.1993, 58, 2201) are suitably introduced by palladium (0) -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). Any other functionalization known for aryl bromides can be used to introduce the substituent R37。
viii: such as by using H2And a catalyst such as palladium on charcoal, in a suitable solvent such as ethanol, DMF and ethyl acetate.
ix: the ester group is suitably hydrolysed under acidic conditions, e.g. using 25% aqueous hydrochloric 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 mixture of solvents such as dioxane and water, or dichloromethane using a base such as sodium carbonate or triethylamine to give 170.
Scheme 35
i: the bis-ortho-bromination of 171 is preferably carried out in acetic acid and dichloromethane using an excess of bromine. In a similar manner, R37＝R38＝NO2Can be prepared by using HNO3Treated in acetic acid to introduce and R37＝R38＝CH2NPht by treatment with hydroxymethylphthalimide in H2SO4Is introduced by middle treatment.
ii: the amino group is protected, suitably Cbz-protected, using a reagent such as benzyloxycarbonyl chloride or succinimide in a suitable solvent such as dioxane in the presence of a base such as aqueous sodium hydroxide.
iii: the carboxylic acid group is preferably esterified using 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 (0) -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). Any other functionalization known for aryl bromides can be used to introduce the substituent R37And R38。
v: such as by using H2And a catalyst such as palladium on charcoal, in a suitable solvent such as ethanol, DMF or ethyl acetate to remove 173 Cbz-groups.
vi: the ester group is suitably hydrolysed under acidic conditions, for example using 25% aqueous hydrochloric acid in a suitable solvent such as dioxane at elevated temperature, suitably 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 mixture of solvents such as dioxane and water, or dichloromethane using a base such as sodium carbonate or triethylamine to give 174.
Scheme 36
i: the methoxy group of 166 is preferably cleaved off by treatment with an excess of boron tribromide in a suitable solvent such as dichloromethane.
ii: the cyano group is hydrolysed under acidic conditions, preferably using 25% aqueous hydrochloric acid in a suitable solvent such as dioxane at elevated temperature, suitably at about 100 ℃.
iii: the resulting acid is treated with a dehydrating agent such as thionyl chloride in a suitable solvent such as dioxane to give 175.
iv: 175 with a suitable triflating agent, preferably trifluoromethanesulfonic anhydride, in the presence of a base such as 2, 6-di-tert-butyl-pyridine in a suitable solvent such as dichloromethane.
v: the intermediate is suitably heated in a suitable solvent such as methanol.
vi: introduction of lower alkyl or aryl-lower alkyl (R) by alkylation35) 177 is obtained. Any other functionalization known for phenolic groups can be used for introducing the substituent R35。
vii: lower alkyl or aryl groups (R.sub.H.sub.R.sub.H.sub.R.sub.H.sub.R.sub.H.sub.T.; Mijaura N.sub.J.org.chem.1993, 58, 2201) are suitably introduced by palladium (0) -catalysed Suzuki-coupling (R.sub.H.sub.E.T.; Mijaura N.sub.A.J.Org.chem.199336) To obtain 178. Any other functionalization known for aryl bromides can be used to introduce the substituent R36。
viii: the ester group is hydrolysed under acidic conditions, suitably with 25% aqueous hydrochloric acid in a suitable solvent such as dioxane at elevated temperature, for example at about 100 ℃.
ix: the phthalimido group is suitably cleaved off by hydrazinolysis, e.g. using 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 mixture of solvents such as dioxane and water, or dichloromethane using a base such as sodium carbonate or triethylamine to give 179.
Scheme 37
i: 175 are brominated using a reagent such as bromine in a mixture of acetic acid and dichloromethane at a temperature of from about 0 deg.c to about room temperature.
ii: the hydroxyl groups are benzoylated to give 180 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.
iii: 180 with methanol and a catalytic amount of an acidic catalyst such as camphorsulfonic acid under heating.
iv: introduction of lower alkyl or aryl-lower alkyl (R) by alkylation with 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)38) Such as by palladium (0) -catalyzed Stille- (Stille, j.k.angelw.chem.1986, 68, 504) and Suzuki-coupling (Oh-e, t.; mijaura, n.; suzuki, a.j.org.chem.1993, 58, 2201). Any known for aryl bromidesOther functionalisations may be used to introduce substituents R38。
vi: to cleave off the benzyloxy group, the intermediate is suitably heated with sodium cyanide and methanol adsorbed on alumina.
vii: treatment with a suitable triflating agent, preferably trifluoromethanesulfonic anhydride, in the presence of a base such as 2, 6-di-tert-butyl-pyridine in a suitable solvent such as dichloromethane.
viii: lower alkyl and aryl substituents (R.J.Org.Chem.1993, 58, 2201) are introduced, for example, by palladium (0) -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)36) Yielding 182. Any other functionalization known for aryl bromides can be used to introduce the substituent R36。
ix: bromination is carried out under standard conditions such as with bromine in acetic acid and dichloromethane at temperatures of about 0 ℃ to about room temperature.
x: lower alkyl, substituted lower alkyl and aryl substituents (R)37) Such as by palladium (0) -catalyzed Stille- (Stille, j.k.angelw.chem.1986, 68, 504) and Suzuki-coupling (Oh-e, t.; mijaura, n.; suzuki, a.j.org.chem.1993, 58, 2201) to obtain 184. Any other functionalization known for aryl bromides can be used to introduce the substituent R37。
xi: the ester group is hydrolysed under acidic conditions, suitably using 25% aqueous hydrochloric acid in a suitable solvent such as dioxane at elevated temperature, for example at about 100 ℃.
xii: the phthalimido group is cleaved off, for example by hydrazinolysis, suitably using 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 mixture of solvents such as dioxane and water, or dichloromethane using a base such as sodium carbonate or triethylamine to afford 185.
(c2) Type templates can be prepared as shown in schemes 38 and 39.
Scheme 38
i: according to Muller, K.; obrecht, d.; kniersinger, a.; spiegler, c.; bannwarth, w.; trzeciak, a.; englert, g.; labhardt, a.;p. medicinal chemical prospecting, 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 (number of pages 131) 3, 7-dimethoxyphenothiazine 186 was prepared and converted to 187. The benzyl radical is suitably prepared, for example, by reacting with H2And a catalyst such as palladium on charcoal, in a suitable solvent such as ethanol, DMF or ethyl acetate, and cleaved from 187.
ii: by using a suitable alkylating agent (R)43-X'; introduction of lower alkyl groups (R) by alkylation of X' ═ OTf, Br, I) with 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-I43). In a similar manner, substituted lower alkyl (R) groups may be introduced43) (ii) a Thus, for example, R43＝CH2COOR55And CH2CH2COOR55Can be introduced by treatment with the appropriate 2-haloacetic acid and 3-halopropionic acid derivatives, respectively. Any other functionalization known for diarylamines can be used to introduce the substituent R43。
iii: the methoxy group 188 is suitably cleaved off by treatment 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: for introducing lower alkyl, substituted lower alkyl or aryl-lower alkyl substituents (R)39And R40) The intermediate bisphenol derivative is suitably reacted with a compound of formula R39-and R40The reagents of-X '(X' ═ OTf, Br, I) are reacted in the presence of a strong base such as sodium hydride in tetrahydrofuran, dioxane or DMF in the presence of a phase transfer catalyst such as TDA-I. Any other functionalization known for phenolic groups can be used for introducing the substituent R39And R40。
v: the cyano groups of 188 and 189, respectively, are suitably hydrolyzed under acidic conditions, such as with 25% aqueous hydrochloric acid in a suitable solvent such as dioxane at elevated temperature, such as at about 100 ℃.
vi: the phthalimide group of the intermediate is suitably cleaved off by hydrazinolysis, e.g. 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 mixture of solvents such as dioxane and water, or dichloromethane using a base such as sodium carbonate or triethylamine to give 190 and 191 respectively.
Scheme 39
i: the cyano group of 188 is suitably hydrolysed under acidic conditions, e.g. using 25% aqueous hydrochloric acid in a suitable solvent such as dioxane at elevated temperature, e.g. at about 100 ℃.
ii: the phthalimide group of the intermediate is suitably cleaved by hydrazinolysis, e.g. using hydrazine hydrate in a suitable solvent such as ethanol, to give 192.
iii: 192 is preferably carried out in acetic acid and dichloromethane using an excess of bromine. In a similar manner, R41＝R42＝NO2Can be prepared by using HNO3Treated in acetic acid to introduce and R41＝R42＝CH2NPht by treatment with hydroxymethylphthalimide in H2SO4Is introduced by middle treatment. It is known that any other functionalization by electrophilic aromatic substitution can be used for introducing the substituents R41And R42。
iv: the amino group is protected, suitably Cbz-protected, using a reagent such as benzyloxycarbonyl chloride or succinimide in a suitable solvent such as dioxane in the presence of a base such as aqueous sodium hydroxide.
v: the carboxylic acid group is preferably esterified using DBU and methyl iodide in DMF to give 193.
vi: 192 is preferably carried out using bromine in acetic acid and dichloromethane. In a similar manner, R41＝NO2Can be prepared by using HNO3Is introduced by treatment in acetic acid and R41＝CH2NPt preparation of the same by reaction with hydroxymethylphthalimide at H2SO4Is introduced by the intermediate treatment. It is known that any other functionalization by electrophilic aromatic substitution can be used for introducing the substituents R41。
vii: the amino group is suitably Cbz-protected using a reagent such as benzyloxycarbonyl chloride or succinimide in a suitable solvent such as dioxane in the presence of a base such as aqueous sodium hydroxide.
viii: the carboxylic acid group is preferably esterified using DBU and methyl iodide in DMF to give 194.
ix：194(R41) And 193 (R)41And R42) The substituted lower alkyl and aryl substituents of (a) are suitably by palladium (0) -catalysed Stille- (Stille, j.k.angelw.chem.1986, 68, 504) and Suzuki-coupling (Oh-e, t.; mijaura, n.; suzuki, a.j.org.chem.1993, 58, 2201). Any other functionalization known for aryl bromides can be used to introduce the substituent R41And R42。
x: such as by using H2And a catalyst such as palladium on charcoal, in a suitable solvent such as ethanol, DMF and ethyl acetate.
xi: the ester groups are suitably hydrolysed under acidic conditions, e.g. using 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 a reagent such as 9-fluorenylmethoxycarbonyl chloride or 9-fluorenylmethoxycarbonyl succinimide by use of a base such as sodium carbonate or triethylamine in a suitable solvent or mixture of solvents such as dioxane and water, or dichloromethane to give 195 and 196.
(c3) Template types can be prepared as shown in schemes 40 and 41.
Scheme 40
i: according to Muller, K.; obrecht, d.; kniersinger, a.; spiegler, c.; bannwarth, w.; trzeciak, a.; englert, g.; labhardt, a.;p. medicinal chemical prospecting, editor Testa, b.; kyburz, e.; fuhrer, w.; giger, r., Weinheim, New York, Basel, Cambridge: verlag Helvetica Chimica Acta, 1993, 513-; bannwarth, w.; gerber, f.; gr ieder, a.; kniersinger, a.; muller, K.; obrecht.d.; trzeciak, a.can.pat.appl.ca2101599 (number of pages 131), 197 available from commercial halogen testLing preparation and conversion to 198. For cleavage of the benzyl group 198 is suitable, for example, for H2And a catalyst such as palladium on charcoal, in a suitable solvent such as ethanol, DMF or ethyl acetate.
ii: by 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-I43-X '(X' ═ OTf, Br, I) alkylation to introduce lower alkyl (R)43)199 is obtained. In a similar manner, substituted lower alkyl (R)43) Can be introduced; thus, for example, R43＝CH2COOR55And CH2CH2COOR55May be introduced by treatment with suitable 2-haloacetic acid and 3-halopropionic acid derivatives, respectively. Any other functionalization known for diarylamino groups can be used to introduce the substituent R43。
iii: 199 is suitably cleaved off by treatment with an excess of boron tribromide in dichloromethane at a temperature of from about-20 ° to about room temperature.
iv: the intermediate bisphenol derivative is preferably reacted with R39And R40-X '(X' ═ OTf, Br, I) is reacted in the presence of a strong base such as sodium hydride in tetrahydrofuran, dioxane or DMF in the presence of a phase transfer catalyst such as TDA-I. Any other functionalization for the phenol group can be used for introducing the substituent R39And R40。
v: 199 and 200 are each hydrolyzed under acidic conditions, such as with 25% aqueous hydrochloric acid in a suitable solvent such as dioxane at elevated temperature, suitably about 100 ℃.
vi: the phthalimide group is suitably cleaved off by hydrazinolysis, e.g. 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 mixture of solvents such as dioxane and water, or dichloromethane using a base such as sodium carbonate or triethylamine to give 201 and 202 respectively.
Scheme 41
i: the cyano group of 199 is suitably hydrolysed under acidic conditions, e.g. using 25% aqueous hydrochloric acid in a suitable solvent such as dioxane at elevated temperature, e.g. at about 100 ℃.
ii: the phthalimide group of the intermediate is suitably cleaved by hydrazinolysis, e.g. using hydrazine hydrate in a suitable solvent such as ethanol, to give 203.
iii: the bis-ortho-bromination of 203 is preferably carried out in acetic acid and dichloromethane using excess bromine. In a similar manner, R41＝R42＝NO2Can be prepared by using HNO3Treated in acetic acid to introduce and R41＝R42＝CH2NPht by treatment with hydroxymethylphthalimide in H2SO4Is introduced by middle treatment. It is known that any other functionalization by electrophilic aromatic substitution can be used for introducing the substituents R41And R42。
iv: the amino group is protected, suitably Cbz-protected, using a reagent such as benzyloxycarbonyl chloride or succinimide in a suitable solvent such as dioxane in the presence of a base such as aqueous sodium hydroxide.
v: the carboxylic acid group is preferably esterified using DBU and methyl iodide in DMF to give 204.
vi: the regioselective bromination of 203 is preferably carried out using bromine in acetic acid and dichloromethane. In a similar manner, R41＝NO2Can be prepared by using HNO3Is introduced by treatment in acetic acid and R41＝CH2NPht by treatment with hydroxymethylphthalimide in H2SO4Is introduced by the middle treatment
vii: the amino group is suitably protected with Cbz-using a reagent such as benzyloxycarbonyl chloride or succinimide in a suitable solvent such as dioxane in the presence of a base such as aqueous sodium hydroxide.
viii: the carboxylic acid group is preferably esterified using DBU and methyl iodide in DMF to give 205.
ix: suitably 205 (R.J.Org.Chem.1993, 58, 2201) by palladium (0) -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 is 204 (R)41And R42) Lower alkyl, substituted lower alkyl and aryl substituents are introduced. Any other functionalization known for aryl bromides can be used to introduce the substituent R41And R42。
x: such as by using H2And a catalyst such as palladium on charcoal, in a suitable solvent such as ethanol, DMF and ethyl acetate.
xi: the ester groups are suitably hydrolysed under acidic conditions, e.g. using 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 by a reagent such as 9-fluorenylmethoxycarbonyl chloride or 9-fluorenylmethoxycarbonyl succinimide in a suitable solvent or mixture of solvents 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 according to d.obrecht, u.bohdal, c.lehmann, P.K.M muller, tetrahedron, 1995, 51, 10883; D.Obrecht, C.Abrecht, M.Altorfer, U.Bohdal, A.Grieder, M.Kleber, P.Pfyffer, K.Muller, Helv.Chim.acta1996, 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.steven son, c.q.sun, e.w.petrillo, d.s.karanewski, m.m.asaad, j.e.bird, t.r.schaeffer, n.c.tripppoo, paper summary, 210 paper summaryth Am.Chem.Soc Meeting，Chicago，I11，MEDI 064(1995)。
Template (k): see d.benishai, a.r.mcmurray, Tetrahedron 1993, 49, 6399.
Template (1): see, e.g., von Roedern, H.Kessler, Angew.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.-H.Pook，Int.J.Pept.Res.1995，45，540-546。
Template (o): see n.dela Figuera, 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 beta-hairpin peptidomimetics of the invention are useful in a wide range of applications to inhibit the growth of or kill microorganisms. In particular, they are useful for selectively inhibiting the growth of or killing microorganisms such as Pseudomonas aeruginosa (Pseudomonas aeruginosa) and Acinetobacter (Acinetobacter).
They can be used, for example, as disinfectants or preservatives for materials such as food, cosmetics, pharmaceuticals and other nutrient-containing materials. 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 a disinfectant or preservative, the β -hairpin peptidomimetics can be added to the desired material individually, as a mixture of several β -hairpin peptidomimetics or in combination with other antimicrobial agents. The β -hairpin peptidomimetic can be administered by itself or can be administered as a suitable formulation with carriers, diluents, or excipients well known in the art.
When used for the treatment or prophylaxis of infections or diseases associated with these infections, in particular infections associated with respiratory diseases such as cystic fibrosis, emphysema and asthma, infections associated with skin or soft tissue diseases such as surgical wounds, wounds and burns, infections associated with gastrointestinal diseases such as epidemic diarrhea, necrotizing enterocolitis and typhlitis, infections associated with eye diseases such as keratitis and endophthalmitis, infections associated with ear diseases such as otitis, infections associated with CNS diseases such as cerebral abscesses and meningitis, infections associated with bone diseases such as osteochondritis and osteomyelitis, infections associated with cardiovascular diseases such as endocortis and pericarditis, infections associated with gastrouroral diseases such as epididymitis, prostatitis and urethritis, the beta-hairpin peptidomimetics may be used individually, as a mixture of several beta-hairpin peptidomimetics, with other antimicrobial or antibiotic agents, or an anti-cancer agent, or an anti-viral (e.g. anti-HIV) agent, or in combination with other pharmaceutically active agents. The β -hairpin peptidomimetics can be administered as such or as a pharmaceutical composition.
Pharmaceutical compositions comprising the β -hairpin peptidomimetics of the invention may be manufactured using conventional mixing, dissolving, granulating, coated tablet manufacturing, levigating, emulsifying, encapsulating, entrapping or lyophilizing processes. The pharmaceutical compositions can be formulated in conventional manner using one or more physiologically acceptable carriers, diluents, excipients or auxiliaries which facilitate processing of the active β -hairpin peptidomimetics into pharmaceutically acceptable preparations. The appropriate formulation depends on the method of administration chosen.
For topical administration, the β -hairpin peptidomimetics of the present invention can be formulated into solutions, gels, ointments, creams, suspensions, and the like, as is well known in the art.
Systemic formulations 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 aqueous 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 suspending, stabilizing and/or dispersing agents. Alternatively, the β -hairpin peptidomimetics of the invention may be in powder form for admixture with a suitable carrier, e.g., sterile pyrogen-free water, prior to use.
For transmucosal administration, penetrants appropriate to the barrier to be permeated are used in the formulation, as is known in the art.
For oral administration, these complexes can be readily formulated by combining the active β -hairpin peptidomimetics of the invention with pharmaceutically acceptable carriers well known in the art. These carriers enable the beta-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 to be treated. For oral formulations such as, for example, 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, such as cross-linked polyvinylpyrrolidone, agar, or alginic acid or a salt thereof, such as sodium alginate, may be added. If desired, the solid dosage form may be sugar coated or enteric coated using standard techniques.
For oral liquid preparations such as, for example, 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 oral administration, the compositions may be in the form of tablets, lozenges, etc., formulated as conventional.
For administration by inhalation, the β -hairpin peptidomimetics of the invention are suitably delivered as an aerosol spray from pressurized packs or a nebulizer, with the use of a suitable propellant, such as 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 deliver a metered amount. Capsules and cartridges of, for example, gelatin for use in an inhaler or insufflator may be formulated containing a powder mix of a 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 formulations previously described, the β -hairpin peptidomimetics of the invention can also be formulated as stock preparations. These long acting formulations may be administered by implantation (e.g. subcutaneously or intramuscularly) or by intramuscular injection. To make these depot formulations, the β -hairpin peptidomimetics of the invention can be formulated with suitable polymers or hydrophobic materials (e.g., as an emulsion in an acceptable oil) or ion exchange resins, or as a nearly insoluble salt.
In addition, other drug delivery systems such as liposomes and emulsions well known in the art may be used. Certain organic solvents such as dimethyl sulfoxide may also be used. In addition, the β -hairpin peptidomimetics of the invention can be delivered using a sustained release system, such as a semipermeable matrix of a solid polymer containing the therapeutic agent. Various sustained release materials are established and are well known to those skilled in the art. Sustained release capsules can release the compound for weeks to over 100 days depending on its chemical nature. Depending on the chemical nature and biological stability of the therapeutic agent, other techniques may be used for protein stabilization.
Because the β -hairpin peptidomimetics of the invention may contain charged residues, they may be included in any of the above formulations as such 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 intended purpose. It will be appreciated that the amount depends 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 to or added to the material to be disinfected or preserved. An antimicrobially effective amount refers to an amount of a β -hairpin peptidomimetic or composition of the invention that inhibits the growth of, or is lethal to, a target microbial population. While an antimicrobially effective amount depends on the particular application, for use as a disinfectant or preservative, the β -hairpin peptidomimetics of the invention, or compositions thereof, are generally added or applied to the material to be disinfected or preserved in relatively low amounts. Typically, the beta-hairpin peptidomimetics of the invention comprise less than about 5% by weight of the disinfecting solution or material to be preserved, preferably less than 1% by weight and more preferably less than 0.1% by weight. The ordinarily skilled artisan can determine, without undue experimentation, an antimicrobially effective amount of a particular β -hairpin peptidomimetic of the invention for a particular application using, for example, the in vitro assays provided in the examples.
For use in treating or preventing microbial infections or diseases associated with such infections, the β -hairpin peptidomimetics of the invention or compositions thereof are administered or administered in a therapeutically effective amount. A therapeutically effective amount is an amount effective to ameliorate the symptoms of, or ameliorate, treat or prevent a microbial infection or a disease associated therewith. Determination of a therapeutically effective amount is well within the capability of those skilled in the art, especially in view of the detailed description provided herein.
As with disinfectants and preservatives, for topical administration for the treatment or prevention of bacterial infections, therapeutically effective dosages can be determined using, for example, the in vitro assays provided in the examples. Treatment may be performed when the infection is visible, or even when it is not visible. One of ordinary skill will be able to determine a therapeutically effective amount for treating a topical infection without undue experimentation.
For systemic administration, a therapeutically effective dose can be initially determined by in vitro analysis. For example, the dose can be formulated in animal models to achieve such circulating beta-hairpin peptidomimeticsConcentration range including IC as determined in cell culture50(i.e., the concentration of test compound that is lethal to 50% of the cell culture), as determined by MIC in the cell culture (i.e., the concentration of test compound that is lethal to 100% of the cell culture). This information can be used to more accurately determine the dosage available to a person.
The starting dose 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 dosing in humans based on animal data.
The dosages used as antimicrobial agents can each be adjusted to provide plasma levels of the beta-hairpin peptidomimetics of the invention sufficient to maintain the therapeutic effect. Therapeutically effective serum levels can be achieved by multiple daily administrations.
In the case of local administration or selective absorption, 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 therapeutically effective topical dosages without undue experimentation.
The amount of β -hairpin peptidomimetic administered will, of course, depend on the subject to be treated, the weight of the subject, the severity of the disease, the mode of administration and the judgment of the prescribing physician.
Antimicrobial treatments may be repeated intermittently when infections are detectable or even when they are not. Treatment may be provided alone or in combination with other drugs, such as antibiotics or other antimicrobial agents.
In general, therapeutically effective doses of the beta-hairpin peptidomimetics described herein provide therapeutic benefit without causing significant toxicity.
Haemolysis of erythrocytes is commonly used to assess the toxicity of related compounds such as protegrin or tachyplesin. Values are given as% lysis of erythrocytes observed at a concentration of 100. mu.g/ml. Typical values for cationic peptides such as protegrin and tacyplesin are 30-40% for a wide range of pathogens, with an average MIC-value of 1-5 μ g/ml. Typically, the β -hairpin peptidomimetics of the invention have a haemolysis value in the range 0.5-10%, typically 1-5%, at a level corresponding to the activity described above for protegrin and tachplesin. Preferred compounds therefore have a low MIC-value and low% hemolysis of red blood cells observed at a concentration of 100 μ g/ml.
Toxicity of the beta-hairpin peptidomimetics of the invention can be determined here by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., by determining the LD50(lethal dose of 50% of the population) or LD100(lethal dose of 100% of the population). 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 determine dosage ranges that are not toxic for human use. The dosage of the beta-hairpin peptidomimetics of the invention is preferably within a range of circulating concentrations that includes an effective dose with little or no toxicity. The dosage may vary within this range depending upon the dosage form employed and the route of administration utilized. The exact formulation, route of administration and dosage can be selected by the individual physician according to the patient's condition (see, e.g., Fingl et al, 1975: pharmacological basis for treatment, 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-hydroxybenzotriazole;
DIEA: diisopropylethylamine;
HOAT: 7-aza-1-hydroxybenzotriazole;
HATU: 0- (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 to the resin
0.5g of 2-chlorotrityl chloride resin (Barlos et al, tetrahedron letters, 1989, 30, 3943-. Suspending the resin in CH2Cl2(2.5ml) and swollen at room temperature for 30min with constant stirring. The resin was treated with 0.415mMol (1eq) of the first suitably protected amino acid residue (see below) and 284. mu.l (4eq) of Diisopropylethylamine (DIEA) in CH2Cl2(2.5ml) and the mixture was shaken at 25 ℃ for 4 hours. The resin color turned purple while the solution remained yellow. Oscillating the resin (CH)2Cl2MeOH/DIEA: 17/2/1), 30ml, 30 min; followed by CH in the following order2Cl2(1x)，DMF(1x)，CH2Cl2(1x)，MeOH(1x)，CH2Cl2(1x)，MeOH(1x)，CH2Cl2(2x)，Et2Washed with O (2 ×) and dried under vacuum for 6 hours.
The loading is typically 0.6-0.7 mMol/g.
The following pre-loaded resins were prepared: Fmoc-ProO-chlorotrityl resin.
Synthesis of fully protected peptide fragments
The synthesis was performed using a Syro-peptide synthesizer (Multisyntech) using 24 to 96 reaction vessels. In each container, more than 60mg (weight of resin before loading) of resin was placed. The following reaction cycles were programmed and performed:
steps 3-6 were repeated to add each amino acid.
Cleavage of fully protected peptide fragments
After completion of the synthesis, the resin was suspended in 1ml (0.39mMol) TFA in CH2Cl2(v/v) in 1% solution for 3 min, filtered and the filtrate was extracted with 1ml (1.17mMol, 3eq.) of DIEA in CH2Cl2(v/v) neutralization of the 20% solution. This step was repeated twice to ensure completion of the cut. The filtrate was evaporated to dryness and the product was completely deprotected [ a cleavage mixture comprising 95% trifluoroacetic acid (TFA), 2.5% water and 2.5% Triisopropylsilane (TIS)]By reverse phase-HPLC (column C)18) And ESI-MS analysis to examine the efficiency of linear peptide synthesis.
Cyclization reaction of linear peptide
100mg of the fully protected linear peptide was dissolved in DMF (9ml, conc.10 mg/ml). 41.8mg (0.110mMol, 3eq.) of HATU, 14.9mg (0.110mMol, 3eq.) of HOAt and 1ml (0.584mMol) of 10% DIEA in DMF (v/v) were then added and the mixture was vortexed at 20 ℃ for 16 h and then concentrated under high vacuum. The residue is in CH2Cl2And H2O/CH3And CN (90/10: v/v). CH (CH)2Cl2The phases were evaporated to give fully protected cyclic peptide.
Deprotection and purification of cyclic peptides:
the resulting cyclic peptide was dissolved in 1ml of a decomposition mixture comprising 95% trifluoroacetic acid (TFA), 2.5% water and 2.5% Triisopropylsilane (TIS). The mixture was left at 20 ℃ for 2.5 hours and then concentrated under vacuum. Dissolving the residue in H2O/acetic acid (75/25: v/v) and the mixture was extracted with di-isopropyl ether.
The aqueous phase was dried under vacuum and the product was subsequently purified by preparative reverse phase HPLC.
After lyophilization, a product was obtained as a white powder and analyzed by ESI-MS. Analytical data including HPLC residence time and ESI-MS are given in Table 1.
Analytical HPLC residence time (RT, min) useVYDAC 218MS5215 column assay, in which the following solvent A (H) was used2O + 0.02% TFA) and B (CH)3CN) and gradient: 0 min: 92% A, 8% B; 8 min: 62% A38% B; 9-12 min: 0% A, 100% B.
Examples 1 to 7 (n-12) are shown in table 1. The peptide is synthesized starting from the amino acid Pro grafted onto the resin. The starting resin was Fmoc-ProO-chlorotrityl resin prepared as described above. The linear peptide was synthesized on a solid support according to the above procedure in the following order: resin-Pro-DPro-P12-P11-P10-P9-P8-P7-P6-P5-P4-P3-P2-P1, cleaved from the resin, cyclized, deprotected and purified as described.
HPLC-retention time (min) was determined using the gradient described above:
example 1 (5.73; 6.29); example 2 (5.13; 5.51; 5.75); example 3 (4.83; 5.37); example 4 (4.79; 5.43); example 5 (5.27; 5.85); example 6 (5.31; 6.03); example 7 (4.59).
Doublets showing correct MS and chiral amino acid analysis. At 60 °, only one peak was observed.
2. Biological method
2.1. And (3) preparing the peptide.
The lyophilized peptide was weighed on a microbalance (Mettler MT5) and dissolved in sterile water containing 0.01% acetic acid.
2.2. Antimicrobial activity of the peptide.
The selective antimicrobial activity of peptides was determined by the standard NCCLS broth microdilution method (see reference 1 below), wherein the peptides were examined in sterile 96-well plates (Nunclon polystyrene microtitre plates) in a total volume of 100 μ Ι. Inoculum of microorganism prepared by 0.5Mcfarland standardPrepared and subsequently diluted in Mueller-Hinton (MH) broth, giving about 10% for bacteria6Individual Colony Forming Units (CFU)/ml. An aliquot of the inoculum (50 μ l) was added to 50 μ l of MH broth containing the peptide in serial two-fold dilutions. To screen for selective peptides, the following microorganisms were used: coli (ATCC 25922), pseudomonas aeruginosa (p. aeruginosa) (ATCC 27853), staphylococcus aureus (ATCC 29213 and ATCC25923), and pseudomonas aeruginosa (p. aeruginosa) V0216085 and acinetobacter (acinetobacter V0419905/1, acinetobacter V1221143/1 and acinetobacter V1221193/1). The antimicrobial activity of the peptide represents the Minimum Inhibitory Concentration (MIC) in μ g/ml at which no visible growth is observed after 18-20 hours incubation of the microtiter plates at 37 ℃.
2.3. Antimicrobial activity of peptides in 0.9% saline
Salt sensitivity of the peptides was tested by a microtiter serial dilution assay as described above. Only MH broth was replaced with MH broth containing 0.9% NaCl.
2.4. Antimicrobial activity of peptides in human serum
Serum binding of the peptides was tested by a microtiter serial dilution assay as described above. Only MH broth was replaced with MH broth containing 90% human serum (BioWhittaker).
2.5. Hemolysis of blood
The peptides were tested for hemolytic activity against human blood red blood cells (hRBC). Fresh hRBC were washed three times with Phosphate Buffered Saline (PBS) by centrifugation at 2000Xg for 10 min. Peptides at a concentration of 100. mu.g/ml were incubated with 20% v/v hRBC at 37 ℃ for 1 hour. The final red blood cell concentration was about 0.9X 109And/ml. 0% and 100% lysis values were obtained in PBS only and 0.1% Triton X-100 (in H)2O) was cultured in the presence of hrbcs. The samples were centrifuged and the supernatants were diluted 20-fold in PBS buffer before determining the Optical Density (OD) of the samples at 540 nM. 100% lysis value (OD)540H2O) to obtain an OD of about 1.6-2.0. The% hemolysis was calculated as follows: (OD)540peptide/OD540H2O)×100％。
2.6. Results
The results of the above experiments are given in tables 2 and 3 below.
Reference to the literature
1. Clinical laboratory national committee on standards 1993, dilution antimicrobial susceptibility testing method for aerobic growing bacteria, third edition, approved standard M7-a3.
2.Mossman T.J Immunol Meth 1983，65，55-63
3.Berridge MV，Tan AS.Archives of Biochemistry &Biophysics 1993，303，474-482
Sequence listing
<110>Polyphor Ltd.
<120> template-fixed peptidomimetics
<130>P1065PCT
<140>PCT/EP 02/09278
<141>2002-08-20
<160>8
<170>PatentIn Ver.2.1
<210>1
<211>14
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<213> Artificial sequence
<220>
<223> Artificial sequence description: cyclic peptides
<220>
<223> Xaa at position 13 is D-Pro
<400>1
Arg Trp Leu Lys Lys Arg Arg Trp Leu Tyr Tyr Arg Xaa Pro
1 5 10
<210>2
<211>14
<212>PRT
<213> Artificial sequence
<220>
<223> Artificial sequence description: cyclic peptides
<220>
<223> Xaa at position 13 is D-Pro
<400>2
Arg Trp Leu Lys Lys Arg Arg Trp Lys Tyr Val Arg Xaa Pro
1 5 10
<210>3
<211>14
<212>PRT
<213> Artificial sequence
<220>
<223> Artificial sequence description: cyclic peptides
<220>
<223> Xaa at position 13 is D-Pro
<400>3
Arg Trp Leu Lys Lys Arg Arg Trp Lys Thr Tyr Arg Xaa Pro
1 5 10
<210>4
<211>14
<212>PRT
<213> Artificial sequence
<220>
<223> Artificial sequence description: cyclic peptides
<220>
<223> Xaa at position 13 is D-Pro
<400>4
Arg Trp Leu Lys Lys Arg Arg Trp Lys Gln Tyr Arg Xaa Pro
1 5 10
<210>5
<211>14
<212>PRT
<213> Artificial sequence
<220>
<223> Artificial sequence description: cyclic peptides
<220>
<223> Xaa at position 13 is D-Pro
<400>5
Arg Trp Leu Val Lys Arg Arg Trp Lys Tyr Tyr Arg Xaa Pro
1 5 10
<210>6
<211>14
<212>PRT
<213> Artificial sequence
<220>
<223> Artificial sequence description: cyclic peptides
<220>
<223> Xaa at position 13 is D-Pro
<400>6
Arg Trp Leu Lys Lys Arg Arg Trp Val Tyr Tyr Arg Xaa pro
1 5 10
<210>7
<211>14
<212>PRT
<213> Artificial sequence
<220>
<223> Artificial sequence description: cyclic peptides
<220>
<223> Xaa at position 13 is D-Pro
<400>7
Arg Trp Leu Lys Lys Arg Arg Trp Lys Tyr Gln Arg Xaa Pro
1 5 10
<210>8
<211>14
<212>PRT
<213> Artificial sequence
<220>
<223> Artificial sequence description: cyclic peptides
<220>
<223> Xaa at position 13 is D-Pro
<400>8
Arg Trp Leu Lys Lys Arg Arg Trp Lys Tyr Leu Arg Xaa Pro
1 5 10

Claims (20)

1. A compound having the formula
Wherein
Is of the formulaDPro-LGroup of Pro
R20Is H; an alkyl group; an alkenyl group; or aryl-alkyl having up to 6 carbon atoms;
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)sSO2R62(ii) a Or- (CH)2)o(CHR61)sC6H4R8；
R34Is H; alkyl having up to 6 carbon atoms; aryl, or aryl-alkyl having up to 6 carbon atoms;
R33and R34Together may form: - (CH)2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-; or
-(CH2)2NR57(CH2)2-；
R37Is H; f; br; cl; NO2；CF3(ii) a Alkyl having up to 6 carbon atoms;
-(CH2)p(CHR61)sOR55；-(CH2)p(CHR61)sNR33R34；
-(CH2)p(CHR61)sOCONR33R75；-(CH2)p(CHR61)sNR20CONR33R32；
-(CH2)o(CHR61)sCOOR57；-(CH2)o(CHR61)sCONR58R59；
-(CH2)o(CHR61)sPO(OR60)2；
-(CH2)o(CHR61)sSO2R62(ii) a Or- (CH)2)o(CHR61)sC6H4R8；
R50Is H; alkyl having up to 6 carbon atoms; or aryl-alkyl having up to 6 carbon atoms;
R55is H; alkyl having up to 6 carbon atoms; alkenyl having up to 6 carbon atoms; aryl-alkyl having up to 6 carbon atoms; - (CH)2)m(CHR61)sOR57；
-(CH2)m(CHR61)sNR34R63；-(CH2)m(CHR61)sOCONR75R82；
-(CH2)m(CHR61)sNR20CONR78R82；-(CH2)o(CHR61)s-COR64；
-(CH2)o(CHR61)COOR57(ii) a Or
-(CH2)o(CHR61)sCONR58R59；
R57Is H; alkyl having up to 6 carbon atoms; alkenyl having up to 6 carbon atoms; aryl is an alkyl group having up to 6 carbon atoms; or heteroaryl having alkyl of up to 6 carbon atoms;
R58is H; alkyl having up to 6 carbon atoms; alkenyl having up to 6 carbon atoms; an aryl group; a heteroaryl group; aryl-alkyl having up to 6 carbon atoms; or heteroaryl-alkyl having up to 6 carbon atoms;
R59is H; alkyl having up to 6 carbon atoms; alkenyl having up to 6 carbon atoms; an aryl group; a heteroaryl group; aryl-alkyl having up to 6 carbon atoms; or heteroaryl-alkyl having up to 6 carbon atoms; or
R58And R59Together may form: - (CH)2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-; or
-(CH2)2NR57(CH2)2-；
R60Is H; alkyl having up to 6 carbon atoms; alkenyl having up to 6 carbon atoms; an aryl group; or aryl-alkyl having up to 6 carbon atoms;
R61is an alkyl group; an alkenyl group; an aryl group; a heteroaryl group; aryl-alkyl having up to 6 carbon atoms; heteroaryl-alkyl having up to 6 carbon atoms; - (CH)2)mOR55；
-(CH2)mNR33R34；-(CH2)mOCONR75R82；-(CH2)mNR20CONR78R82；-(CH2)oCOOR37；
-(CH2)oNR58R59(ii) a Or- (CH)2)oPO(COR60)2；
R62Is alkyl having up to 6 carbon atoms; alkenyl having up to 6 carbon atoms; aryl, heteroaryl; or aryl-alkyl having up to 6 carbon atoms;
R63is H; alkyl having up to 6 carbon atoms; alkenyl having up to 6 carbon atoms; aryl, heteroaryl;aryl-alkyl having up to 6 carbon atoms; heteroaryl-alkyl having up to 6 carbon atoms;
-COR64；-COOR57；-CONR58R59；-SO2R62(ii) a OR-PO (OR)60)2；
R34And R63Together may form: - (CH)2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-; or
-(CH2)2NR57(CH2)2-；
R64Is H; alkyl having up to 6 carbon atoms; alkenyl having up to 6 carbon atoms; an aryl group; a heteroaryl group; aryl-alkyl having up to 6 carbon atoms; heteroaryl-alkyl having up to 6 carbon atoms;
-(CH2)p(CHR61)sOR65；-(CH2)p(CHR61)sSR66(ii) a Or- (CH)2)p(CHR61)sNR34R63；
-(CH2)P(CHR61)sOCONR75R82；-(CH2)P(CHR61)sNR20CONR78R82；
R65Is H; alkyl having up to 6 carbon atoms; alkenyl having up to 6 carbon atoms; aryl, aryl-alkyl having up to 6 carbon atoms; heteroaryl-alkyl having up to 6 carbon atoms; -COR57；
-COOR57(ii) a or-CONR58R59；
R66Is H; alkyl having up to 6 carbon atoms; alkenyl having up to 6 carbon atoms; an aryl group; aryl-alkyl having up to 6 carbon atoms; heteroaryl-alkyl having up to 6 carbon atoms; 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;
z is a chain of 12 alpha-amino acid residues, the positions of said amino acid residues in said chain being counted starting from the N-terminal amino acid, such that these amino acid residues are Gly or Pro, or one of the following, depending on their position in the chain
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-；
R72is H; alkyl having up to 6 carbon atoms; alkenyl having up to 6 carbon atoms; - (CH)2)p(CHR61)sOR85(ii) a Or- (CH)2)p(CHR61)sSR85；
R73Is- (CH)2)oR77；-(CH2)rO(CH2)oR77；-(CH2)rS(CH2)oR77(ii) a Or- (CH)2)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)pNR80COR54；
-(CH2)pNR80COR77；
-(CH2)pNR80CONR78R79(ii) a Or- (CH)2)pC6H4NR80CONR78R79；
R75Is alkyl having up to 6 carbon atoms; alkenyl having up to 6 carbon atoms; or aryl-alkyl having up to 6 carbon atoms;
R33and R75Together may form: - (CH)2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-; or
-(CH2)2NR57(CH2)2-；
R75And R82Together may form: - (CH)2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-; or
-(CH2)2NR57(CH2)2-；
R77Is R86(ii) a Or a heteroaryl group having one of the following structural formulae
R78Is H; alkyl having up to 6 carbon atoms; an aryl group; or aryl-alkyl having up to 6 carbon atoms;
R78and R82Together may form: - (CH)2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-; or
-(CH2)2NR57(CH2)2-；
R79Is H; alkyl having up to 6 carbon atoms; an aryl group; or aryl-alkyl having up to 6 carbon atoms; or
R78And R79Taken together, may be- (CH)2)2-7-；-(CH2)2O(CH2)2-; or- (CH)2)2NR57(CH2)2-；
R80Is H; or an alkyl group having up to 6 carbon atoms;
R81is H; alkyl having up to 6 carbon atoms; or aryl-alkyl having up to 6 carbon atoms;
R82is H; alkyl having up to 6 carbon atoms; an aryl group; a heteroaryl group; or aryl-alkyl having up to 6 carbon atoms;
R33and R82Together may form: - (CH)2)2-6-；-(CH2)2O(CH2)2-；-(CH2)2S(CH2)2-; or
-(CH2)2NR57(CH2)2-；
R83Is H; alkyl having up to 6 carbon atoms; an aryl group; or-NR78R79；
R84Is- (CH)2)m(CHR61)sOH；-(CH2)pCONR78R79；-(CH2)pNR80CONR78R79；-(CH2)pC6H4CONR78R79(ii) a Or
-(CH2)pC6H4NR80CONR78R79；
R85Is alkyl having up to 6 carbon atoms; or alkenyl having up to 6 carbon atoms;
R86is phenyl, p-hydroxyphenyl, 2-naphthyl, 1-naphthyl, 4-chlorophenyl, 3-chlorophenyl, 2-chlorophenyl, 3, 4-dichlorophenyl, 4-fluorophenyl, 3-fluorophenyl, 2-fluorophenyl, p-benzyloxyphenyl, p-biphenylyl or p-benzoylphenyl;
with the proviso that in the chain Z of 12 α -amino acid residues the amino acid residues in positions 1 to 12 are:
p1: a species E;
p2: a species D;
p3: class C;
p4: class C, or class E;
p5: a species E;
p6: a species E;
p7: a species E;
p8: a species D;
p9: class C, or class E;
p10: class F, or class D;
p11: class D or class C or class F; and
p12: a species E; or
P4 and P9 and/or P2 and P11 together may form a group of the kind H;
a further prerequisite is that
-the amino acid residue in P4 is of the type C; and/or
-the amino acid residue in P9 is of the type C; and/or
-the amino acid residue in P10 is of the species F; and/or
-the amino acid residue in P11 is of the type C or of the type F;
and pharmaceutically acceptable salts thereof.
2. The compound according to claim 1, wherein the amino acid residue at position P6 and/or the amino acid residue at position P7 is the D-isomer.
3. The compound according to claim 1, wherein the α -amino acid residues in positions 1 to 12 of chain Z are:
·P1：Arg；
·P2：Trp；
·P3：Leu；
p4: lys or Val;
·P5：Lys；
·P6：Arg；
·P7：Arg；
·P8：Trp；
p9: leu, Val or Lys;
p10: tyr, Thr, or Gln;
p11: val, Leu, Tyr or Gln; and
·P12：Arg；
provided that
-the amino acid residue in position P4 is Val; and/or
-the amino acid residue in position P9 is Leu or Val; and/or
-the amino acid residue in position P10 is Thr or Gln; and/or
The amino acid residue in position-P11 is Val or Leu or Gln.
4. A compound of formula I according to claim 1, wherein the amino acid residues in positions 1-12 are:
·P1：Arg；
·P2：Trp；
·P3：Leu；
·P4：Lys；
·P5：Lys；
·P6：Arg；
·P7：Arg；
·P8：Trp；
·P9：Leu；
·P10：Tyr；
p11: tyr; and
·P12：Arg。
5. a compound of formula I according to claim 1, wherein the amino acid residues in 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: val; and
·P12：Arg。
6. a compound of formula I according to claim 1, wherein the amino acid residues in positions 1-12 are:
·P1：Arg；
·P2：Trp；
·P3：Leu；
·P4：Lys；
·P5：Lys；
·P6：Arg；
·P7：Arg；
·P8：Trp；
·P9：Lys；
·P10：Thr；
p11: tyr; and
·P12：Arg。
7. a compound of formula I according to claim 1, wherein the amino acid residues in positions 1-12 are:
·P1：Arg；
·P2：Trp；
·P3：Leu；
·P4：Lys；
·P5：Lys；
·P6：Arg；
·P7：Arg；
·P8：Trp；
·P9：Lys；
·P10：Gln；
p11: tyr; and
·P12：Arg。
8. a compound of formula I according to claim 1, wherein the amino acid residues in positions 1-12 are:
·P1：Arg；
·P2：Trp；
·P3：Leu；
·P4：Val；
·P5：Lys；
·P6：Arg；
·P7：Arg；
·P8：Trp；
·P9：Lys；
·P10：Tyr；
p11: tyr; and
·P12：Arg。
9. a compound of formula I according to claim 1, wherein the amino acid residues in positions 1-12 are:
·P1：Arg；
·P2：Trp；
·P3：Leu；
·P4：Lys；
·P5：Lys；
·P6：Arg；
·P7：Arg；
·P8：Trp；
·P9：Val；
·P10：Tyr；
p11: tyr; and
·P12：Arg。
10. a compound of formula I according to claim 1, wherein the amino acid residues in 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: gln; and
·P12：Arg。
11. a pharmaceutical composition comprising a compound according to any one of claims 1 to 10 and a pharmaceutically inert carrier.
12. A composition according to claim 11 in a form suitable for oral, topical, transdermal, injection, buccal, transmucosal, pulmonary or inhalation administration.
13. A composition according to claim 11 or 12 in the form of a tablet, dragee, capsule, solution, liquid, gel, plaster, cream, ointment, syrup, slurry, suspension, spray or suppository.
14. The use of a compound according to any one of claims 1 to 10 in the manufacture of a medicament for the treatment or prophylaxis of infections or diseases associated with such infections.
15. Use according to claim 14, wherein the infection is associated with: respiratory diseases; skin or soft tissue diseases; gastrointestinal diseases; eye diseases; ear diseases; CNS disorders; bone disease; cardiovascular diseases; gastrourinal disease; cancer; or HIV.
16. Use according to claim 15, wherein the respiratory disease is selected from the group consisting of cystic fibrosis, emphysema and asthma; the skin or soft tissue disorder is selected from the group consisting of surgical wounds, and burns; the gastrointestinal disease is selected from the group consisting of epidemic diarrhea, necrotizing enterocolitis and cececeatitis; the eye disease is selected from keratitis and endophthalmitis; the otic disorder is otitis; the CNS disease is selected from brain abscess and meningitis; the bone disease is selected from osteochondritis and osteomyelitis; the cardiovascular disease is selected from endocarditis and pericarditis; the gastrourorinal disease is selected from epididymitis, prostatitis and urethritis.
17. Use of a compound according to any one of claims 1 to 10 for the preparation of disinfectants or preservatives for food, cosmetics and other nutrient-containing materials.
18. The use of a compound according to any one of claims 1 to 10 as a disinfectant or preservative for medicaments in the manufacture of medicaments.
19. A process for the manufacture of a compound according to any one of claims 1 to 10, which process comprises
(a) Coupling a suitably functionalized solid support with a suitably N-protected derivative of an amino acid at position 5, 6 or 7 in the desired end product, any functional groups that may be present in said N-protected amino acid derivative also being suitably protected;
(b) removing the N-protecting group from the product thus obtained;
(c) coupling the product thus obtained with a suitable N-protected derivative of an amino acid at a position closer to the N-terminal amino acid residue in the desired end product, any functional groups which may be present in said N-protected amino acid derivative also being suitably protected;
(d) removing the N-protecting group from the product thus obtained;
(e) repeating steps (c) and (d) until the N-terminal amino acid residue has been introduced;
(f) the product thus obtained is subjected to
(fa) withLCoupling of an appropriately N-protected derivative of Pro;
(fb) removing the N-protecting group from the product thus obtained;
(fc) reaction of the product thus obtained withDCoupling of an appropriately N-protected derivative of Pro;
(g) removing the N-protecting group from the product obtained in step (fc);
(h) coupling the product thus obtained with a suitable N-protected derivative of the amino acid at position 12 in the desired end product, any functional groups which may be present in said N-protected amino acid derivative also being suitably protected;
(i) removing the N-protecting group from the product thus obtained;
(j) coupling the product thus obtained with a suitable N-protected derivative of an amino acid at a position further away from position 12 in the desired end product, any functional groups which may be present in said N-protected amino acid derivative also being suitably protected;
(k) removing the N-protecting group from the product thus obtained;
(l) Repeating steps (j) and (k) until all amino acid residues have been introduced;
(m) optionally, selectively deprotecting one or several protected functional groups present in the molecule and appropriately substituting the reactive groups thus released;
(o) detaching the product thus obtained from the solid support;
(p) cyclizing the cleaved product from the solid support;
(q) optionally, forming one or two interchain bonds between side chains of appropriate amino acid residues at opposite positions of the β -strand region;
(r) removing any protecting groups present on the functional groups of any members of the chain of amino acid residues and, optionally, any protecting groups that may additionally be present in the molecule; and
(s) optionally, converting the product thus obtained into a pharmaceutically acceptable salt or converting a pharmaceutically acceptable or unacceptable salt thus obtained into the corresponding free compound of structural formula I or into a different pharmaceutically acceptable salt.
20. A process for the manufacture of a compound according to any one of claims 1 to 10, which process comprises
(a') A suitably functionalized solid support
(a' a) withLCoupling of an appropriately N-protected derivative of Pro;
(a' b) removing the N-protecting group from the product thus obtained;
(a' c) reacting the product thus obtained withDCoupling of an appropriately N-protected derivative of Pro;
(b ') removing the N-protecting group from the product obtained in step (a' c);
(c') coupling the product thus obtained with a suitable N-protected derivative of the amino acid at position 12 in the desired end product, any functional groups which may be present in said N-protected amino acid derivative also being suitably protected;
(d') removing the N-protecting group from the product thus obtained;
(e') coupling the product thus obtained with a suitable N-protected derivative of an amino acid at a position further away from position 12 in the desired end product, any functional groups which may be present in said N-protected amino acid derivative also being suitably protected;
(f') removing the N-protecting group from the product thus obtained;
(g ') repeating steps (e ') and (f ') until all amino acid residues have been introduced;
(h') optionally, selectively deprotecting one or several protected functional groups present in the molecule and appropriately substituting the reactive groups thus released;
(i') detaching the product thus obtained from the solid support;
(j') cyclizing the product cleaved from the solid support;
(k') optionally, forming one or two interchain bonds between side chains of appropriate amino acid residues at opposite positions of the β -strand region;
(l') removing any protecting groups present on the functional groups of any members of the chain of amino acid residues and, optionally, any protecting groups that may additionally be present in the molecule; and
(m') optionally, 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.
HK06101924.3A 2002-08-20 Template-fixed peptidomimetics with antibacterial activity HK1081561B (en)

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/EP2002/009278 WO2004018503A1 (en) 2002-08-20 2002-08-20 Template-fixed peptidomimetics with antibacterial activity

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Publication Number Publication Date
HK1081561A1 HK1081561A1 (en) 2006-05-19
HK1081561B true HK1081561B (en) 2010-11-26

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