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WO2001005748A1 - Oligomeric amino acid derivatives useful as nitric oxide synthase inhibitors - Google Patents

Oligomeric amino acid derivatives useful as nitric oxide synthase inhibitors Download PDF

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Publication number
WO2001005748A1
WO2001005748A1 PCT/US2000/019373 US0019373W WO0105748A1 WO 2001005748 A1 WO2001005748 A1 WO 2001005748A1 US 0019373 W US0019373 W US 0019373W WO 0105748 A1 WO0105748 A1 WO 0105748A1
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amino
independently selected
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French (fr)
Inventor
R. Keith Webber
Melvin L. Reuppel
Donald W. Hansen, Jr.
E. Ann Hallinan
Timothy J. Hagen
Barnett S. Pitzele
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Monsanto Co
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Monsanto Co
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    • C07C257/10—Compounds containing carboxyl groups, the doubly-bound oxygen atom of a carboxyl group being replaced by a doubly-bound nitrogen atom, this nitrogen atom not being further bound to an oxygen atom, e.g. imino-ethers, amidines with replacement of the other oxygen atom of the carboxyl group by nitrogen atoms, e.g. amidines
    • C07C257/14—Compounds containing carboxyl groups, the doubly-bound oxygen atom of a carboxyl group being replaced by a doubly-bound nitrogen atom, this nitrogen atom not being further bound to an oxygen atom, e.g. imino-ethers, amidines with replacement of the other oxygen atom of the carboxyl group by nitrogen atoms, e.g. amidines having carbon atoms of amidino groups bound to acyclic carbon atoms
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    • C07C323/60—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton with the carbon atom of at least one of the carboxyl groups bound to nitrogen atoms
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    • C07D241/06—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having one or two double bonds between ring members or between ring members and non-ring members
    • C07D241/08—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having one or two double bonds between ring members or between ring members and non-ring members with oxygen atoms directly attached to ring carbon atoms
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    • C07F9/28—Phosphorus compounds with one or more P—C bonds
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    • C07F9/44—Amides thereof
    • C07F9/4403—Amides thereof the acid moiety containing a substituent or a structure which is considered as characteristic
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    • C07F9/4461—Amides thereof the amide moiety containing a substituent or a structure which is considered as characteristic
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    • C07F9/6584—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms having phosphorus and nitrogen atoms with or without oxygen or sulfur atoms, as ring hetero atoms having one phosphorus atom as ring hetero atom
    • C07F9/65842—Cyclic amide derivatives of acids of phosphorus, in which one nitrogen atom belongs to the ring
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    • C07F9/6584—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms having phosphorus and nitrogen atoms with or without oxygen or sulfur atoms, as ring hetero atoms having one phosphorus atom as ring hetero atom
    • C07F9/65842—Cyclic amide derivatives of acids of phosphorus, in which one nitrogen atom belongs to the ring
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Definitions

  • the present invention relates to novel oligomeric amino acid derivatives and their use in therapy, in particular their use as nitric oxide synthase inhibitors.
  • NO nitric oxide
  • Nitric oxide is the endogenous stimulator of the soluble guanylate cyclase. In addition to endothelium-dependent relaxation, NO is involved in a number of biological
  • the NO released by the two constitutive enzymes acts as a transduction mechanism underlying several physiological responses.
  • the NO produced by the inducible enzyme is a cytotoxic molecule for tumor cells and invading microorganisms. It also appears that the adverse effects of excess NO production, in particular pathological vasodilation and tissue damage, may result largely from the effects of NO synthesized by the inducible NO synthase (Knowles and Moncada, Biochem J., 298, 249-258, 1994 Billiar et al., Annals of Surgery, 221, 339-349, 1995; Davies et al., 1995)
  • conditions in which there is an advantage in inhibiting NO production from L-arginine include autoimmune and/or inflammatory conditions affecting the joints, for example arthritis, and also inflammatory bowel disease, cardivascular ischemia, diabetes, congestive heart failure, myocarditis, atherosclerosis, migraine, reflux esophagitis, diarrhea, irritable bowel syndrome, cystic fibrosis, emphysema, asthma, bronchiectasis, hyperalgesia (allodynia), cerebral ischemia (both focal ischemia, thrombotic stroke and global ischemia (secondary to cardiac arrest), multiple sclerosis and other central nervous system disorders mediated by NO, for example Parkinson's disease and Alzheimer's disease, and other disorders mediated by NO including opiate tolerance in patients needing protracted opiate analgesics, and benzodiazepine tolerance in patients taking benzodiazepines, and other addictive behaviour, for example, nicotine and eating disorders (Kerwin et al., J.
  • Use of such a non-selective NO synthase inhibitor requires that great care be taken in order to avoid the potentially serious consequences of over- inhibition of the constitutive NO-synthase including hypertension and possible thrombosis and tissue damage.
  • L-NMMA for the treatment of toxic shock it has been recommended that the patient must be subject to continuous blood pressure monitoring throughout the treatment.
  • NO synthase inhibitors which are selective in the sense that they inhibit the inducible NO synthase to a considerably greater extent than the constitutive isoforms of NO synthase would be of even greater therapeutic benefit and easier to use (S. Moncada and E. Higgs, FASEB J., 9, 1319-1330, 1995).
  • the present invention is directed to novel compounds, pharmaceutical compositions and methods of using said compounds and compositions for inhibiting or modulating nitric oxide synthesis in a subject in need of such inhibition or modulation by administering a compound which preferentially inhibits or modulates the inducible isoform of nitric oxide synthase over the constitutive isoforms of nitric oxide synthase. It is also another object of the present invention to lower nitric oxide levels in a subject in need of such lowering.
  • I a , l , Ic, and I(j are independently selected from a structure of Formula II:
  • Formula (II) has a point of attachment for bonding to a linker B by replacement of a substituent group of Formula (II) independently selected from the group consisting of J ,
  • J and J are independently selected from the group consisting of OR , SR ,
  • OR S OR S, SR S, OR NR and SR NR with the proviso that A is R ;
  • J and J can be taken together forming J wherein J is connected to the carbon of
  • J 1 and J 2 by a covalent double bond and wherein J is independently selected from the
  • G is independently selected from the group consisting of O, S, CH2, CHR ,
  • A is independently selected from the group consisting of O, N(R ), S and heterocyclyl;
  • A can be independently selected from the group consisting of O, N(R ) and S
  • A can be independently selected from the group consisting of O, N(R ) and S
  • A can be independently selected from the group consisting of O, N(R ) and S
  • a spacer group selected from a linear moiety having a chain length of 1 to 3 atoms to form a heterocyclyl having from 7 to 10 members;
  • A can be independently selected from the group consisting of O, N(R ) and S
  • a spacer group selected from a linear moiety having a chain length of 1 to 4 atoms to form a heterocyclyl having from 6 to 10 members;
  • A can be independently selected from the group consisting of O, N(R ) and S connected to X by a substituent selected from hydroxyl, sulfhydryl, amino, carboxyl, and carbonyl substituents of group X by a spacer selected from the group consisting of a covalent bond and a linear moiety having a chain length of 1 to 4 atoms to form a heterocyclyl having from 5 to 10 members; 26 26
  • A can be R , wherein R is independently selected from the group consisting of hydrogen, formyl, hydroxyalkyl, alkenyl, alkynyl, acyl, aroyl, aralkanoyl, heteroaroyl, alkylsulfinylalkyl, alkylsulfonylalkyl, heteroaralkylthioalkyl, alkoxyalkyl, alkenyloxyalkyl, alkylthioalkyl, cycloalkylalkenyl, cycloalkenyl, haloalkyl, haloalkenyl, haloalkoxyalkyl, haloalkenyl oxy alkyl, halocycloalkenyloxyalkyl, cyanoalkyl, carboxy, carboxamido, carboalkoxy, dicyanoalkyl, carboxamidoalkyl, dicarboxamidoalkyl, cyanocarboalkoxyal
  • A can be R , wherein R is independently selected from the group consisting of
  • R and R are independently selected from the group consisting of hydrogen, hydroxyalkyl, aminoalkyl, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, haloalkyl,
  • R and R can be taken together forming a group selected from the group consisting of cycloalkyl radicals, cycloalkenyl radicals wherein said cycloalkyl radicals
  • cycloalkenyl radicals may be optionally substituted with one or more R or R substituents, aryl radicals, heteroaryl radicals, saturated heterocyclic radicals and partially saturated heterocyclic radicals wherein said radicals are 1 ,2-disubstituted and said 1,2-
  • R and R can be taken together forming a group selected from the group consisting of cis-l,2-disubstituted alkyls and cis-l,2-disubstituted alkenyls wherein said
  • R and R are independently selected from the group consisting of hydrogen
  • R and R can be taken together to form the group L-U-V wherein L is not identical to V, and L, U, and V are independently selected from the group consisting of O,
  • J H is independently selected from OR , SR , NHR ,
  • R and R can be taken together to form the group L-U-V wherein L is not identical to V, and L, U, and V are independently selected from the group consisting of cycloalkyl radical, cycloalkenyl radical wherein said cycloalkyl radical and cycloalkenyl
  • 30 31 radical may be optionally substituted with one or more R and R substituents, aryl radical, heteroaryl radical, saturated heterocyclic radical and partially saturated heterocyclic radical wherein said radicals are 1,2-disubstituted and said 1,2-substitutents
  • R is independently selected from the group consisting of hydrogen, aryl, heteroaralkyl, hydroxy, alkyl, alkenyl, alkynyl, amino, cyanoalkyl, dicyanoalkyl, carboxamidoalkyl, hydroxyalkyl, dicarboxamidoalkyl, cyanocarboalkoxyalkyl, carboalkoxyalkyl, dicarboalkoxyalkyl, cyanocycloalkyl, dicyanocycloalkyl, carboxamidocycloalkyl, dicarboxamidocycloalkyl, carboalkoxycyanocycloalkyl,
  • CH 2 OC(O)GR 15 CH 2 NR 19 C(O)GR 15 , CH 2 NR 19 C(S)GR 15 , CH 2 OC(S)GR 15 , 15 CH2SC(S)GR , heteroaryloxyalkyl, aralkyl, aryloxyalkyl, aralkoxyalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl, aralkylthioalkyl, heteroaralkoxythioalkyl, alkoxyalkyl, heteroaryloxyalkyl, alkenyloxyalkyl, alkylthioalkyl, arylthioalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkenyl, cycloalkenylalkyl, haloalkyl, haloalkenyl, halocycloalkyl, aralkyl
  • R , R and R can be taken together to form a spacer group consisting of a linear moiety having a chain length of 1 to 4 atoms to form a heterocyclyl having from 5 through 8 members;
  • R can be selected from a heterocyclyl radical in which there is at least one carbon in one ring and in which 1 to about 4 members of said ring are heteroatoms independently selected from oxygen, nitrogen and sulfur and said heterocyclyl radical may be optionally substituted with heteroarylamino, N-aryl-N-alkylamino, N-heteroarylamino-N-alkylamino, haloalkylthio, alkanoyloxy, alkoxy, heteroaralkoxy, cycloalkoxy, cycloalkenyloxy, hydroxy, amino, thio, nitro, lower alkylamino, alkylthio, alkylthioalkyl, arylamino, aralkylamino, arylthio, alkylsulfmyl, alkyl sulfonyl, alkylsulfonamido, alkylaminosulfonyl, amidosulfonyl, monoalkyl amidosulfon
  • R is independently selected from the group consisting of hydroxyalkyl, aminoalkyl, heteroaryloxyalkyl, alkyl, alkenyl, alkynyl, aryl, aralkyl, aryloxyalkyl, aralkoxyalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl, aralkylthioalkyl, heteroaralkoxythioalkyl, alkoxyalkyl, heteroaryloxyalkyl, alkenyloxyalkyl, alkylthioalkyl, arylthioalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkenyl, cycloalkenylalkyl, haloalkyl, haloalkenyl, halocycaralkylsulfinylalkyl, aralkylsulfonylalkyl
  • R is selected from the group consisting of hydrogen, aryl, heteroaralkyl, hydroxy, alkyl, alkenyl, alkynyl, amino, cyanoalkyl, dicyanoalkyl, carboxamidoalkyl, hydroxyalkyl, dicarboxamidoalkyl, cyanocarboalkoxyalkyl, carboalkoxyalkyl, dicarboalkoxyalkyl, cyanocycloalkyl, dicyanocycloalkyl, carboxamidocycloalkyl, dicarboxamidocycloalkyl, carboalkoxycyanocycloalkyl, carboalkoxycycloalkyl, dicarboalkoxycycloalkyl,
  • CH2OC(S)GR , CH2SC(S)GR heteroaryloxyalkyl, aralkyl, aryloxyalkyl, aralkoxyalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl, aralkylthioalkyl, heteroaralkoxythioalkyl, alkoxyalkyl, heteroaryloxyalkyl, alkenyloxyalkyl, alkylthioalkyl, arylthioalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkenyl, cycloalkenylalkyl, haloalkyl, haloalkenyl, halocycloalkyl, aralkylsulfinylalkyl, aralkylsulfonylalkyl, carboxyalkyl, carboalkoxyalkyl,
  • R , R and R can be taken together to form a spacer group selected from a linear moiety having a chain length of 1 to 4 atoms to form a heterocyclyl having from 5 to 8 members;
  • heterocyclyl radical in which there is at least one carbon in one ring and in which 1 to about 4 members of said ring are heteroatoms independently selected from oxygen, nitrogen and sulfur and said heterocyclyl radical may be optionally substituted with heteroarylamino, N-aryl-N-alkylamino, N-heteroarylamino-N-alkylamino, haloalkylthio, alkanoyloxy, alkoxy, heteroaralkoxy, cycloalkoxy, cycloalkenyloxy, hydroxy, amino, thio, nitro, lower alkylamino, alkylthio, alkylthioalkyl, arylamino, aralkylamino, arylthio, alkylsulfmyl, alkylsulfonyl, alkylsulfonamido, alkylaminosulfonyl, amidosulfonyl, monoalkyl amidosulfonyl, monoalkyl am
  • R 7 C(S)A-R ? , CH OC(O)A-R 7 , CH 2 NR 19 C(O)A-R 7 , CH 2 NR 19 C(S)A-R 7 ,
  • g R may be taken together with X to form a carbocyclic or a heterocyclic ring having from 3 to 8 members;
  • R is independently selected from aryloxy, amino, alkylamino, dialkylamino, hydroxyalkyl, heteroaryloxyalkyl, alkoxy, alkylthio, arylthio, alkyl, alkenyl, alkynyl, aryl, aralkyl, aryloxyalkyl, aralkoxyalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl, aralkylthioalkyl, heteroaralkoxythioalkyl, alkoxyalkyl, heteroaryloxyalkyl, alkenyloxyalkyl, alkylthioalkyl, arylthioalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkenyl, cycloalkenylalkyl, haloalkyl, haloalkenyl, haloaralkyl
  • R is independently selected from hydrido, aryloxy, amino, alkylamino, dialkylamino, hydroxyalkyl, heteroaryloxyalkyl, alkoxy, alkylthio, arylthio, alkyl, alkenyl, alkynyl, aryl, aralkyl, aryloxyalkyl, aralkoxyalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl, aralkylthioalkyl, heteroaralkoxythioalkyl, alkoxyalkyl, heteroaryloxyalkyl, alkenyloxyalkyl, alkylthioalkyl, arylthioalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkenyl, cycloalkenylalkyl, haloalkyl, haloalkenyl,
  • M is a pharmaceutically acceptable cation
  • X is selected from the group consisting of alkylene, alkenylene, alkynylene, -
  • R is selected from hydrogen, hydroxyl, alkyl, hydroxyalkyl, aminoalkyl, alkylaminoalkyl, alkoxyalkyl, haloalkyl, aryl, aralkyl, cycloalkylalkyl, and heterocyclylalkyl;
  • R is selected from hydroxyl and alkyl
  • Y is selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxyalkyl, cycloalkyl, cycloalkenyl, cycloalkenyloxy, alkenyloxyalkyl, alkylthioalkyl,
  • 9 10 9 10 alkylaminoalkyl and NR R wherein R and R are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, nitro, amino, hydroxy, alkoxy, aryl, heterocyclyl, and aralkyl; 9 10
  • R and R can be taken together to form a spacer group selected from a linear moiety having a chain length of 2 to 7 atoms to form a heterocyclyl having from 3 through 8 members;
  • R and R are independently selected from the group consisting of hydrogen, hydroxyalkyl, alkyl, alkenyl, alkynyl, aryl, aralkyl, aryloxyalkyl, acyl, aroyl, aralkanoyl, heteroaroyl, aralkoxyalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl, aralkylthioalkyl, heteroaralkylthioalkyl, alkoxyalkyl, heteroaryloxyalkyl, alkenyloxyalkyl, alkylthioalkyl, arylthioalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkenyl, cycloalkenylalkyl, haloalkyl, haloalkenyl, halocycloalkyl
  • R and R can be taken together to form a linear moiety spacer group having a chain length of 2 to 7 atoms and selected from the group consisting of a cycloalkyl having from 3 through 8 members, a cycloalkenyl having from 3 through 8 members, and a heterocyclyl having from 3 through 8 members;
  • R and R are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aralkyl, aryloxyalkyl, aralkoxyalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl, aralkylthioalkyl, heteroaralkylthioalkyl, alkoxyalkyl, heteroaryloxyalkyl, alkenyloxyalkyl, alkylthioalkyl, arylthioalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkenyl, cycloalkenylalkyl, haloalkyl, haloalkenyl, halocycloalkyl, halocycloalkenyl, halocycloalkyl, halocycloalkenyl, hal
  • R and R are independently selected from the group consisting of hydrogen, hydroxyalkyl, alkyl, alkenyl, alkynyl, aryl, aralkyl, aryloxyalkyl, aralkoxyalkyl, alkoxy, alkylsulfinylalkyl, alkylsulfonylalkyl, aralkylthioalkyl, heteroaralkylthioalkyl, alkoxyalkyl, heteroaryloxyalkyl, alkenyloxyalkyl, alkylthioalkyl, arylthioalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkenyl, cycloalkenylalkyl, haloalkyl, haloalkenyl, halocycloalkyl, halocycloalkenyl, haloalkoxyalkyl, haloalkenyl
  • R and R can be taken to form a linear moiety spacer group having a chain length of 4 to 7 atoms to form a heterocyclyl having from 5 through 8 members;
  • 26 R is independently selected from hydrogen, formyl, hydroxyalkyl, alkenyl, alkynyl, acyl, aroyl, aralkanoyl, heteroaroyl, alkylsulfinylalkyl, alkylsulfonylalkyl, heteroaralkylthioalkyl, alkoxyalkyl, alkenyloxyalkyl, alkylthioalkyl, cycloalkylalkenyl, cycloalkenyl, haloalkyl, haloalkenyl, haloalkoxyalkyl, haloalkenyloxyalkyl, halocycloalkenyloxyalkyl, cyanoalkyl, carboxy, carboxamido, carboalkoxy, dicyanoalkyl, carboxamidoalkyl, dicarboxamidoalkyl, cyanocarboalkoxyalkyl, carboalkoxyalkyl, di
  • R is independently selected from a group consisting of CH(R )CH2,
  • R and R are independently selected from hydroxy, thiol, aryloxy, amino, alkylamino, dialkylamino, hydroxyalkyl, heteroaryloxyalkyl, alkoxy, alkylthio, arylthio, alkyl, alkenyl, alkynyl, aryl, aralkyl, aryloxyalkyl, aralkoxyalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl, aralkylthioalkyl, heteroaralkoxythioalkyl, alkoxyalkyl, heteroaryloxyalkyl, alkenyloxyalkyl, alkylthioalkyl, arylthioalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkenyl, cycloalkenylalkyl, haloalkyl, haloal
  • R and R can be taken to form a linear moiety spacer group having a chain length of 2 to 7 atoms to form a group selected from the group consisting of a cycloalkyl having from 3 through 8 members, a cycloalkenyl having from 3 through 8 members, and a heterocyclyl having from 3 through 8 members;
  • B is a linker selected from the group consisting of B i , B2, B3, B4, B5, B6, B7, Bg,
  • B j is a linker connecting a first group independently selected from the group
  • linker is selected from the group consisting of a covalent single bond with the proviso that only one A is simultaneously O and S,
  • B2 is a linker connecting a first group independently selected from the group
  • 19 20 19 20 19 20 19 20 19 20 19 20 19 20 linker is selected from the group consisting of H]j nk -CR R (CR R )jCR R -Hji nk
  • H link -CR 7 R 20 (CR 7 R 2 °)jCR 7 R 20 -H link
  • H link -(CH2) u QQ(CH 2 )w-Hiink H link -
  • B2 can be a linker selected from the group consisting of natural amino acids and synthetic amino acids wherein said amino acids have two or more acylateable functional groups selected from the group consisting of primary amino, secondary amino, thiol, and hydroxy;
  • B3 is a linker connecting groups independently selected from the group consisting of
  • kk is an integer selected from 2 to 20 wherein said integer represents the number of acylateable functions present on said linker with a range of from two to the maximum number of acylateable functions present on said linker with the proviso that no more than 5 each of I a , l , Ic, and j are simultaneously.
  • linker is selected from the group consisting of polyhydroxy compound of carbon selected from the group consisting of polyhydroxyalkanes, saccharides, disaccharides, polysaccharides, inositols, alditols, alditol acetals, alditol ketals, aldaric acids, aldonic acids, aldonic acid lactones, and hydroxyalkylamines having 2 to 20 acylateable hydroxy groups;
  • B3 can be a linker selected from the group consisting of polyamino compounds of carbon selected from the group consisting of diaminoalkanes, diaminocycloalkanes, diaminoaryls, diaminoheterocycyls, diaminoalkylamines, triaminoalkylamines, diaminoalkylaminoalkylamines, and triaminoalkylaminoalkylamines, wherein said polyamino compounds have two to twenty acylateable amino groups, and compounds of carbon having one to nineteen hydroxy functions, one to nineteen amino functions and zero to eighteen thiol functions;
  • B4 is a linker connecting a first group independently selected from the group
  • R , R and R are independently selected from the group consisting of g hydrogen, hydroxy, and sulfhydryl and R is selected from the group consisting of hydroxyalkyl, aminoalkyl, alkylaminoalkyl and sulfhydrylalkyl to a second group independently selected from the group consisting of I a , lb, I c , and Ij through the point of bonding of a removable hydrogen of a substituent independently selected from a group of
  • B4 can be a linker selected from the group consisting of Ajj nk -
  • B5 is a linker connecting a first group independently selected from the group
  • R , R and R are independently selected from the group consisting of
  • R is selected from the group consisting of hydroxyalkyl, aminoalkyl, alkylaminoalkyl and sulfhydrylalkyl to a second group independently selected from the group consisting of I a , lb, I c , and lj through the points of
  • linker is selected from the group consisting of Du nk -
  • T is selected from the group consisting of a carbocyclic radical, aryl radical and a heterocyclyl radical, Dij nk is selected from a covalent single bond and
  • E ⁇ n is selected from the group consisting of a covalent single bond and
  • B6 is a linker connecting a first group independently selected from the group
  • R and R are both removeable hydrogens to a second group independently
  • linker is selected from the group consisting of Fij nk -CR R (CR R );CR R -
  • T-Gi jnk and Gij nk -T-E]j nk wherein j is selected from an integer of 0 to 18, u and w are independently selected from an integer of 1 to 8, x and y are independently selected from an integer of 0 to 8, Eij nk is selected from the group consisting of a covalent single bond
  • Fjj nk C(R ), and Gij n is a covalent double bond;
  • B7 is an amide and ester forming linker connecting groups independently selected
  • R , R and R are independently selected from g the group consisting of hydrogen, hydroxy, and sulfhydryl and R is selected from the group consisting of hydroxyalkyl, aminoalkyl, alkylaminoalkyl and sulfhydrylalkyl of said I a , l , I c , and Ij groups wherein the number of groups attached to said linker through the point of bonding of a removable hydrogen of a substituent independently selected from a
  • R , R and R are independently selected from the group consisting of hydrogen, hydroxy, and sulfhydryl g and R is selected from the group consisting of hydroxyalkyl, aminoalkyl, alkylaminoalkyl and sulfhydrylalkyl is kk wherein kk is an integer selected from 2 to 20 wherein said integer represents the number of amide and ester forming functions present on said linker with a range of from two to the ⁇ maximum number of amide and ester forming functions present on said linker with the proviso that no more than 5 each of I a , lb, Ic, and Ij are connected by said amide and ester forming linker wherein said amide and ester forming linker is selected from the group consisting of carboxylic acid compounds of carbon selected from synthetic amino acids, natural amino acids, aldaric acids, citric acid cycle intermediates, alkylpolycarbox
  • B7 can be an amide and ester forming linker selected from the group consisting of phosphoric acid compounds of carbon selected from the group consisting of phosphoric acid esters of saccharides, hydroxyaryls and heterocycles, phosphoric acid amides of amines, anilines, and arninoheterocycles wherein 2 to 20 acylating groups are present and said phosphoric acid compounds of carbon may be optionally substituted with acylating substituents selected from the group consisting of carboxylates, phosphonates, sulfonates, and sulfates and optionally substituted with one or more acylateable substituents selected from the group selected from amino, hydroxy, and sulfhydryl; B7 can be an amide and ester forming linker selected from the group consisting of phosphonic acid compounds of carbon selected from the group consisting of multiply phosphonoalkylated ammonia, primary amines, primary and secondary diamines, primary and secondary triamines, primary and secondary t
  • B7 can be an amide and ester forming linker selected from the group consisting of sulfonic acid compounds of carbon selected from the group consisting of multiply sulfonoalkylated ammonia, primary amines, primary and secondary diamines, primary and secondary triamines, primary and secondary tetramines, primary and secondary ethyleneimines, and primary and secondary propyleneiminines and multisulfonated alkanes, alkenes, alcohols, carboxylic acids, arenes, heterocyclyl radicals, and amino acids wherein 2 to 20 acylating groups are present and said sulfonic acid compounds of carbon may be optionally substituted with one or more acylating substituents selected from the group consisting of carboxylates, phosphates, phosphonates, and sulfates and optionally substituted with one or more acylateable substituents selected from the group selected from amino, hydroxy, and sulfhydryl;
  • B7 can be an amide and ester forming linker selected from the group consisting of sulfuric acid compounds of carbon selected from the group consisting of sulfuric acid esters of saccharides, hydroxy aryls and heterocycles, and sulfuric acid amides of amines, anilines, and aminoheterocycles wherein 2 to 20 acylating groups are present and said sulfuric acid compounds of carbon may be optionally substituted with one or more acylating substituents selected from the group consisting of carboxylates, phosphates, sulfonates, and phosphonates and optionally substituted with one or more acylateable substituents selected from the group selected from amino, hydroxy, and sulfhydryl;
  • B ⁇ is a linker connecting a first group independently selected from the group
  • R , R and R are independently selected from hydrogen, hydroxy, and sulfhydryl wherein said linker is selected from the group consisting of a covalent single bond with the proviso that R is other than hydroxy and sulfhydryl,
  • B9 is a linker connecting a first group independently selected from the group
  • R , R and R are independently g selected from the group consisting of hydrogen, hydroxy, and sulfhydryl and R is selected from the group consisting of hydroxyalkyl, aminoalkyl, alkylaminoalkyl and sulfhydrylalkyl and wherein said linker is selected from the group consisting of Hu n k- 1 90 19 20 19 20 7 20 7 20 7 20
  • B9 can be selected from the group consisting of bifunctional compounds of carbon wherein said compounds of carbon have one or more acylateable groups selected from the group consisting of primary amino, secondary amino, hydroxy, and sulfhydryl and one or more acylating groups selected from carboxy, thionocarboxy, sulfonyl, sulfate, sulfinyl, phosphate, and phosphonyl, wherein said compounds of carbon may be optionally
  • B 10 is linker connecting a first group independently selected from the group
  • x and y are independently selected from an integer of 0 to 8
  • Dij nk is selected from
  • Eij nk is selected from a group consisting of a covalent single bond and a covalent double bond with the proviso
  • B j j is a linker connecting a first group independently selected from the group
  • linker is selected from the group consisting of Hu n -
  • u and w are independently selected from an integer of 1 to 8
  • x and y are independently selected from an integer of 0 to 8
  • Dij nk is selected from a covalent single
  • B 12 is a linker connecting a first group independently selected from the group
  • B i3 is a linker connecting a first group independently selected from the group
  • B i4 is a linker connecting a first group independently selected from the group
  • R and R to a second group independently selected from the group consisting of I a , lb,
  • said linker consists of a double covalent bond connecting the point of attachment of J and
  • B i5 is a linker connecting a first group independently selected from the group
  • A is R , from the points of attachment of J , J and R where said linker
  • Alink is independently selected from the group consisting of covalent single bond,
  • Hunk is independently selected from the group consisting of a covalent single
  • N(R )P(O)R S N(R )P(S)R S, N(R )P(OR )R , N(R )P(O)R ,
  • NIL which is disclosed in WO 93/13055 when the hydrochloride salt can be isolated as a colorless crystal, but has the property of deliquescence. The compound quickly becomes a very viscous sticky oil upon exposure to moisture in normal room air which makes it difficult to handle.
  • pharmaceutically-acceptable salts embraces salts commonly used to form alkali metal salts and to form addition salts of free acids or free bases. The nature of the salt is not critical, provided that it is pharmaceutically acceptable.
  • Suitable pharmaceutically-acceptable acid addition salts of compounds of Formula I may be prepared from inorganic acid or from an organic acid. Examples of such inorganic acids are hydrochloric, hydrobromic, hydroiodic, nitric, carbonic, sulfuric and phosphoric acid.
  • Appropriate organic acids may be selected from aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic, carboxylic and sulfonic classes of organic acids, examples of which are formic, acetic, propionic, succinic, glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic, glucoronic, maleic, fumaric, pyruvic, aspartic, glutamic, benzoic, anthranilic, mesylic, salicylic, p-hydroxy benzoic, phenylacetic, mandelic, embonic (pamoic), methanesulfonic, ethylsulfonic, benzenesulfonic, sulfanilic, stearic, cyclohexylaminosulfonic, algenic, galacturonic acid.
  • organic acids may be selected from aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic
  • Suitable pharmaceutically- acceptable base addition salts of compounds of Formula I include metallic salts made from aluminum, calcium, lithium, magnesium, potassium, sodium and zinc or organic salts made from N,N'-dibenzylethyleneldiamine, choline, chloroprocaine, diethanolamine, ethylenediamine, meglumine (N-methylglucamine) and procain. All of these salts may be prepared by conventional means from the corresponding compound of Formula I by reacting, for example, the appropriate acid or base with the compound of Formula I.
  • the present invention provides a pharmaceutical composition comprising a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof, together with one or more pharmaceutically acceptable carriers thereof and optionally one or more other therapeutic ingredients.
  • the carrier(s) must be ⁇ acceptable ⁇ in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
  • the formulations include those suitable for oral, parenteral (including subcutaneous, intradermal, intramuscular, intravenous and intraarticular), rectal and topical (including dermal, buccal, sublingual and intraocular) administration although the most suitable route may depend upon for example the condition and disorder of the recipient.
  • the formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. All methods include the step of bringing into association a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof (iactive ingredient!) with the carrier which constitutes one or more accessory ingredients.
  • the formulations are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both and then, if necessary, shaping the product into the desired formulation.
  • Formulations of the present invention suitable for oral administration may be presented as discrete units such as capsules, cachets or tablets each containing a predetermined amount of the a ⁇ tive ingredient; as a powder or granules; as a solution or a suspension in an aqueous liquid or a non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion.
  • the active ingredient may also be presented as a bolus, electuary or paste.
  • a tablet may be made by compression or moulding, optionally with one or more accessory ingredients.
  • Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, lubricating, surface active or dispersing agent.
  • Molded tablets may be made by moulding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.
  • the tablets may optionally be coated or scored and may be formulated so as to provide slow or controlled release of the active ingredient therein.
  • Formulations for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain anti-oxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents.
  • the formulations may be presented in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example, saline, water-for-injection, immediately prior to use.
  • Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the kind previously described.
  • Formulations for rectal administration may be presented as a suppository with the usual carriers such as cocoa butter or polyethylene glycol.
  • Formulations for topical administration in the mouth include lozenges comprising the active ingredient in a flavored basis such as sucrose and acacia or tragacanth, and pastilles comprising the active ingredient in a basis such as gelatin and glycerin or sucrose and acacia.
  • Preferred unit dosage formulations are those containing an effective dose, as hereinbelow recited, or an appropriate fraction thereof, of the active ingredient.
  • formulations of this invention may include other agents conventional in the art having regard to the type of formulation in question, for example those suitable for oral administration may include flavoring agents.
  • the compounds of the invention may be administered orally or via injection at a dose of from 0.001 to 2500 mg/kg per day.
  • the dose range for adult humans is generally from 0.005 mg to 10 g/day.
  • Tablets or other forms of presentation provided in discrete units may conveniently contain an amount of compound of the invention which is effective at such dosage or as a multiple of the same, for instance, units containing 5 mg to 500 mg, usually around 10 mg to 200 mg.
  • the compounds of Formula I are preferably administered orally or by injection (intravenous or subcutaneous).
  • the precise amount of compound administered to a patient will be the responsibility of the attendant physician. However, the dose employed will depend on a number of factors, including the age and sex of the patient, the precise disorder being treated, and its severity. Also, the route of administration may vary depending on the condition and its severity.
  • the use of generic terms in the description of the compounds are herein defined for clarity.
  • alkyl either alone or within other terms such as “haloalkyl” and “alkylthio”, means an acyclic alkyl radical containing from 1 to about 10, preferably from 1 to about 8 carbon atoms and more preferably 1 to about 6 carbon atoms. Said alkyl radicals may be optionally substituted with groups as defined below.
  • radicals include methyl, ethyl, chloroethyl, hydroxyethyl, n-propyl, oxopropyl, isopropyl, n-butyl, cyanobutyl, isobutyl, sec -butyl, tert-butyl, pentyl, aminopentyl, iso- amyl, hexyl, octyl and the like.
  • alkenyl refers to an unsaturated, acyclic hydrocarbon radical in so much as it contains at least one double bond. Such radicals containing from about 2 to about 10 carbon atoms, preferably from about 2 to about 8 carbon atoms and more preferably 2 to about 6 carbon atoms. Said alkenyl radicals may be optionally substituted with groups as defined below.
  • alkenyl radicals examples include propylenyl, 2-chloropropylenyl, buten-1-yl, isobutenyl, pentenylen-1-yl, 2-2-methylbuten-l-yl, 3- methylbuten-1-yl, hexen-1-yl, 3-hydroxyhexen-l-yl, hepten-1-yl, and octen-1-yl, and the like.
  • alkynyl refers to an unsaturated, acyclic hydrocarbon radical in so much as it contains one or more triple bonds, such radicals containing about 2 to about 10 carbon atoms, preferably having from about 2 to about 8 carbon atoms and more preferably having 2 to about 6 carbon atoms. Said alkynyl radicals may be optionally substituted with groups as defined below.
  • alkynyl radicals examples include ethynyl, propynyl, hydroxypropynyl, butyn-1-yl, butyn-2-yl, pentyn-1-yl, pentyn-2-yl, 4-methoxypentyn-2-yl, 3-methylbutyn-l-yl, hexyn-1-yl, hexyn-2-yl, hexyn-3-yl, 3,3-dimethylbutyn-l-yl radicals and the like.
  • hydro denotes a single hydrogen atom (H). This hydrido radical may be attached, for example, to an oxygen atom to form a "hydroxyl” radical, one hydrido radical may be attached to a carbon atom to form a "methine” radical
  • carbon radical denotes a carbon atom without any covalent bonds and capable of forming four covalent bonds.
  • cyano denotes a carbon radical having three of four covalent bonds shared by a nitrogen atom.
  • hydroxyalkyl embraces radicals wherein any one or more of the alkyl carbon atoms is substituted with a hydroxyl as defined above. Specifically embraced are monohydroxyalkyl, dihydroxyalkyl and polyhydroxyalkyl radicals.
  • alkanoyl embraces radicals wherein one or more of the terminal alkyl carbon atoms are substituted with one or more carbonyl radicals as defined below. Specifically embraced are monocarbonylalkyl and dicarbonylalkyl radicals. Examples of monocarbonylalkyl radicals include formyl, acetyl, and pentanoyl. Examples of dicarbonylalkyl radicals include oxalyl, malonyl, and succinyl.
  • alkylene radical denotes linear or branched radicals having from 1 to about 10 carbon atoms and having attachment points for two or more covalent bonds. Examples of such radicals are methylene, ethylene, methylethylene, and isopropylidene.
  • halo means halogens such as fluorine, chlorine, bromine or iodine atoms.
  • haloalkyl embraces radicals wherein any one or more of the alkyl carbon atoms is substituted with halo as defined above. Specifically embraced are monohaloalkyl, dihaloalkyl and polyhaloalkyl radicals.
  • a monohaloalkyl radical for one example, may have either a bromo, chloro or a fluoro atom within the radical.
  • Dihalo radicals may have two or more of the same halo atoms or a combination of different halo radicals and polyhaloalkyl radicals may have more than two of the same halo atoms or a combination of different halo radicals.
  • More preferred haloalkyl radicals are "lower haloalkyl" radicals having one to about six carbon atoms.
  • haloalkyl radicals include fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl and dichloropropyl.
  • hydroxyhaloalkyl embraces radicals wherein any one or more of the haloalkyl carbon atoms is substituted with hydroxy as defined above.
  • haloalkylene radical denotes alkylene radicals wherein any one or more of the alkylene carbon atoms is substituted with halo as defined above.
  • Dihalo alkylene radicals may have two or more of the same halo atoms or a combination of different halo radicals and polyhaloalkylene radicals may have more than two of the same halo atoms or a combination of different halo radicals.
  • More preferred haloalkylene radicals are "lower haloalkylene” radicals having one to about six carbon atoms. Examples of “haloalkylene” radicals include difluoromethylene, tetrafluoroethylene, tetrachloroethylene, alkyl substituted monofluoromethylene, and aryl substituted trifluoromethylene.
  • haloalkenyl denotes linear or branched radicals having from 1 to about 10 carbon atoms and having one or more double bonds wherein any one or more of the alkenyl carbon atoms is substituted with halo as defined above.
  • Dihaloalkenyl radicals may have two or more of the same halo atoms or a combination of different halo radicals and polyhaloalkenyl radicals may have more than two of the same halo atoms or a combination of different halo radicals.
  • alkoxy and “alkoxyalkyl” embrace linear or branched oxy- containing radicals each having alkyl portions of one to about ten carbon atoms, such as methoxy radical.
  • alkoxyalkyl also embraces alkyl radicals having one or more alkoxy radicals attached to the alkyl radical, that is, to form monoalkoxyalkyl and dialkoxyalkyl radicals. More preferred alkoxy radicals are "lower alkoxy" radicals having one to six carbon atoms. Examples of such radicals include methoxy, ethoxy, propoxy, butoxy and tert-butoxy alkyls.
  • the "alkoxy" radicals may be further substituted with one or more halo atoms, such as fluoro, chloro or bromo, to provide "haloalkoxy" radicals.
  • radicals include fluoromethoxy, chloromethoxy, trifluorometh ⁇ xy, difluoromethoxy, trifluoroethoxy, fluoroethoxy, tetrafluoroethoxy, pentafluoroethoxy, and fluoropropoxy.
  • haloalkoxyalkyl also embraces alkyl radicals having one or more haloalkoxy radicals attached to the alkyl radical, that is, to form monohaloalkoxyalkyl and dihaloalkoxyalkyl radicals.
  • haloalkenyloxy also embraces oxygen radicals having one or more haloalkenyloxy radicals attached to the oxygen radical, that is, to form monohaloalkenyloxy and dihaloalkenyloxy radicals.
  • haloalkenyloxyalkyl also embraces alkyl radicals having one or more haloalkenyloxy radicals attached to the alkyl radical, that is, to form monohaloalkenyloxyalkyl and dihaloalkenyloxyalkyl radicals.
  • alkylenedioxy denotes alkylene radicals having at least two oxygens bonded to a single alkylene group.
  • alkylenedioxy examples include methylenedioxy, ethylenedioxy, alkylsubstituted methylenedioxy, and arylsubstituted methylenedioxy.
  • haloalkylenedioxy denotes haloalkylene radicals having at least two oxy groups bonded to a single haloalkyl group.
  • haloalkylenedioxy radicals include difluoromethylenedioxy, tetrafluoroethylenedioxy, tetrachluoroethylenedioxy, alkylsubstituted monofluoromethylenedioxy, and arylsubstituted monofluoromethylenedioxy.
  • aryl alone or in combination, means a carbocyclic aromatic system containing one, two or three rings wherein such rings may be attached together in a pendent manner or may be fused.
  • aryl embraces aromatic radicals such as phenyl, naphthyl, tetrahydronaphthyl, indane and biphenyl.
  • perhaloaryl embraces aromatic radicals such as phenyl, naphthyl, tetrahydronaphthyl, indane and biphenyl wherein the aryl radical is substituted with 3 or more halo radicals as defined below.
  • heterocyclyl embraces saturated, partially saturated and unsaturated heteroatom-containing ring-shaped radicals, where the heteroatoms may be selected from nitrogen, sulfur and oxygen.
  • saturated heterocyclic radicals include saturated 3 to 6-membered heteromonocylic group containing 1 to 4 nitrogen atoms[e.g. pyrrolidinyl, imidazolidinyl, piperidino, piperazinyl, etc.]; saturated 3 to 6- membered heteromonocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms [e.g.
  • saturated 3 to 6-membered heteromonocyclic group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms e.g., thiazolidinyl, etc.
  • partially saturated heterocyclyl radicals include dihydrothiophene, dihydropyran, dihydrofuran and dihydrothiazole.
  • heteroaryl radicals examples include unsaturated 5 to 6 membered heteromonocyclyl group containing 1 to 4 nitrogen atoms, for example, pyrrolyl, pyrrolinyl, imidazolyl, pyraz ⁇ lyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, triazolyl [e.g., 4H-l,2,4-triazolyl, lH-l,2,3-triazolyl, 2H-1,2,3- triazolyl, etc.] tetrazolyl [e.g.
  • unsaturated condensed heterocyclic group containing 1 to 5 nitrogen atoms for example, indolyl, isoindolyl, indolizinyl, benzimidazolyl, quinolyl, isoquinolyl, indazolyl, benzotriazolyl, tetrazolopyridazinyl [e.g., tetrazolo [l,5-b]pyridazinyl, etc.], etc.; unsaturated 3 to 6-membered heteromonocyclic group containing an oxygen atom, for example, pyranyl, 2-furyl, 3-furyl, etc.; unsaturated 5 to 6-membered heteromonocyclic group containing a sulfur atom, for example, 2-thienyl, 3-thienyl, etc.; unsaturated 5- to 6-membered heteromonocyclic group containing 1 to 2 oxygen
  • benzoxazolyl, benzoxadiazolyl, etc.] unsaturated 5 to 6-membered heteromonocyclic group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms, for example, thiazolyl, thiadiazolyl [e.g., 1,2,4- thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5- thiadiazolyl, etc.] etc.; unsaturated condensed heterocyclic group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms [e.g., benzothiazolyl, benzothiadiazolyl, etc.] and the like.
  • the term also embraces radicals where heterocyclic radicals are fused with aryl radicals.
  • fused bicyclic radicals examples include benzofuran, benzothiophene, and the like.
  • Said "heterocyclyl" group may have 1 to 3 substituents as defined below.
  • Preferred heterocyclic radicals include five to ten membered fused or unfused radicals.
  • heterocyclic radicals include pyrrolyl, pyridinyl, pyrazolyl, triazolyl, pyrimidinyl, pyridazinyl, oxazolyl, thiazolyl, imidazolyl, indolyl, thiophenyl, furanyl, tetrazolyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrrolindinyl, 1 ,3-dioxolanyl, 2-imidazolinyl, imidazolidinyl, 2-pyrazolinyl, pyrazolidinyl, isoxazolyl, isothiazolyl, 1,2,3-oxadiazolyl, 1 ,2,3-triazolyl, 1,3,4- thiadiazolyl, 2H-pyranyl, 4H-pyranyl, piperidinyl, 1,4-dioxanyl, morpholinyl, 1,4- dithianyl,
  • alkylsulfonyl embraces alkyl radicals attached to a sulfonyl radical, where alkyl is defined as above.
  • Alkylsulfonylalkyl embraces alkylsulfonyl radicals attached to an alkyl radical, where alkyl is defined as above.
  • Haloalkylsulfonyl embraces haloalkyl radicals attached to a sulfonyl radical, where haloalkyl is defined as above.
  • Haloalkylsulfonylalkyl embraces haloalkylsulfonyl radicals attached to an alkyl radical, where alkyl is defined as above.
  • the term “aminosulfonyl” denotes an amino radical attached to a sulfonyl radical.
  • Alkylsulfmyl embraces alkyl radicals attached to a sulfinyl radical, where alkyl is defined as above.
  • Alkylsulfinylalkyl embraces alkylsulfmyl radicals attached to an alkyl radical, where alkyl is defined as above.
  • Haloalkylsulfinyl embraces haloalkyl radicals attached to a sulfinyl radical, where haloalkyl is defined as above.
  • Haloalkylsulfinylalkyl embraces haloalkylsulfinyl radicals attached to an alkyl radical, where alkyl is defined as above.
  • aralkyl embraces aryl-substituted alkyl radicals.
  • Preferable aralkyl radicals are "lower aralkyl” radicals having aryl radicals attached to alkyl radicals having one to six carbon atoms. Examples of such radicals include benzyl, diphenylmethyl, triphenylmethyl, phenylethyl and diphenylethyl. The terms benzyl and phenylmethyl are interchangeable.
  • heteroarylkyl embraces heteroaryl-substituted alkyl radicals wherein the heteroaralkyl radical may be additionally substituted with three or more substituents as defined above for aralkyl radicals.
  • perhaloaralkyl embraces aryl-substituted alkyl radicals wherein the aralkyl radical is substituted with three or more halo radicals as defined above.
  • aralkylsulfinyl embraces aralkyl radicals attached to a sulfinyl radical, where aralkyl is defined as above.
  • Aralkylsulfinylalkyl embraces aralkylsulfinyl radicals attached to an alkyl radical, where alkyl is defined as above.
  • Alkylsulfonyl embraces aralkyl radicals attached to a sulfonyl radical, where aralkyl is defined as above.
  • Alkylsulfonylalkyl embraces aralkylsulfonyl radicals attached to an alkyl radical, where alkyl is defined as above.
  • cycloalkyl embraces radicals having three to ten carbon atoms.
  • More preferred cycloalkyl radicals are "lower cycloalkyl” radicals having three to seven carbon atoms. Examples include radicals such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.
  • the term "cycloalkylalkyl” embraces cycloalkyl-substituted alkyl radicals.
  • Preferable cycloalkylalkyl radicals are "lower cycloalkylalkyl” radicals having cycloalkyl radicals attached to alkyl radicals having one to six carbon atoms. Examples of such radicals include cyclohexylhexyl.
  • cycloalkenyl embraces radicals having three to ten carbon atoms and one or more carbon-carbon double bonds.
  • Preferred cycloalkenyl radicals are "lower cycloalkenyl” radicals having three to seven carbon atoms. Examples include radicals such as cyclobutenyl, cyclopentenyl, cyclohexenyl and cycloheptenyl.
  • halocycloalkyl embraces radicals wherein any one or more of the cycloalkyl carbon atoms is substituted with halo as defined above. Specifically embraced are monohalocycloalkyl, dihalocycloalkyl and polyhalocycloalkyl radicals.
  • a monohalocycloalkyl radical may have either a bromo, chloro or a fluoro atom within the radical.
  • Dihalo radicals may have two or more of the same halo atoms or a combination of different halo radicals and polyhalocycloalkyl radicals may have more than two of the same halo atoms or a combination of different halo radicals.
  • More preferred halocycloalkyl radicals are "lower halocycloalkyl" radicals having three to about eight carbon atoms.
  • halocycloalkyl radicals examples include fluorocyclopropyl, difluorocyclobutyl, trifluorocyclopentyl, tetrafluorocyclohexyl, and dichlorocyclopropyl.
  • halocycloalkenyl embraces radicals wherein any one or more of the cycloalkenyl carbon atoms is substituted with halo as defined above. Specifically embraced are monohalocycloalkenyl, dihalocycloalkenyl and polyhalocycloalkenyl radicals.
  • halocycloalkoxy also embraces cycloalkoxy radicals having one or more halo radicals attached to the cycloalkoxy radical, that is, to form monohalocycloalkoxy, dihalocycloalkoxy, and polycycloalkoxy radicals.
  • Cycloalkylsulfinyl embraces cycloalkyl radicals attached to a sulfinyl radical, where cycloalkyl is defined as above.
  • Cycloalkylsulfinylalkyl embraces cycloalkylsulfinyl radicals attached to an alkyl radical, where alkyl is defined as above.
  • Cycloalkylsulfonyl embraces cycloalkyl radicals attached to a sulfonyl radical, where cycloalkyl is defined as above.
  • Cycloalkylsulfonylalkyl embraces cycloalkylsulfonyl radicals attached to an alkyl radical, where alkyl is defined as above.
  • alkylthio embraces radicals containing a linear or branched alkyl radical, of one to ten carbon atoms, attached to a divalent sulfur atom. More preferred alkylthio radicals are "lower alkylthio" radicals having one to six carbon atoms. An example of “lower alkylthio” is methylthio (CH3-S-).
  • alkylamino denotes “monoalkylamino” and “dialkylamino” containing one or two alkyl radicals, respectively, attached to an amino radical.
  • arylamino denotes “monoarylamino” and “diarylamino” containing one or two aryl radicals, respectively, attached to an amino radical.
  • Aralkylamino embraces aralkyl radicals attached to an amino radical, where aralkyl is defined as above.
  • aralkylamino denotes “monoaralkylamino” and “diaralkylamino” containing one or two aralkyl radicals, respectively, attached to an amino radical.
  • aralkylamino further denotes "monoaralkyl monoalkylamino" containing one aralkyl radical and one alkyl radical attached to an amino radical.
  • arylsulfinylalkyl denotes arylsulfinyl radicals attached to a linear or branched alkyl radical, of one to ten carbon atoms.
  • Arylsulfonyl embraces aryl radicals attached to a sulfonyl radical, where aryl is defined as above.
  • Arylsulfonylalkyl embraces arylsulfonyl radicals attached to an alkyl radical, where alkyl is defined as above.
  • heteroarylsulfinylalkyl denotes heteroarylsulfinyl radicals attached to a linear or branched alkyl radical, of one to ten carbon atoms.
  • Heteroarylsulfonyl embraces heteroaryl radicals attached to a sulfonyl radical, where heteroaryl is defined as above.
  • Heteroarylsulfonylalkyl embraces heteroarylsulfonyl radicals attached to an alkyl radical, where alkyl is defined as above.
  • aryloxy embraces aryl radicals, as defined above, attached to an oxygen atom. Examples of such radicals include phenoxy.
  • aroyl embraces aryl radicals, as defined above, attached to an carbonyl radical as defined above. Examples of such radicals include benzoyl and toluoyl.
  • aralkanoyl embraces aralkyl radicals, as defined herein, attached to an carbonyl radical as defined above. Examples of such radicals include, for example, phenylacetyl.
  • aralkoxy embraces oxy-containing aralkyl radicals attached through an oxygen atom to other radicals. More preferred aralkoxy radicals are "lower aralkoxy” radicals having phenyl radicals attached to lower alkoxy radical as described above.
  • aryloxyalkyl embraces aryloxy radicals, as defined above, attached to an alkyl group. Examples of such radicals include phenoxymethyl.
  • haloaryloxyalkyl embraces aryloxyalkyl radicals, as defined above, wherein one to five halo radicals are attached to an aryloxy group.
  • heteroaryloxy embraces heteroaryl radicals, as defined above, attached to an oxygen atom. Examples of such radicals include pyridyloxy and furyloxy.
  • heteroaroyl embraces heteroaryl radicals, as defined above, attached to an carbonyl radical as defined above. Examples of such radicals include furoyl and nicotinyl.
  • heteroaralkanoyl embraces heteroaralkyl radicals, as defined herein, attached to an carbonyl radical as defined above. Examples of such radicals include, for example, pyridylacetyl and furylbutyryl.
  • heteroaralkoxy embraces oxy-containing heteroaralkyl radicals attached through an oxygen afom to other radicals. More preferred heteroaralkoxy radicals are "lower heteroaralkoxy” radicals having heteroaryl radicals attached to lower alkoxy radical as described above.
  • heteroaryloxyalkyl embraces heteroaryloxy radicals, as defined above, attached to an alkyl group. Examples of such radicals include pyridyloxy methyl .
  • haloheteroaryloxyalkyl embraces heteroaryloxyalkyl radicals, as defined above, wherein one to four halo radicals are attached to an heteroaryloxy group.
  • arylthio embraces aryl radicals, as defined above, attached to an sulfur atom. Examples of such radicals include phenylthio.
  • arylthioalkyl embraces arylthio radicals, as defined above, attached to an alkyl group. Examples of such radicals include phenylfhiomefhyl.
  • alkylthioalkyl embraces alkylthio radicals, as defined above, attached to an alkyl group. Examples of such radicals include methylthiomethyl.
  • alkoxyalkyl embraces alkoxy radicals, as defined above, attached to an alkyl group. Examples of such radicals include methoxy methyl.
  • carbonyl denotes a carbon radical having two of the four covalent bonds shared with an oxygen atom.
  • carboxy embraces a hydroxyl radical, as defined above, attached to one of two unshared bonds in a carbonyl group.
  • carboxamide embraces amino, monoalkylamino, and dialkylamino radicals, attached to one of two unshared bonds in a carbonyl group.
  • carboxyalkyl embraces carboxamide radicals, as defined above, attached to an alkyl group.
  • carboxy radical as defined above, attached to an alkyl group.
  • carbboalkoxy embraces alkoxy radicals, as defined above, attached to one of two unshared bonds in a carbonyl group.
  • carboaralkoxy embraces aralkoxy radicals, as defined above, attached to one of two unshared bonds in a carbonyl group.
  • the term "monocarboalkoxyalkyl” embraces one carboalkoxy radical, as defined above, attached to an alkyl group.
  • the term “dicarboalkoxyalkyl” embraces two carboalkoxy radicals, as defined above, attached to an alkylene group.
  • the term “monocyanoalkyl” embraces one cyano radical, as defined above, attached to an alkyl group.
  • the term “dicyanoalkylene” embraces two cyano radicals, as defined above, attached to an alkyl group.
  • the term “carboalkoxycyanoalkyl” embraces one cyano radical, as defined above, attached to an alkylene group.
  • acyl alone or in combination, means a carbonyl or thionocarbonyl group bonded to a radical selected from, for example, hydrido, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, alkoxyalkyl, haloalkoxy, aryl, heterocyclyl, heteroaryl, alkylsulfinylalkyl, alkylsulfonylalkyl, aralkyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, alkylthio, arylthio, amino, alkylamino, dialkylamino, aralkoxy, arylthio, and alkylthioalkyl.
  • acyl are formyl, acetyl, benzoyl, trifluoroacetyl, phthaloyl, malonyl, nicotinyl, and the like.
  • haloalkanoyl embraces one or more halo radicals, as defined herein, attached to an alkanoyl radical as defined above. Examples of such radicals include, for example, chloroacetyl, trifluoroacetyl, bromopropanoyl, and heptafluorobutyryl.
  • phosphono embraces a pentavalent phosphorus attached with two covalent bonds to an oxygen radical.
  • dialkoxyphosphono denotes two alkoxy radicals, as defined above, attached to a phosphono radical with two covalent bonds.
  • diaralkoxyphosphono denotes two aralkoxy radicals, as defined above, attached to a phosphono radical with two covalent bonds.
  • dialkoxyphosphonoalkyl denotes dialkoxyphosphono radicals, as defined above, attached to an alkyl radical.
  • diaralkoxyphosphonoalkyl denotes diaralkoxyphosphono radicals, as defined above, attached to an alkyl radical.
  • alkylsulfonyl "alkylsulfonyl", “alkylsulfonylalkyl", “haloalkylsulfonylalkyl", “alkylsulfmyl", “alkylsulfinylalkyl”, “haloalkylsulfinylalkyl", “aralkyl”, “heteroaralkyl”, “perhaloaralkyl”, “aralkylsulfonyl”, “aralkylsulfonylalkylalkyl", “aralkylsulfinylalkylalkyl", “cycloalkyl", “cycloalkenyl”, “halocycloalkyl”, “halocycloalkenyl”, “cyclocycloalkenyl”, “cyclocycloalkenyl”, “cyclocycloalkenyl”, “cyclocycloalkenyl”, “cyclocycloalkenyl”, “cyclocycloalkenyl",
  • spacer can include a covalent bond and a linear moiety having a backbone of 1 to 7 continuous atoms.
  • the spacer may have 1 to 7 atoms of a univalent or multi-valent chain.
  • Multi-valent chains may consist of a straight chain of 1 or 2 or 3 or 4 or 5 or 6 or 7 atoms or a straight chain of 1 or 2 or 3 or 4 or 5 or 6 or 7 atoms with a side chain.
  • Side chains may include substituents such as heteroarylamino, N-aryl-N-alkylamino, N-heteroarylamino-N-alkylamino, haloalkylthio, alkanoyloxy, alkoxy, heteroaralkoxy, cycloalkoxy, cycloalkenyloxy, hydroxy, amino, thio, lower alkylamino, alkylthio, alkylthioalkyl, arylamino, aralkylamino, arylthio, alkylsulfmyl, alkylsulfonyl, alkylsulfonamido, alkylaminosulfonyl, amidosulfonyl, monoalkyl amidosulfonyl, dialkyl amidosulfonyl, monoarylamidosulfonyl, arylsulfonamido, diarylamidosulfonyl, monoalkyl monoaryl amidosulf
  • prodrug refers to a compound that is made more active in vivo.
  • treatment of a patient is intended to include prophylaxis.
  • Compounds of the present invention can exist in tautomeric, geometric or stereoisomeric forms.
  • the present invention contemplates all such compounds, including cis- and trans-geometric isomers, E- and Z-geometric isomers, R- and S-enantiomers, diastereomers, d-isomers, 1-isomers, the racemic mixtures thereof and other mixtures thereof, as falling within the scope of the invention.
  • Pharmaceutically acceptable sales of such tautomeric, geometric or stereoisomeric forms are also included within the invention.
  • cis and trans denote a form of geometric isomerism in which two carbon atoms connected by a double bond will each have two highes ranking groups on the same side of the double bond ("cis") or on opposite sides of the double bond (“trans”).
  • Some of the compounds described contain alkenyl groups, and are meant to include both cis and trans or "E” and “Z” geometric forms.
  • oligomeric denotes a form of compound in which two to about twenty analogous units of similar function and biological activity are covalently joined one to another directly, through a linker compound, through a mixture of linker compounds, or through a combination of the aforementioned means.
  • linker denotes a covalent bond and any group of atoms that covalently joins together two to twenty analogous units of similar function and biological activity.
  • linker compound denotes any inorganic and organic material and compound able to covalently join together two to twenty analogous units of similar function and biological activity.
  • removable hydrogen denotes a hydrogen that can be removed by reaction with a base or removed by replacement by an alkylating or acylating reagent.
  • Said hydrogen removing base will have a pK a of a minimum of about 15 relative to water when, for example, a hydrogen is to be removed from a carboxylic acid, a phenol, a sulfate acid, a phosphate acid, an acetoacetate, a malonate, mercaptan, dinitriles, nitroalkane, and the like.
  • Suitable bases having a pKa of about 15 include potassium hydroxide, sodium carbonate, sodium methoxide, triethylamine, sodium ethoxide, tetrabutylammonium hydroxide, and the like.
  • the base will have a pK a up to about 30 so that a hydrogen can be removed in a substantially complete manner from alcohols, amides, mononitriles, monoesters, and the like.
  • Examples of preferable bases include potassium tert-butoxide, sodium hydride, sodium amide, lithium diisopropylamine and the like.
  • Acylating reagents able to remove a hydrogen by replacement include anhydrides of carboxylic acids and halides (for example, chloride) of carboxylic acids, sulfate acids, phosphate acids, phosphonate acids and the like.
  • the term "bifunctional compounds of carbon” denotes linker compounds having two types of functional substituents.
  • One type of functional substituent group can be acylated.
  • Acylateable groups include primary amino, secondary amino, hydroxy, sulfhydryl, and the like.
  • the second type of functional substituent are those that can acylate functional substituents.
  • Acylating groups include carboxy, thionocarboxy, sulfonyl, sulfate, sulfinyl, phosphate, and phosphonyl. Most preferred are activated forms of the said acylating groups where the hydroxy function or salt form are converted into more reactive intermediates such as esters, chlorides, azides, cyanides, oxyimides, isoureas, mixed anhydrides, and the like.
  • bifunctional compounds of carbon include natural and synthetic amino acids such as glycine, alanine, lysine, glutamate, ornithine, serine, threonine, phenylalanine, tyrosine, valine, 4-aminobutanoic acid, and the like, peptides, sugar phosphates such as glycerol phosphate, glucose-6- phosphate, aldonic acids such glucuronic acid, aldaric acids such as glucaric acid, aminoalkylphosphonic acids such as aminomethylphosphonic acid, N,N-bis- phosphonome thy 1 amine, aminoarylcarboxylic acids such as 4-aminobenzoic acid.
  • natural and synthetic amino acids such as glycine, alanine, lysine, glutamate, ornithine, serine, threonine, phenylalanine, tyrosine, valine, 4-aminobutanoic acid, and the like, peptid
  • Some of the compounds described contain one or more stereocenters and are meant to include R, S, and mixtures of R and S forms for each stereocenter present.
  • Some of the compounds described herein may contain one or more ketonic or aldehydic carbonyl groups or combinations thereof alone or as part of a heterocyclic ring system.
  • Such carbonyl groups may exist in part or principally in the "keto” form and in part or principally as one or more "enol” forms of each aldehyde and ketone group present.
  • Compounds of the present invention having aldehydic or ketonic carbonyl groups are meant to include both “keto” and “enol” tautomeric forms.
  • Some of the compounds described herein may contain one or more imine or enamine groups or combinations thereof. Such groups may exist in part or principally in the “imine” form and in part or principally as one or more "enamine” forms of each group present. Compounds of the present invention having said imine or enamine groups are meant to include both “imine” and “enamine” tautomeric forms. The following general synthetic sequences are useful in making the present invention.
  • AA represents amino acids
  • Boc represents tert-butyloxycarbonyl
  • BOP represents benzotriazol- 1 -yl-oxy- tris-(dimethylamino)phosphonium hexafluorophosphate
  • Bz represents a benzyl group
  • CMR-C1 represents a chloromethylation or bromomethylation reagent such as Cl- CH 2 OC(O)R 15 , Cl-CH 2 NR 19 C(O)R 15 , C1-CH NR 19 C(S)R 15 , Cl-CH 2 SC(O)R 15 , Cl- CH 2 SC(S)R 15 , Cl-CH 2 OC(O)GR 15 , Cl-CH 2 NR 19 C(O)GR 15 , C1-CH 2 NR 19 C(S)GR 15 , Cl-CH 2 OC(S)GR 15 , or C1-CH 2 SC(S)GR 15
  • R a carboxylic acid choride or anhydride, a chloroformate, an isocyanate, a sulfonyl chloride, sulfinyl chloride, or phosphating or phosphonating reagent with standard conditions
  • R a carboxylic acid choride or anhydride, a chloroformate, an isocyanate, a sulfonyl chloride, sulfinyl chloride, or phosphating or phosphonating reagent with standard conditions
  • R -reagent such as R -Br, R -OTs, R -oxirane, thiirane, or aziridine, or CMR-Cl
  • R -reagent such as R -Br, R -OTs, R° -oxirane
  • EX-lb) 1 ,5-Bis-[6-(N-Z-amino)-2-(N-Boc-amino)-2-methylhexanamido]pentane is dissolved in ethanol containing acetic acid and is combined with a hydrogenation catalyst such as palladium on carbon and hydrogen. This reaction is shaken under pressure for an extended period of time in a standard Parr hydrogenation apparatus to remove the Z- functions generating the amino product l,5-Bis-[6-amino-2-(N-Boc-amino)-2- methylhexanamido]pentane.
  • the crude product is purified by then adjusting the pH to 7.5 with IN HCl and poured onto a Dowex 50 Cation exchange column. The column is washed with water. The Boc-protected product is then eluted with 10% aqueous pyridine and concentrated in vacuo to give l,5-Bis-[6-(N- (l-iminoethyl)amino)-2-(N-Boc-amino)-2-methylhexanamido]pentane.
  • EX-2b 4-trifluoroacetamido)-l-[(6-(N-Z-amino)-2-(N-Boc-amino)-2- methylhexanamido] butane (9.3 mmol) is dissolved in methanol/water and treated with potassium carbonate (10 mmol) in water. The mixture is stirred until the trifluoroacetyl protecting group is hydrolyzed. The product is passed through a reverse phase column to yield 4-[6-(N-Z-amino)-2-(N-Boc-amino)-2-methylhexanamido]- 1 -butanamine.
  • EX-2e 6-phthalimido-2-(N-Boc-amino)-2-methylhexanoic acid (9 mmol) is dissolved in anhydrous THF, cooled in an ice bath and treated with ethyl chloroformate (9.1 mmol) and triethyl amine (11 mmol). . The mixture is allowed to warm to room temperature. Upon completion, the mixture is again cooled in an ice bath and 4-[6-(N-Z-amino)-2-(N- Boc-amino)-2-methylhexanamido]-l -butanamine from EX -2b (9.2 mmol) is added.
  • This reaction is shaken under pressure for an extended period of time in a standard Parr hydrogenation apparatus to remove the Z-function generating the amino product 4-[6-(N-(l-iminoethyl)amino)-2-(N-Boc-amino)-2-methylhexanamido]-l-[6- amino-2-(N-Boc-amino)-2-methylhexanamido]butane.
  • reaction mixture is filtered to remove the phthalolyl hydrazide and concentrated to give l,5-bis[3-(2-(N-(l-iminoethyl)amino)ethylthio)-2- aminopropanamido]-pent-3-one tetrahydrochloride.
  • EX -4a The lithium salt of N-ethyl-6-(N-( 1 -(N-benzyloxyimino) ethyl)amino)-2- phthalimido-2-methylhexanamide (10 mmol) is prepared as in EX-3b from N-ethyl-6-(N- (1 -(N-benzyloxyimino) ethyl)amino)-2-phthalimido-2-methylhexanamide is reacted in anhydrous THF at -78°C by adding to l,3-bis(bromomethyl) benzene (5 mmol) in THF. After warming to room temperature, the reaction mixture is allowed to warm to room temperature and heated.
  • reaction mixture Upon cooling, the reaction mixture is filtered to remove the precipitant, concentrated in vacuo and purified by column chromatography to give a,a'- bis [N-ethyl-6-(N-( 1 -(N-benzyloxyimino)ethyl)amino)-2-phthalimido-2- methylhexanamido]-m-xylene.
  • a,a'-Bis[N-ethyl-6-(N-(l-(N-benzyloxyimino)ethyl)amino)-2-amino-2- methylhexanamido]-m-xylene (4 mmol) is dissolved in ethanol/acetic acid and is combined with a hydrogenation catalyst such as palladium on carbon and hydrogen.
  • EX-5a The lithium salt of N-methyl-6-(N-(l-(N-benzyloxyimino)ethyl)amino)-2- phthalimido-2-methylhexanamide (10 mmol) is made following the procedure in EX -3b from N-methyl-6-(N-(l-(N-benzyloxyimino)ethyl)amino)-2-phthalimido-2- methylhexanamide is added in anhydrous THF at -78°C to a-bromo-a'-(2- tetrahydropyranyloxy)- -xylene (10 mmol) in THF.
  • reaction mixture is purified by chromatography to give 3-[N-methyl-6-(N-(l-(N-benzyloxyimino)ethyl)amino)-2-amino- 2-methylhexanamidomethyl]-benzyl 6-(N-( 1 -(N-benzyloxyimino) ethyl)amino)-2-(N-Z- amino)-2-methylhexanoate.
  • EX-6a The lithium salt of N-methyl-6-(N-(l-(N-benzyloxyimino)ethyl)amino)-2- phthalimido-2-methylhexanamide (10 mmol) is made following the procedure in EX -3b from N-methyl-6-(N-( 1 -(N-benzyloxyimino)ethyl)amino)-2-phthalimido-2- methylhexanamide is added in anhydrous THF at -78°C to 2-bromoethyl 2-(2-tetrahydropyranyloxy)ethyl ether (10 mmol) in THF.
  • reaction mixture After filtering to remove phthaloyl hydrazide and concentrating, the reaction mixture is purified by chromatography to give 2-[2-[N-Methyl-6-(N-(l-(N-benzyloxyimino)ethyl)amino)-2- amino-2-methylhexanamido]ethoxy]ethyl 6-(N-( 1 -(N-benzyloxyimino)ethyl)amino)-2-(N- Z-amino)-2-methylhexanoate.

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Abstract

The current invention discloses novel oligomeric amidino aminocarboxylate derivatves useful as nitric oxide synthase inhibitors.

Description

OLIGOMERIC AMINO ACID DERIVATIVES USEFUL AS NITRIC OX IDE SYNTHASE INHI BITORS
5 Background of the Invention
Field of the Invention
The present invention relates to novel oligomeric amino acid derivatives and their use in therapy, in particular their use as nitric oxide synthase inhibitors.
Related Art
10 It has been known since the early 1980's that the vascular relaxation caused by acetylcholine is dependent on the presence of the vascular endothelium and this activity was ascribed to a labile humoral factor termed endothelium-derived relaxing factor (EDRF). The activity of nitric oxide (NO) as a vasodilator has been known for well over 100 years. In addition, NO is the active component of amylnitrite, glyceryltrinitrate and
15 other nitrovasodilators. The recent identification of EDRF as NO has coincided with the discovery of a biochemical pathway by which NO is synthesized from the amino acid L- arginine by the enzyme NO synthase.
Nitric oxide is the endogenous stimulator of the soluble guanylate cyclase. In addition to endothelium-dependent relaxation, NO is involved in a number of biological
20 actions including cytotoxicity of phagocytic cells and cell-to-cell communication in the central nervous system (see Moncada et al., Biochemical Pharmacology, 38, 1709-1715, 1989; Moncada et al., Pharmacological Reviews, 43, 109-142, 1991). Excess NO production appears to be involved in a number of pathological conditions, particularly conditions which involve systemic hypotension such as toxic shock, septic shock and
25 therapy with certain cytokines (Kerwin et al., J. Medicinal Chemistry, 38, 4343-4362, 1995). The synthesis of NO from L-arginine can be inhibited by the L-arginine analogue, L-N-monomethyl-arginine (L-NMMA) and the therapeutic use of L-NMMA for the treatment of toxic shock and other types of systemic hypotension has been proposed (WO 91/04024 and GB-A-2240041). The therapeutic use of certain other NO synthase inhibitors apart from L-NMMA for the same purpose has also been proposed in WO 91/04024 and in EP-A-0446699.
It has recently become apparent that there are at least three types of NO synthase as follows:
(i) a constitutive, Ca++/calmodulin dependent enzyme, located in the endothelium, that releases NO in response to receptor or physical stimulation.
(ii) a constitutive, Ca++/calmodulin dependent enzyme, located in the brain, that releases NO response to receptor or physical stimulation.
(iii) a Ca++ independent enzyme which is induced after activation of vascular smooth muscle,macrophages, endothelial cells, and a number of other cells by endotoxin and cytokines. Once expressed this inducible NO synthase generates NO continuously for long periods.
The NO released by the two constitutive enzymes acts as a transduction mechanism underlying several physiological responses. The NO produced by the inducible enzyme is a cytotoxic molecule for tumor cells and invading microorganisms. It also appears that the adverse effects of excess NO production, in particular pathological vasodilation and tissue damage, may result largely from the effects of NO synthesized by the inducible NO synthase (Knowles and Moncada, Biochem J., 298, 249-258, 1994 Billiar et al., Annals of Surgery, 221, 339-349, 1995; Davies et al., 1995)
There is also a growing body of evidence that NO may be involved in the degeneration of cartilage which takes place in cerain conditions such as arthritis and it is also known that NO synthesis is increased in rheumatoid arthritis and in osteoarthritis (Mclnnes et al., J. Exp. Med, 184, 1519-1524, 1996; Sakurai et al., J. Clin. Investig., 96, 2357-2363, 1995). Accordingly, conditions in which there is an advantage in inhibiting NO production from L-arginine include autoimmune and/or inflammatory conditions affecting the joints, for example arthritis, and also inflammatory bowel disease, cardivascular ischemia, diabetes, congestive heart failure, myocarditis, atherosclerosis, migraine, reflux esophagitis, diarrhea, irritable bowel syndrome, cystic fibrosis, emphysema, asthma, bronchiectasis, hyperalgesia (allodynia), cerebral ischemia (both focal ischemia, thrombotic stroke and global ischemia (secondary to cardiac arrest), multiple sclerosis and other central nervous system disorders mediated by NO, for example Parkinson's disease and Alzheimer's disease, and other disorders mediated by NO including opiate tolerance in patients needing protracted opiate analgesics, and benzodiazepine tolerance in patients taking benzodiazepines, and other addictive behaviour, for example, nicotine and eating disorders (Kerwin et al., J. Medicinal Chemistry, 38, 4343-4362, 1995; Knowles and Moncada, Biochem J., 298, 249-258, 1994; Davies et al., 1995; Pfeilschifter et al., Cell Biology International, 20, 51-58, 1996).
Further conditions in which there is an advantage in inhibiting NO production from L-arginine include systemic hypotension associated with septic and/or toxic shock induced by a wide variety of agents; therapy with cytokines such as TNF, IL-1 and IL-2; and as an adjuvant to short term immunosuppression in transplant therapy (E. Kelly et al., J. Partent. Ent. Nutri., 19, 234-238, 1995; S. Moncada and E. Higgs, FASEB J., 9, 1319- 1330, 1995; R. G. Kilbourn et al, Crit. Care Med., 23, 1018-1024, 1995).
Some of the NO synthase inhibitors proposed for therapeutic use so far, and in particular L-NMMA, are non-selective; they inhibit both the constitutive and the inducible NO synthases. Use of such a non-selective NO synthase inhibitor requires that great care be taken in order to avoid the potentially serious consequences of over- inhibition of the constitutive NO-synthase including hypertension and possible thrombosis and tissue damage. In particular, in the case of the therapeutic use of L-NMMA for the treatment of toxic shock it has been recommended that the patient must be subject to continuous blood pressure monitoring throughout the treatment. Thus, while non- selective NO synthase inhibitors have therapeutic utility provided that appropriate precautions are taken, NO synthase inhibitors which are selective in the sense that they inhibit the inducible NO synthase to a considerably greater extent than the constitutive isoforms of NO synthase would be of even greater therapeutic benefit and easier to use (S. Moncada and E. Higgs, FASEB J., 9, 1319-1330, 1995).
WO 96/35677, WO 96/33175, WO 96/15120, WO 95/11014, WO 95/11231 WO
95/25717, WO 95/24382, WO94/12165, WO94/14780, WO93/13055, EP0446699A1 and U.S. Patent No. 5,132,453 disclose compounds that inhibit nitric oxide synthesis and preferentially inhibit the inducible isoform of nitric oxide synthase. The disclosures of which are hereby incorporated by reference in their entirety as if written herein.
Summary of the Invention
In a broad aspect, the present invention is directed to novel compounds, pharmaceutical compositions and methods of using said compounds and compositions for inhibiting or modulating nitric oxide synthesis in a subject in need of such inhibition or modulation by administering a compound which preferentially inhibits or modulates the inducible isoform of nitric oxide synthase over the constitutive isoforms of nitric oxide synthase. It is also another object of the present invention to lower nitric oxide levels in a subject in need of such lowering.
Compounds of the present invention are represented by the following chemical formula:
[ Id k f [ Ib ] g
: ιc j h
(I)
or a pharmaceutically acceptable salt thereof, wherein; Ia, l , Ic, and I(j are independently selected from a structure of Formula II:
Figure imgf000006_0001
(H)
wherein Formula (II) has a point of attachment for bonding to a linker B by replacement of a substituent group of Formula (II) independently selected from the group consisting of J ,
2 7
J , A-R , and a removable hydrogen from a substituent independently selected from the
1 2 3 4 7 8 group consisting of R , R , R , R , R and R ;
1 2 23 23
J and J are independently selected from the group consisting of OR , SR ,
24 J xτ/τ-24 25 . , , , A . 26
NHR and N(R )R with the proviso that A is R ;
1 2 J and J can be taken together forming a group selected from the group consisting
28 28 28 28 24 28 24 26 of OR O, OR S, SR S, OR NR and SR NR with the proviso that A is R ;
1 2
J and J can be taken together forming J wherein J is connected to the carbon of
J1 and J2 by a covalent double bond and wherein J is independently selected from the
22 group consisting of O, NR and S with the proviso that A is selected from other than
.,26 R ;
G is independently selected from the group consisting of O, S, CH2, CHR ,
C(RI 5)2, NH, and NR15; A is independently selected from the group consisting of O, N(R ), S and heterocyclyl;
A can be independently selected from the group consisting of O, N(R ) and S
1 2 connected to the point of attachment of any one of R and R by a spacer group selected from a linear moiety having a chain length of 1 to 6 atoms to form a heterocyclyl having from 5 to 10 members;
A can be independently selected from the group consisting of O, N(R ) and S
1 2 connected to the points of attachment of R and R by a spacer group selected from a linear moiety having a chain length of 1 to 6 to form a heterocyclyl having from 5 to 10 members;
A can be independently selected from the group consisting of O, N(R ) and S
3 connected to the point of attachment of R by a spacer group selected from a linear moiety having a chain length of 1 to 3 atoms to form a heterocyclyl having from 7 to 10 members;
A can be independently selected from the group consisting of O, N(R ) and S
4 connected to the point of attachment of R by a spacer group selected from a linear moiety having a chain length of 1 to 4 atoms to form a heterocyclyl having from 6 to 10 members;
A can be independently selected from the group consisting of O, N(R ) and S connected to X by a substituent selected from hydroxyl, sulfhydryl, amino, carboxyl, and carbonyl substituents of group X by a spacer selected from the group consisting of a covalent bond and a linear moiety having a chain length of 1 to 4 atoms to form a heterocyclyl having from 5 to 10 members; 26 26
A can be R , wherein R is independently selected from the group consisting of hydrogen, formyl, hydroxyalkyl, alkenyl, alkynyl, acyl, aroyl, aralkanoyl, heteroaroyl, alkylsulfinylalkyl, alkylsulfonylalkyl, heteroaralkylthioalkyl, alkoxyalkyl, alkenyloxyalkyl, alkylthioalkyl, cycloalkylalkenyl, cycloalkenyl, haloalkyl, haloalkenyl, haloalkoxyalkyl, haloalkenyl oxy alkyl, halocycloalkenyloxyalkyl, cyanoalkyl, carboxy, carboxamido, carboalkoxy, dicyanoalkyl, carboxamidoalkyl, dicarboxamidoalkyl, cyanocarboalkoxyalkyl, carboalkoxyalkyl, dicarboalkoxyalkyl, formylalkyl, and acylalkyl;
27 27
A can be R , wherein R is independently selected from the group consisting of
N(R5)OR?, N(R5)SR?, N(R5)N(R?)R25, N(R5)SO2R13, N(R5)C(O)R15,
5 15 19 20 5 19 20 N(R )C(S)R , R (R )C=N-N(R ), R (R )C=N-O, natural amino acids, synthetic
amino acids, N(R )P(O)(OR )]R and N(R )P(O)(OR )2;
1 2
R and R are independently selected from the group consisting of hydrogen, hydroxyalkyl, aminoalkyl, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, haloalkyl,
13 haloalkenyl, cyanoalkyl, dicyanoalkyl, cyanocycloalkyl, dicyanocycloalkyl, S(O)R ,
SO2R , C(O)R , CH2OC(O)R , hydroxyl, sulfhydryl, OR , SR , carboxamidoalkyl, dicarboxamidoalkyl, cyanocarboalkoxyalkyl, carboalkoxyalkyl, dicarboalkoxyalkyl, carboxamidocycloalkyl, dicarboxamidocycloalkyl, carboalkoxycyanocycloalkyl, carboalkoxycycloalkyl, dicarboalkoxycycloalkyl, formylalkyl, acylalkyl, CH2SO3" M ,
CH2CH2SO3" M+, CH2PO3 "2 2M+, CH2CH2PO3 '2 2M+, CH(OR6)CF3, P(O)R3°R31,
P(O)(R3°)2 R31, C(S)R15, CH2NR19C(O)R15, CH2NR19C(S)R15, CH2SC(O)R15,
CH2SC(S)R15, CH2OC(O)GR15, CH2NR19C(O)GR15, CH2NR19C(S)GR15,
CH2OC(S)GR15, CH2SC(S)GR15, OSO2R13, OS(O)R13, OC(S)R15, SC(S)R15, OC(S)GR , SC(S)GR , OC(O)R15, SC(O)R15, OC(O)GR15, SC(O)GR15, and
R19(R20)CH;
1 J n2 R and R can be taken together forming a group selected from the group
19 20 30 31 19 20 1Q 90 consisting of R (R )C=, D(C(R )(R ))ZD, and D((R )R C)eW(C(R )R )kD wherein z is 2 to 5, e is 1 to 2, k is 1 to 2, D is selected from the group consisting of oxygen, C=O, C=S, S(O)m wherein m is 0 to 2, OP(OR31)R3°, P(O)R3°, P(S)R3° and
19 20 Si(R )R and W is selected from the group consisting of oxygen, C=O, C=S, S(O)m,
S(O)m where m is 0 to 2, P(O)R3°, P(S)R3°, N(R19), and Si(R19)R2° with the proviso that only one D can be oxygen or sulfur at any time;
1 2 R and R can be taken together forming a group selected from the group consisting of cycloalkyl radicals, cycloalkenyl radicals wherein said cycloalkyl radicals
30 31 and cycloalkenyl radicals may be optionally substituted with one or more R or R substituents, aryl radicals, heteroaryl radicals, saturated heterocyclic radicals and partially saturated heterocyclic radicals wherein said radicals are 1 ,2-disubstituted and said 1,2-
19 32 substitutents are independently selected from C=O, C=S, C(R )R , S(O), S(O)2,
OP(OR31)R3° P(O)R3° P(S)R3° and Si(R19)R2°;
1 2
R and R can be taken together forming a group selected from the group consisting of cis-l,2-disubstituted alkyls and cis-l,2-disubstituted alkenyls wherein said
19 32 1,2-substιtutents are independently selected from C=O, C=S, C(R )R , S(O), S(O)2,
OP(OR )R , P(O)R , P(S)R . and S^R1 )R2° and said alkyl and alkenyl may be
30 31 optionally substituted with one or more R or R substituents; 3 4
R and R are independently selected from the group consisting of hydrogen,
hydroxyl, sulfhydryl, OR
Figure imgf000010_0001
,
CH2CH2PO3 '2 2M+, CH(OR6)CF3, S(O)R13, SO2R13, P(O)R3°R31 , P(O)(R3°)2R3 1,
C(O)R15, C(S)R15, CH2OC(O)R15, CH2NR19C(O)R15, CH2NR19C(S)R15,
CH2SC(O)R15, CH2SC(S)R15, CH2OC(O)GR15, CH2NR19C(O)GR15,
CH2NR19C(S)GR15, CH2OC(S)GR15, CH2SC(S)GR15, OSO2R13, OS(O)R13,
OC(S)R15, SC(S)R15, OC(S)GR15, SC(S)GR15, OC(O)R15, SC(O)R15, OC(O)GR15
and SC(O)GR15;
3 4
R and R can be taken together to form the group L-U-V wherein L is not identical to V, and L, U, and V are independently selected from the group consisting of O,
23 23 24
S, C(O), C(S), C(JH)2 wherein JH is independently selected from OR , SR , NHR ,
24 25 29 31 30 30 30 30 31 and N(R )R , CR , S(O), SO2, OP(OR )R , P(O)R , P(S)R , C(R )R ,
30 31 30 30 19 20 19 20 19 20
C=C(R )R , (O)2POP(O)2, R (O)POP(O)R , Si(R )R , Si(R )R Si(R )R ,
Sidt'VW 20 (R'VW 20 (R19)R 0CSC(R ,9)R2°,
30 31 30 31 30 31 30 31 C(O)C(R )=C(R ), C(S)C(R )=C(R ), S(O)C(R )=C(R ), SO2C(R )=C(R ),
30 30 31 30 30 31 30 30 31
PR C(R )=C(R ), P(O)R C(R )=C(R ), P(S)R C(R )=C(R ),
30 31 DC(R )(R )D wherein D is selected from the group consisting of oxygen, C=O, C=S,
31 30 30 30 19 20 30
S(O)m wherein m is 0 to 2, OP(OR )R , P(O)R , P(S)R , Si(R )R and N(R ), and a covalent bond with the proviso that no more than any two of L, U and V are simultaneously covalent bonds and the heterocycle comprised of by L, U, and V is greater than a 4-membered ring; τ, 3 J T- 4
R and R can be taken together to form the group L-U-V wherein L is not identical to V, and L, U, and V are independently selected from the group consisting of cycloalkyl radical, cycloalkenyl radical wherein said cycloalkyl radical and cycloalkenyl
30 31 radical may be optionally substituted with one or more R and R substituents, aryl radical, heteroaryl radical, saturated heterocyclic radical and partially saturated heterocyclic radical wherein said radicals are 1,2-disubstituted and said 1,2-substitutents
19 32 31 ^0 are independently selected from C=O, C=S, C(R )R , S(O), S(O)2, OP(OR )R ,
P(O)R3°, P(S)R3° and Si(R1.9)R2°;
3 4
R and R can be taken together to form the group L-U-V wherein L, U, and V are independently selected from the group consisting of cis- 1 ,2-disubstituted alkanyl and cis- 1 ,2-disubstituted alkenyl radicals wherein said 1,2-substitutents are independently selected from C=O, C=S, C(R19)R32, S(O), S(O)2, OP(OR31)R3°, P(O)R3°, P(S)R3° and
19 20 Si(R )R and said alkanes and alkenes may be optionally substituted with one or more
^30 31 .
R or R substituents;
R is independently selected from the group consisting of hydrogen, aryl, heteroaralkyl, hydroxy, alkyl, alkenyl, alkynyl, amino, cyanoalkyl, dicyanoalkyl, carboxamidoalkyl, hydroxyalkyl, dicarboxamidoalkyl, cyanocarboalkoxyalkyl, carboalkoxyalkyl, dicarboalkoxyalkyl, cyanocycloalkyl, dicyanocycloalkyl, carboxamidocycloalkyl, dicarboxamidocycloalkyl, carboalkoxycyanocycloalkyl,
13 carboalkoxycycloalkyl, dicarboalkoxycycloalkyl, formylalkyl, acylalkyl, S(O)R ,
SO2R13, P(O)R3°R31, P(O)(R3°)2R31, C(O)R15, C(S)R15, CH2OC(O)R15,
CH2NR19C(O)R15, CH2NR19C(S)R15, CH2SC(O)R15, CH2SC(S)R15,
CH2OC(O)GR15, CH2NR19C(O)GR15, CH2NR19C(S)GR15, CH2OC(S)GR15, 15 CH2SC(S)GR , heteroaryloxyalkyl, aralkyl, aryloxyalkyl, aralkoxyalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl, aralkylthioalkyl, heteroaralkoxythioalkyl, alkoxyalkyl, heteroaryloxyalkyl, alkenyloxyalkyl, alkylthioalkyl, arylthioalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkenyl, cycloalkenylalkyl, haloalkyl, haloalkenyl, halocycloalkyl, aralkylsulfinylalkyl, aralkylsulfonylalkyl, carboxyalkyl, carboalkoxyalkyl, dialkoxyphosphonoalkyl, diaralkoxyphosphonoalkyl, phosphonoalkyl, dialkoxyphosphonoalkylamino, diaralkoxyphosphonoalkylamino, phosphonoalkylamino, dialkoxyphosphonoalkyl, diaralkoxyphosphonoalkyl, sulfonylalkyl, alkoxysulfonylalkyl, aralkoxysulfonylalkyl, alkoxysulfonylalkylamino, aralkoxysulfonylalkylamino and sulfonylalkylamino;
5 1 2
R , R and R can be taken together to form a spacer group consisting of a linear moiety having a chain length of 1 to 4 atoms to form a heterocyclyl having from 5 through 8 members;
R can be selected from a heterocyclyl radical in which there is at least one carbon in one ring and in which 1 to about 4 members of said ring are heteroatoms independently selected from oxygen, nitrogen and sulfur and said heterocyclyl radical may be optionally substituted with heteroarylamino, N-aryl-N-alkylamino, N-heteroarylamino-N-alkylamino, haloalkylthio, alkanoyloxy, alkoxy, heteroaralkoxy, cycloalkoxy, cycloalkenyloxy, hydroxy, amino, thio, nitro, lower alkylamino, alkylthio, alkylthioalkyl, arylamino, aralkylamino, arylthio, alkylsulfmyl, alkyl sulfonyl, alkylsulfonamido, alkylaminosulfonyl, amidosulfonyl, monoalkyl amidosulfonyl, dialkyl amidosulfonyl, monoarylamidosulfonyl, arylsulfonamido, diarylamidosulfonyl, monoalkyl monoaryl amidosulfonyl, arylsulfinyl, arylsulfonyl, heteroarylthio, heteroarylsulfϊnyl, heteroarylsulfonyl, alkanoyl, alkenoyl, aroyl, heteroaroyl, aralkanoyl, heteroaralkanoyl, haloalkanoyl, alkyl, alkenyl, alkynyl, alkylenedioxy, haloalkylenedioxy, cycloalkyl, cycloalkenyl, lower cycloalkylalkyl, lower cycloalkenylalkyl, halo, haloalkyl, haloalkoxy, hydroxyhaloalkyl, hydroxyaralkyl, hydroxyalkyl, hydoxyheteroaralkyl, haloalkoxy alkyl, aryl, aralkyl, aryloxy, aralkoxy, aryloxyalkyl, saturated heterocyclyl, partially saturated heterocyclyl, heteroaryl, heteroaryloxy, heteroaryloxyalkyl, arylalkyl, heteroarylalkyl, arylalkenyl, heteroarylalkenyl, cyanoalkyl, dicyanoalkyl, carboxamidoalkyl, dicarboxamidoalkyl, cyanocarboalkoxyalkyl, carboalkoxyalkyl, dicarboalkoxyalkyl, cyanocycloalkyl, dicyanocycloalkyl, carboxamidocycloalkyl, dicarboxamidocycloalkyl, carboalkoxycyanocycloalkyl, carboalkoxycycloalkyl, dicarboalkoxycycloalkyl, formylalkyl, acylalkyl, dialkoxyphosphonoalkyl, diaralkoxyphosphonoalkyl, phosphonoalkyl, dialkoxyphosphonoalkoxy, diaralkoxyphosphonoalkoxy, phosphonoalkoxy, dialkoxyphosphonoalkylamino, diaralkoxyphosphonoalkylamino, phosphonoalkylamino, dialkoxyphosphonoalkyl, diaralkoxyphosphonoalkyl, guanidino, amidino, and acylamino;
R is independently selected from the group consisting of hydroxyalkyl, aminoalkyl, heteroaryloxyalkyl, alkyl, alkenyl, alkynyl, aryl, aralkyl, aryloxyalkyl, aralkoxyalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl, aralkylthioalkyl, heteroaralkoxythioalkyl, alkoxyalkyl, heteroaryloxyalkyl, alkenyloxyalkyl, alkylthioalkyl, arylthioalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkenyl, cycloalkenylalkyl, haloalkyl, haloalkenyl, halocycaralkylsulfinylalkyl, aralkylsulfonylalkyl, cyanoalkyl, dicyanoalkyl, carboxamidoalkyl, dicarboxamidoalkyl, cyanocarboalkoxyalkyl, carboalkoxyalkyl, dicarboalkoxyalkyl, cyanocycloalkyl, dicyanocycloalkyl, carboxamidocycloalkyl, dicarboxamidocycloalkyl, carboalkoxycyanocycloalkyl, carboalkoxycycloalkyl, dicarboalkoxycycloalkyl, formylalkyl, acylalkyl, dialkoxyphosphonoalkyl, diaralkoxyphosphonoalkyl, phosphonoalkyl, dialkoxyphosphonoalkylamino, diaralkoxyphosphonoalkylamino, phosphonoalkylamino, dialkoxyphosphonoalkyl, diaralkoxyphosphonoalkyl, sulfonylalkyl, alkoxysulfonylalkyl, aralkoxysulfonylalkyl, alkoxysulfonylalkylamino, aralkoxysulfonylalkylamino, sulfonylalkylamino, a natural amino acid, synthetic amino acid, and a polyhydroxy compound of carbon;
7 R is selected from the group consisting of hydrogen, aryl, heteroaralkyl, hydroxy, alkyl, alkenyl, alkynyl, amino, cyanoalkyl, dicyanoalkyl, carboxamidoalkyl, hydroxyalkyl, dicarboxamidoalkyl, cyanocarboalkoxyalkyl, carboalkoxyalkyl, dicarboalkoxyalkyl, cyanocycloalkyl, dicyanocycloalkyl, carboxamidocycloalkyl, dicarboxamidocycloalkyl, carboalkoxycyanocycloalkyl, carboalkoxycycloalkyl, dicarboalkoxycycloalkyl,
13 13 30 31 30 31 15 formylalkyl, acylalkyl, S(O)R , SO2R , P(O)R R , P(O)(R tøR , C(O)R ,
C(S)R15, CH2OC(O)R15, CH2NR19C(O)R15, CH2NR19C(S)R15, CH2SC(O)R15,
CH2SC(S)R15, CH2OC(O)GR15, CH2NR19C(O)GR15, CH2NR19C(S)GR15,
15 15
CH2OC(S)GR , CH2SC(S)GR , heteroaryloxyalkyl, aralkyl, aryloxyalkyl, aralkoxyalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl, aralkylthioalkyl, heteroaralkoxythioalkyl, alkoxyalkyl, heteroaryloxyalkyl, alkenyloxyalkyl, alkylthioalkyl, arylthioalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkenyl, cycloalkenylalkyl, haloalkyl, haloalkenyl, halocycloalkyl, aralkylsulfinylalkyl, aralkylsulfonylalkyl, carboxyalkyl, carboalkoxyalkyl, dialkoxyphosphonoalkyl, diaralkoxyphosphonoalkyl, phosphonoalkyl, dialkoxyphosphonoalkylamino, diaralkoxyphosphonoalkylamino, phosphonoalkylamino, dialkoxyphosphonoalkyl, diaralkoxyphosphonoalkyl, sulfonylalkyl, alkoxysulfonylalkyl, aralkoxysulfonylalkyl, alkoxysulfonylalkylamino, aralkoxysulfonylalkylamino and sulfonylalkylamino;
7 1 2
R , R and R can be taken together to form a spacer group selected from a linear moiety having a chain length of 1 to 4 atoms to form a heterocyclyl having from 5 to 8 members;
7 R can be selected from a heterocyclyl radical in which there is at least one carbon in one ring and in which 1 to about 4 members of said ring are heteroatoms independently selected from oxygen, nitrogen and sulfur and said heterocyclyl radical may be optionally substituted with heteroarylamino, N-aryl-N-alkylamino, N-heteroarylamino-N-alkylamino, haloalkylthio, alkanoyloxy, alkoxy, heteroaralkoxy, cycloalkoxy, cycloalkenyloxy, hydroxy, amino, thio, nitro, lower alkylamino, alkylthio, alkylthioalkyl, arylamino, aralkylamino, arylthio, alkylsulfmyl, alkylsulfonyl, alkylsulfonamido, alkylaminosulfonyl, amidosulfonyl, monoalkyl amidosulfonyl, dialkyl amidosulfonyl, monoarylamidosulfonyl, arylsulfonamido, diarylamidosulfonyl, monoalkyl monoaryl amidosulfonyl, arylsulfinyl, arylsulfonyl, heteroarylthio, heteroarylsulfinyl, heteroarylsulfonyl, alkanoyl, alkenoyl, aroyl, heteroaroyl, aralkanoyl, heteroaralkanoyl, haloalkanoyl, alkyl, alkenyl, alkynyl, alkylenedioxy, haloalkylenedioxy, cycloalkyl, cycloalkenyl, lower cycloalkylalkyl, lower cycloalkenylalkyl, halo, haloalkyl, haloalkoxy, hydroxyhaloalkyl, hydroxyaralkyl, hydroxyalkyl, hydoxyheteroaralkyl, haloalkoxyalkyl, aryl, aralkyl, aryloxy, aralkoxy, aryloxyalkyl, saturated heterocyclyl, partially saturated heterocyclyl, heteroaryl, heteroaryloxy, heteroaryloxyalkyl, arylalkyl, heteroarylalkyl, arylalkenyl, heteroarylalkenyl, cyanoalkyl, dicyanoalkyl, carboxamidoalkyl, dicarboxamidoalkyl, cyanocarboalkoxyalkyl, carboalkoxyalkyl, dicarboalkoxyalkyl, cyanocycloalkyl, dicyanocycloalkyl, carboxamidocycloalkyl, dicarboxamidocycloalkyl, carboalkoxycyanocycloalkyl, carboalkoxycycloalkyl, dicarboalkoxycycloalkyl, formylalkyl, acylalkyl, dialkoxyphosphonoalkyl, diaralkoxyphosphonoalkyl, phosphonoalkyl, dialkoxyphosphonoalkoxy, diaralkoxyphosphonoalkoxy, phosphonoalkoxy, dialkoxyphosphonoalkylamino, diaralkoxyphosphonoalkylamino, phosphonoalkylamino, dialkoxyphosphonoalkyl, diaralkoxyphosphonoalkyl, guanidino, amidino, and acylamino; g R is selected from hydrogen, hydroxyalkyl, haloalkyl, alkyl, alkoxyalkyl, aminoalkyl, alkylaminoalkyl, alkylthioalkyl, cyanoalkyl, sulfhydrylalkyl, formyl, C(O)A-
R7, C(S)A-R?, CH OC(O)A-R7, CH2NR19C(O)A-R7, CH2NR19C(S)A-R7,
CH SC(O)A-R7, CH2SC(S)A-R7, CH2OC(O)GR15, CH2NR19C(O)GR15,
CH2NR19C(S)GR15, CH2OC(S)GR15, CH2SC(S)GR15 and acyl;
g R may be taken together with X to form a carbocyclic or a heterocyclic ring having from 3 to 8 members;
13 R is independently selected from aryloxy, amino, alkylamino, dialkylamino, hydroxyalkyl, heteroaryloxyalkyl, alkoxy, alkylthio, arylthio, alkyl, alkenyl, alkynyl, aryl, aralkyl, aryloxyalkyl, aralkoxyalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl, aralkylthioalkyl, heteroaralkoxythioalkyl, alkoxyalkyl, heteroaryloxyalkyl, alkenyloxyalkyl, alkylthioalkyl, arylthioalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkenyl, cycloalkenylalkyl, haloalkyl, haloalkenyl, haloaralkylsulfinylalkyl, aralkylsulfonylalkyl, cyanoalkyl, dicyanoalkyl, carboxamidoalkyl, dicarboxamidoalkyl, cyanocarboalkoxyalkyl, carboalkoxyalkyl, dicarboalkoxyalkyl, cyanocycloalkyl, dicyanocycloalkyl, carboxamidocycloalkyl, dicarboxamidocycloalkyl, carboalkoxycyanocycloalkyl, carboalkoxycycloalkyl, dicarboalkoxycycloalkyl, formylalkyl, acylalkyl, dialkoxyphosphonoalkyl, diaralkoxyphosphonoalkyl, phosphonoalkyl, dialkoxyphosphonoalkoxy, diaralkoxyphosphonoalkoxy, pnosphonoalkoxy, dialkoxyphosphonoalkylamino, diaralkoxyphosphonoalkylamino, phosphonoalkylamino, dialkoxyphosphonoalkyl, diaralkoxyphosphonoalkyl, sulfonylalkyl, alkoxysulfonylalkyl, aralkoxysulfonylalkyl, alkoxysulfonylalkoxy, aralkoxysulfonylalkoxy, sulfonylalkoxy, alkoxysulfonylalkylamino, aralkoxysulfonylalkylamino, sulfonylalkylamino, a natural amino acid, synthetic amino acid, and a polyhydroxy compound of carbon;
15 R is independently selected from hydrido, aryloxy, amino, alkylamino, dialkylamino, hydroxyalkyl, heteroaryloxyalkyl, alkoxy, alkylthio, arylthio, alkyl, alkenyl, alkynyl, aryl, aralkyl, aryloxyalkyl, aralkoxyalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl, aralkylthioalkyl, heteroaralkoxythioalkyl, alkoxyalkyl, heteroaryloxyalkyl, alkenyloxyalkyl, alkylthioalkyl, arylthioalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkenyl, cycloalkenylalkyl, haloalkyl, haloalkenyl, haloaralkylsulfinylalkyl, aralkylsulfonylalkyl, carboxy, cyanoalkyl, dicyanoalkyl, carboxamidoalkyl, dicarboxamidoalkyl, cyanocarboalkoxyalkyl, carboalkoxyalkyl, dicarboalkoxyalkyl, cyanocycloalkyl, dicyanocycloalkyl, carboxamidocycloalkyl, dicarboxamidocycloalkyl, carboalkoxycyanocycloalkyl, carboalkoxycycloalkyl, dicarboalkoxycycloalkyl, formylalkyl, acylalkyl, dialkoxyphosphonoalkyl, diaralkoxyphosphonoalkyl, phosphonoalkyl, dialkoxyphosphonoalkoxy, diaralkoxyphosphonoalkoxy, phosphonoalkoxy, dialkoxyphosphonoalkylamino, diaralkoxyphosphonoalkylamino, phosphonoalkylamino, dialkoxyphosphonoalkyl, diaralkoxyphosphonoalkyl, sulfonylalkyl, alkoxysulfonylalkyl, aralkoxysulfonylalkyl, alkoxysulfonylalkoxy, aralkoxysulfonylalkoxy, sulfonylalkoxy, alkoxysulfonylalkylamino, aralkoxysulfonylalkylamino, sulfonylalkylamino, a natural amino acid, a synthetic amino acid, and a polyhydroxy compound of carbon;
M is a pharmaceutically acceptable cation;
X is selected from the group consisting of alkylene, alkenylene, alkynylene, -
(CH2)nQ(CH2) wherein p is 1 to 3, r is 1 to 3 and Q is selected from oxygen, C=O,
N(R12)SO2, SO2N(R12), S(O)t, Se(O)t wherein t is 0 to 2,
Figure imgf000017_0001
-(CH2)sT(CH2)v- wherein s is O to 2, v is 0 to 2 and T is selected from 3 to 6 membered carbocyclic
12 radicals, aryl radicals and heterocyclyl radicals, and N(R ) wherein n is 1 to 2, wherein all positions on X may be optionally substituted with one or more selected from the group consisting of halogen, CI-CJO alkyl, Cj-Cio alkoxy, hydroxy, haloalkyl, nitro, cyano, and amino;
12 R is selected from hydrogen, hydroxyl, alkyl, hydroxyalkyl, aminoalkyl, alkylaminoalkyl, alkoxyalkyl, haloalkyl, aryl, aralkyl, cycloalkylalkyl, and heterocyclylalkyl;
21 R is selected from hydroxyl and alkyl;
Y is selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxyalkyl, cycloalkyl, cycloalkenyl, cycloalkenyloxy, alkenyloxyalkyl, alkylthioalkyl,
9 10 9 10 alkylaminoalkyl and NR R wherein R and R are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, nitro, amino, hydroxy, alkoxy, aryl, heterocyclyl, and aralkyl; 9 10
R and R can be taken together to form a spacer group selected from a linear moiety having a chain length of 2 to 7 atoms to form a heterocyclyl having from 3 through 8 members;
19 20
R and R are independently selected from the group consisting of hydrogen, hydroxyalkyl, alkyl, alkenyl, alkynyl, aryl, aralkyl, aryloxyalkyl, acyl, aroyl, aralkanoyl, heteroaroyl, aralkoxyalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl, aralkylthioalkyl, heteroaralkylthioalkyl, alkoxyalkyl, heteroaryloxyalkyl, alkenyloxyalkyl, alkylthioalkyl, arylthioalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkenyl, cycloalkenylalkyl, haloalkyl, haloalkenyl, halocycloalkyl, halocycloalkenyl, haloalkoxyalkyl, haloalkenyloxyalkyl, halocycloalkoxy, halocycloalkoxyalkyl, halocycloalkenyloxyalkyl, perhaloaryl, perhaloaralkyl, perhaloaryloxyalkyl, heteroaryl, heteroarylalkyl, heteroarylthioalkyl, heteroaralkylthioalkyl, cyanoalkyl, dicyanoalkyl, carboxamidoalkyl, dicarboxamidoalkyl, cyanocarboalkoxyalkyl, carboalkoxyalkyl, dicarboalkoxyalkyl, cyanocycloalkyl, dicyanocycloalkyl, carboxamidocycloalkyl, dicarboxamidocycloalkyl, carboalkoxycyanocycloalkyl, carboalkoxycycloalkyl, dicarboalkoxycycloalkyl, formylalkyl, acylalkyl, arylsulfinylalkyl, arylsulfonylalkyl, aralkylsulfinyl, cycloalkylsulfinylalkyl, cycloalkylsufonylalkyl, heteroarylsulfonylalkyl, heteroarylsulfϊnylalkyl, aralkylsulfinylalkyl, aralkylsulfonylalkyl, carboxy, dialkoxyphosphono, diaralkoxyphosphono, dialkoxyphosphonoalkyl and diaralkoxyphosphonoalkyl;
19 20
R and R can be taken together to form a linear moiety spacer group having a chain length of 2 to 7 atoms and selected from the group consisting of a cycloalkyl having from 3 through 8 members, a cycloalkenyl having from 3 through 8 members, and a heterocyclyl having from 3 through 8 members;
22 23 R and R are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aralkyl, aryloxyalkyl, aralkoxyalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl, aralkylthioalkyl, heteroaralkylthioalkyl, alkoxyalkyl, heteroaryloxyalkyl, alkenyloxyalkyl, alkylthioalkyl, arylthioalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkenyl, cycloalkenylalkyl, haloalkyl, haloalkenyl, halocycloalkyl, halocycloalkenyl, haloalkoxyalkyl, haloalkenyloxyalkyl, halocycloalkoxyalkyl, halocycloalkenyloxyalkyl, perhaloaryloxyalkyl, heteroaryl, heteroarylalkyl, heteroarylthioalkyl, heteroaralkylthioalkyl, arylsulfinylalkyl, arylsulfonylalkyl, cycloalkylsulfinylalkyl, cycloalkylsufonylalkyl, heteroarylsulfonylalkyl, heteroarylsulfinylalkyl, aralkylsulfinylalkyl and aralkylsulfonylalkyl;
24 25
R and R are independently selected from the group consisting of hydrogen, hydroxyalkyl, alkyl, alkenyl, alkynyl, aryl, aralkyl, aryloxyalkyl, aralkoxyalkyl, alkoxy, alkylsulfinylalkyl, alkylsulfonylalkyl, aralkylthioalkyl, heteroaralkylthioalkyl, alkoxyalkyl, heteroaryloxyalkyl, alkenyloxyalkyl, alkylthioalkyl, arylthioalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkenyl, cycloalkenylalkyl, haloalkyl, haloalkenyl, halocycloalkyl, halocycloalkenyl, haloalkoxyalkyl, haloalkenyloxyalkyl, cycloalkoxy, halocycloalkoxyalkyl, halocycloalkenyloxyalkyl, perhaloaryl, perhaloaralkyl, perhaloaryloxyalkyl, heteroaryl, heteroarylalkyl, heteroarylthioalkyl, heteroaralkylthioalkyl, arylsulfinylalkyl, arylsulfonylalkyl, cycloalkylsulfinylalkyl, cycloalkylsufonylalkyl, heteroarylsulfonylalkyl, heteroarylsulfinylalkyl, aralkylsulfinylalkyl and aralkylsulfonylalkyl;
24 25
R and R can be taken to form a linear moiety spacer group having a chain length of 4 to 7 atoms to form a heterocyclyl having from 5 through 8 members;
26 R is independently selected from hydrogen, formyl, hydroxyalkyl, alkenyl, alkynyl, acyl, aroyl, aralkanoyl, heteroaroyl, alkylsulfinylalkyl, alkylsulfonylalkyl, heteroaralkylthioalkyl, alkoxyalkyl, alkenyloxyalkyl, alkylthioalkyl, cycloalkylalkenyl, cycloalkenyl, haloalkyl, haloalkenyl, haloalkoxyalkyl, haloalkenyloxyalkyl, halocycloalkenyloxyalkyl, cyanoalkyl, carboxy, carboxamido, carboalkoxy, dicyanoalkyl, carboxamidoalkyl, dicarboxamidoalkyl, cyanocarboalkoxyalkyl, carboalkoxyalkyl, dicarboalkoxyalkyl, formylalkyl and acylalkyl; 28 23
R is independently selected from a group consisting of CH(R )CH2,
23 23
CH(R )CH2CH2, CH2CH(R )CH2, cycloalkylene, and heterocyclylene;
30 31
R and R are independently selected from hydroxy, thiol, aryloxy, amino, alkylamino, dialkylamino, hydroxyalkyl, heteroaryloxyalkyl, alkoxy, alkylthio, arylthio, alkyl, alkenyl, alkynyl, aryl, aralkyl, aryloxyalkyl, aralkoxyalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl, aralkylthioalkyl, heteroaralkoxythioalkyl, alkoxyalkyl, heteroaryloxyalkyl, alkenyloxyalkyl, alkylthioalkyl, arylthioalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkenyl, cycloalkenylalkyl, haloalkyl, haloalkenyl, haloaralkylsulfinylalkyl, aralkylsulfonylalkyl, cyanoalkyl, dicyanoalkyl, carboxamidoalkyl, dicarboxamidoalkyl, cyanocarboalkoxyalkyl, carboalkoxyalkyl, dicarboalkoxyalkyl, cyanocycloalkyl, dicyanocycloalkyl, carboxamidocycloalkyl, dicarboxamidocycloalkyl, carboalkoxycyanocycloalkyl, carboalkoxycycloalkyl, dicarboalkoxycycloalkyl, formylalkyl, acylalkyl, dialkoxyphosphonoalkyl, diaralkoxyphosphonoalkyl, phosphonoalkyl, dialkoxyphosphonoalkoxy, diaralkoxyphosphonoalkoxy, phosphonoalkoxy, dialkoxyphosphonoalkylamino, diaralkoxyphosphonoalkylamino, phosphonoalkylamino, dialkoxyphosphonoalkyl, diaralkoxyphosphonoalkyl, sulfonylalkyl, alkoxysulfonylalkyl, aralkoxysulfonylalkyl, alkoxysulfonylalkoxy, aralkoxysulfonylalkoxy, sulfonylalkoxy, alkoxysulfonylalkylamino, aralkoxysulfonylalkylamino, sulfonylalkylamino, a natural amino acid, a synthetic amino acid, and poly hydroxy compound of carbon;
30 31
R and R can be taken to form a linear moiety spacer group having a chain length of 2 to 7 atoms to form a group selected from the group consisting of a cycloalkyl having from 3 through 8 members, a cycloalkenyl having from 3 through 8 members, and a heterocyclyl having from 3 through 8 members;
B is a linker selected from the group consisting of B i , B2, B3, B4, B5, B6, B7, Bg,
B9, Bjo> Bj j, Bj , B13, B]4, and B 15 wherein f, g, h, and i are integers independently selected from the group consisting of 0, 1, 2, 3, 4, and 5 representing the number of attachments to B, with the proviso that the sum of f, g, h, and i must be at least two;
B j is a linker connecting a first group independently selected from the group
consisting of Ia, lb, Ic, and Lj through the point of bonding of a removable hydrogen of a
7 group selected independently from the group consisting of A and R to a second group
independently selected from the group consisting of Ia, lb, I<> and Ij through the point of bonding of a removable hydrogen of a group selected independently from the group
7 consisting of A and R wherein said linker is selected from the group consisting of a covalent single bond with the proviso that only one A is simultaneously O and S,
19 20 19 20 19 20 7 20 7 20 7 20 19 20 CR R (CR R )jC R R , CR R (CR R )jC R R , (CR R )UQQ(C
1 Q 90 7 20 7 20 19 20 19 20
R R )W, (CR R )UQQ(CR R )w, (CH2)xT(CH2)y, (CR R )XT(CR R )y and
7 20 7 20
(CR R )XT(CR R )y wherein j is selected from an integer of 0 to 18, x and y are selected from an integer of 0 to 8, and u and w are selected from an integer of 1 to 8;
B2 is a linker connecting a first group independently selected from the group
7 consisting of Ia, l , Ic> and I<j from the point of attachment of A-R to a second group
independently selected from the group consisting of Ia, lb, Ic, and Ij from the point of
7 attachment of A-R wherein said
19 20 19 20 19 20 linker is selected from the group consisting of H]jnk-CR R (CR R )jCR R -Hjink
, Hlink-CR7R20(CR7R2°)jCR7R20-Hlink, Hlink-(CH2)uQQ(CH2)w-Hiink, Hlink-
19 20 19 20 7 20 7 20 (CR R )UQQ(C R R )W-Hlink, Hlink-(CR R )UQQ(CR R )W-Hιink, Hlink-
19 20 19 20
(CH2)xT(CH2)y-Hlink, Hiink-(CR R )XT(CR R )y-Hlink, and HHnk- 7 20 7 20
(CR R )XT(CR R )y-Hijnk wherein j is selected from an integer of 0 to 18, u and w are independently selected from an integer of 1 to 8, and x and y are independently selected from an integer of 0 to 8 with the proviso that only one H]jnk can be simultaneously a covalent single bond;
B2 can be a linker selected from the group consisting of natural amino acids and synthetic amino acids wherein said amino acids have two or more acylateable functional groups selected from the group consisting of primary amino, secondary amino, thiol, and hydroxy;
B3 is a linker connecting groups independently selected from the group consisting
7 of Ia, lb, Ic and Ij from the point of attachment of A-R of said Ia, lb, I^, and j groups wherein the number of groups attached to said linker from the point of attachment of A-
7 R is kk wherein kk is an integer selected from 2 to 20 wherein said integer represents the number of acylateable functions present on said linker with a range of from two to the maximum number of acylateable functions present on said linker with the proviso that no more than 5 each of Ia, l , Ic, and j are simultaneously. present on said linker and wherein said linker is selected from the group consisting of polyhydroxy compound of carbon selected from the group consisting of polyhydroxyalkanes, saccharides, disaccharides, polysaccharides, inositols, alditols, alditol acetals, alditol ketals, aldaric acids, aldonic acids, aldonic acid lactones, and hydroxyalkylamines having 2 to 20 acylateable hydroxy groups;
B3 can be a linker selected from the group consisting of polyamino compounds of carbon selected from the group consisting of diaminoalkanes, diaminocycloalkanes, diaminoaryls, diaminoheterocycyls, diaminoalkylamines, triaminoalkylamines, diaminoalkylaminoalkylamines, and triaminoalkylaminoalkylamines, wherein said polyamino compounds have two to twenty acylateable amino groups, and compounds of carbon having one to nineteen hydroxy functions, one to nineteen amino functions and zero to eighteen thiol functions;
B4 is a linker connecting a first group independently selected from the group
consisting of Ia, lb, Ic, and Id through the point of bonding of a removable hydrogen of a
1 3 4 substituent independently selected from a group of substituents consisting of R , R , R
and R wherein R , R and R are independently selected from the group consisting of g hydrogen, hydroxy, and sulfhydryl and R is selected from the group consisting of hydroxyalkyl, aminoalkyl, alkylaminoalkyl and sulfhydrylalkyl to a second group independently selected from the group consisting of Ia, lb, Ic, and Ij through the point of bonding of a removable hydrogen of a substituent independently selected from a group of
1 3 4 8 1 3 4 substituents consisting of R , R , R and R wherein R , R and R are independently
8 selected from the group consisting of hydrogen, hydroxy, and sulfhydryl and R is selected from the group consisting of hydroxyalkyl, aminoalkyl, alkylaminoalkyl and sulfhydrylalkyl wherein said linker is selected from the group consisting of C=O,
24 25 30 30 C(O)C(O), C=S, S=O, SO2, Si(R )(R ), P(O)R , P(S)R , (O)2POP(O)2,
R30(O)POP(O)R3° Si(R19)R20Si(R19)R2° Si(R19)R2°OSi(R19)R20;
B4 can be a linker selected from the group consisting of Ajjnk-
19 20 19 20, m 19 20 ,.^20 7 20N 7 20 A
CR R (CR R )jCR R -Alink, Alink-CR R (CR R )jCR R -Aιink, Alink-
19 20 19 20 7 20 7 20
(CR R )UQQ(C R R )w-Aiink, Aιink-(CR R )UQQ(CR R )W-Alink, Alink-
19 20 19 20 (CH2)χT(CH2)y-Alink, Alink-(CR R )XT(CR R )y-Alink and Alink-
7 20 7 20
(CR R )XT(CR R )y-Aijn , wherein j is selected from an integer of 0 to 18, u and w are independently selected from an integer of 1 to 8 and x and y are independently selected from an integer of 0 to 8 with the proviso that only one A)jnk can be a covalent single bond;
B5 is a linker connecting a first group independently selected from the group
consisting of Ia, lb, Ic, and Lj through the point of bonding of a removable hydrogen of a
1 3 4 substituent independently selected from a group of substituents consisting of R , R , R
and R wherein R , R and R are independently selected from the group consisting of
hydrogen, hydroxy, and sulfhydryl and R is selected from the group consisting of hydroxyalkyl, aminoalkyl, alkylaminoalkyl and sulfhydrylalkyl to a second group independently selected from the group consisting of Ia, lb, Ic, and lj through the points of
1 2 1 2 bonding of both substituents R and R wherein R and R are both removable hydrogens
wherein said linker is selected from the group consisting of Dunk-
19 20 19 20 19 20 7 20 7 20 7 20
CR R (CR R )jCR R -Alink, Dlink-CR R (CR R )jCR R -Alink, Dlink-
19 20 19 20 7 20 7 20
(CR R )UQQ(C R R )w-Aιink, Dlink-(CR R )UQQ(CR R )W-Alink, Dlink-
19 20 19 20
(CH2)χT(CH2)y-Alink, Dlink-(CR R )XT(CR R )y-Alink, Dlink-
7 20 7 20 19 20 (CR R )XT(CR R )y-Alink, Elink-T(CH2)y-Alink, Elink-T(CR R )y-Alink and Elink-
7 20 T(CR R ) -Aijnk, wherein j is selected from an integer of 0 to 18, u and w are independently selected from an integer of 1 to 8, x and y are independently selected from an integer of 0 to 8, T is selected from the group consisting of a carbocyclic radical, aryl radical and a heterocyclyl radical, Dijnk is selected from a covalent single bond and
=C(R ), and Eπn is selected from the group consisting of a covalent single bond and
covalent double bond with the provisos that only one of A]jnk, D]jnk and Ejjnk can be simultaneously a covalent single bond and that only Dijnk and E]jnk can bond to the points
1 2 of bonding of R and R ;
B6 is a linker connecting a first group independently selected from the group
consisting of Ia, l , Iς, and j through the points of bonding of both substituents R and
2 1 2 R wherein R and R are both removeable hydrogens to a second group independently
selected from the group consisting of Ia, lb, Ic and Ij through the points of bonding of
1 2 ' 1 2 both substituents R and R wherein R and R are both removeable hydrogens wherein
19 20 19 20 19 20 said linker is selected from the group consisting of Fijnk-CR R (CR R );CR R -
7 20 7 20 7 20 19 20 19 20
Fiink. Flink-CR R (CR R )jCR R -Flink, Flink-(CR R )UQQ(C R R )W-Flink,
7 20 7 20 19 20 19 20 Flink-(CR R )UQQ(CR R )W-Flink, Flink-(CR R )XT(CR R )y-Flink, Flink-
7 20 7 20 19 20 7 20
(CR R )XT(CR R )y-Flink, Elink-T(CR R )y-Flink, Eιink-T(CR R )y-Flink, Elink-
T-Gijnk and Gijnk-T-E]jnk wherein j is selected from an integer of 0 to 18, u and w are independently selected from an integer of 1 to 8, x and y are independently selected from an integer of 0 to 8, Eijnk is selected from the group consisting of a covalent single bond
15 and covalent double bond, Fjjnk is =C(R ), and Gijn is a covalent double bond;
B7 is an amide and ester forming linker connecting groups independently selected
from the group consisting of Ia, lb, Ic, and Lj through the point of bonding of a removable hydrogen of a substituent independently selected from a group of substituents consisting
1 3 4 8 1 3 4 of the group R , R , R and R wherein R , R and R are independently selected from g the group consisting of hydrogen, hydroxy, and sulfhydryl and R is selected from the group consisting of hydroxyalkyl, aminoalkyl, alkylaminoalkyl and sulfhydrylalkyl of said Ia, l , Ic, and Ij groups wherein the number of groups attached to said linker through the point of bonding of a removable hydrogen of a substituent independently selected from a
1 3 4 8 1 3 4 group of substituents consisting of R , R , R and R wherein R , R and R are independently selected from the group consisting of hydrogen, hydroxy, and sulfhydryl g and R is selected from the group consisting of hydroxyalkyl, aminoalkyl, alkylaminoalkyl and sulfhydrylalkyl is kk wherein kk is an integer selected from 2 to 20 wherein said integer represents the number of amide and ester forming functions present on said linker with a range of from two to the^maximum number of amide and ester forming functions present on said linker with the proviso that no more than 5 each of Ia, lb, Ic, and Ij are connected by said amide and ester forming linker wherein said amide and ester forming linker is selected from the group consisting of carboxylic acid compounds of carbon selected from synthetic amino acids, natural amino acids, aldaric acids, citric acid cycle intermediates, alkylpolycarboxylic acids, arylpolycarboxylic acids and heteroarylpolycarboxylic acids wherein 2 to 20 acylating groups are present, said carboxylic acid compounds of carbon may be optionally substituted with one or more acylating substituents selected from the group consisting of phosphates, phosphonates, sulfonates, and sulfates, and said carboxylic acid compounds can be optionally substituted with acylateable substituents selected from the group consisting of amino, hydroxy, and sulfhydryl;
B7 can be an amide and ester forming linker selected from the group consisting of phosphoric acid compounds of carbon selected from the group consisting of phosphoric acid esters of saccharides, hydroxyaryls and heterocycles, phosphoric acid amides of amines, anilines, and arninoheterocycles wherein 2 to 20 acylating groups are present and said phosphoric acid compounds of carbon may be optionally substituted with acylating substituents selected from the group consisting of carboxylates, phosphonates, sulfonates, and sulfates and optionally substituted with one or more acylateable substituents selected from the group selected from amino, hydroxy, and sulfhydryl; B7 can be an amide and ester forming linker selected from the group consisting of phosphonic acid compounds of carbon selected from the group consisting of multiply phosphonoalkylated ammonia, primary amines, primary and secondary diamines, primary and secondary triamines, primary and secondary tetramines, primary and secondary ethyleneimines, and primary and secondary propyleneiminines and multiphosphonated alkanes, alkenes, alcohols, carboxylic acids, arenes, heterocyclyl radicals, and amino acids wherein 2 to 20 acylating groups are present and said phosphonic acid compounds of carbon may be optionally substituted with one or more acylating substituents selected from the group consisting of carboxylates, phosphates, sulfonates, and sulfates and optionally substituted with one or more acylateable substituents selected from the group selected from amino, hydroxy, and sulfhydryl;
B7 can be an amide and ester forming linker selected from the group consisting of sulfonic acid compounds of carbon selected from the group consisting of multiply sulfonoalkylated ammonia, primary amines, primary and secondary diamines, primary and secondary triamines, primary and secondary tetramines, primary and secondary ethyleneimines, and primary and secondary propyleneiminines and multisulfonated alkanes, alkenes, alcohols, carboxylic acids, arenes, heterocyclyl radicals, and amino acids wherein 2 to 20 acylating groups are present and said sulfonic acid compounds of carbon may be optionally substituted with one or more acylating substituents selected from the group consisting of carboxylates, phosphates, phosphonates, and sulfates and optionally substituted with one or more acylateable substituents selected from the group selected from amino, hydroxy, and sulfhydryl;
B7 can be an amide and ester forming linker selected from the group consisting of sulfuric acid compounds of carbon selected from the group consisting of sulfuric acid esters of saccharides, hydroxy aryls and heterocycles, and sulfuric acid amides of amines, anilines, and aminoheterocycles wherein 2 to 20 acylating groups are present and said sulfuric acid compounds of carbon may be optionally substituted with one or more acylating substituents selected from the group consisting of carboxylates, phosphates, sulfonates, and phosphonates and optionally substituted with one or more acylateable substituents selected from the group selected from amino, hydroxy, and sulfhydryl;
Bξ is a linker connecting a first group independently selected from the group
consisting of Ia, lb, Ic, and Lj through the point of bonding of a removable hydrogen of a
7 group selected independently from A and R to a second group independently selected
from the group consisting of Ia, lb, Ic, and Id through the point of bonding of a removable hydrogen of a substituent independently selected from a group of substituents consisting
1 3 4 1 3 4 of R , R and R wherein R , R and R are independently selected from hydrogen, hydroxy, and sulfhydryl wherein said linker is selected from the group consisting of a covalent single bond with the proviso that R is other than hydroxy and sulfhydryl,
19 20 19 20 19 20 7 20 7 20 7 20 19 20
CR R (CR R )jC R R , CR R (CR R )jC R R (CR R )UQQ(C
R19R20)W, (CR7R20)UQQ(CR7R20)W , (CR19R2°)xT(CR19R2°)y and
7 20 7 20
(CR R )XT(CR R )y wherein j is selected from an integer of 0 to 18, u and w are independently selected from an integer of 1 to 8, and x and y are independently selected from an integer of 0 to 8 ;
B9 is a linker connecting a first group independently selected from the group
7 consisting of Ia, lb, Ic, and Id from the point of attachment of A-R to a second group
independently selected from the group consisting of Ia, lb, Ic, and Id through the point of bonding of a removable hydrogen of a substituent independently selected from a group of
1 3 4 8 1 3 4 substituents consisting of R , R , R and R wherein R , R and R are independently g selected from the group consisting of hydrogen, hydroxy, and sulfhydryl and R is selected from the group consisting of hydroxyalkyl, aminoalkyl, alkylaminoalkyl and sulfhydrylalkyl and wherein said linker is selected from the group consisting of Hunk- 1 90 19 20 19 20 7 20 7 20 7 20
CR R (CR R )jCR R -Alink, Hιink-CR R (CR R )jCR R -AIink, Hlink-
19 20 19 20 7 20 7 20
(CR R )UQQ(C R R )W-Alink, Hlink-(CR R )UQQ(CR R )W-Aιink, Hlink-
19 20 19 20 7 20 7 20
(CR R )XT(CR R )y-Alink, and Hlink-(CR R )XT(CR R )y-Alink wherein j is selected from an integer of 0 to 18, u and w are independently selected from an integer of 1 to 8, and x and y are independently selected from an integer of 0 to 8 with the provisos that only one Aijnk and Hijn can be simultaneously a covalent single bond, Aijnk is connected to the point of bonding of a removable hydrogen of a group of substituents consisting of R , R , R and R , and Hijnk is connected only to the point of bonding of A-
R7;
B9 can be selected from the group consisting of bifunctional compounds of carbon wherein said compounds of carbon have one or more acylateable groups selected from the group consisting of primary amino, secondary amino, hydroxy, and sulfhydryl and one or more acylating groups selected from carboxy, thionocarboxy, sulfonyl, sulfate, sulfinyl, phosphate, and phosphonyl, wherein said compounds of carbon may be optionally
substituted with one or more R groups, wherein said acylateable group is connected to
7 the point of bonding of A-R and wherein said acylating group is connected to the point of
bonding of a removable hydrogen of a substituent group selected from R , R , R and R ;
B 10 is linker connecting a first group independently selected from the group
consisting of Ia, lb, I and Id through the point of bonding of a removable hydrogen of a
7 group selected independently from A and R to a second group independently selected
from the group consisting of Ia, lb, Ic, and Id through the points of bonding of both
1 2 1 2 substituents R and R wherein R and R are both removable hydrogens and wherein 19 20 19 20 19 20 said linker is selected from the group consisting of CR R (CR R )jCR R -Dijnk
7 20 7 20 7 20 19 20 19 20 and CR R (CR R )jC R R -Dlink, (CR R )UQQ(C R R )W-Dlink,
7 90 7 20 19 20 19 20
(CR 'R )UQQ(CR R )W-Dlink, (CR R )XT(CR R )y-Dlink,
7 20 7 20 19 20 7 20
(CR R )XT(CR R )y-Dlink, Eιink-T(CR R )y and EHnk-T(CR R )y wherein j is selected from an integer of 0 to 18, u and w are independently selected from an integer of
1 to 8, x and y are independently selected from an integer of 0 to 8, Dijnk is selected from
15 a group consisting of a covalent single bond and =C(R ), and Eijnk is selected from a group consisting of a covalent single bond and a covalent double bond with the proviso
1 2 that only Dijnk and Eijnk can bond to the points of bonding of R and R ;
B j j is a linker connecting a first group independently selected from the group
7 consisting of Ia, lb, I and Id from the point of attachment of A-R to a second group
independently selected from the group consisting of Ia, lb, I , and Id through the points of
1 2 1 2 bonding of both substituents R and R wherein R and R are both removable hydrogens
and wherein said linker is selected from the group consisting of Hun -
19 20 _ 19 20N „„ 19 20 _ , 7 20, 7 20, 7 0 ^ CR R (CR R )jCR R -Dlink, Hlink-CR R (CR R )jCR R -Dlink, Hlink-
19 20 19 20 7 20 7 20
(CR R )UQQ(C R R )w-Dlink, Hlink-(CR R )UQQ(CR R )W-Diink. Hιink-
19 20 19 20 7 20 7 20
(CRi yR )XT(CR R )y-Dlink, Hlink-(CR R )XT(CR R )y-Dlink, Hlink-
19 20 7 20
(CR R )χT-Eijnk and Hijnk-(CR R )χT-Eijnk wherein j is selected from an integer of
0 to 18, u and w are independently selected from an integer of 1 to 8, x and y are independently selected from an integer of 0 to 8, Dijnk is selected from a covalent single
bond and =C(R ) and Eijn is selected from the group consisting of a covalent single
bond and covalent double bond with the provisos that only one D]jnk and Hj,nk can be simultaneously a covalent single bond, and Hijnk is connected only to the point of bonding
of A-R7;
B 12 is a linker connecting a first group independently selected from the group
7 consisting of Ia, lb, Ic, and Id from the point of attachment of A-R to a second group
independently selected from the group consisting of Ia, lb, Ic, and Id through the point of bonding of a removable hydrogen of a group selected independently from the group
7 consisting of A and R wherein said linker is selected from the group consisting of
19 20 19 20 19 20 7 20 7 20 covalent single bond, Hιink-CR R (CR R )jC R R , Hlink-CR R (CR R )jC
7 20 19 20 19 20 7 20 7 20
R R , Hlink-(CR R )UQQ(C R R )w, Hιink-(CR R )UQQ(CR R )w, Hlink-
19 20 19 20 7 20 7 20 (CR R )XT(CR R )y and Hlink-(CR R )XT(CR R )y wherein j is selected from an integer of 0 to 18, u and w are independently selected from an integer of 1 to 8, and x and y are independently selected from an integer of 0 to 8 with the proviso that only Hnnk
7 can be bonded to the point of attachment of A-R ;
B i3 is a linker connecting a first group independently selected from the group
7 1 consisting of Ia, lb, Ic and Id fr°m e points of attachment of A-R and R to a second
group independently selected from the group consisting of Ia, lb, I , and Id from the point
7 1 of attachment of A-R and R wherein said linker consists of a single covalent bond
7 1 connecting A-R point of attachment of said first group to the point of attachment of R
7 of said second group and a single covalent bond connecting A-R point of attachment of
said second group to the point of attachment of R of said first group; B i4 is a linker connecting a first group independently selected from the group
consisting of Ia, lb, Ic, and Id, wherein A is R , from the points of attachment of J , J ,
1 2
R and R to a second group independently selected from the group consisting of Ia, lb,
Ic, and Id, wherein A is R , from the points of attachment of J , J , R and R wherein
said linker consists of a double covalent bond connecting the point of attachment of J and
2 1 2
J of said first group to the points of attachment of R and R of said second group and a
1 2 double covalent bond connecting the point of attachment of J and J of said second group
1 2 to the points of attachment of R and R of said first group;
B i5 is a linker connecting a first group independently selected from the group
7 1 2 consisting of Ia, lb, Ic, and Id from the points of attachment of A-R , R and R to a
second group independently selected from the group consisting of Ia, l , Ic, and I ,
wherein A is R , from the points of attachment of J , J and R where said linker
7 consists of a single covalent bond connecting A-R point of attachment of said first group
to the point of attachment of R of said second group and a double covalent bond
1 2 connecting the point of attachment of J and J of said second group to the points of
1 2 attachment of R and R of said first group;
Alink is independently selected from the group consisting of covalent single bond,
24 25 30 30
C=O, C(O)C(O), C=S, S=O, SO2, S(O)2O, Si(R R )2, P(O)R , P(O)R O and
C(OR6)(R] ); Hunk is independently selected from the group consisting of a covalent single
30 30 30 30 30 30 31 bond, O, S, N(R ), ON(R ), SN(R ), N(R )O, N(R )S, N(R )N(R ),
N(R3°)C(0), N(R3°)C(S), ON(R3°)C(O), ON(R3°)C(S), N(R3°)N(R31)C(O),
30 31 30 31 31 30 30 31 30 N(R )N(R )C(S),N(R )N(R )P(OR )R , N(R )N(R )P(O)R ,
30 31 30 30 30 30 30 30 30 N(R )N(R )P(S)R , ON(R )P(O)R , ON(R )P(S)R , SN(R )P(O)R ,
30 30 30 30 30 30 30
SN(R )P(S)R ,ON(R )C(O)O, ON(R )C(S)O, ON(R )C(O)N(R ), ON(R )C(S)
30 30 30 31 30 31 N(R ),ON(R )C(S)S,N(R )N(R )C(O)O, N(R )N(R )C(O)S,
30 31 31 30 31 30 31 N(R )N(R )C(O)N(R ), N(R )N(R )C(S)O, N(R )N(R )C(S)S,
30 31 31 30 31 31 30 30 31 30 N(R )N(R )C(S)N(R ),N(R )N(R )P(OR )R , N(R )N(R )P(O)R ,
30 31 30 30 31 30 30 31 30 N(R )N(R )P(S)R ,N(R )N(R )P(O)R O, N(R )N(R )P(S)R O,
30 31 30 30 31 30 30 31 31 30 N(R )N(R )P(O)R S,N(R )N(R )P(S)R S, N(R )N(R )P(OR )R ,
31 30 31 30 31 30 31 30 N(R )P(O)R ,N(R )P(S)R , N(R )P(O)R O, N(R )P(S)R O,
31 30 31 30 31 31 30 31 30
N(R )P(O)R S, N(R )P(S)R S, N(R )P(OR )R , N(R )P(O)R ,
/
31 30 30 30 30 30 30 30
N(R )P(S)R , ON(R )P(O)R , ON(R )P(S)R , SN(R )P(O)R ,
30 30 30 30 30 SN(R )P(S)R , ON(R )S(O)tt, SN(R )S(O)tt, and N(R )S(O)tt,
30 31 N(R )N(R )S(O)tt where tt is 1 to 2;
30 QQ is selected from the group consisting of O, ON(R ), C=O, C=S, S(O)t, Se(O)t
wherein t is 0 to 2, ON(R3°)S(O)tt, N(R3°)S(O)tt, N(R3°)Se(O)tt, ON(R3°)Se(O)tt
24 25 30 30 30 wherein tt is 1 to 2, Si(R R )2, N(R )n wherein n = 1 to 2, P(O)R and OP(O)(R ). It is an object of the present invention to provide compounds that have usefulness as inhibitors of nitric oxide synthase. These compounds also preferentially inhibit the inducible form over the constitutive form by at least 3 fold.
It is an advantage of the present invention that the compounds are more selective than those known in the art.
It is an object of the present invention to provide compounds that also are more selective than those known in the art.
It is an object of the present invention to provide compounds that have usefulness as inhibitors of nitric oxide synthase for longer periods of time.
It is an advantage of the present invention that the compounds are more useful for longer period of time than those known in the art.
It is an object of the present invention to provide compounds that have usefulness as inhibitors of nitric oxide synthase with control of the concentration of the inhibitor in the body.
It is an advantage of the present invention that the compounds control the concentration of the inhibitor in the body better than those known in the art.
It is also an advantage in that compounds of the present invention have preferred physical properties as compared to compounds known in the art. In contrast, NIL, which is disclosed in WO 93/13055 when the hydrochloride salt can be isolated as a colorless crystal, but has the property of deliquescence. The compound quickly becomes a very viscous sticky oil upon exposure to moisture in normal room air which makes it difficult to handle.
Also included in the family of compounds of Formula I, are the pharmaceutically- acceptable salts thereof. The term "pharmaceutically-acceptable salts" embraces salts commonly used to form alkali metal salts and to form addition salts of free acids or free bases. The nature of the salt is not critical, provided that it is pharmaceutically acceptable. Suitable pharmaceutically-acceptable acid addition salts of compounds of Formula I may be prepared from inorganic acid or from an organic acid. Examples of such inorganic acids are hydrochloric, hydrobromic, hydroiodic, nitric, carbonic, sulfuric and phosphoric acid. Appropriate organic acids may be selected from aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic, carboxylic and sulfonic classes of organic acids, examples of which are formic, acetic, propionic, succinic, glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic, glucoronic, maleic, fumaric, pyruvic, aspartic, glutamic, benzoic, anthranilic, mesylic, salicylic, p-hydroxy benzoic, phenylacetic, mandelic, embonic (pamoic), methanesulfonic, ethylsulfonic, benzenesulfonic, sulfanilic, stearic, cyclohexylaminosulfonic, algenic, galacturonic acid. Suitable pharmaceutically- acceptable base addition salts of compounds of Formula I include metallic salts made from aluminum, calcium, lithium, magnesium, potassium, sodium and zinc or organic salts made from N,N'-dibenzylethyleneldiamine, choline, chloroprocaine, diethanolamine, ethylenediamine, meglumine (N-methylglucamine) and procain. All of these salts may be prepared by conventional means from the corresponding compound of Formula I by reacting, for example, the appropriate acid or base with the compound of Formula I.
While it may be possible for the compounds of Formula I to be administered as the raw chemical, it is preferable to present them as a pharmaceutical composition. According to a further aspect, the present invention provides a pharmaceutical composition comprising a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof, together with one or more pharmaceutically acceptable carriers thereof and optionally one or more other therapeutic ingredients. The carrier(s) must be ϊacceptableϊ in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
The formulations include those suitable for oral, parenteral (including subcutaneous, intradermal, intramuscular, intravenous and intraarticular), rectal and topical (including dermal, buccal, sublingual and intraocular) administration although the most suitable route may depend upon for example the condition and disorder of the recipient. The formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. All methods include the step of bringing into association a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof (iactive ingredient!) with the carrier which constitutes one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both and then, if necessary, shaping the product into the desired formulation.
Formulations of the present invention suitable for oral administration may be presented as discrete units such as capsules, cachets or tablets each containing a predetermined amount of the aςtive ingredient; as a powder or granules; as a solution or a suspension in an aqueous liquid or a non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion. The active ingredient may also be presented as a bolus, electuary or paste.
A tablet may be made by compression or moulding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, lubricating, surface active or dispersing agent. Molded tablets may be made by moulding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. The tablets may optionally be coated or scored and may be formulated so as to provide slow or controlled release of the active ingredient therein.
Formulations for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain anti-oxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents. The formulations may be presented in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example, saline, water-for-injection, immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the kind previously described.
Formulations for rectal administration may be presented as a suppository with the usual carriers such as cocoa butter or polyethylene glycol.
Formulations for topical administration in the mouth, for example buccally or sublingually, include lozenges comprising the active ingredient in a flavored basis such as sucrose and acacia or tragacanth, and pastilles comprising the active ingredient in a basis such as gelatin and glycerin or sucrose and acacia.
Preferred unit dosage formulations are those containing an effective dose, as hereinbelow recited, or an appropriate fraction thereof, of the active ingredient.
It should be understood that in addition to the ingredients particularly mentioned above, the formulations of this invention may include other agents conventional in the art having regard to the type of formulation in question, for example those suitable for oral administration may include flavoring agents.
The compounds of the invention may be administered orally or via injection at a dose of from 0.001 to 2500 mg/kg per day. The dose range for adult humans is generally from 0.005 mg to 10 g/day. Tablets or other forms of presentation provided in discrete units may conveniently contain an amount of compound of the invention which is effective at such dosage or as a multiple of the same, for instance, units containing 5 mg to 500 mg, usually around 10 mg to 200 mg.
The compounds of Formula I are preferably administered orally or by injection (intravenous or subcutaneous). The precise amount of compound administered to a patient will be the responsibility of the attendant physician. However, the dose employed will depend on a number of factors, including the age and sex of the patient, the precise disorder being treated, and its severity. Also, the route of administration may vary depending on the condition and its severity. The use of generic terms in the description of the compounds are herein defined for clarity.
As utilized herein, the term "alkyl", either alone or within other terms such as "haloalkyl" and "alkylthio", means an acyclic alkyl radical containing from 1 to about 10, preferably from 1 to about 8 carbon atoms and more preferably 1 to about 6 carbon atoms. Said alkyl radicals may be optionally substituted with groups as defined below. Examples of such radicals include methyl, ethyl, chloroethyl, hydroxyethyl, n-propyl, oxopropyl, isopropyl, n-butyl, cyanobutyl, isobutyl, sec -butyl, tert-butyl, pentyl, aminopentyl, iso- amyl, hexyl, octyl and the like..
The term "alkenyl" refers to an unsaturated, acyclic hydrocarbon radical in so much as it contains at least one double bond. Such radicals containing from about 2 to about 10 carbon atoms, preferably from about 2 to about 8 carbon atoms and more preferably 2 to about 6 carbon atoms. Said alkenyl radicals may be optionally substituted with groups as defined below. Examples of suitable alkenyl radicals include propylenyl, 2-chloropropylenyl, buten-1-yl, isobutenyl, pentenylen-1-yl, 2-2-methylbuten-l-yl, 3- methylbuten-1-yl, hexen-1-yl, 3-hydroxyhexen-l-yl, hepten-1-yl, and octen-1-yl, and the like.
The term "alkynyl" refers to an unsaturated, acyclic hydrocarbon radical in so much as it contains one or more triple bonds, such radicals containing about 2 to about 10 carbon atoms, preferably having from about 2 to about 8 carbon atoms and more preferably having 2 to about 6 carbon atoms. Said alkynyl radicals may be optionally substituted with groups as defined below. Examples of suitable alkynyl radicals include ethynyl, propynyl, hydroxypropynyl, butyn-1-yl, butyn-2-yl, pentyn-1-yl, pentyn-2-yl, 4-methoxypentyn-2-yl, 3-methylbutyn-l-yl, hexyn-1-yl, hexyn-2-yl, hexyn-3-yl, 3,3-dimethylbutyn-l-yl radicals and the like.
The term "hydrido" denotes a single hydrogen atom (H). This hydrido radical may be attached, for example, to an oxygen atom to form a "hydroxyl" radical, one hydrido radical may be attached to a carbon atom to form a "methine" radical
I ,
( rμ ) -/π , or two hydrido radicals may be attached to a carbon atom to form a "methylene" (-CH2-) radical.
The term "carbon" radical denotes a carbon atom without any covalent bonds and capable of forming four covalent bonds.
The term "cyano" radical denotes a carbon radical having three of four covalent bonds shared by a nitrogen atom.
The term "hydroxyalkyl" embraces radicals wherein any one or more of the alkyl carbon atoms is substituted with a hydroxyl as defined above. Specifically embraced are monohydroxyalkyl, dihydroxyalkyl and polyhydroxyalkyl radicals.
The term "alkanoyl" embraces radicals wherein one or more of the terminal alkyl carbon atoms are substituted with one or more carbonyl radicals as defined below. Specifically embraced are monocarbonylalkyl and dicarbonylalkyl radicals. Examples of monocarbonylalkyl radicals include formyl, acetyl, and pentanoyl. Examples of dicarbonylalkyl radicals include oxalyl, malonyl, and succinyl.
The term "alkylene" radical denotes linear or branched radicals having from 1 to about 10 carbon atoms and having attachment points for two or more covalent bonds. Examples of such radicals are methylene, ethylene, methylethylene, and isopropylidene.
The term "halo" means halogens such as fluorine, chlorine, bromine or iodine atoms.
The term "haloalkyl" embraces radicals wherein any one or more of the alkyl carbon atoms is substituted with halo as defined above. Specifically embraced are monohaloalkyl, dihaloalkyl and polyhaloalkyl radicals. A monohaloalkyl radical, for one example, may have either a bromo, chloro or a fluoro atom within the radical. Dihalo radicals may have two or more of the same halo atoms or a combination of different halo radicals and polyhaloalkyl radicals may have more than two of the same halo atoms or a combination of different halo radicals. More preferred haloalkyl radicals are "lower haloalkyl" radicals having one to about six carbon atoms. Examples of such haloalkyl radicals include fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl and dichloropropyl.
The term "hydroxyhaloalkyl" embraces radicals wherein any one or more of the haloalkyl carbon atoms is substituted with hydroxy as defined above.
The term "haloalkylene radical" denotes alkylene radicals wherein any one or more of the alkylene carbon atoms is substituted with halo as defined above. Dihalo alkylene radicals may have two or more of the same halo atoms or a combination of different halo radicals and polyhaloalkylene radicals may have more than two of the same halo atoms or a combination of different halo radicals. More preferred haloalkylene radicals are "lower haloalkylene" radicals having one to about six carbon atoms. Examples of "haloalkylene" radicals include difluoromethylene, tetrafluoroethylene, tetrachloroethylene, alkyl substituted monofluoromethylene, and aryl substituted trifluoromethylene.
The term "haloalkenyl" denotes linear or branched radicals having from 1 to about 10 carbon atoms and having one or more double bonds wherein any one or more of the alkenyl carbon atoms is substituted with halo as defined above. Dihaloalkenyl radicals may have two or more of the same halo atoms or a combination of different halo radicals and polyhaloalkenyl radicals may have more than two of the same halo atoms or a combination of different halo radicals. The terms "alkoxy" and "alkoxyalkyl" embrace linear or branched oxy- containing radicals each having alkyl portions of one to about ten carbon atoms, such as methoxy radical. The term "alkoxyalkyl" also embraces alkyl radicals having one or more alkoxy radicals attached to the alkyl radical, that is, to form monoalkoxyalkyl and dialkoxyalkyl radicals. More preferred alkoxy radicals are "lower alkoxy" radicals having one to six carbon atoms. Examples of such radicals include methoxy, ethoxy, propoxy, butoxy and tert-butoxy alkyls. The "alkoxy" radicals may be further substituted with one or more halo atoms, such as fluoro, chloro or bromo, to provide "haloalkoxy" radicals. Examples of such radicals include fluoromethoxy, chloromethoxy, trifluoromethόxy, difluoromethoxy, trifluoroethoxy, fluoroethoxy, tetrafluoroethoxy, pentafluoroethoxy, and fluoropropoxy.
The term "haloalkoxyalkyl" also embraces alkyl radicals having one or more haloalkoxy radicals attached to the alkyl radical, that is, to form monohaloalkoxyalkyl and dihaloalkoxyalkyl radicals. The term "haloalkenyloxy" also embraces oxygen radicals having one or more haloalkenyloxy radicals attached to the oxygen radical, that is, to form monohaloalkenyloxy and dihaloalkenyloxy radicals. The term "haloalkenyloxyalkyl" also embraces alkyl radicals having one or more haloalkenyloxy radicals attached to the alkyl radical, that is, to form monohaloalkenyloxyalkyl and dihaloalkenyloxyalkyl radicals.
The term "alkylenedioxy" radicals denotes alkylene radicals having at least two oxygens bonded to a single alkylene group. Examples of "alkylenedioxy" radicals include methylenedioxy, ethylenedioxy, alkylsubstituted methylenedioxy, and arylsubstituted methylenedioxy. The term "haloalkylenedioxy" radicals denotes haloalkylene radicals having at least two oxy groups bonded to a single haloalkyl group. Examples of "haloalkylenedioxy" radicals include difluoromethylenedioxy, tetrafluoroethylenedioxy, tetrachluoroethylenedioxy, alkylsubstituted monofluoromethylenedioxy, and arylsubstituted monofluoromethylenedioxy. The term "aryl", alone or in combination, means a carbocyclic aromatic system containing one, two or three rings wherein such rings may be attached together in a pendent manner or may be fused. The term "aryl" embraces aromatic radicals such as phenyl, naphthyl, tetrahydronaphthyl, indane and biphenyl.
The term "perhaloaryl" embraces aromatic radicals such as phenyl, naphthyl, tetrahydronaphthyl, indane and biphenyl wherein the aryl radical is substituted with 3 or more halo radicals as defined below.
The term "heterocyclyl" embraces saturated, partially saturated and unsaturated heteroatom-containing ring-shaped radicals, where the heteroatoms may be selected from nitrogen, sulfur and oxygen. Examples of saturated heterocyclic radicals include saturated 3 to 6-membered heteromonocylic group containing 1 to 4 nitrogen atoms[e.g. pyrrolidinyl, imidazolidinyl, piperidino, piperazinyl, etc.]; saturated 3 to 6- membered heteromonocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms [e.g. morpholinyl, etc.]; saturated 3 to 6-membered heteromonocyclic group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms [e.g., thiazolidinyl, etc.]. Examples of partially saturated heterocyclyl radicals include dihydrothiophene, dihydropyran, dihydrofuran and dihydrothiazole. Examples of unsaturated heterocyclic radicals, also termed "heteroaryl" radicals, include unsaturated 5 to 6 membered heteromonocyclyl group containing 1 to 4 nitrogen atoms, for example, pyrrolyl, pyrrolinyl, imidazolyl, pyrazόlyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, triazolyl [e.g., 4H-l,2,4-triazolyl, lH-l,2,3-triazolyl, 2H-1,2,3- triazolyl, etc.] tetrazolyl [e.g. lH-tetrazolyl, 2H-tetrazolyl, etc.], etc.; unsaturated condensed heterocyclic group containing 1 to 5 nitrogen atoms, for example, indolyl, isoindolyl, indolizinyl, benzimidazolyl, quinolyl, isoquinolyl, indazolyl, benzotriazolyl, tetrazolopyridazinyl [e.g., tetrazolo [l,5-b]pyridazinyl, etc.], etc.; unsaturated 3 to 6-membered heteromonocyclic group containing an oxygen atom, for example, pyranyl, 2-furyl, 3-furyl, etc.; unsaturated 5 to 6-membered heteromonocyclic group containing a sulfur atom, for example, 2-thienyl, 3-thienyl, etc.; unsaturated 5- to 6-membered heteromonocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, for example, oxazolyl, isoxazolyl, oxadiazolyl [e.g., 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl, etc.] etc.; unsaturated condensed heterocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms [e.g. benzoxazolyl, benzoxadiazolyl, etc.]; unsaturated 5 to 6-membered heteromonocyclic group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms, for example, thiazolyl, thiadiazolyl [e.g., 1,2,4- thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5- thiadiazolyl, etc.] etc.; unsaturated condensed heterocyclic group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms [e.g., benzothiazolyl, benzothiadiazolyl, etc.] and the like. The term also embraces radicals where heterocyclic radicals are fused with aryl radicals. Examples of such fused bicyclic radicals include benzofuran, benzothiophene, and the like. Said "heterocyclyl" group may have 1 to 3 substituents as defined below. Preferred heterocyclic radicals include five to ten membered fused or unfused radicals. Non-limiting examples of heterocyclic radicals include pyrrolyl, pyridinyl, pyrazolyl, triazolyl, pyrimidinyl, pyridazinyl, oxazolyl, thiazolyl, imidazolyl, indolyl, thiophenyl, furanyl, tetrazolyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrrolindinyl, 1 ,3-dioxolanyl, 2-imidazolinyl, imidazolidinyl, 2-pyrazolinyl, pyrazolidinyl, isoxazolyl, isothiazolyl, 1,2,3-oxadiazolyl, 1 ,2,3-triazolyl, 1,3,4- thiadiazolyl, 2H-pyranyl, 4H-pyranyl, piperidinyl, 1,4-dioxanyl, morpholinyl, 1,4- dithianyl, thiomorpholinyl, pyrazinyl, piperazinyl, 1,3,5-triazinyl, 1,3,5-trithianyl, benzo(b)thiophenyl, benzimidazonyl, quinolinyl, tetraazolyl, and the like.
The term "sulfonyl", whether used alone or linked to other terms such as alkylsulfonyl, denotes respectively divalent radicals -SO2-. "Alkylsulfonyl", embraces alkyl radicals attached to a sulfonyl radical, where alkyl is defined as above. "Alkylsulfonylalkyl", embraces alkylsulfonyl radicals attached to an alkyl radical, where alkyl is defined as above. "Haloalkylsulfonyl", embraces haloalkyl radicals attached to a sulfonyl radical, where haloalkyl is defined as above. "Haloalkylsulfonylalkyl", embraces haloalkylsulfonyl radicals attached to an alkyl radical, where alkyl is defined as above. The term "aminosulfonyl" denotes an amino radical attached to a sulfonyl radical. The term "sulfinyl", whether used alone or linked to other terms such as alkylsulfmyl, denotes respectively divalent radicals -S(O)-. "Alkylsulfmyl", embraces alkyl radicals attached to a sulfinyl radical, where alkyl is defined as above. "Alkylsulfinylalkyl", embraces alkylsulfmyl radicals attached to an alkyl radical, where alkyl is defined as above. "Haloalkylsulfinyl", embraces haloalkyl radicals attached to a sulfinyl radical, where haloalkyl is defined as above. "Haloalkylsulfinylalkyl", embraces haloalkylsulfinyl radicals attached to an alkyl radical, where alkyl is defined as above.
The term "aralkyl" embraces aryl-substituted alkyl radicals. Preferable aralkyl radicals are "lower aralkyl" radicals having aryl radicals attached to alkyl radicals having one to six carbon atoms. Examples of such radicals include benzyl, diphenylmethyl, triphenylmethyl, phenylethyl and diphenylethyl. The terms benzyl and phenylmethyl are interchangeable.
The term "heteroaralkyl" embraces heteroaryl-substituted alkyl radicals wherein the heteroaralkyl radical may be additionally substituted with three or more substituents as defined above for aralkyl radicals. The term "perhaloaralkyl" embraces aryl-substituted alkyl radicals wherein the aralkyl radical is substituted with three or more halo radicals as defined above.
The term "aralkylsulfinyl", embraces aralkyl radicals attached to a sulfinyl radical, where aralkyl is defined as above. "Aralkylsulfinylalkyl", embraces aralkylsulfinyl radicals attached to an alkyl radical, where alkyl is defined as above.
The term "Aralkylsulfonyl", embraces aralkyl radicals attached to a sulfonyl radical, where aralkyl is defined as above. "Aralkylsulfonylalkyl", embraces aralkylsulfonyl radicals attached to an alkyl radical, where alkyl is defined as above.
The term "cycloalkyl" embraces radicals having three to ten carbon atoms.
More preferred cycloalkyl radicals are "lower cycloalkyl" radicals having three to seven carbon atoms. Examples include radicals such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. The term "cycloalkylalkyl" embraces cycloalkyl-substituted alkyl radicals. Preferable cycloalkylalkyl radicals are "lower cycloalkylalkyl" radicals having cycloalkyl radicals attached to alkyl radicals having one to six carbon atoms. Examples of such radicals include cyclohexylhexyl. The term "cycloalkenyl" embraces radicals having three to ten carbon atoms and one or more carbon-carbon double bonds. Preferred cycloalkenyl radicals are "lower cycloalkenyl" radicals having three to seven carbon atoms. Examples include radicals such as cyclobutenyl, cyclopentenyl, cyclohexenyl and cycloheptenyl. The term "halocycloalkyl" embraces radicals wherein any one or more of the cycloalkyl carbon atoms is substituted with halo as defined above. Specifically embraced are monohalocycloalkyl, dihalocycloalkyl and polyhalocycloalkyl radicals. A monohalocycloalkyl radical, for one example, may have either a bromo, chloro or a fluoro atom within the radical. Dihalo radicals may have two or more of the same halo atoms or a combination of different halo radicals and polyhalocycloalkyl radicals may have more than two of the same halo atoms or a combination of different halo radicals. More preferred halocycloalkyl radicals are "lower halocycloalkyl" radicals having three to about eight carbon atoms. Examples of such halocycloalkyl radicals include fluorocyclopropyl, difluorocyclobutyl, trifluorocyclopentyl, tetrafluorocyclohexyl, and dichlorocyclopropyl. The term "halocycloalkenyl" embraces radicals wherein any one or more of the cycloalkenyl carbon atoms is substituted with halo as defined above. Specifically embraced are monohalocycloalkenyl, dihalocycloalkenyl and polyhalocycloalkenyl radicals. The term "halocycloalkoxy" also embraces cycloalkoxy radicals having one or more halo radicals attached to the cycloalkoxy radical, that is, to form monohalocycloalkoxy, dihalocycloalkoxy, and polycycloalkoxy radicals.
The term "Cycloalkylsulfinyl", embraces cycloalkyl radicals attached to a sulfinyl radical, where cycloalkyl is defined as above. "Cycloalkylsulfinylalkyl", embraces cycloalkylsulfinyl radicals attached to an alkyl radical, where alkyl is defined as above. The term "Cycloalkylsulfonyl", embraces cycloalkyl radicals attached to a sulfonyl radical, where cycloalkyl is defined as above. "Cycloalkylsulfonylalkyl", embraces cycloalkylsulfonyl radicals attached to an alkyl radical, where alkyl is defined as above.
The term "alkylthio" embraces radicals containing a linear or branched alkyl radical, of one to ten carbon atoms, attached to a divalent sulfur atom. More preferred alkylthio radicals are "lower alkylthio" radicals having one to six carbon atoms. An example of "lower alkylthio" is methylthio (CH3-S-). The term "alkylsulfmyl" embraces radicals containing a linear or branched alkyl radical, of one to ten carbon atoms, attached to a divalent -S(=O)- atom.
The terms alkylamino denotes "monoalkylamino" and "dialkylamino" containing one or two alkyl radicals, respectively, attached to an amino radical. The terms arylamino denotes "monoarylamino" and "diarylamino" containing one or two aryl radicals, respectively, attached to an amino radical. The term "Aralkylamino", embraces aralkyl radicals attached to an amino radical, where aralkyl is defined as above. The term aralkylamino denotes "monoaralkylamino" and "diaralkylamino" containing one or two aralkyl radicals, respectively, attached to an amino radical. The term aralkylamino further denotes "monoaralkyl monoalkylamino" containing one aralkyl radical and one alkyl radical attached to an amino radical.
The term "arylsulfinyl" embraces radicals containing an aryl radical, as defined above, attached to a divalent -S(=O)- atom. The term "arylsulfinylalkyl" denotes arylsulfinyl radicals attached to a linear or branched alkyl radical, of one to ten carbon atoms.
The term "Arylsulfonyl", embraces aryl radicals attached to a sulfonyl radical, where aryl is defined as above. "Arylsulfonylalkyl", embraces arylsulfonyl radicals attached to an alkyl radical, where alkyl is defined as above. The term "heteroarylsulfinyl" embraces radicals containing an heteroaryl radical, as defined above, attached to a divalent -S(=O)- atom. The term "heteroarylsulfinylalkyl" denotes heteroarylsulfinyl radicals attached to a linear or branched alkyl radical, of one to ten carbon atoms. The term "Heteroarylsulfonyl", embraces heteroaryl radicals attached to a sulfonyl radical, where heteroaryl is defined as above. "Heteroarylsulfonylalkyl", embraces heteroarylsulfonyl radicals attached to an alkyl radical, where alkyl is defined as above.
The term "aryloxy" embraces aryl radicals, as defined above, attached to an oxygen atom. Examples of such radicals include phenoxy.
The term "aroyl" embraces aryl radicals, as defined above, attached to an carbonyl radical as defined above. Examples of such radicals include benzoyl and toluoyl.
The term "aralkanoyl" embraces aralkyl radicals, as defined herein, attached to an carbonyl radical as defined above. Examples of such radicals include, for example, phenylacetyl.
The term "aralkoxy" embraces oxy-containing aralkyl radicals attached through an oxygen atom to other radicals. More preferred aralkoxy radicals are "lower aralkoxy" radicals having phenyl radicals attached to lower alkoxy radical as described above.
The term "aryloxyalkyl" embraces aryloxy radicals, as defined above, attached to an alkyl group. Examples of such radicals include phenoxymethyl.
The term "haloaryloxyalkyl" embraces aryloxyalkyl radicals, as defined above, wherein one to five halo radicals are attached to an aryloxy group. The term "heteroaryloxy" embraces heteroaryl radicals, as defined above, attached to an oxygen atom. Examples of such radicals include pyridyloxy and furyloxy. The term "heteroaroyl" embraces heteroaryl radicals, as defined above, attached to an carbonyl radical as defined above. Examples of such radicals include furoyl and nicotinyl.
The term "heteroaralkanoyl" embraces heteroaralkyl radicals, as defined herein, attached to an carbonyl radical as defined above. Examples of such radicals include, for example, pyridylacetyl and furylbutyryl.
The term "heteroaralkoxy" embraces oxy-containing heteroaralkyl radicals attached through an oxygen afom to other radicals. More preferred heteroaralkoxy radicals are "lower heteroaralkoxy" radicals having heteroaryl radicals attached to lower alkoxy radical as described above.
The term "heteroaryloxyalkyl" embraces heteroaryloxy radicals, as defined above, attached to an alkyl group. Examples of such radicals include pyridyloxy methyl .
The term "haloheteroaryloxyalkyl" embraces heteroaryloxyalkyl radicals, as defined above, wherein one to four halo radicals are attached to an heteroaryloxy group.
The term "arylthio" embraces aryl radicals, as defined above, attached to an sulfur atom. Examples of such radicals include phenylthio.
The term "arylthioalkyl" embraces arylthio radicals, as defined above, attached to an alkyl group. Examples of such radicals include phenylfhiomefhyl.
The term "alkylthioalkyl" embraces alkylthio radicals, as defined above, attached to an alkyl group. Examples of such radicals include methylthiomethyl. The term "alkoxyalkyl" embraces alkoxy radicals, as defined above, attached to an alkyl group. Examples of such radicals include methoxy methyl. The term "carbonyl" denotes a carbon radical having two of the four covalent bonds shared with an oxygen atom. The term "carboxy" embraces a hydroxyl radical, as defined above, attached to one of two unshared bonds in a carbonyl group. The term "carboxamide" embraces amino, monoalkylamino, and dialkylamino radicals, attached to one of two unshared bonds in a carbonyl group. The term "carboxamidoalkyl" embraces carboxamide radicals, as defined above, attached to an alkyl group. The term "carboxyalkyl" embraces a carboxy radical, as defined above, attached to an alkyl group. The term "carboalkoxy" embraces alkoxy radicals, as defined above, attached to one of two unshared bonds in a carbonyl group. The term "carboaralkoxy" embraces aralkoxy radicals, as defined above, attached to one of two unshared bonds in a carbonyl group. The term "monocarboalkoxyalkyl" embraces one carboalkoxy radical, as defined above, attached to an alkyl group. The term "dicarboalkoxyalkyl" embraces two carboalkoxy radicals, as defined above, attached to an alkylene group. The term "monocyanoalkyl" embraces one cyano radical, as defined above, attached to an alkyl group. The term "dicyanoalkylene" embraces two cyano radicals, as defined above, attached to an alkyl group. The term "carboalkoxycyanoalkyl" embraces one cyano radical, as defined above, attached to an alkylene group.
The term "acyl", alone or in combination, means a carbonyl or thionocarbonyl group bonded to a radical selected from, for example, hydrido, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, alkoxyalkyl, haloalkoxy, aryl, heterocyclyl, heteroaryl, alkylsulfinylalkyl, alkylsulfonylalkyl, aralkyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, alkylthio, arylthio, amino, alkylamino, dialkylamino, aralkoxy, arylthio, and alkylthioalkyl. Examples of "acyl" are formyl, acetyl, benzoyl, trifluoroacetyl, phthaloyl, malonyl, nicotinyl, and the like. The term "haloalkanoyl" embraces one or more halo radicals, as defined herein, attached to an alkanoyl radical as defined above. Examples of such radicals include, for example, chloroacetyl, trifluoroacetyl, bromopropanoyl, and heptafluorobutyryl. The term "phosphono" embraces a pentavalent phosphorus attached with two covalent bonds to an oxygen radical. The term "dialkoxyphosphono" denotes two alkoxy radicals, as defined above, attached to a phosphono radical with two covalent bonds. The term "diaralkoxyphosphono" denotes two aralkoxy radicals, as defined above, attached to a phosphono radical with two covalent bonds. The term "dialkoxyphosphonoalkyl" denotes dialkoxyphosphono radicals, as defined above, attached to an alkyl radical. The term "diaralkoxyphosphonoalkyl" denotes diaralkoxyphosphono radicals, as defined above, attached to an alkyl radical.
The structural term, H(W)C=C(K)E, alone or in combination, means cyanoalkyl, dicyanoalkyl, carboxamidoalkyl, dicarboxamidoalkyl, cyanocarboalkoxyalkyl, carboalkoxyalkyl, dicarboalkoxyalkyl, cyanocycloalkyl, dicyanocycloalkyl, carboxamidocycloalkyl, dicarboxamidocycloalkyl, cyanocarboalkoxycycloalkyl, carboalkoxycycloalkyl, dicarboalkoxycycloalkyl, formylalkyl, or acylalkyl wherein at least one of W, E, and K are independently selected from carboxy, thionocarboxy, thiolcarboxy, cyano, carboxamido, thionocarboxamido, carboalkoxy, thionocarboalkoxy, thiocarboalkoxy, acyl, thionoacyl, formyl or thionofoπnyl provided any two of W, E, or K may be taken together to form a spacer group selected from a linear moiety having a chain length of 1 to 4 atoms to form a C5 to C8 saturated carbocyclyl, a C5 to C8 partially saturated carbocyclyl, a C5 to C8 saturated heterocyclyl or a C5 to C8 partially saturated heterocyclyl substituted independently and optionally with, for example, one or more alkyl, haloalkyl, aryl, heteroaryl, alkoxyalkyl, alkoxy, haloalkoxy, cyano, carboalkoxy, hydroxy, hydroxyalkyl, and halo groups.
Said "alkyl", "alkenyl", "alkynyl", "alkanoyl", "alkylene", "hydroxyalkyl", "haloalkyl", "haloalkylene", "haloalkenyl", "alkoxy", "alkoxyalkyl", "aryl", "haloalkoxyalkyl", "alkylenedioxy", "heterocyclyl", "heteroaryl", "hydroxyhaloalkyl",
"alkylsulfonyl", "alkylsulfonylalkyl", "haloalkylsulfonylalkyl", "alkylsulfmyl", "alkylsulfinylalkyl", "haloalkylsulfinylalkyl", "aralkyl", "heteroaralkyl", "perhaloaralkyl", "aralkylsulfonyl", "aralkylsulfonylalkyl", "aralkylsulfinyl", "aralkylsulfinylalkyl", "cycloalkyl", "cycloalkenyl", "halocycloalkyl", "halocycloalkenyl", "cycloalkylsulfinyl", "cycloalkylsulfinylalkyl", "cycloalkylsulfonyl", "cycloalkylsulfonylalkyl", "cycloalkoxy", "alkylthio", "alkylsulfmyl", "alkylamino", "arylamino", "aralkylamino", "arylsulfinyl", "arylsulfinylalkyl", "arylsulfonyl", "arylsulfonylalkyl", "heteroarylsulfinyl", "heteroarylsulfinylalkyl", "heteroarylsulfonyl", "heteroarylsulfonylalkyl", "aryloxy", "aroyl", "aralkanoyl", "aralkoxy", "aryloxyalkyl", "haloaryloxyalkyl", "heteroaroyl", "heteroaralkanoyl", "heteroaralkoxy", "heteroaralkoxyalkyl", "arylthio", "arylthioalkyl", "alkoxyalkyl", and "acyl" groups defined above may optionally have 1 to 3 substituents such as heteroarylamino, N-aryl-N-alkylamino, N-heteroarylamino-N-alkylamino, haloalkylthio, alkanoyloxy, alkoxy, heteroaralkoxy, cycloalkoxy, cycloalkenyloxy, hydroxy, amino, thio, nitro, lower alkylamino, alkylthio, alkylthioalkyl, arylamino, aralkylamino, arylthio, alkylsuliinyl, alkylsulfonyl, alkylsulfonamido, alkylaminosulfonyl, amidosulfonyl, monoalkyl amidosulfonyl, dialkyl amidosulfonyl, monoarylamidosulfonyl, arylsulfonamido, diarylamidosulfonyl, monoalkyl monoaryl amidosulfonyl, arylsulfinyl, arylsulfonyl, heteroarylthio, heteroarylsulfinyl, heteroarylsulfonyl, alkanoyl, alkenoyl, aroyl, heteroaroyl, aralkanoyl, heteroaralkanoyl, haloalkanoyl, alkyl, alkenyl, alkynyl, alkylenedioxy, haloalkylenedioxy, cycloalkyl, cycloalkenyl, lower cycloalkylalkyl, lower cycloalkenylalkyl, halo, haloalkyl, haloalkoxy, hydroxyhaloalkyl, hydroxyaralkyl, hydroxyalkyl, hydoxyheteroaralkyl, haloalkoxyalkyl, aryl, aralkyl, aryloxy, aralkoxy, aryloxyalkyl, saturated heterocyclyl, partially saturated heterocyclyl, heteroaryl, heteroaryloxy, heteroaryloxyalkyl, arylalkyl, heteroarylalkyl, arylalkenyl, heteroarylalkenyl, carboalkoxy, carboaralkoxy, cyano, and carbohaloalkoxy.
The term "spacer" can include a covalent bond and a linear moiety having a backbone of 1 to 7 continuous atoms. The spacer may have 1 to 7 atoms of a univalent or multi-valent chain. Univalent chains may be constituted by a radical selected from =C(H)- , =C(R6)-, -O-, -S-, -S(O)-, -S(O)2-, -NH-, -N(R6)-,-N=, -CH(OH)-, =C(OH)-, -CH(OR6)-, =C(OR6)-, and -C(O)-. Multi-valent chains may consist of a straight chain of 1 or 2 or 3 or 4 or 5 or 6 or 7 atoms or a straight chain of 1 or 2 or 3 or 4 or 5 or 6 or 7 atoms with a side chain. The chain may be constituted of one or more radicals selected from: lower alkylene, lower alkenyl, -O-, -O-CH2-, -S-CH2-, -CH2CH2-, ethenyl, -CH=CH(OH)-, - OCH2O-, -O(CH2)2O-, -NHCH2-, -OCH(R6)O-, -O(CH2CHR6)O-, -OCF2O-, -O(CF2)2O-, -S-, -S(O)-, -S(O)2-, -N(H)-, -N(H)O-, -N(R6)O-, -N(R6)-, -C(O)-, -C(O)NH-, -C(O)NR6-, -N=, -OCH2-, -SCH2-, S(O)CH2-, -CH2C(O)-, -CH(OH)-, =C(OH)-, -CH(OR6)-, =C(OR6)-, S(O)2CH2-, and -NR6CH2- and many others radicals defined above or generally known or ascertained by one of skill-in-the art. Side chains may include substituents such as heteroarylamino, N-aryl-N-alkylamino, N-heteroarylamino-N-alkylamino, haloalkylthio, alkanoyloxy, alkoxy, heteroaralkoxy, cycloalkoxy, cycloalkenyloxy, hydroxy, amino, thio, lower alkylamino, alkylthio, alkylthioalkyl, arylamino, aralkylamino, arylthio, alkylsulfmyl, alkylsulfonyl, alkylsulfonamido, alkylaminosulfonyl, amidosulfonyl, monoalkyl amidosulfonyl, dialkyl amidosulfonyl, monoarylamidosulfonyl, arylsulfonamido, diarylamidosulfonyl, monoalkyl monoaryl amidosulfonyl, arylsulfinyl, arylsulfonyl, heteroarylthio, heteroarylsulfinyl, heteroarylsulfonyl, alkanoyl, alkenoyl, aroyl, heteroaroyl, aralkanoyl, heteroaralkanoyl, haloalkanoyl, alkyl, alkenyl, alkynyl, alkylenedioxy, haloalkylenedioxy, cycloalkyl, cycloalkenyl, lower cycloalkylalkyl, lower cycloalkenylalkyl, halo, haloalkyl, haloalkoxy, hydroxyhaloalkyl, hydroxyaralkyl, hydroxyalkyl, hydoxyheteroaralkyl, haloalkoxyalkyl, aryl, aralkyl, aryloxy, aralkoxy, aryloxyalkyl, saturated heterocyclyl, partially saturated heterocyclyl, heteroaryl, heteroaryloxy, heteroaryloxyalkyl, arylalkyl, heteroarylalkyl, arylalkenyl, heteroarylalkenyl, carboalkoxy, carboaralkoxy, cyano, and carbohaloalkoxy.
The term "prodrug" refers to a compound that is made more active in vivo.
As used herein, reference to "treatment" of a patient is intended to include prophylaxis.
All references, patents or applications, U.S. or foreign, cited in the application are hereby incorporated by reference as if written herein.
Compounds of the present invention can exist in tautomeric, geometric or stereoisomeric forms. The present invention contemplates all such compounds, including cis- and trans-geometric isomers, E- and Z-geometric isomers, R- and S-enantiomers, diastereomers, d-isomers, 1-isomers, the racemic mixtures thereof and other mixtures thereof, as falling within the scope of the invention. Pharmaceutically acceptable sales of such tautomeric, geometric or stereoisomeric forms are also included within the invention. The terms "cis" and "trans" denote a form of geometric isomerism in which two carbon atoms connected by a double bond will each have two highes ranking groups on the same side of the double bond ("cis") or on opposite sides of the double bond ("trans"). Some of the compounds described contain alkenyl groups, and are meant to include both cis and trans or "E" and "Z" geometric forms.
The term "oligomeric" denotes a form of compound in which two to about twenty analogous units of similar function and biological activity are covalently joined one to another directly, through a linker compound, through a mixture of linker compounds, or through a combination of the aforementioned means.
The term "linker" denotes a covalent bond and any group of atoms that covalently joins together two to twenty analogous units of similar function and biological activity.
The term "linker compound" denotes any inorganic and organic material and compound able to covalently join together two to twenty analogous units of similar function and biological activity.
The term "removable hydrogen" denotes a hydrogen that can be removed by reaction with a base or removed by replacement by an alkylating or acylating reagent. Said hydrogen removing base will have a pKa of a minimum of about 15 relative to water when, for example, a hydrogen is to be removed from a carboxylic acid, a phenol, a sulfate acid, a phosphate acid, an acetoacetate, a malonate, mercaptan, dinitriles, nitroalkane, and the like. Suitable bases having a pKa of about 15 include potassium hydroxide, sodium carbonate, sodium methoxide, triethylamine, sodium ethoxide, tetrabutylammonium hydroxide, and the like. Preferably, the base will have a pKa up to about 30 so that a hydrogen can be removed in a substantially complete manner from alcohols, amides, mononitriles, monoesters, and the like. Examples of preferable bases include potassium tert-butoxide, sodium hydride, sodium amide, lithium diisopropylamine and the like. Acylating reagents able to remove a hydrogen by replacement include anhydrides of carboxylic acids and halides (for example, chloride) of carboxylic acids, sulfate acids, phosphate acids, phosphonate acids and the like. The term "bifunctional compounds of carbon" denotes linker compounds having two types of functional substituents. One type of functional substituent group can be acylated. Acylateable groups include primary amino, secondary amino, hydroxy, sulfhydryl, and the like. The second type of functional substituent are those that can acylate functional substituents. Acylating groups include carboxy, thionocarboxy, sulfonyl, sulfate, sulfinyl, phosphate, and phosphonyl. Most preferred are activated forms of the said acylating groups where the hydroxy function or salt form are converted into more reactive intermediates such as esters, chlorides, azides, cyanides, oxyimides, isoureas, mixed anhydrides, and the like. Examples of "bifunctional compounds of carbon" include natural and synthetic amino acids such as glycine, alanine, lysine, glutamate, ornithine, serine, threonine, phenylalanine, tyrosine, valine, 4-aminobutanoic acid, and the like, peptides, sugar phosphates such as glycerol phosphate, glucose-6- phosphate, aldonic acids such glucuronic acid, aldaric acids such as glucaric acid, aminoalkylphosphonic acids such as aminomethylphosphonic acid, N,N-bis- phosphonome thy 1 amine, aminoarylcarboxylic acids such as 4-aminobenzoic acid.
Some of the compounds described contain one or more stereocenters and are meant to include R, S, and mixtures of R and S forms for each stereocenter present.
Some of the compounds described herein may contain one or more ketonic or aldehydic carbonyl groups or combinations thereof alone or as part of a heterocyclic ring system. Such carbonyl groups may exist in part or principally in the "keto" form and in part or principally as one or more "enol" forms of each aldehyde and ketone group present. Compounds of the present invention having aldehydic or ketonic carbonyl groups are meant to include both "keto" and "enol" tautomeric forms.
Some of the compounds described herein may contain one or more imine or enamine groups or combinations thereof. Such groups may exist in part or principally in the "imine" form and in part or principally as one or more "enamine" forms of each group present. Compounds of the present invention having said imine or enamine groups are meant to include both "imine" and "enamine" tautomeric forms. The following general synthetic sequences are useful in making the present invention. Abbreviations used in the schemes are as follows: "AA" represents amino acids, "Boc" represents tert-butyloxycarbonyl, "BOP" represents benzotriazol- 1 -yl-oxy- tris-(dimethylamino)phosphonium hexafluorophosphate, "Bz" represents a benzyl group, "CMR-C1" represents a chloromethylation or bromomethylation reagent such as Cl- CH2OC(O)R15, Cl-CH2NR19C(O)R15, C1-CH NR19C(S)R15, Cl-CH2SC(O)R15, Cl- CH2SC(S)R15, Cl-CH2OC(O)GR15, Cl-CH2NR19C(O)GR15, C1-CH2NR19C(S)GR15, Cl-CH2OC(S)GR15, or C1-CH2SC(S)GR15, "DCC" represents 1,3- dicyclohexylcarbodiimide, "DIB AH" represents diisobutylaluminum hydride, "DIPEA" represents diisopropylethylamiήe, "DMF" represents dimethylformamide, "DMSO" represents dimethylsulfoxide, "Fmoc" represents 9-fluorenylmethoxycarbonyl, "LDA" represents lithium diisopropylamide, "PHTH" represents a phthaloyl group, "pnZ" represents 4-nitrobenzyloxycarbonyl, "PTC" represents a phase transfer catalyst, "TCC" represents trichloroethoxy carbonyl, "p-TsOH" represents paratoluenesulfonic acid, "TBTU" represents 2-(lH-benzotriozole-l-yl)-l,l,3,3-tetramethyl uronium tetrafluoroborate, "TEA" represents triethylamine, "TFA" represents trifluoroacetyl, "THF" represents tetrahydrofuran, "THP" represents tetrahydropyranyl, and "Z" represents benzyloxycarbonyl.
Disclosed are eighty-eight synthetic processes useful in the preparation of intermediates (ie, precursors) to the compounds of the present invention. The use of "E" in the structures of these preparatory methods refers to the substituent "E" as defined in structural term, H(W)C=C(K)E, above. The use of "Z" in the structures of these preparatory methods refers to the use of "Z" refers to the benzyloxycarbonyl group as defined in the paragraph immediately above.
The following examples are provided to illustrate the present invention and are not intended to limit the scope thereof. Those skilled in the art will readily understand that known variations of the conditions and processes of the following preparative procedures can be used to prepare these compounds.
Figure imgf000056_0001
BocHN (4! BocHN (3)
(a) R -NH2 (aa) N-chlorosuccimide, DMF
(b) BOP, DIPEA, DMF
(c) Pd, H2, Ethanol/Acetic Acid
(d) H20, pH 9-10
(e) HCI, dioxane or trifluoroacetic acid. Scheme 2
Figure imgf000057_0001
(a) HCI, Methanol
(b) BOP, DIPEA, DMF
(c) Pd, H2, Ethanol/Acetic Acid
(d) TEA, DMF
(e) HCI, dioxane or trifluoroacetic acid
Figure imgf000058_0001
Z-HN (9)
(a) R3 -NH2 (aa) N-chlorosuccimide, DMF
(b) BOP, DIPEA, DMF
(c) HCI, dioxane or trifluoroacetic acid
(d) H2O, pH 9-10 (e) Pd, H , Ethanol/Acetic Acid
Scheme 4
Figure imgf000059_0001
(a) HCI, Methanol
(b) BOP, DIPEA, DMF
(c) HCI, dioxane or trifluoroacetic acid
(d) TEA, DMF
(e) Pd, H2, Ethanol/Acetic Acid
Figure imgf000060_0001
(a) t-Butoxycarbonyl azide, H2O, dioxane, MgO
(b) Pd, H2, Ethanol/Acetic Acid
(c) TEA, 0-80 °C
Figure imgf000061_0001
(a) TEA, 0-80 °C
(b) HCI, dioxane
Figure imgf000062_0001
(R1= hydroxyl, sulfhydryl, OR 6 or SR6) (a) 1. t-butoxycarbonylazide, H 20, dioxane, MgO 2. acetic anhydride, TEA (b) BOP, DIPEA, DMF (c) 1 equiv. NaOH, ethanol (d) DMSO, DCC, H 3PO4 (e) R1-NH2, ethanol, sodium carbonate Scheme 8
Figure imgf000063_0001
(R1= hydroxyl, sulfhydryl, OR6 or SR6 ) (a) BH3 , THF
(b) Acylation with R : a carboxylic acid choride or anhydride, a chloroformate, an isocyanate, a sulfonyl chloride, sulfinyl chloride, or phosphating or phosphonating reagent with standard conditions
(c) HCI, dioxane or trifluoroacetic acid
(d) H20, pH 9-10 with (2) or TEA, DMF with (2b) Scheme 9
H
Figure imgf000064_0001
(a) 1. t-butoxycarbonylazide, H 20, dioxane, MgO 2. acetic anhydride, TEA
(b) BOP, DIPEA, DMF
(c) 1 equiv. NaOH, ethanol
(d) DMSO, DCC, H3PO4
(e) R2-NH2 (R2 = hydroxyl, sulfhydryl, OR6 or SR6), ethanol , sodium carbonate Scheme 10
R 7
Figure imgf000065_0001
(R^= hydroxyl, sulfhydryl, OR0 or SRd ) (a) BH3 , THF
(b) Acylation with R : a carboxylic acid choride or anhydride, a chloroformate, an isocyanate, a sulfonyl chloride, sulfinyl chloride, or phosphating or phosphonating reagent with standard conditions
(c) HCI, dioxane or trifluoroacetic acid
(d) H20, pH 9-10 with (2) or TEA, DMF with (2b)
Figure imgf000066_0001
( a) R -NH2 ( aa) N-chlorosuccimide , DMF
(b) HCI , dioxane or trif luoroacetic acid
1
(c) Acylation with R : a carboxylic acid choride or anhydride, a chloroformate, an isocyanate, a sulfonyl chloride, sulfinyl chloride, or phosphating or phosphonating reagent with standard conditions
(d) Pd, H2, Ethanol/Acetic Acid (e) H20, pH 9-10
Figure imgf000067_0001
(a) HCI, Methanol
(b) HCI, dioxane or trifluoroacetic acid
(c) Acylation with R : a carboxylic acid choride or anhydride, a chloroformate, an isocyanate, a sulfonyl chloride, sulfinyl chloride, or phosphating or phosphonating reagent with standard conditions
(d) Pd, H2, Ethanol/Acetic Acid
(e) TEA, DMF
Figure imgf000068_0001
(a) R -NH (aa) N-chlorosuccimide, DMF
(b) HCI, dioxane or trifluoroacetic acid
(c) Acylation with R : carboxylic acid choride or anhydride, chloroformate, isocyanate, sulfonyl chloride, sulfinyl chloride, or phosphating or phosphonating eagent with standard conditions
(d) Pd, H , Ethanol/Acetic Acid
(e) H 0, pH 9-10
Figure imgf000069_0001
(a) HCI, methanol
(b) HCI, dioxane or trifluoroacetic acid
2
(c) Acylation with R : carboxylic acid choride or anhydride, chloroformate, isocyanate, sulfonyl chloride, sulfinyl chloride, or phosphating or phosphonating reagent with standard conditions
(d) Pd, H2, Ethanol/Acetic Acid
(e) TEA, DMF
Figure imgf000070_0001
(a) Benzyl chloroformate, Na C03 THF, Water
(b) HCl, dioxane or trifluoroacetic acid
(c) catalytic p-TsOH, hexane or toluene, azeotropic distillation (d) Pd, H , Ethanol/Acetic Acid (e) Acylation with R 1 or R2 : carboxylic ac d choride or anhydride, chloroformate, isocyanate, sulfonyl chloride or sulfinyl chloride with standard conditions.
Figure imgf000071_0001
( a) catalytic p-TsOH, hexane or toluene , azeotropic distillation
(b) Pd, H , Ethanol /Acetic Acid
(c) Acylation with R 1or R2 : carboxylic ac d choride or anhydride, chloroformate, isocyanate, sulfonyl chloride or sulfinyl chloride with standard conditions.
Figure imgf000072_0001
(a) Naθ3SCH2OH, pH 10-11 [see . Maier, Phosphorus, Sulfur Silicon Related Elements (1990), 47, 43-46]
(b) 1. Aldehyde, acetal with trace of acid, or ketone, methanol or ethanol, 2. NaCNBH3 , methanol, KOH [see R. F. Borch, Organic Synthesis, 52, 124 (1972)
Figure imgf000073_0001
(a) Trichloroethyl chloroformate, Na 2C03' H 2 0' THF [see D. Gravel et al . , Canadian Journal of Chemistry, 50, 3846(1972] (b) Lawesson's Reagent, [Jones and Bradshaw, Chem. Reviews (1984), 84, 17-30 and cited references.
(c) 1. Zinc dust, Acetic Acid, 2. Na 2C03' H 2°
(d) Acylation with R : carboxylic acid choride or anhydride, chloroformate, isocyanate, sulfonyl chloride, or sulfinyl chloride with standard conditions
(e) Acylation with R 2 with (d) -conditions .
Figure imgf000074_0001
(a) catalytic p-TsOH, hexane or toluene, azeotropic distillation
(b) NaCNBH3 , methanol, KOH [see R. F. Borch, Organic
Synthesis, 52, 124 (1972)
(c) Acylation with R 1or R2 : carboxylic acid choride or anhydride, chloroformate, isocyanate, sulfonyl chloride, or sulfinyl chloride with standard conditions
Figure imgf000075_0001
(a) 2 equivalents of Lithium Diisopropylamide, THF, C(0)C12 or C(S)C12
(b) HCI, dioxane or trifluoroacetic acid
(c) 1. Lithium Diisopropylamide, THF, 2. 2-haloalkanoate ester (R)
(d) Na2Cθ3, toluene, heat
Figure imgf000076_0001
(c) Lithium Diisopropylamide, THF, then dialkyl acetal of a bromoalkanone
Figure imgf000077_0001
(a) R -NH2 (aa) N-chlorosuccimide, DMF
(b) an aldehyde or ketone precursor toR , catalytic p-TsOH, hexane or toluene, azeotropic distillation
(c) NaCNBH3 , methanol, KOH [see R. F. Borch, Organic Synthesis, 52, 124 (1972)]
(d) H20, pH 9-10
(e) HCl, dioxane or trifluoroacetic acid
Figure imgf000078_0001
(a) Na2 θ3, aqueous dioxane; Acylation with a carboxylic acid choride or anhydride
(b) Na2Cθ3 , aqueous dioxane; sulfonation with a sulfonyl chloride or sulfinyl chloride with standard conditions
Figure imgf000079_0001
(a) a2Cθ3 , aqueous dioxane; Acylation with carboxylic acid choride or anhydride
(b) a2C03 , aqueous dioxane; sulfonation with sulfonyl chloride or sulfinyl chloride with standard conditions
(c) trifluoroacetic acid anhydride
(d) NaBH4, R -OH, aprotic polar solvent
Figure imgf000080_0001
Z-HN (75;
(a) TEA, DMF
(b) benzyl chloroformate, Na2Cθ3, dioxane, water
(c) NaOH, H20
(d) BOP, DIPEA, DMF
(e) DMF, heat
(f) Pd, H , Ethanol
Figure imgf000081_0001
(b) an aldehyde or ketone precursor to R , catalytic p-TsOH, hexane or toluene, azeotropic distillation
(c) NaCNBH 3 , methanol, KOH [see R. F. Borch, Organic Synthesis, 52, 124 (1972)] (d) Pd, H 2, Ethanol
(e) TEA, 0-80 °C (f) Acylation with R 2: carboxylic acid choride or anhydride, chloroformate, isocyanate, sulfonyl chloride, sulfinyl chloride, or phosphating or phosphonation reagent with standard conditions
Figure imgf000082_0001
(a) Phthalic anhydride, THF at reflux
(b) LDA, THF, then Alkylation with a chloromethylation reagent (CMR-Cl)
(c) Pd, H2, Ethanol
(d) H20, pH 9-10
(e) Hydrazine, methanol, reflux.
Figure imgf000083_0001
(a) Phthalic anhydride, THF at reflux
(b) LDA, THF Alkylation with a chloromethylation reagent (CMR-Cl)
(c) Hydrazine, methanol, reflux
(d) H20, pH 9-10
(e) Pd, H2, Ethanol
Figure imgf000084_0001
(a) A t-Butoxycarbonyl amino acid (Boc-AA) , BOP, DIPEA, DMF
(b) A 4-nitrobenzyloxycarbonyl amino acid (pnZ-AA) , BOP, DIPEA, DMF
(c) Pd, H , Ethanol
(d) HCl, dioxane, H20
Figure imgf000085_0001
(a) LDA, THF Alkylation with a chloromethylation reagent (CMR-Cl)
(b) Hydrazine, methanol, reflux
(c) H20, pH 9-10
(d) Pd, H , Ethanol
Figure imgf000086_0001
(a) 2 equivalents of Lithium Diisopropylamide, THF, C(0)C12 or C(S)C12
(b) HCl, dioxane or trifluoroacetic acid
(c) 1. Lithium Diisopropylamide, THF, 2. 2-haloalkanoate ester (R)
(d) a2C03, toluene, heat
Figure imgf000087_0001
(a) 2 equivalents of Lithium Diisopropylamide, THF, C(0)C12 or C(S)C12
(b) Pd, H2, ethanol/acetic acid
(c) 1. Lithium Diisopropylamide, THF, 2. 2-haloalkanoate ester (R)
(d) Na2C03, toluene, heat
Figure imgf000088_0001
(c) Lithium Diisopropylamide, THF, then dialkyl acetal of a bromoalkanone
Figure imgf000089_0001
(c) Lithium Diisopropylamide, THF, then dialkyl acetal of a bromoalkanone
Figure imgf000090_0001
(a) Pd, H2, Ethanol/Acetic Acid
(b) Heat up to 150 °C to decarboxylate
(c) BH3 in Tetrahydrofuran (d) DMSO, DCC, H 3 PO4
(e) p-TsOH, R 3-OH, hexane, heat
(f) BF3 etherate with an R23-OH or R23 -SH in an aprotic solvent
(g) 1. Aqueous Na2C03 wash, 2. thoroughly dry, then 3. HCl in dioxane
Figure imgf000091_0001
(a) H20, pH 9-10
(b) Hydrazine, methanol, reflux
Figure imgf000092_0001
(a) BF3 etherate with HOR >2ώ8ϋ,OH,
Figure imgf000092_0002
HSR ,2ώ8"SH, HOR28NR2 H, or HSR28NR H in an aprotic solvent or, with HOR28OH, p-TsOH, R 3-OH, hexane, heat
(b) HCl, dixoane or trifluoroacetic acid
(c) H2O, pH 9-10 (d) Hydrazine, methanol, reflux
Figure imgf000093_0001
(a) HCl/dioxane or trifluoroacetic acid, then SOCl 2/DMF
(b) 1 equivalent DIBAH/THF at -78 °C
(c) p-TsOH, R23-OH, hexane, heat
(d) 1. 1 equivalent NaOH/alcohol, 2. HCl (1 mole), dry
3. BOP, DIPEA, DMF, 4. H-A-R ' (e) BF3 etherate with an R23-OH or R23 -SH in an aprotic solvent
Figure imgf000094_0001
(a) Pd, H2, ethanol/acetic acid
(b) H20, pH 9-10
(c) Hydrazine, methanol, reflux Scheme 40
H3
Figure imgf000095_0001
(a) 1 equivalent NaOH in ethanol, then 1 equivalent of HCl, then heat to 150 °C to decarboxylate
(b) Hydrazine, methanol, reflux
(c) Intermediate (2) or (2b), pH 9-10, H20
(d) R7-SH, CH2C12, -10 °C, HCl
(e) R7-0H, CH2C12, -10 °C, HCl Scheme 41
Figure imgf000096_0001
(a) Hydrazine, ethanol, reflux
(b) Intermediate (2) or (2b), pH 9-10, H 0
(c) R7-SH, CH2C12, -10 °C, HCl
(d) R7-OH, CH2C12, -10 °C, HCl
Scheme 42
Figure imgf000097_0001
(a) H-NR ,5 R„7 , toluene, reflux
(b) R7-OH, CH2C12, -10 °C, HCl
(c) R7-SH, CH2C12, -10 °C, HCl
(d) 1. 1 equivalent NaOH in ethanol, 2. 1 equivalent of HCl, 3. BOP, DIPEA, DMF, H-NR5R7
Figure imgf000098_0001
(a) Pd, H2, Ethanol/Acetic Acid
(b) Intermediate (2) or (2b), pH 9-10, H 0
(c) H2 , Pt, Acetic acid
(d) C1-C(0)R15, triethylamine
(e) 1. Hydrazine, methanol, reflux, 2. HCl, dioxane Scheme 44
Figure imgf000099_0001
(a) 1. 1 equivalent LDA/THF at -78 °C, 2. bromoacetal (166)
(b) 1. 1 equivalent LDA/THF at -78 °C, 2. Br-CH CH 0-Bz
(c) catalytic p-TsOH, H20, 0-5 °C
(d) H2N-R4 , NaCNBH3, methanol, KOH [see R. F. Borch, Organic Synthesis, 52, 124 (1972)
Figure imgf000100_0001
(a) Intermediate (2) or (2b), pH 9-10, H 20
(b) HCl/Acetic acid
(c) 1. BOP, DIPEA, DMF, 2. H-A-R 7
(d) Pd, H2, Ethanol/Acetic Acid
(e) Hydrazine, methanol, reflux
Figure imgf000101_0001
(a) Tosyl Chloride (TsCl), Pyridine, H20, 0-5 °C
(b) 1. NaCN, DMF, heat, 2. Hydrazine, methanol, reflux
(c) 1. Sodium thioacetate, DMF, heat, 2. Hydrazine, methanol, reflux, 3. Hydrolysis with TsOH
(d) 1. Sodium thioacetate, DMF, heat, 2. Hydrolysis with 1 equiv. NaOH, 3. CMR-Cl, 4. Hydrazine, methanol, reflux Scheme 47
Figure imgf000102_0001
(a) 1. HCl, dioxane, 2. BOP, DIPEA, DMF, 3. H0CH CC13
(b) 1. 1 equivalent LDA/THF at -78 °C, 2. CMR-Cl
(c) catalytic p-TsOH, H20, 0-5 °C
(d) H2N-R4 , NaCNBH3, methanol, KOH [see R. F. Borch, Organic Synthesis, 52, 124 (1972)
Figure imgf000103_0001
(a) Intermediate (2) or (2b) , pH 9-10, H 20
(b) Zinc dust/THF
(c) 1. BOP, DIPEA, DMF, 2. H-A-R 7
(d) Hydrazine, methanol, reflux
Figure imgf000104_0001
( a) 1 . 1 equivalent LDA/THF at -78 °C , 2 . alkylation
Q p O Q with an R -reagent such as R -Br, R -OTs, R -oxirane, thiirane, or aziridine, or CMR-Cl
(b) catalytic p-TsOH, H20, 0-5 °C
(c) H N-R4 , NaCNBH3, methanol, KOH
(d) Intermediate (2) or (2b), pH 9-10, H20
Figure imgf000105_0001
(a) HCl in dioxane or ethyl acetate
(b) 1. BOP, DIPEA, DMF, 2. H-R 27such as HN(R 22)0R6, HN(R22 )N(R24)R25, R19 (R20 )C=N-N(R22 )H, R 19 (R20 ) C=N-OH
(c) Hydrazine, methanol, reflux
(d) 1. ClC02Et, TEA, THF, -10 °C, 2. CH2C12, PTC, NaOH, H-R27such as HN(R 22 ) S0 R13 , HN (R22 ) C (0) R 15
15
HN(R 22 C(S)R HN(R22 )P(0) (OR 13 n R^
Figure imgf000106_0001
(a) 1. BOP, DIPEA, DMF,
2. t-butyl ester of amino acid with t-butoxycarbonyl protected OH or SH group (H2 -AA)
(b) Hydrazine, methanol, reflux
(c) HCl in dioxane or ethyl acetate
(d) 1. BOP, DIPEA, DMF,
2. t-butyl N-t-butoxycarbonyl amino acid with unprotected OH or SH group (HO/S-AA) Scheme 52
Figure imgf000107_0001
ion
Q Q p p
(c) R -reagent such as R -Br, R -OTs, R° -oxirane,
(d) HCl in dioxane or ethyl acetate
(e) Intermediate (2) or (2b), pH 9-10, H 2°
(f) BF3 etherate with an R 23 -OH or R23-SH
(g) BF3 etherate with HOR 28OH, HOR28 SH, HSR28SH, HOR28NR2 H, or HSR 28N H
(h) H2 , Pd/C, Ammonium Formate
Figure imgf000108_0001
(a) t-Butoxycarbonyl azide, H20, dioxane, MgO
(b) H20, phosphoric acid
(c) R 92 -NH2 , catalyti.c p-TsOH, toluene, azeotropic distillation (d) N-chlorosuccinimide, DMF (e) R7-OH, toluene, reflux (f) HCl, dioxane
Figure imgf000109_0001
(b) HCl, dioxane or trifluoroacetic acid
(c) C1-C(0)C(R30) (R31)C(0)-C1, pyridine
(d) R19C(0)R20, catalytic p-TsOH, toluene, azeotropic distillation.
Figure imgf000110_0001
(a) R30-PC12 where R30 is not OH, SH, or NH 2 , pyridine
(b) HCl, dioxane or trifluoroacetic acid
(c) PCI3 , pyridine
(d) R30-OH where R30 is not OH or SH, pyridine
Figure imgf000111_0001
(a) R19R20SiCl , pyridine
(b) Pd, H2, methyl cyclohexane
(c) Cl-SiR19R20SiR19R20-Cl, pyridine
Figure imgf000112_0001
(a) C1-S(0)2C(R3°) (R31)S(0)2-C1, pyridine
(b) HCl, dioxane or trifluoroacetic acid
(c) C1-S(0)C(R30) (R31)S(0)-C1, pyridine
Figure imgf000113_0001
(a) S0C12, pyridine
(b) HCl, dioxane or trifluoroacetic acid
(c) S(0)2C1 , pyridine
Figure imgf000114_0001
(a) R ,3-30 -P(0)C12 where R ,3J0U is not OH, SH, or NH2 , pyridine
(b) HCl, dioxane or trifluoroacetic acid
(c) P(0)Cl3, pyridine
(d) R30-OH where R30 is not OH or SH, pyridine
Figure imgf000115_0001
(a) C12-P(0)C(R30 ) (R31 )P(0)-C12, pyridine
(b) R30-OH where R30 is not OH or SH, pyridine
(c) HCl, dioxane or trifluoroacetic acid
(d) Cl-(R30)P(O)C(R30) (R31)P(R30) (O)-Cl, pyridine
Figure imgf000116_0001
(a) Cl2-P(0)-0-P(0)-Cl2 , pyridine
(b) R30-OH where R30 is not OH or SH, pyridine
(c) HCl, dioxane or trifluoroacetic acid
(d) Cl-(R30)P(O)-O-P(R30 ) (O)-Cl, pyridine
Figure imgf000117_0001
(a) phosgene, pyridine
(b) HCl, dioxane or trifluoroacetic acid
(c) C(S)C12, pyridine
Figure imgf000118_0001
(a) Cl-CR19R20-O-CR19R20-Cl, pyridine
(b) Pd, H2 , methyl cyclohexane
(c) Cl-SiR19R20-O-SiR19R20-Cl, pyridine
Figure imgf000119_0001
(a) pyridine, 1, 2-cyclopentyldicarbonyl chloride as an example of a 1 , 2-dicarbonyl chloride or anhydride of a substituted cycloalkane, cycloalkene, aryl radical, or heterocyclyl (b) Pd, H , ethanol (c) CH3CH2θ-C(R31)=C(R30 )C(0)-0CH 2CH3, heat (-ethanol)
Figure imgf000120_0001
(a) C1-C(0)C(0)-C1, pyridine
(b) HCl, dioxane or trifluoroacetic acid
(c) C1-C(0)C(R30) (R31)C(0)-C1, pyridine
Figure imgf000121_0001
(a) C1-S(0) C(R30 ) (R31)S(0)2-C1, pyridine
(b) HCl, dioxane or trifluoroacetic acid
(c) C1-S(0)C(R30) (R31)S(0)-C1, pyridine
Figure imgf000122_0001
(a) C12-P(0)C(R30 ) (R31 )P(0)-C12, pyridine
(b) R30-OH where R30 is not OH or SH, pyridine
(c) HCl, dioxane or trifluoroacetic acid
(d) Cl-(R30)P(O)C(R30) (R31)P(R30) (O)-Cl, pyridine
Figure imgf000123_0001
(a) Cl2-P(0)-0-P(0)-Cl2 , pyridine
(b) R30-OH where R 30 is not OH or SH, pyridine
(c) HCl, dioxane or trif luoroacetic acid
(d) Cl-(R30)P(O)-O-P(R30 ) (O)-Cl, pyridine
Figure imgf000124_0001
(a) Cl-CR19R20-O-CR19R20-Cl, pyridine
(b) Pd, H2 , methylcyclohexane
(c) Cl-SiR19R20-O-SiR19R20-Cl, pyridine
Figure imgf000125_0001
(a) pyridine, 1, 2-cyclopentyldicarbonyl chloride as an example of a 1, 2-dicarbonyl chloride or anhydride of a substituted cycloalkane, cycloalkene, aryl radical, or heterocyclyl (b) Pd, H 2, ethanol (c) CH3CH20-C(R31)=C(R3° ) C (0) -OCH 2CH3 , heat ( -ethanol )
Figure imgf000126_0001
(a) pyridine, phthaloyl chloride as an example of a 1, 2-dicarbonyl chloride or anhydride of a substituted cycloalkane, cycloalkene, aryl radical, or heterocyclyl (b) Pd, H 2 , ethanol
(c) C1(0)CC(R 31)=C(R30)C(O)Cl, heat ( -ethanol)
Figure imgf000127_0001
(a) pyridine, phthaloyl chloride as an example of a 1, 2-dicarbonyl chloride or anhydride of a substituted cycloalkane, cycloalkene, aryl radical, or heterocyclyl (b) Pd, H 2 , ethanol
(c) C1(0)CCH(R 31)-CH(R30 )C(0)C1, heat ( -ethanol )
Figure imgf000128_0001
(a) C1-C(0)C(0)-C1, pyridine
(b) C1-C(0)-C1, pyridine
(c) C1-C(0)C(R30) (R31)C(0)-C1, pyridine
(d) C1-S(0)2C(R30 ) (R31 )S(0)2-C1, pyridine
Figure imgf000129_0001
(a) C1-C(0)C(0)-C1, pyridine
(b) Cl-SiR19R20SiR19R20-Cl, pyridine
(c) C1-C(0)C(R30) (R31)C(0)-C1, pyridine
(d) Cl-S(O) 2C(R30 ) (R31)S(0)2-C1, pyridine
Figure imgf000130_0001
(a) C1-C(0)C(0)-C1, pyridine
(b) Cl-SiR19R20SiR19R20-Cl, pyridine
(c) C1-C(0)C(R30) (R31)C(0)-C1, pyridine
(d) Cl-S(O) 2C(R30 ) (R31 )S(0)2-C1, pyridine
Figure imgf000131_0001
(a) C1-C(0)C(0)-C1, pyridine
(b) C1-C(0)-C1, pyridine
(c) C1-C(0)C(R30) (R31)C(0)-C1, pyridine
(d) C1-S(0)2C(R3°) (R31)S(0)2-C1, pyridine
Figure imgf000132_0001
(a) C1-C(0)C(0) -CI, pyridine
(b) Cl-SiR19R20SiR19R20-Cl, pyridine
(c) C1-C(0)C(R30) (R31)C(0)-C1, pyridine
(d) Cl-S(O) 2C(R30 ) (R31 )S(0) 2-C1, pyridine
Figure imgf000133_0001
(b) Cl-SiR19R20SiR19R20-Cl, pyridine
(c) C1-C(0)C(R30) (R31)C(0)-C1, pyridine
(d) Cl-S(O) 2C(R30 ) (R31)S(0)2-C1, pyridine
Figure imgf000134_0001
(a) C1-C(0)C(0)-C1, pyridine
(b) HCl, dioxane, then one equivalent water
(c) Cl-C(0)C(R3°) (R31)C(0)-C1, pyridine
Figure imgf000135_0001
(b) HCl, dioxane or trifluoroacetic acid
(c) C1-C(0)C(R30) (R31)C(0)-C1, pyridine
(d) R C(0)R , catalytic p-TsOH, toluene, azeotropic distillation.
Figure imgf000136_0001
(a) R 3J0 -PC12 where R 30 u is not OH, SH, or NH 2- pyridine
(b) HCl, dioxane or trif luoroacetic acid
(c) PCI 3 , pyridine
(d) R30-OH where R 30 is not OH or SH, pyridine
Figure imgf000137_0001
(a) R19R20SiCl2, pyridine
(b) Pd, H , methylcyclohexane
(c) Cl-SiR19R20SiR19R20-Cl, pyridine
Figure imgf000138_0001
(b) HCl, dioxane or trifluoroacetic acid
(c) S(0)2C12, pyridine
Figure imgf000139_0001
(a) phosgene, pyridine
(b) HCl, dioxane or trifluoroacetic acid
(c) C(S)C12, pyridine
Figure imgf000140_0001
(a) Cl-CR19R20-O-CR19R20-Cl, pyridine
(b) Pd, H , methylcyclohexane
(c) Cl-SiR19R20-O-SiR19R20-Cl, pyridine
Figure imgf000141_0001
(a) C1-C(0)C(0) -CI, pyridine
(b) Pd, H2, ethanol
(c) C1-C(0)C(R3°) (R31)C(0)-C1, pyridine
Figure imgf000142_0001
(a) C(0)C12, pyridine
(b) Pd, H2, ethanol
(c) S(0)2C12, pyridine
Figure imgf000143_0001
(a) Benzyl chloroformate, Na2C03, THF, water
(b) C1-C(0)C(0)-C1, pyridine
(c) Pd, H2, ethanol
(d) C1-C(0)C(R30) (R31)C(0)-C1, pyridine Disclosed are 34 synthetic processes useful in the preparation of the compounds of the present invention.
The following examples are provided to illustrate the present invention and are not intended to limit the scope thereof. Those skilled in the art will readily understand that known variations of the conditions and processes of the following preparative procedures can be used to prepare these compounds .
Figure imgf000145_0001
BocHN (3)
(a) Triethylamine, ethyl chloroformate
(b) HACH2(CH2) jCH2AH (A = 0, S, NR5 )
(c) Pd, H , Ethanol/Acetic Acid
(d) H20, pH 9-10 with (2) or DMF, TEA with (2b)
(e) HCl, dioxane or trifluoroacetic acid. Scheme 90
Figure imgf000146_0001
(a) Triethylamine, ethyl chloroformate
(b) TFA-ACH2 (CH ) CH2AH (A = 0, S, NR5 )
(c) Pd, H2, Ethanol/Acetic Acid
(d) Phthalic Anhydride, THF at reflux
(e) K2C03, H20, methanol
Figure imgf000147_0001
Figure imgf000148_0001
(a) HCl, dioxane (b) TEA, phthalic anhydride, THF
(c) Lithium diisopropylamide, THF,
(d) Br-(CH 2)UQ( H2)W-Br, THF (e) (368) in THF (f) Hydrazine, methanol, reflux Scheme 93
Figure imgf000149_0001
(a) Br-(CH2)χT(CH2)y-Br, THF
(b) (368), (372) in THF, reflux
(c) Hydrazine, methanol, reflux
Figure imgf000150_0001
(a) Br-(CH2 )χT(CH2)y-0-THP, THF (b) Acetic Acid, reflux
(c) (6; A-R equals OH) in THF/acetonitrile, DCC
(d) Hydrazine, methanol, reflux (e) HCl, ethyl acetate
Figure imgf000151_0001
(a) Br- (CH )uQ(CH2)w-0-THP, THF (b) Acetic Acid, reflux
(c) (6; A-R7 equals OH) in THF/acetonitrile, DCC
(d) Hydrazine, methanol, reflux (e) HCl, ethyl acetate
Figure imgf000152_0001
(a) R15 (0)C-(CH2)uQ(CH2) -C(0)R15, 2 moles (7), 4 moles p-TsOH, hexane or toluene, azeotropic distillation
(b) bis-dimethyl or bis-diethyl acetal/ketal of
R15 (0)C-(CH2)uQ(CH2) -C(0)R15, 2 moles (7),
4 moles p-TsOH, toluene, distillation of alcohol
Figure imgf000153_0001
(a) R15(0)C-(CH2)χT(CH2)y-C(0)R15, 2 moles (7), 4 moles p-TsOH, hexane or toluene, azeotropic distillation
(b) bis-dimethyl or bis-diethyl acetal/ketal of R15 (0)C-(CH2)χT(CH2)y-C(0)R15, 2 moles (7),
4 moles p-TsOH, toluene, distillation of alcohol
Figure imgf000154_0001
(a) Cl(0)C(CH2)χT(CH2)yC(OCH3 )2R15, TEA
(b) Compound (7; 1 mole), 3 moles p-TsOH, toluene, distillation of alcohol
Figure imgf000155_0001
(a) Cl(0)C(CH2)uQ(CH2)WC(0CH3)2R15, TEA
(b) Compound (7; 1 mole), 3 moles p-TsOH, toluene, distillation of alcohol
Figure imgf000156_0001
(a) C(0)Cl2, moles TEA, 2 moles (7)
(b) S(0)2Cl2 moles pyridine, 2 moles (7)
(c) CIC(O) C(0)C1, 2 moles TEA, 2 moles (7)
Figure imgf000157_0001
distillation of alcohol (R-OH)
(c) HCl, dioxane
Figure imgf000158_0001
(a) 2 Moles (12), C1(0)C-CR 19 R2o (CR 19 R20 ) j CR19 R20 _c (°) ci> TEA, toluene
(b) Zinc dust, acetic acid
(c) Pd, H 2, Ethanol/Acetic Acid to (390)
(d) (390) with HCl, dioxane
Figure imgf000159_0001
(a) 1 Mole (12), Cl(0)C-(CH 2 > χT(CH 2 )y-C(0)Cl, TEA, toluene (b) 1 Mole (7), TEA, toluene
(c) Zinc dust, acetic acid to (394)
(d) Pd, H 2 > Ethanol/Acetic Acid to (395)
(e) (395) with HCl, dioxane Scheme 104
Figure imgf000160_0001
(a) 2 Moles (123) , 4 Moles HCl, water
Scheme 105
Figure imgf000161_0001
0
(a) DCC, THF/Acetonitrile (b) HCl, dioxane (c) 2 Moles HCl, water Scheme 106
Figure imgf000162_0001
0
(a) DCC, THF/Acetonitrile
(b) HCl, dioxane
Figure imgf000163_0001
(a) 1. ClC02Et, TEA, THF, -10 °C, 2. then (404)
(b) HCl in dioxane or ethyl acetate
(c) 1. 11 (A-R7 = OH) , ClC02Et, TEA, THF, -10 °C, 2. add to 406 in THF
(d) Hydrazine, methanol, reflux to form (408)
(e) (408) with Pd, H , Ethanol/Acetic Acid
Figure imgf000164_0001
[417) (418) [419)
(a) ClC02Et, TEA, THF, -10 °C
(b) Pd, H2, Ethanol/Acetic Acid Scheme 109 (see Scheme 108)
H
Figure imgf000165_0001
(a) CICO 2Et- TEA- THF, -10 °C
(b) Pd, H 2' Ethanol/Acetic Acid
Figure imgf000166_0001
(a) DCC, THF/acetonitrile
(b) Pd, H2, Ethanol/Acetic Acid Scheme 111 (see Scheme 110)
Figure imgf000167_0001
(a) DCC, THF/acetonitrile
(b) Pd, H , Ethanol/Acetic Acid
Figure imgf000168_0001
(a) DCC, THF/acetonitrile
(b) HCl, dioxane
(c) Pd, H2, Ethanol/Acetic Acid
Figure imgf000169_0001
(a) DCC, THF/acetonitrile
(b) HCl, dioxane
(c) Hydrazine, methanol, reflux
(d) Pd, H2, Ethanol/Acetic Acid
Figure imgf000170_0001
(a) 5% aqueous phosphoric acid
(b) 4 Moles p-TsOH, hexane, azeotropic distillation
(c) HCl, dioxane or trifluoroacetic acid, evaporate Scheme 115
Figure imgf000171_0001
(a) Hydrazine, methanol, reflux
(b) t-Buotxycarbonyl azide, dioxane, H 20, MgO
(c) DMSO, DCC, H 3PO4
(d) 1 Mole (7), 2 Moles p-TsOH, hexane, azeotropic distillation to give (445)
(e) HCl, ethyl acetate Scheme 116
Figure imgf000172_0001
(a) Hydrazine, methanol, reflux
(b) t-Buotxycarbonyl azide, dioxane, H 20' M9°
(c) DMSO, DCC, H 3PO4
(d) 1 Mole (7), 2 Moles p-TsOH, hexane, azeotropic distillation to give (454)
(e) HCl, ethyl acetate
Figure imgf000173_0001
H2N
(a) DCC, THF/Acetonitrile (b) 3 Moles HCl, water (c) HCl, dioxane or ethyl acetate
Figure imgf000174_0001
(a) HO-(CH2 )uQ(CH2)w-°H ' moles (7), 4.1 moles p-TsOH, toluene, distillation to remove methanol
Figure imgf000175_0001
(a) HO- (CH2)χT(CH2 )y-OH, 2 moles (7), 4.1 moles p-TsOH, oluene, distillation to remove methanol
3
Figure imgf000176_0001
(a) TEA, THF/acetonitrile (b) Zinc dust, acetic acid (c) ClC02Et, TEA, THF (d) Pd, H2 , Acetic Acid (e) HCl, dioxane [See "Glyphosate" , ACS Monograph 189, 1997, page 301 for source of (479)] Scheme 121
Figure imgf000177_0001
(a) trifluoroacetic acid
(b) Z-Ic-OH (410), ClC02Et, TEA, THF added to (485)
(c) Pd, H2 , Acetic Acid
Figure imgf000178_0001
(a) Phthalic anhydride (2 moles) , THF, reflux
(b) Z-Ib-OH (410; 3 moles), ClCO 2Et, TEA, THF added to (489) (c) Hydrazine (1 mole), methanol, reflux
(d) Z-Ia-OH (410; 1 mole), ClCO 2Et, TEA, THF added to (491) (e) Pd, H 2- Acetic Acid (f) Z-I -OH (410; 1 mole), ClCO Et, TEA, THF added to (494)
Without further elaboration, it is believed that one skilled in the art can, using the preceding descriptions, utilize the present invention to its fullest extent. Therefore the following preferred specific embodiments are to be construed as merely illustrative and not limitative of the remainder of the disclosure in any way whatsoever. Compounds ' containing multiple variations of the structural modifications illustrated in the preceding schemes or the following examples are also contemplated.
All experiments were performed under either dry nitrogen or argon. All solvents and reagents were used without further purification unless otherwise noted. The routine work-up of the reactions involved the addition of the reaction mixture to a mixture of either neutral, or acidic, or basic aqueous solutions and organic solvent. The aqueous layer was extracted n times (x) with the indicated organic solvent. The combined organic extracts were washed n times (x) with the indicated aqueous solutions, dried over anhydrous Na2SO4, filtered, concentrated in vacuo, and purified as indicated. Separations by column chromatography were achieved with conditions described by Still. (Still, W. C; Kahn, M.; Mitra, A. Rapid Chromatograhic Technique for Preparative Separation with Moderate Resolution. J. Org. Chem., 1978, 43, 2923-2925.) The hydrochloride salts were made from IN HCl, HCl in ethanol (EtOH), 2 N in MeOH, or 6 N HCl in dioxane. Thin layer chromatograms were run on 0.25 mm EM precoated plates of silica gel 60 F254. High performance liquid chromatograms (HPLC) were obtained from C-8 or C-18 reverse phase columns which were obtained from several vendors. Analytical samples were dried in an Abderhalden apparatus at either 56°C or 78°C. ^H NMR spectra were obtained from either General Electric QE-300 or Varian VXR 400 MHz spectrometer. 13C NMR spectra were obtained from a Varian spectrometer at 125.8 MHz.
Figure imgf000179_0001
(1) Example 1
EX-la) 6-(N-Z-amino)-2-(N-Boc-amino)-2-methylhexanoic acid (10 mmol) is dissolved in anhydrous THF, cooled in an ice bath and treated with ethyl chloroformate (10.1 mmol) and triethyl amine (TEA) (11 mmol). The mixture is allowed to warm to room temperature. Upon completion, the mixture is again cooled in an ice bath and 1,5- diaminopentane (5.0 mmol) is added. The mixture is allowed to warm to room temperature. Upon completion, the mixture is concentrated in vacuum. The resulting material is passed through a reverse phase chromatographic column, giving l,5-bis-[6-(N- Z-amino)-2-(N-Boc-amino)-2-methylhexanamido]pentane.
EX-lb) 1 ,5-Bis-[6-(N-Z-amino)-2-(N-Boc-amino)-2-methylhexanamido]pentane is dissolved in ethanol containing acetic acid and is combined with a hydrogenation catalyst such as palladium on carbon and hydrogen. This reaction is shaken under pressure for an extended period of time in a standard Parr hydrogenation apparatus to remove the Z- functions generating the amino product l,5-Bis-[6-amino-2-(N-Boc-amino)-2- methylhexanamido]pentane.
EX-lc) To a 125 mL flask is added (9 mmol) of l,5-Bis-[6-amino-2-(N-Boc-amino)-2- methylhexanamido]pentane and 70mL of DMF. To this solution is added 4.38 g of methyl acetimidate hydrochloride. Triethylamine (TEA) (0.06 mol) is added. After the addition is complete, the solution is allowed to stand at 25°C for 16 hours. The reaction mixture is filtered from triethylamine hydrochloride, and the filtrate is concentrated in vacuum. The residue is dissolved in 50% acetic acid and lyophilized. The crude product is purified by then adjusting the pH to 7.5 with IN HCl and poured onto a Dowex 50 Cation exchange column. The column is washed with water. The Boc-protected product is then eluted with 10% aqueous pyridine and concentrated in vacuo to give l,5-Bis-[6-(N- (l-iminoethyl)amino)-2-(N-Boc-amino)-2-methylhexanamido]pentane.
l,5-Bis-[6-(N-(l-iminoethyl)amino)-2-(N-Boc-amino)-2-methylhexanamido]pentane is deprotected by allowing it to stand in 2N HCl and dioxane at 25°C for two hours. Concentrating in vacuo affords l,5-Bis-[6-(N-(l-iminoethyl)amino)-2-amino-2- methylhexanamido]pentane tetrahydrochloride.
Figure imgf000181_0001
(2)
Example 2
EX-2a) 6-(N-Z-amino)-2-(N-Boc-amino)-2-methylhexanoic acid (10 mmol) is dissolved in anhydrous THF, cooled in an ice bath and treated with ethyl chloroformate (10.1 mmol) and triethyl amine (11 mmol). The mixture is allowed to warm to room temperature. Upon completion, the mixture is again cooled in an ice bath and 4-trifluoroacetamido-l- butanamine (10.1 mmol) is added. After warming to room temperature and standing for 2 hours, the reaction mixture is concentrated in vacuo, 50 mL of methylene chloride is added along with 20 mL of water. The methylene chloride layer is separated, back washed with water, dried over MgSO and concentrated. The resulting material is purified chromatographically to yield 4-trifluoroacetamido)-l-[6-(N-Z-amino)-2-(N-Boc-amino)-2- methylhexanamido]butane .
EX-2b) 4-trifluoroacetamido)-l-[(6-(N-Z-amino)-2-(N-Boc-amino)-2- methylhexanamido] butane (9.3 mmol) is dissolved in methanol/water and treated with potassium carbonate (10 mmol) in water. The mixture is stirred until the trifluoroacetyl protecting group is hydrolyzed. The product is passed through a reverse phase column to yield 4-[6-(N-Z-amino)-2-(N-Boc-amino)-2-methylhexanamido]- 1 -butanamine.
EX-2c) 6-(N-Z-amino)-2-(N-Boc-amino)-2-methylhexanoic acid (10 mmol) is dissolved in ethanol/acetic acid and is combined with a hydrogenation catalyst such as palladium on carbon and hydrogen. This reaction is shaken under pressure for an extended period of time in a standard Parr hydrogenation apparatus to remove the Z-function generating the amino product 6-amino-2-(N-Boc-amino)-2-methylhexanoic acid.
EX-2d) 6-amino-2-(N-Boc-amino)-2-methylhexanoic acid (9.8 mmol) is dissolved in anhydrous THF and treated with phthalic anhydride (10.3 mmol). The mixture is heated to reflux until the phthaloyl protecting group is added. The product is purified by chromatography to give 6-phthalimido-2-(N-Boc-amino)-2-methylhexanoic acid.
EX-2e) 6-phthalimido-2-(N-Boc-amino)-2-methylhexanoic acid (9 mmol) is dissolved in anhydrous THF, cooled in an ice bath and treated with ethyl chloroformate (9.1 mmol) and triethyl amine (11 mmol). .The mixture is allowed to warm to room temperature. Upon completion, the mixture is again cooled in an ice bath and 4-[6-(N-Z-amino)-2-(N- Boc-amino)-2-methylhexanamido]-l -butanamine from EX -2b (9.2 mmol) is added. After warming to room temperature and standing for 2 hours, the reaction mixture is concentrated in vacuo, 50 mL of methylene chloride is added along with 20 mL of water. The methylene chloride layer is separated, back washed with water, dried over MgSO and concentrated. The resulting material is purified chromatographically to yield 4-[6- phthalimido-2-(N-Boc-amino)-2-methylhexanamido]-l-[6-(N-Z-amino)-2-(N-Boc- amino)-2-methylhexanamido]butane.
EX-2f) 4-[6-phthalimido-2-(N-Boc-amino)-2-methylhexanamido]-l-[6-(N-Z-amino)-2- (N-Boc-amino)-2-methylhexanamido]butane (8 mmol) is dissolved in methanol, treated with hydrazine (8.2 mmol), and heated to reflux to remove the phthaloyl protecting group. The mixture is concentrated and purified by chromatography to give 4-[6-amino-2-(N- Boc-amino)-2-methylhexanamido]-l-[6-(N-Z-amino)-2-(N-Boc-amino)-2- methylhexanamido]butane .
EX-2g) To a 125 mL flask is added (7 mmol) 4-[6-amino-2-(N-Boc-amino)-2- methylhexanamido]-l-[6-(N-Z-amino)-2-(N-Boc-amino)-2-methylhexanamido]butane and 70mL of water. This solution is adjusted to pH = 9.5 by addition of 2.5 N NaOH. To this solution is added portion wise, 1.31 g of methyl acetimidate. During methyl acetimidate addition, the pH is kept at 9.5 via concomitant addition of 2.5 N NaOH. After the addition is complete, the solution is allowed to stand at 25°C for 25 minutes. The solution is then adjusted to pH = 7.5 with IN HCl and poured onto a Dowex 50 Cation exchange column. The column is washed with water. The protected product 4-[6-(N-(l- iminoethyl)amino)-2-(N-Boc-amino)-2-methylhexanamido]-l-[6-(N-Z-amino)-2-(N-Boc- amino)-2-methylhexanamido]butane is then eluted with 10% aqueous pyridine. EX-2h) 4-[6-(N-(l-iminoethyl)amino)-2-(N-Boc-amino)-2-methylhexanamido]-l-[6-(N- Z-amino)-2-(N-Boc-amino)-2-methylhexanamido]butane is dissolved in ethanol/acetic acid and is combined with a hydrogenation catalyst such as palladium on carbon and hydrogen. This reaction is shaken under pressure for an extended period of time in a standard Parr hydrogenation apparatus to remove the Z-function generating the amino product 4-[6-(N-(l-iminoethyl)amino)-2-(N-Boc-amino)-2-methylhexanamido]-l-[6- amino-2-(N-Boc-amino)-2-methylhexanamido]butane.
EX-2i) To a 125 mL flask is added (6 mmol) of 4-[6-(N-( l-iminoethyl)amino)-2-(N-Boc- amino)-2-methylhexanamido] - 1 - [6-amino-2-(N-Boc-amino)-2-methylhexanamido]butane and 70mL of water. This solution is adjusted to pH = 9.5 by addition of 2.5 N NaOH. To this solution is added portion wise, 1.49 g of chloroacetaldoxime which is prepared immediately prior to use. During the chloroacetaldoxime addition, the pH is kept at 9.5 via concomitant addition of 2.5 N NaOH. After the addition is complete, the solution is allowed to stand at 25°C for 25 minutes. The solution is then adjusted to pH 7.5 with IN
HCl and poured onto a Dowex 50 Cation exchange column. The column is washed with water. The Boc -protected product is then eluted with 10% aqueous pyridine.
After concentrating the product, 4-[6-(N-( l-iminoethyl)amino)-2-(N-Boc-amino)-2- methylhexanamido]-l-[6-(N-(l-oximinoethyl)amino)-2-(N-Boc-amino)-2- methylhexanamidojbutane is deprotected by allowing it to stand in 2N HCl and dioxane at 25°C for two hours. Concentrating in vacuo affords 4-[6-(N-(l-iminoethyl)amino)-2- amino-2-methylhexanamido]-l-[6-(N-(l-oximinoethyl)amino)-2-amino-2- methylhexanamidojbutane tetrahydrochloride.
Figure imgf000184_0001
(3)
Example 3
EX-3a) S-(2-(N-(l-iminoethyl)amino)ethyl)cysteinamide (10 mmol) is added to anhydrous THF and treated with phthalic anhydride (10.1 mmol). The mixture is heated to reflux until the phthalimide protecting group is formed. The product is purified by chromatography to give 3-(2-(N-(l-iminoethyl)amino)ethylthio)-2- phthalimidopropanamide .
EX-3b) 3-(2-(N-(l-iminoethyl)amino)ethylthio)-2-phthalimidopropanamide (9 mmol) is thoroughly dried and dissolved in 25 ml of anhydrous THF. To the THF solution cooled to -78 °C, is added 1.1 equivalents of diisopropylamine followed by 1 equivalent of n- butyl lithium in hexane to form the lithium salt of 3-(2-(N-( 1 - iminoethyl)amino)ethylthio)-2-phthalimidopropanamide. Subsequently, (5 mmol) of dry l,5-dibromo-3,3-dimethoxypentane is dissolved in anhydrous THF and is added to the solution of the lithium salt. After warming to room temperature, the reaction is heated. Upon cooling, the reaction mixture is filtered to remove the precipitant, concentrated in vacuo and is purified by chromatography to give l,5-bis[3-(2-(N-(l- iminoethyl)amino)ethylthio)-2-phthalimidopropanamido]-3,3-dimethoxypentane.
l,5-bis[3-(2-(N-(l-iminoethyl)amino)ethylthio)-2-phthalimidopropanamido]-3,3- dimethoxypentane (4 mmol) is added to 25 mL methanol, treated with hydrazine (8.2 mmol), and heated to reflux to remove the phthaloyl protecting groups. The solvent is removed in vacuo. The residue is slurried with 25 mL 2 M aqueous HCl for 2 hours to hydrolyze the ketal groups. The reaction mixture is filtered to remove the phthalolyl hydrazide and concentrated to give l,5-bis[3-(2-(N-(l-iminoethyl)amino)ethylthio)-2- aminopropanamido]-pent-3-one tetrahydrochloride.
Figure imgf000185_0001
(4)
Example 4
EX -4a) The lithium salt of N-ethyl-6-(N-( 1 -(N-benzyloxyimino) ethyl)amino)-2- phthalimido-2-methylhexanamide (10 mmol) is prepared as in EX-3b from N-ethyl-6-(N- (1 -(N-benzyloxyimino) ethyl)amino)-2-phthalimido-2-methylhexanamide is reacted in anhydrous THF at -78°C by adding to l,3-bis(bromomethyl) benzene (5 mmol) in THF. After warming to room temperature, the reaction mixture is allowed to warm to room temperature and heated. Upon cooling, the reaction mixture is filtered to remove the precipitant, concentrated in vacuo and purified by column chromatography to give a,a'- bis [N-ethyl-6-(N-( 1 -(N-benzyloxyimino)ethyl)amino)-2-phthalimido-2- methylhexanamido]-m-xylene.
EX-4b) a,a' -Bis [N-ethyl-6-(N-( 1 -(N-benzyloxyimino)ethyl) amino)-2-phthalimido-2- methylhexanamido]-m-xylene (5 mmol) is dissolved in methanol, treated with hydrazine (10.2 mmol), and heated to reflux to remove the phthaloyl protecting group. The mixture is concentrated and purified through by column chromatography to to give a,a'-bis[N- ethyl-6-(N-(l-(N-benzyloxyimino)ethyl)amino)-2-amino-2-methylhexanamido]-m-xylene. a,a'-Bis[N-ethyl-6-(N-(l-(N-benzyloxyimino)ethyl)amino)-2-amino-2- methylhexanamido]-m-xylene (4 mmol) is dissolved in ethanol/acetic acid and is combined with a hydrogenation catalyst such as palladium on carbon and hydrogen. This reaction is shaken under pressure for an extended period of time in a standard Parr hydrogenation apparatus to remove the Z-function, the catalyst is removed by filtration, and the solvent is removed in vacuo generating the amino product a,a'-Bis[N-ethyl-6-(N- (l-oximinoethyl)amino)-2-amino-2-methylhexanamido]-An-xylene.
Figure imgf000186_0001
(5)
Example 5
EX-5a) The lithium salt of N-methyl-6-(N-(l-(N-benzyloxyimino)ethyl)amino)-2- phthalimido-2-methylhexanamide (10 mmol) is made following the procedure in EX -3b from N-methyl-6-(N-(l-(N-benzyloxyimino)ethyl)amino)-2-phthalimido-2- methylhexanamide is added in anhydrous THF at -78°C to a-bromo-a'-(2- tetrahydropyranyloxy)- -xylene (10 mmol) in THF. After warming to room temperature, the reaction is filtered to remove the precipitant, is concentrated in vacuo and is purified by chromatography to give 3-[N-methyl-6-(N-(l-(N-benzyloxyimino)ethyl)amino)-2- phthalimido-2-methylhexanamidomethyl]benzyl 2-tetrahydropyranyloxy ether. EX-5b) 3-[N-methyl-6-(N-( 1 -(N-benzyloxyimino)ethyl)amino)-2-phthalimido-2- methylhexanamidomethyljbenzyl 2-tetrahydropyranyloxy ether is dissolved in acetic acid and heated to reflux. When the THP group is completely removed, the reaction mixture is concentrated in vacuo to yield 3-[N-methyl-6-(N-(l-(N-benzyloxyimino)ethyl)amino)-2- phthalimido-2-methylhexanamidomethyl]phenylmethanol .
EX-5c) 3-[N-methyl-6-(N-(l-(N-benzyloxyimino)ethyl)amino)-2-phthalimido-2- methylhexanamidomethyl]phenylmethanol (9 mmol) and 6-(N-(l-(N- benzyloxyimino)ethyl)amino)-2-(N-Z-amino)-2-methylhexanoic acid (9 mmol) are dissolved in THF and acetonitrile and treated with 1,3-dicyclohexylcarbodiimide (9.5 mmol). The reaction is stirred until the coupling is complete, concentrated, and is purified by chromatography to give 3-[N-methyl-6-(N-(l-(N-benzyloxyimino)ethyl)amino)-2- phthalimido-2-methylhexanamidomethyl]-benzyl 6-(N-( 1-(N- benzyloxyimino)ethyl)amino)-2-(N-Z-amino)-2-methylhexanoate.
EX-5d) 3-[N-methyl-6-(N-(l-(N-benzyloxyimino)ethyl)amino)-2-phthalimido-2- methylhexanamidomethylj-benzyl 6-(N-(l-(N-benzyloxyimino)ethyl)amino)-2-(N-Z- amino)-2-methylhexanoate (8 mmol) is dissolved in methanol, treated with hydrazine (8.4 mmol), and heated to reflux to remove the phthaloyl protecting group. After filtering to remove phthaloyl hydrazide and concentrating, the reaction mixture is purified by chromatography to give 3-[N-methyl-6-(N-(l-(N-benzyloxyimino)ethyl)amino)-2-amino- 2-methylhexanamidomethyl]-benzyl 6-(N-( 1 -(N-benzyloxyimino) ethyl)amino)-2-(N-Z- amino)-2-methylhexanoate.
3-[N-Methyl-6-(N-(l-(N-benzyloxyimino)ethyl)amino)-2-amino-2- methylhexanamidomethyl] -benzyl 6-(N-( 1 -(N-benzyloxyimino) ethyl)amino)-2-(N-Z- amino)-2-methylhexanoate is dissolved in ethanol/acetic acid and is combined with a hydrogenation catalyst such as palladium on carbon and hydrogen. This reaction is shaken under pressure for an extended period of time in a standard Parr hydrogenation apparatus to remove the Z-function, the catalyst is removed by filtration, and the solvent is removed in vacuo. The residue is dissolved in 25 mL of 1 M HCl in ethyl acetate and then taken to dryness to give 3-[N-methyl-6-(N-(l-oximinoethyl)amino)-2-amino-2- methylhexanamidomethylj-benzyl 6-(N-( 1 -oximinoethyl)amino)-2-amino-2- methylhexanoate tetrahydrochloride.
Figure imgf000188_0001
(6)
Example 6
EX-6a) The lithium salt of N-methyl-6-(N-(l-(N-benzyloxyimino)ethyl)amino)-2- phthalimido-2-methylhexanamide (10 mmol) is made following the procedure in EX -3b from N-methyl-6-(N-( 1 -(N-benzyloxyimino)ethyl)amino)-2-phthalimido-2- methylhexanamide is added in anhydrous THF at -78°C to 2-bromoethyl 2-(2-tetrahydropyranyloxy)ethyl ether (10 mmol) in THF. After warming to room temperature, the reaction is filtered to remove the precipitant, is concentrated in vacuo and is purified through a chromatography column to give 2-[N-methyl-6-(N-(l-(N- benzyloxyimino)ethyl)amino)-2-phthalimido-2-methylhexanamido]ethyl 2-(2- tetrahydropyranyloxy)ethyl ether.
EX-6b) 2-[N-Methyl-6-(N-( 1 -(N-benzyloxyimino)ethyl)amino)-2-phthalimido-2- methylhexanamidojethyl 2-(2-tetrahydropyranyloxy)ethyl ether is dissolved in acetic acid and heated to reflux. When the THP group is completely removed the reaction mixture is concentrated in vacuo to yield 2-[2-[N-Methyl-6-(N-(l-(N-benzyloxyimino)ethyl)amino)- 2-phthalimido-2-methylhexanamido]ethoxy]ethanol.
EX-6c) 2-[2-[N-Methyl-6-(N-(l-(N-benzyloxyimino)ethyl)amino)-2-phthalimido-2- methylhexanamido]ethoxy]ethanol (9 mmol) and 6-(N-(l-(N- benzyloxyimino)ethyl)amino)-2-(N-Z-amino)-2-methylhexanoic acid (9 mmol) are dissolved in THF and acetonitrile and treated with 1,3-dicyclohexylcarbodiimide (9.5 mmol). The reaction is stirred until the coupling is complete, concentrated and is purified by chromatography to give 2-[2-[N-Methyl-6-(N-(l-(N-benzyloxyimino)ethyl)amino)-2- phthalimido-2-methylhexanamido]ethoxy]ethyl 6-(N-(l-(N-benzyloxyimino)ethyl)amino)- 2-(N-Z-amino)-2-methylhexanoate.
EX-6d) 2- [2- [N-Methyl-6-(N-( 1 -(N-benzyloxyimino)ethyl)amino)-2-phthalimido-2- methylhexanamido]ethoxy]ethyl 6-(N-( 1 -(N-benzyloxyimino)ethyl)amino)-2-(N-Z- amino)-2-methylhexanoate (8 mmol) is dissolved in methanol, treated with hydrazine (8.4 mmol), and heated to reflux to remove the phthaloyl protecting group. After filtering to remove phthaloyl hydrazide and concentrating, the reaction mixture is purified by chromatography to give 2-[2-[N-Methyl-6-(N-(l-(N-benzyloxyimino)ethyl)amino)-2- amino-2-methylhexanamido]ethoxy]ethyl 6-(N-( 1 -(N-benzyloxyimino)ethyl)amino)-2-(N- Z-amino)-2-methylhexanoate.
2- [2- [N-Methyl-6-(N-( 1 -(N-benzyloxyimino)ethyl)amino)-2-amino-2- methylhexanamido]ethoxy]ethyl 6-(N-( 1 -(N-benzyloxyimino)ethyl)amino)-2-(N-Z- amino)-2-methylhexanoate is dissolved in ethanol/acetic acid and is combined with a hydrogenation catalyst such as palladium on carbon and hydrogen. This reaction is shaken under pressure for an extended period of time in a standard Parr hydrogenation apparatus to remove the Z-function, the catalyst is removed by filtration, and the solvent is removed in vacuo. The residue is dissolved in 25 mL of 1 M HCl in ethyl acetate and then taken to dryness to give 2-[2-[N-Methyl-6-(N-(l-oximinoethyl)amino)-2-amino-2- methylhexanamido]ethoxy]ethyl 6-(N-(l-oximinoethyl)amino)-2-amino-2- methylhexanoate tetrahy drochloride .
Figure imgf000190_0001
(7)
Example 7
N-(5-Tetrazolyl)-S-(2-(N-(l-oximinoethyl)amino)ethyl) cysteinamide (20 mmol) is added to 50 ml of toluene in 100 ml reaction flask. After adding (50 mmol) p-toluenesulfonic acid, (10 mmol) N,N-bis(4,4-dimethoxybutyl)methylamine, and 50 mmol water, the reaction mixture is refluxed with azeotropic distillation until all alcohol and excess water is removed. After cooling, the solvent is removed in vacuo to give N,N-bis[4-[N-(3-(2- (N-( 1 -oximoethyl)amino)ethylthio)- 1 -(N-tetrazolylamidocarbonyl)propyl)imino]butyl]-N- methylamine penta-p-toluenesulfonic acid salt.
Figure imgf000191_0001
(8)
Example 8
6-(N-( 1 -Iminoethyl)amino)-2-aminohexanoic acid
(20 mmol) is added to 50 ml of toluene in 100 ml reaction flask. After adding (40 mmol) p-toluenesulfonic acid and (10 mmol) 1,3-diacetonylbenzene, the reaction mixture is refluxed with azeotropic distillation for complete removal of water using a Dean-Stark trap. After cooling, the solvent and is removed in vacuo to give l,3-bis[2-[N-(5-(N-(l- iminoethyl) amino)- l-carboxypentyl)iminopropyl]benzene tetra-/?-toluenesulfonic acid salt.
Figure imgf000192_0001
(9)
Example 9
EX-9a) tert-Butyl 6-(N-(l-iminoethyl)amino)-2-aminohexanoate hydrochloride (10 mmol) and 25 mL dimethylformamide are cooled in an ice bath, 21 mmol triethylamine is added, and then the reaction mixture is treated with (10.5 mmol) 3-(2,2- dimethoxypropyl)phenylacetyl chloride. After warming to room temperature and standing for 2 hours, the reaction mixture is concentrated in vacuo. Water is added, the solution is then adjusted to pH = 7.5, and then it is poured onto a Dowex 50 Cation exchange column. The column is washed with water. The product tert-butyl 6-(N-(l- iminoethyl)amino)-2-(3-(2,2-dimethoxypropyl)phenylacetamido)-hexanoate is then eluted with 10% aqueous pyridine.
EX-9b) tert-butyl 6-(N-(l-iminoethyl)amino)-2-(3-(2,2- dimethoxypropyl)phenylacetamido)-hexanoate (9 mmol) is added to 50 ml of toluene in 100 ml reaction flask. After adding 27 mmol of p-toluenesulfonic acid, 40 mmol of water, and 9 mmol of 6-(N-(l-iminoethyl)amino)-2-aminohexanoic acid, the reaction mixture is refluxed with azeotropic distillation for complete removal of methanol and excess water using a Dean-Stark trap. After cooling, the solvent and is removed in vacuo to give tert- butyl 6-(N-(l-iminoethyl)amino)-2-[3-[2-(N-(5-(N-(l-iminoethyl)amino)-l- carboxypentyl)imino)propyl] phenylacetamido]-hexanoate tri-p-toluenesulfonic acid salt.
terr-Butyl 6-(N-( 1 -iminoethyl)amino)-2-[3-[2-(N-(5-(N-( 1 -iminoethyl)amino)- 1 - carboxypentyl)imino)propyl] phenylacetamidoj-hexanoate tri-/?-toluenesulfonic acid salt is deprotected by allowing it to stand in 2N HCl and dioxane at 25 °C for two hours. Concentrating in vacuo affords 6-(N-(l-iminoethyl)amino)-2-[3-[2-(N-(5-(N-(l- iminoethyl)amino)- 1 -carboxypentyl)imino)propyl]phenylacetamido]-hexanoic acid tή-p- toluenesulfonic acid salt.
Figure imgf000193_0001
(10)
Example 10
EX-lOa) tert-Butyl 6-(N-(l-iminoethyl)amino)-2-aminohexanoate dihydrochloride (10 mmol) and 25 mL dimethylformamide are cooled in an ice bath, 31 mmol triethylamine is added, and then the reaction mixture is treated with 4-(4,4-dimethoxypentylthio)butanoyl chloride (10.5 mmol). After warming to room temperature and standing for 2 hours, the reaction mixture is concentrated in vacuo, 50 mL of methylene chloride is added along with 20 mL of IM aqueous sodium carbonate. The methylene chloride layer is separated, the aqueous solution is extracted three times with 50 mL methylene chloride, the combined extracts are dried over MgSO and concentrated. The resulting material is purified chromatographically to yield tert-Butyl 6-(N-(l-iminoethyl) amino)-2-(4-(4,4- dimethoxypentylthio)butanamido)-hexanoate.
EX-lOb) tert-Butyl 6-(N-(l-iminoethyl) amino)-2-(4-(4,4- dimethoxypentylthio)butanamido)-hexanoate (9 mmol) is added to 50 ml of toluene in 100 ml reaction flask. After adding p-toluenesulfonic acid (27 mmol), 40 mmol water and 6- (N-(l-iminoethyl)amino)-2-aminohexanoic acid (9 mmol), the reaction mixture is refluxed with azeotropic distillation for complete removal of methanol and excess water using a Dean-Stark trap. After cooling, the solvent is removed in vacuo to give tert-Butyl 6-(N- ( 1 -iminoethyl)amino)-2-[4- [4-(N-(5-(N-( 1 -iminoethyl)amino)- 1 - carboxypentyl)imino)pentylthio] butanamidoj-hexanoate tri- -toluenesulfonic acid salt.
tert-Butyl 6-(N-(l-iminoethyl)amino)-2-[4-[4-(N-(5-(N-(l-iminoethyl)amino)-l- carboxypentyl)imino)pentylthio] butanamidoj-hexanoate tri -p-toluenesulfonic acid salt is deprotected by allowing it to stand in 2N HCl and dioxane at 25 °C for two hours. Concentrating in vacuo affords 6-(N-(l-iminoethyl)amino)-2-[4-[4-(N-(5-(N-(l- iminoethyl)amino)- 1 -carboxypentyl)imino)pentylthio]butanamido] -hexanoate tή-p- toluenesulfonic acid salt.
Figure imgf000194_0001
(11)
Example 11 EX-lla) tert-Butyl 6-(N-(l-iminoethyl)amino)-2-aminohexanoate dihydrochloride (10 mmol) and 50 mL methylene chloride are cooled in an ice bath, 31 mmol triethylamine is added, and then the reaction mixture is treated with (5 mmol) oxalyl chloride. After warming to room temperature and standing for 2 hours, 20 mL of IM aqueous sodium carbonate is added. The methylene chloride layer is separated, the aqueous solution is extracted three times with 50 mL methylene chloride, the combined extracts are dried over MgSO and concentrated. The resulting material is purified chromatographically to yield N,N'-bis[5-(N-(l-iminoethyl)amino)-l-tert-butoxycarbonylpentyl]oxamide.
N,N'-bis[5-(N-(l-iminoethyl)amino)-l-tert-butoxycarbonylpentyl]oxamide is deprotected by allowing it to stand in 2N HCl and dioxane at 25°C for two hours. Concentrating in vacuo affords N,N'-bis[5-(N-(l-iminoethyl)amino)-l-carboxypentyl]oxamide dihydrochloride.
Figure imgf000195_0001
(12)
Example 12
EX-12a) rt-Butyl 6-(N-(l-oximinoethyl)amino)-2-(N-Boc-amino)hexanoate (10 mmol) is dissolved in 25 ml of anhydrous toluene and treated-with sodium hydride (0.5 mmol) in an ice bath. Methyl N-[6-(N-(l-iminoethyl)amino)-2-(N-Boc-amino)hexanoyl]glycinate (10 mmol) is added and the reaction mixture is refluxed for complete removal of methanol using a Dean-Stark trap. After cooling, the solvent is removed in vacuo and the mixture is purified by chromatography to give tert-Butyl 6-[N-[l-[N-(2-(6-(N-(l-iminoethyl)amino)- 2-(N-Boc-amino)hexanamido)acetoxy)imino]ethyl]amino]-2-(N-Boc-amino)hexanoate.
tert-Butyl 6-[N-[l-[N-(2-(6-(N-(l-iminoethyl)amino)-2-(N-Boc- amino)hexanamido)acetoxy)imino]ethyl]amino]-2-(N-Boc-amino)hexanoate is deprotected by allowing it to stand in 2N HCl and dioxane at 25°C for two hours. Concentrating in vacuo affords 6-[N-[l-[N-(2-(6-(N-(l-iminoethyl)amino)-2- aminohexanamido)acetoxy)imino]ethyl]amino]-2-aminohexanoic acid tetrahydrochloride.
Figure imgf000196_0001
(13)
Example 13
EX-13a) 2,2,2-trichloroethyl 6-(N-(l-(N-Boc-imino)ethyl) amino)-2-(N-Z- amino)hexanoate (10 mmol) is dissolved in 25 ml of toluene containing (10.5 mmol) TEA and cooled in an ice bath. Glutaryl dichloride (5 mmol) in 25 mL toluene is added. After warming to room temperature and standing for 2 hours, the reaction mixture is concentrated in vacuo, 50 mL of methylene chloride is added along with 20 mL of water. The methylene chloride layer is separated, back washed with water, dried over MgSO_ι, and concentrated. The resulting material is purified chromatographically to yield N,N'- bis[5-(N-Z-amino)-5-(2,2,2-trichloroethoxycarbonyl)pentyl]-N,N'-bis[l-(N-Boc- imino)ethyl] glutaramide .
EX-13b) N,N'-Bis[5-(N-Z-amino)-5-(2,2,2-trichloroethoxycarbonyl)pentyl]-N,N'-bis[l- (N-Boc-imino)ethyl]glutaramide is dissolved in acetic acid and treated with excess zinc dust. The reaction is stirred until the trichloroethyl protecting group is removed. The reaction is filtered and concentrated in vacuo. 100 mL of methylene chloride is added along with 20 mL of water. The methylene chloride layer is separated, dried over MgSO and concentrated. The resulting material is purified chromatographically to yield N,N'- bis[5-(N-Z-amino)-5-carboxypentyl]-N,N'-bis[l-(N-Boc-imino)ethyl]glutar amide.
EX-13c) N,N'-bis(5-(N-Z-amino)-5-carboxypentyl)-N,N'-bis[l-(N-Boc- imino)ethyl]glutaramide is dissolved in ethanol/acetic acid and is combined with a hydrogenation catalyst such as palladium on carbon and hydrogen. This reaction is shaken under pressure for an extended period of time in a standard Parr hydrogenation apparatus to remove the Z-function generating the amino product. Concentration gives N,N'-bis(5- amino-5-carboxypentyl)-N,N'-bis[l-(N-Boc-imino)ethyl]glutaramide.
N,N'-bis(5-amino-5-carboxypentyl)-N,N'-bis[l-(N-Boc-imino)ethyl]glutaramide is deprotected by allowing it to stand in 2N HCl and dioxane at 25°C for two hours. Concentrating in vacuo affords N,N'-bis(5-amino-5-carboxypentyl)-N,N'-bis(l- iminoethyl)glutaramide tetrahydrochloride.
Figure imgf000197_0001
(14)
Example 14 EX- 14a) 1 ,4-Phenylenediacetyl chloride (10 mmol) is dissolved in 50 ml of toluene containing (10 mmol) TEA and cooled in an ice bath. 2,2,2-Trichloroethyl 6-(N-(l-(N- Boc-imino)ethyl)amino)-2-(N-Z-amino)hexanoate (10 mmol) in toluene is added. After standing at room temperature for 2 hours, the product, 4-[N-[5-(N-Z-amino)-5-( 2,2,2- trichloroethoxycarbonyl)pentyl]-N-(l-(N-Boc-imino)ethyl)- amidocarbonylmethyljphenylacetyl chloride, is formed.
EX-14b) To 4-[N-[5-(N-Z-amino)-5-( 2,2,2-trichloroethoxycarbonyl)pentyl]-N-(l-(N- Boc-imino)ethyl)-amidocarbonylmethyl]phenylacetyl chloride (10 mmol) in 50 ml of toluene containing (11 mmol) TEA and cooled in an ice bath, tert-Butyl 6-(N-(l-(N-Boc- imino)ethyl)amino)-2-aminohexanoate (10 mmol) in toluene is added. After warming to room temperature and standing for 2 hours, the reaction mixture is concentrated in vacuo, 50 mL of methylene chloride is added along with 20 mL of water. The methylene chloride layer is separated, back washed with water, dried over MgSO and concentrated. The resulting material is purified chromatographically to yield tert-Butyl 6-[N-(l-(N-Boc- imino)ethyl)amino]-2-[4-[N-(5-(N-Z-amino)-5-(2,2,2-trichloroethoxycarbonyl)pentyl)-N- (l-(N-Boc-imino)ethyl))-amidocarbonylmethyl]phenylacetamido]hexanoate.
EX- 14c) tert-Butyl 6-[N-(l-(N-Boc-imino)ethyl)amino]-2-[4-[N-(5-(N-Z-amino)-5-(2,2,2- trichloroethoxycarbonyl)pentyl)-N-(l-(N-Boc-imino)ethyl))- amidocarbonylmethyljphenylacetamido] hexanoate is dissolved in acetic acid and treated with excess zinc dust. The reaction is stirred until the trichloroethyl protecting group is removed. The reaction is filtered and concentrated in vacuo. 100 mL of methylene chloride is added along with 20 mL of water. The methylene chloride layer is separated, dried over MgSO and concentrated. The resulting material is purified chromatographically to yield tert-Butyl 6-[N-(l-(N-Boc-imino)ethyl)amino]-2-[4-[N-(5-
(N-Z-amino)-5-carboxypentyl)-N-(l-(N-Boc-imino)ethyl))-amidocarbonylmethyl] phenylacetamidojhexanoate.
EX-14d) tert-Butyl 6-[N-(l-(N-Boc-imino)ethyl)amino]-2-[4-[N-(5-(N-Z-amino)-5- carboxypentyl)-N-( 1 -(N-Boc-imino)ethyl))- amidocarbonylmethyl]phenylacetamido]hexanoate is dissolved in ethanol and is combined with a hydrogenation catalyst such as palladium on carbon and hydrogen. This reaction is shaken under pressure for an extended period of time in a standard Parr hydrogenation apparatus to remove the Z- functions generating the amino product. Concentration gives tert-Butyl 6- [N-(l-(N-Boc-imino)ethyl)amino]-2-[4-[N-(5-amino-5-carboxypentyl)-N-(l- (N-Boc-imino)ethyl))-amidocarbonylmethyl] phenylacetamido]hexanoate.
tert-Butyl 6-[N-( l-(N-Boc-imino)ethyl)amino]-2-[4-[N-(5-amino-5-carboxypentyl)-N-( 1- (N-Boc-imino)ethyl))-amidocarbonylmethyl] phenylacetamidojhexanoate is deprotected by allowing it to stand in 2N HCl and dioxane at 25 °C for two hours. Concentrating in vacuo affords 6-[N-(l-iminoethyl) amino]-2-[4-[N-(5-amino-5-carboxypentyl)-N-(l- iminoethyl))-amidocarbonylmethyl]phenylacetamido]hexanoic acid trihydrochloride.
Figure imgf000199_0001
(15)
Example 15
6-(N-( 1 -iminoethyl)amino)-2-amino- 1 , 1 -diethoxyhexane ( 10 mmol) is added to 30 mL 2M HCl. The reaction is stirred at room temperature until complete hydrolysis of the acetal and then the solution is taken to dryness to give 2,5-bis(4-(N-(l- iminoethyl)amino)butyl)-2,5-dihydropyrazine tetrahydrochloride.
Figure imgf000199_0002
(16)
Example 16
EX-16a) 6-(N-(l-iminoethyl)amino)-2-amino- 1,1 -diethoxyhexane (10 mmol) and 6-(N- (l-iminoethyl)amino)-2-(N-Boc-amino)hexanoic acid (10 mmol) are dissolved in dry THF and acetonitrile and cooled in an ice bath. 1,3-Dicyclohexylcarbodiimide (10.5 mmol) in dry THF is added, and the mixture is allowed to warm to room temperature. The reaction is stirred until the coupling is complete, concentrated and purified by chromatography to give 6-(N-(l-iminoethyl)amino)-2-[6-[N-(l-iminoethyl)amino)-2-(N-Boc- aminojhexanamido]- 1 , 1 -diethoxyhexane.
EX-16b) 6-(N-( 1 -Iminoethyl)amino)-2- [6- [N-( 1 -iminoethyl) amino)-2-(N-B oc- aminojhexanamido]- 1,1 -diethoxyhexane is deprotected by allowing it to stand in 2N HCl and dioxane at 25 °C for two hours. Concentrating in vacuo affords 6-(N-(l- iminoethyl)amino)-2- [6- [N-( 1 -iminoethyl)amino)-2-aminohexanamido] -1,1- diethoxyhexane trihydrochloride.
6-(N-( 1 -Iminoethyl)amino)-2- [6- [N-( 1 -iminoethyl)amino)-2-aminohexanamido] -1,1- diethoxyhexane trihydrochloride (9 mmol) is added to water. The reaction is stirred until completion and is concentrated in vacuo to give 2,5-bis[4-(N-(l-iminoethyl)amino)butyl]- 2 , 3 ,4,5 -tetrahy dro-3 -oxopy razine trihydrochloride .
Figure imgf000200_0001
(17)
Example 17
EX-17a) tert-Butyl 6-(N-(l-iminoethyl)amino)-2-amino-hexanoate (10 mmol) and 6-(N- (l-iminoethyl)amino)-2-(N-Boc-amino)-2-methylhexanoic acid (10 mmol) are dissolved in dry THF and acetonitrile and cooled in an ice bath. 1,3-Dicyclohexylcarbodiimide (10.5 mmol) in dry THF is added, and the mixture is allowed to warm to room temperature. The reaction is stirred until the coupling is complete, concentrated and purified by chromatography to give tert-Butyl 6-(N-(l-iminoethyl)amino)-2-[6-(N-(l- iminoethyl)amino)-2-(N-Boc-amino)-2-methylhexanamido]hexanoate. EX-17b) tert-Butyl 6-(N-(l -iminoethyl)amino)-2-[6-(N-(l-iminoethyl)amino)-2-(N-Boc- amino)-2-methylhexanamido] hexanoate is deprotected by allowing it to stand in 2N HCl and dioxane at 25°C for two hours. Concentrating in vacuo affords 6-(N-(l- iminoethy l)amino)-2- [6-(N-( 1 -iminoethy 1) amino)-2-(N-B oc-amino)-2- methylhexanamidojhexanoic acid trihydrochloride.
6-(N-(l-Iminoethyl)amino)-2-[6-(N-(l-iminoethyl)amino)-2-(N-Boc-amino)-2- methylhexanamidojhexanoic acid trihydrochloride. (9 mmol) is dissolved in dry THF and acetonitrile and cooled in an ice bath. 1,3-Dicyclohexylcarbodiimide (9.5 mmol) in dry THF is added and the mixture is allowed to warm to room temperature. The reaction is stirred until the coupling is complete, concentrated and purified by chromatography to give 3-methyl-3,6-bis(4-(N-(l-iminoethyl)amino)butyl)-2,5-dioxopiperazine.
Figure imgf000201_0001
(18)
Example 18
EX-18a) 6-(N-(2-fluoro-l-iminoethyl)amino)-2-phthalimidohexanoic acid (10 mmol) is dissolved in anhydrous THF, cooled in an ice bath and treated with ethyl chloroformate (10.1 mmol) and triethyl amine (TEA) (21 mmol). Upon completion, benzyl 5-amino-2- (N-Boc-amino)pentanoate hydrochloride (10 mmol) is added. After warming to room temperature and standing for 2 hours, the reaction mixture is concentrated in vacuo, 50 mL of methylene chloride is added along with 20 mL of water. The methylene chloride layer is separated, the aqueous layer is extracted three times with methylene chloride, the combined extracts are dried over MgSO and concentrated. The resulting material is purified chromatographically to yield benzyl 5-[6-(N-(2-fluoro-l-iminoethyl)amino)-2- phthalimidohexanamido] -2-(N-B oc-amino)pentanoate.
EX-18b) Benzyl 5-[6-(N-(2-fluoro-l-iminoethyl)amino)-2-phthalimidohexanamido]-2- (N-Boc-amino)pentanoate is deprotected by allowing it to stand in 2N HCl and dioxane at 25°C for two hours. Concentrating in vacuo affords benzyl 5-[6-(N-(2-fluoro-l- iminoethyl)amino)-2-phthalimidohexanamido]-2-aminopentanoate dihydrochloride.
EX- 18c) 6-(N-(2-fluoro-l-iminoethyl)amino)-2-(N-Z-amino)hexanoic acid (9.1 mmol) is dissolved in anhydrous THF, cooled in an ice bath and treated with ethyl chloroformate (9.1 mmol) and triethyl amine (27 mmol). Upon completion, benzyl 5-[6-(N-(2-fluoro-l- iminoethyl)amino)-2-phthalimidohexanamido]-2-aminopentanoate dihydrochloride (9 mmol) is added. After warming to room temperature and standing for 2 hours, the reaction mixture is concentrated in vacuo, 50 mL of methylene chloride is added along with 20 mL of water. The methylene chloride layer is separated, the aqueous layer is extracted three times with methylene chloride, the combined extracts are dried over MgSO_ι, and concentrated. The resulting material is purified chromatographically to yield benzyl 5-[6-
(N-(2-fluoro-l-iminoethyl)amino)-2-phthalimidohexanamido]-2-[6-(N-(2-fluoro-l- iminoethyl)amino)-2-(N-Z-amino)hexanamido]pentanoate.
EX-18d) Benzyl 5-[6-(N-(2-fluoro-l-iminoethyl)amino)-2-phthalimidohexanamido]-2-[6- (N-(2-fluoro-l-iminoethyl)amino)-2-(N-Z-amino)hexanamido]pentanoate (8 mmol) is dissolved in methanol, treated with hydrazine (8.4 mmol), and heated to reflux to remove the phthaloyl protecting group. After filtering to remove phthaloyl hydrazide and concentrating, the reaction mixture is purified by chromatography to give Benzyl 5-[6-(N- (2-fluoro-l-iminoethyl)amino)-2-aminohexanamido]-2-[6-(N-(2-fluoro-l- iminoethyl)amino)-2-(N-Z-amino)hexanamido]pentanoate.
Benzyl 5-[6-(N-(2-fluoro-l-iminoethyl)amino)-2-aminohexanamido]-2-[6-(N-(2-fluoro-l- iminoethyl)amino)-2-(N-Z-amino)hexanamido]pentanoate is dissolved in ethanol containing acetic acid, and is combined with a hydrogenation catalyst such as palladium on carbon and hydrogen. This reaction is shaken under pressure for an extended period of time in a standard Parr hydrogenation apparatus to remove the Z-function generating the amino product 2,5-bis[6-(N-(2-fluoro-l-iminoethyl)amino)-2- aminohexanamido]pentanoic acid.
Figure imgf000203_0001
(19)
Example 19
EX-19a) 6-(N-(2-Fluoro-l-iminoethyl)amino)-2-(N-Z-amino)hexanoic acid (10 mmol) and triethyl amine (11 mmol) are added to anhydrous THF, cooled in an ice bath and treated with ethyl chloroformate (10.1 mmol). Upon completion, erythritol (10.1 mmol) is added. After warming to room temperature and standing for 2 hours, the reaction mixture is concentrated in vacuo, and the resulting material is purified chromatographically to separate isomeric products and yield 2,3,4-trihydroxybutyl 6-(N-(2-fluoro-l- iminoethyl)amino)-2-(N-Z-amino)hexanoate.
EX-19b) 6-(N-(l-iminoethyl)amino)-2-(N-Z-amino)hexanoic acid (4.1 mmol) (4 mmol) and triethyl amine (5 mmol) are added to anhydrous THF, cooled in an ice bath and treated with ethyl chloroformate (4.1 mmol). Upon completion, 2,3,4-trihydroxybutyl 6- (N-(2-fluoro-l-iminoethyl)amino)-2-(N-Z-amino)hexanoate (4.1 mmol) is added. After warming to room temperature and standing for 2 hours, the reaction mixture is concentrated in vacuo, and the resulting material is purified chromatographically to separate the three isomers and yield 2,4-dihydroxy-3-[6-(N-(l-iminoethyl)amino)-2-(N-Z- amino) hexanoyloxyjbutyl 6-(N-(2-fluoro-l-iminoethyl)amino)-2-(N-Z-amino)hexanoate.
2,4-dihydroxy-3-[6-(N-(l-iminoethyl)amino)-2-(N-Z-amino)hexanoyloxy]butyl 6-(N-(2- fluoro- l-iminoethyl)amino)-2-(N-Z-amino)hexanoate (2 mmol) is mixed with tert-butanol containing 8 mmol p-toluenesulfonic acid, and a hydrogenation catalyst such as palladium on carbon and hydrogen is added. This reaction is shaken under pressure for an extended period of time in a standard Parr hydrogenation apparatus to remove the Z-function, the catalyst is filtered, and the solvent is removed in vacuo generating the amino product 2,4- dihydroxy-3-[6-(N-( 1 -iminoethyl)amino)-2-aminohexanoyloxy]butyl 6-(N-(2-fluoro- 1 - iminoethyl)amino)-2-aminohexanoate tetra-p-toluenesulfonic acid salt.
Figure imgf000204_0001
(20)
Example 20
EX-20a) 6-(N-(l-(N-benzyloxyimino)ethyl)amino)-2-(N-Z-amino)hexanoic acid (4.1 mmol) and triethyl amine (5 mmol) are added to anhydrous THF, cooled in an ice bath and treated with ethyl chloroformate (4.2 mmol). Upon completion, 2,4-dihydroxy-3-[6-(N- (1 -iminoethyl)amino)-2-(N-Z-amino) hexanoyloxyjbutyl 6-(N-(2-fluoro- 1 - iminoethyl)amino)-2-(N-Z-amino)hexanoate (4.1 mmol), as prepared in EX-19b), is added. After warming to room temperature and standing for 2 hours, the reaction mixture is concentrated in vacuo. Methylene chloride (100 mL) and 20 mL of IM aqueous sodium bicarbonate are added. The methylene chloride layer is separated, the aqueous solution is extracted three times with 50 mL methylene chloride, the combined extracts are dried over MgSO and concentrated. The resulting material is purified chromatographically to separate isomers and yield 2-hydroxy-3-[6-(N-(l-iminoethyl)amino)-2-(N-Z- amino)hexanoyloxy]-4-[6-(N-(l-(N-benzyloxyimino)ethyl)amino)-2-(N-Z-amino) hexanoyloxy]butyl 6-(N-(2-fluoro- 1 -iminoethyl)amino)-2-(N-Z-amino)hexanoate.
EX-20b) 3-(2-(N-(l-Iminoethyl)amino)ethylthio)-2-(N-Z-amino)propanoic acid (3.1 mmol) and triethyl amine (4 mmol) are added to anhydrous THF, cooled in an ice bath and treated with ethyl chloroformate (3.2 mmol). 2-Hydroxy-3-[6-(N-(l-iminoethyl)amino)-2- (N-Z-amino)hexanoyloxy]-4- [6-(N-( 1 -(N-benzyloxyimino)ethyl)amino)-2-(N-Z- amino)hexanoyloxy]butyl 6-(N-(2-fluoro-l-iminoethyl)amino)-2-(N-Z-amino)hexanoate (3 mmol) is then added in anhydrous THF. After warming to room temperature and standing for 2 hours, the reaction mixture is concentrated in vacuo. Methylene chloride (100 mL) and 20 mL of IM aqueous sodium bicarbonate are added. The methylene chloride layer is separated, the aqueous solution is extracted three times with 50 mL methylene chloride, the combined extracts are dried over MgSO and concentrated in vacuo. The resulting material is purified chromato-graphically to yield 2-[3-(2-(N-(l- iminoethyl) amino) ethylthio)-2-(N-Z-amino)propanoyloxy]-3-[6-(N-(l-iminoethyl) amino)-2-(N-Z-amino)hexanoyloxy ] -4- [6-(N-( 1 -(N-benzyloxyimino)ethyl)amino)-2-(N-Z- amino)hexanoyloxy]butyl 6-(N-(2-fluoro- 1 -iminoethyl)amino)-2-(N-Z-amino)hexanoate.
2-[3-(2-(N-( 1 -Iminoethyl)amino)ethylthio)-2-(N-Z-amino) ρropanoyloxy]-3-[6-(N-( 1 - iminoethyl)amino)-2-(N-Z-amino) hexanoyloxy]-4-[6-(N-(l-(N- benzyloxyimino)ethyl)amino)-2-(N-Z-amino)hexanoyloxy]butyl 6-(N-(2-fluoro- 1 - iminoethyl)amino)-2-(N-Z-amino)hexanoate (2 mmol) is mixed with tert-butanol containing 16 mmol p-toluenesulfonic acid, and a hydrogenation catalyst such as palladium on carbon and hydrogen is added. This reaction is shaken under pressure for an extended period of time in a standard Parr hydrogenation apparatus to remove the Z- functions, the catalyst is filtered, and the solvent is removed in vacuo generating the amino product 2-[3-(2-(N-(l-iminoethyl)amino) ethylthio)-2-aminopropanoyloxy]-3-[6- (N-( 1 -iminoethyl)amino)-2-aminohexanoyloxy]-4-[6-(N-( 1 -oxyiminoethyl)amino)-2- aminohexanoyloxyjbutyl 6-(N-(2-fluoro- 1 -iminoethyl)amino)-2-aminohexanoate octyl-p- toluenesulfonic acid salt.
Figure imgf000206_0001
(21)
Example 21
EX-21a) 1,2,3,4-butanetetracarboxylic acid (10 mmol) and benzyl 6-(N-(l- iminoethyl)amino)-2-aminohexanoate hydrochloride (10 mmol) are dissolved in dry THF and acetonitrile and cooled in an ice bath. Triethylamine (11 mmol) and 1,3- dicyclohexylcarbodiimide (10.5 mmol) in dry THF are added, and the mixture is allowed to warm to room temperature. When the coupling is complete, the mixture is concentrated, and the reaction is purified by chromatography to separate isomers and give l-[N-[5-(N-(l-iminoethyl)amino)-l-(benzyloxycarbonyl)pentyl]amidocarbonyl]-2,3,4- butanetricarboxylic acid.
EX-21b) l-[N-[5-(N-(l-iminoethyl)amino)-l-(benzyloxycarbonyl) pentyl]amidocarbonyl]-2,3,4-butanetricarboxylic acid (5 mmol) and benzyl 6-(N-(2- fluoro-l-iminoethyl)amino)-2-aminohexanoate hydrochoride(5 mmol) are dissolved in dry THF and acetonitrile and cooled in an ice bath. 1,3-Dicyclohexylcarbodiimide (5.5 mmol) and triethylamine (5 mmol) in dry THF are added, and the mixture is allowed to warm to room temperature. When the coupling is complete, the mixture is concentrated, and the reaction is purified by chromatography to separate isomers and give l-[N-[5-(N-(l- iminoethyl)amino)-l-(benzyloxycarbonyl)pentyl] amidocarbonyl]-4-[N-[5-(N-(2-fluoro-l- iminoethyl)amino)-l-(benzyloxycarbonyl)pentyl]amidocarbonyl]-2,3-butanedicarboxylic acid.
l-[N-[5-(N-(l-Iminoethyl)amino)-l-(benzyloxycarbonyl)pentyl] amidocarbonyl]-4-[N-[5- (N-(2-fluoro-l-iminoethyl)amino)-l-(benzyloxycarbonyl)pentyl]amidocarbonyl]-2,3- butanedicarboxylic acid is dissolved in tert-butanol and is combined with a hydrogenation catalyst such as palladium on carbon and hydrogen. This reaction is shaken under pressure for an extended period of time in a standard Parr hydrogenation apparatus to remove the Z-function, the catalyst is filtered, and the solvent is removed in vacuo generating the amino product l-[N-[5-(N-(l-iminoethyl)amino)-l-carboxypentyl]amidocarbonyl]-4-[N- [5-(N-(2-fluoro-l-iminoethyl)amino)-l-carboxypentyl]amidocarbonyl]-2,3- butanedicarboxylic acid.
Figure imgf000207_0001
(22)
Example 22 EX-22a) 1 -[N-[5-(N-( 1 -iminoethyl)amino)- 1 -(benzyloxycarbonyl) pentyl]amidocarbonyl]-4-[N-[5-(N-(2-fluoro-l-iminoethyl) amino)- 1- (benzyloxycarbonyl)pentyl]amidocarbonyl]-2,3-butanedicarboxylic acid (10 mmol) as prepared in EX-21b and benzyl 3-(2-(N-(l-Iminoethyl)amino)ethylthio)-2- aminopropanoate hydrochloride (10 mmol) are dissolved in dry THF and acetonitrile and cooled in an ice bath. 1,3-Dicyclohexylcarbodiimide (10.5 mmol) and triethylamine (11 mmol) in dry THF are added, and the mixture is allowed to warm to room temperature. When the coupling is complete, the mixture is concentrated, and the reaction is purified by chromatography column to separate isomers and give l-[N-[5-(N-(l-iminoethyl)amino)-l- (benzyloxycarbonyl)pentyl] amidocarbonyl]-3-[N-[2-(2-(N-(l- iminoethyl)amino)ethylthio)-l-(benzyloxycarbonyl)ethyl]amidocarbonyl]-4-[N-[5-(N-(2- fluoro- 1 -iminoethyl)amino)- 1 -(benzyloxycarbonyl)pentyl] amidocarbonyl]-2- butanecarboxylic acid.
1 - [N- [5-(N-( 1 -iminoethyl)amino)- 1 -(benzyloxycarbonyl)pentyl] amidocarbonyl ]-3- [N- [2- (2-(N-( 1 -iminoethyl)amino)ethylthio)- 1 -(benzyloxycarbonyl)ethyl]amidocarbonyl]-4- [N- [5-(N-(2-fluoro-l-iminoethyl)amino)-l-(benzyloxycarbonyl)pentyl] amidocarbonyl] -2- butanecarboxylic acid (4 mmol) and benzyl 6-(N-(l-(N-benzyloxyimino)ethyl)amino)-2- aminohexanoate hydrochloride (4 mmol) are dissolved in dry THF and acetonitrile and cooled in an ice bath. 1,3-Dicyclohexylcarbodiimide (4.5 mmol) and triethylamine (5 mmol) in dry THF are added and the mixture is allowed to warm to room temperature. When the coupling is complete, the mixture is concentrated and purified by chromatography to give l-[N-[5-(N-(l-iminoethyl)amino)-l-(benzyloxycarbonyl) pentyl]amidocarbonyl]-2-[N-[5-(N-(l-(N-benzyloxyimino)ethyl) amino)-l- (benzyloxycarbonyl)pentyl]amidocarbonyl]-3-[N-[2-(2-(N-(l- iminoethyl)amino)ethylthio)-l -(benzyloxycarbonyl) ethyl]amidocarbonyl]-4-[N-[5-(N-(2- fluoro-1-iminoethyl) amino)- l-(benzyloxycarbonyl)pentyl]amidocarbonyl]butane.
l-[N-[5-(N-(l-Iminoethyl)amino)-l-(benzyloxycarbonyl) pentyl]amidocarbonyl]-2-[N-[5- (N-( 1 -(N-benzyloxyimino)ethyl) amino)- 1 -(benzyloxycarbonyl)penty ljamidocarbonyl] -3 - [N-[2-(2-(N-( l-iminoethyl)amino)ethylthio)-l -(benzyloxycarbonyl) ethyljamidocarbonyl]- 4- [N- [5-(N-(2-fluoro- 1 -iminoethyl) amino)- 1 - (benzyloxycarbonyl)pentyl]amidocarbonyl]butane is dissolved in ethanol/acetic acid and is combined with a hydrogenation catalyst such as palladium on carbon and hydrogen. This reaction is shaken under pressure for an extended period of time in a standard Parr hydrogenation apparatus to remove the benzyl-function, the catalyst is filtered, and the solvent is removed to give l-[N-[5-(N-(l-iminoethyl)amino)-l- carboxypentyl]amidocarbonyl]-2-[N-[5-(N-(l-oximinoethyl)amino)-l- carboxypentyl]amidocarbonyl]-3-[N-[2-(2-(N-(l-iminoethyl)amino)ethylthio)-l- carboxyethyl] amidocarbonyl]-4-[N-[5-(N-(2-fluoro-l-iminoethyl)amino)-l- carboxypentyl]amidocarbonyl]butane.
Figure imgf000209_0001
(23)
Example 23
EX-23a) 4-(N-(l-iminoethyl)amino)-2-(N-Z-amino)hexanoic acid (10 mmol) and tert- butyl 2-hydroxy acetate (10 mmol) are dissolved in dry THF and acetonitrile and cooled in an ice bath. 1,3-Dicyclohexylcarbodiimide (10.5 mmol) in dry THF is added, and the mixture is allowed to warm to room temperature. When coupling is complete, the mixture is concentrated and purified by chromatography to give tert-butyl 2-[6-(N-(l- iminoethyl)amino)-2-(N-Z-amino)hexanoyloxy] acetate.
EX-23b) tert-Butyl 2-[6-(N-(l-iminoethyl)amino)-2-(N-Z-amino) hexanoyloxy] acetate is deprotected by allowing it to stand in 2N HCl and dioxane at 25°C for two hours. Concentrating in vacuo affords 2-[6-(N-(l-iminoethyl)amino)-2-(N-Z-amino) hexanoyloxy] acetic acid hydrochloride.
EX-23c) 2-[6-(N-(l-Iminoethyl)amino)-2-(N-Z-amino) hexanoyloxy] acetic acid hydrochloride (5 mmol) and benzyl 6-(N-(l-iminoethyl)amino)-2-amino-2- methylhexanoate hydrochloride (5 mmol) are dissolved in dry THF and acetonitrile and cooled in an ice bath. 1,3-Dicyclohexylcarbodiimide (5.5 mmol) and triethylamine (11 mmol) in dry THF are added, and the mixture is allowed to warm to room temperature. When coupling is complete, the mixture is concentrated and purified by chromatography to give N-[5-(N-( 1 -iminoethyl)amino)- 1 -methyl- 1 -(benzyloxycarbonyl)pentyl]-2-[6-(N-( 1 - iminoethyl)amino)-2-(N-Z-amino)hexanoyloxy]acetamide.
N-[5-(N-( l-iminoethyl)amino)- 1-methyl- 1 -(benzyloxycarbonyl) pentyl]-2-[6-(N-( 1 - iminoethyl)amino)-2-(N-Z-amino) hexanoyloxy] acetamide (3 mmol) is dissolved in tert- butanol containing 9 mmol of p-toluenesulfonic acid and is combined with a hydrogenation catalyst such as palladium on carbon and hydrogen. This reaction is shaken under pressure for an extended period of time in a standard Parr hydrogenation apparatus to remove the protecting groups, filtered to remove catalyst, and concentrated to give N- [5-(N-( 1 -iminoethyl)amino)- 1-methyl- 1 -carboxypentyl]-2-[6-(N-( 1 -iminoethyl)amino)-2- aminohexanoyloxy] acetamide tri-p-toluenesulfonic acid salt.
Figure imgf000210_0001
(24)
Example 24
EX-24a) 2-[6-(N-(l-iminoethyl)amino)-2-(N-Z- amino) hexanoyloxy] acetic acid hydrochloride (10 mmol) and tert-butyl 6-(N-(2-fluoro-l-iminoethyl)amino)-2- aminomethyl-2-phthalimidohexanoate dihydrochloride (10 mmol) are dissolved in dry THF and acetonitrile and cooled in an ice bath. 1,3-Dicyclohexylcarbodiimide (10.5 mmol) and triethylamine (32 mmol) in dry THF are added, and the mixture is allowed to warm to room temperature. When the coupling is complete, the mixture is concentrated and purified by chromatography to give tert-butyl 6-(N-(2-fluoro-l-iminoethyl)amino)-2- [2-(6-(N-(l-iminoethyl)amino)-2-(N-Z-amino)hexanoyloxy) acetamidomethyl]-2- phthalimidohexanoate.
EX-24b) tert-Butyl 6-(N-(2-fluoro-l-iminoethyl)amino)-2-[2-(6-(N-(l- iminoethyl)amino)-2-(N-Z-amino)hexanoyloxy) acetamidomethyl]-2- phthalimidohexanoate is deprotected by allowing it to stand in 2N HCl and dioxane at 25°C for two hours. Concentrating in vacuo affords 6-(N-(2-fluoro-l-iminoethyl)amino)- 2-[2-(6-(N-(l-iminoethyl)amino)-2-(N-Z-amino)hexanoyloxy)acetamidomethyl]-2- phthalimidohexanoic acid dihydrochloride.
EX-24c) 6-(N-(2-fluoro-l-iminoethyl)amino)-2-[2-(6-(N-(l-iminoethyl)amino)-2-(N-Z- amino)hexanoyloxy)acetamidomethyl]-2-phthalimidohexanoic acid dihydrochloride (9 mmol) is dissolved in methanol and treated with hydrazine (9 mmol). The mixture is heated to reflux. After complete removal of the phthaloyl protecting group, the reaction is concentrated and purified by chromatography to give 6-(N-(2-fluoro-l-iminoethyl)amino)- 2-[2-(6-(N-(l-iminoethyl)amino)-2-(N-Z-amino)hexanoyloxy)acetamidomethyl]-2- aminohexanoic acid.
6-(N-(2-fluoro- 1 -iminoethyl)amino)-2- [2-(6-(N-( 1 -iminoethyl) amino)-2-(N-Z- amino)hexanoyloxy)acetamidomethyl]-2-aminohexanoic acid (5 mmol) is dissolved in tert-butanol containing 20 mmol p-toluenesulfonic acid and is combined with a hydrogenation catalyst such as palladium on carbon and hydrogen. This reaction is shaken under pressure for an extended period of time in a standard Parr hydrogenation apparatus to remove the Z-function, filtered to remove the catalyst, and concentrated generating the amino product 6-(N-(2-fluoro-l-iminoethyl)amino)-2-[2-(6-(N-(l -iminoethyl) amino)-2- aminohexanoyloxy)acetamidomethyl]-2-aminohexanoic acid tetra-/?-toluenesulfonic acid salt.
Figure imgf000212_0001
(25)
Example 25
EX-25a) 2,2-diethoxy- 1 -propyl 6-(N-( 1 -iminoethyl)amino)-2-(N-Boc-amino)hexanoate (10 mmol) is treated with 5% aqueous phosphoric acid in 20 mL of water at ice bath temperature. After hydrolysis of the ketal, the pH is adjusted to pH 10 with sodium carbonate in an ice bath, and the product is rapidly extracted three times with 50 mL of methylene chloride. The solvent is dried over anhydrous MgSO4, 10 mmol p- toluenesulfonic acid is added, and the solvent removed to give 2-acetonyl 6-(N-(l- iminoethyl)amino)-2-(N-Boc-amino)hexanoate p-toluenesulfonic acid salt.
EX-25b) Hexane (50 mL) is added to the 2-acetonyl 6-(N-( 1 -iminoethyl)amino)-2-(N- Boc-amino)hexanoate p-toluenesulfonic acid salt (10 mmol). Ethyl 6-(N-(l- iminoethyl)amino)-2-aminohexanoate di-p-toluenesulfonic acid salt (10 mmol) is added. The reaction mixture is refluxed with azeotropic distillation until complete removal of water using a Dean-Stark trap. After cooling, the solv'ent is removed in vacuo to give 2- [N-[6-(N-(l-iminoethyl)amino)-l-carboethoxypentyl] imino]propyl 6-(N-(l- iminoethyl)amino)-2-(N-Boc-amino) hexanoate tri-p-toluenesulfonic acid salt.
p-Toluenesulfonic acid (10 mmol) and 2-[N-[6-(N-(l-iminoethyl)amino)-l- carboethoxypentyl]imino]propyl 6-(N-(l-iminoethyl)amino)-2-(N-Boc-amino)hexanoate tri-p-toluenesulfonic acid salt (10 mmol) is deprotected by allowing it to stand in 2N HCl and anhydrous dioxane at 25°C for two hours. Concentrating in vacuo affords 2-[N-[6- (N-( 1 -iminoethyl)amino)- 1 -carboethoxypentyl]imino]propyl 6-(N-( 1 -iminoethyl)amino)- 2-aminohexanoate tetra-p-toluenesulfonic acid salt.
Figure imgf000213_0001
(26)
Example 26
EX-26a) N-(2-(3-Hydroxypropoxy)ethyl)-6-(N-( 1 -iminoethyl) amino)-2- phthalimidohexanamide (10 mmol) is dissolved in methanol and treated with hydrazine (10 mmol). The mixture is heated to reflux. After complete removal of the phthaloyl protecting group, the reaction is concentrated and purified by chromatography to give N- (2-(3-hydroxypropoxy)ethyl)-6-(N-(l-iminoethyl)amiιlo)-2-aminohexanamide.
EX-26b) N-(2-(3-Hydroxypropoxy)ethyl)-6-(N-(l -iminoethyl) amino)-2- aminohexanamide (9.5 mmol) is allowed to stir with t-butoxycarbonylazide (10 mmol) and MgO (10 mmol) in dioxane/water solution. Upon completion, the magnesium salts are removed by filtration. The mixture is concentrated in vacuum and chromatographed giving N-(2-(3-hydroxypropoxy) ethyl)-6-(N-( 1 -iminoethyl)amino)-2-(N-Boc- amino)hexanamide. EX-26c) N-(2-(3-hydroxypropoxy)ethyl)-6-(N-( 1 -iminoethyl) amino)-2-(N-Boc- amino)hexanamide (8 mmol) is dissolved in 20 mL DMSO and treated with 1,3- dicyclohexylcarbodiimide (DCC) (8 mmol) and phosphoric acid. The reaction is stirred at room temperature. Upon completion, 100 mL methylene chloride is added to the mixture, and it is washed with 10% aqueous sodium bicarbonate, water and brine. The methylene chloride layer is dried over MgSO , filtered, and solvents are removed in vacuo to give N-(2-(2-formylethoxy)ethyl)-6-(N-(l-iminoethyl)amino)-2-(N-Boc- amino)hexanamide.
EX-26d) N-(2-(2-Formylethoxy)ethyl)-6-(N-( 1 -iminoethyl) amino)-2-(N-Boc- amino)hexanamide (7 mmol) is dissolved in 25 ml of hexane and treated with p- toluenesulfonic acid (14 mmol) and ethyl 6-(N-(l-iminoethyl)amino)-2-aminohexanoate p-toluenesulfonic acid salt (7 mmol). The reaction mixture is refluxed with azeotropic distillation for complete removal of water using a Dean-Stark trap. After cooling, the solvent is removed in vacuo to give N-[2-[2-[3-(5-(N-(l-iminoethyl) amino)-l- ethoxycarbonylpentyl)imino]propoxy]ethyl]-6-(N-(l-iminoethyl)amino)-2-(N-Boc- amino)hexanamide tri-p-toluenesulfonic acid salt.
N-[2-[2-[3-(5-(N-(l-Iminoethyl)amino)-l-ethoxycarbonylpentyl)imino]propoxy]ethyl]-6- (N-(l-iminoethyl)amino)-2-(N-Boc-amino)hexanamide tri-p-toluenesulfonic acid salt (6 mmol) is deprotected by allowing it to stand in 2N HCl and dioxane containing 6 mmol p- toluenesulfonic acid at 25°C for two hours. Concentrating in vacuo affords N-[2-[2-[3-(5- (N-( 1 -Iminoethyl)amino)- 1 -ethoxycarbonylpentyl)imino]propoxy]ethyl]-6-(N-( 1 - iminoethyl) amino)-2-aminohexanamide tetra-p-toluenesulfonic acid salt.
Figure imgf000214_0001
(27)
Example 27
EX-27a) N- [2-(4-(4-hy droxybutyl)phenyl)ethyl] -N-methyl-6-(N-( 1 -iminoethyl)amino)-2- phthalimidohexanamide (10 mmol) is dissolved in methanol and treated with hydrazine (10 mmol). The mixture is heated to reflux. After complete removal of the phthaloyl protecting group, the reaction is concentrated and passed through a chromatography column to give N-[2-(4-(4-hydroxybutyl)phenyl)ethyl]-N-methyl-6-(N-( 1 - iminoethyl)amino)-2-aminohexanamide.
EX-27b) N-[2-(4-(4-Hydroxybutyl)phenyl)ethyl]-N-methyl-6-(N-( 1 -iminoethyl)amino)-2- aminohexanamide (9.5 mmol) is allowed to stir with t-butoxycarbonylazide (10 mmol) and MgO (10 mmol) in dioxane/water solution. Upon completion, the magnesium salts are removed by filtration. The mixture is concentrated in vacuum giving, after chromatography, N-[2-(4-(4-hydroxybutyl)phenyl)ethyl]-N-methyl-6-(N-(l- iminoethyl)amino)-2-(N-Boc-amino)hexanamide.
EX-27c) N-[2-(4-(4-hydroxybutyl)phenyl)ethyl]-N-methyl-6-(N-(l-iminoethyl)amino)-2-
(N-Boc-amino)hexanamide (8 mmol) is dissolved in 20 mL DMSO and treated with 1,3- dicyclohexylcarbodiimide (DCC) (8 mmol) and phosphoric acid. The reaction is stirred at room temperature. Upon completion of the oxidation, 200 mL methylene chloride is added to the mixture, and it is washed sequentially with 25 mL of brine , water and finally 10% aqueous sodium bicarbonate. The methylene chloride layer is dried over MgSO4, filtered, solvents are removed in vacuo and the product is purified by column chromatography to give N-[2-(4-(3-formylpropyl)phenyl) ethyl]-N-methyl-6-(N-(l- iminoethyl)amino)-2-(N-Boc-amino) hexanamide.
EX-27d) N-[2-(4-(3-formylpropyl)phenyl)ethyl]-N-methyl-6-(N-(l-iminoethyl)amino)-2-
(N-Boc-amino)hexanamide (7 mmol) is dissolved in 25 ml of hexane and treated with p- toluenesulfonic acid (7 mmol) and methyl 6-(N-(l-iminoethyl)amino)-2-aminohexanoate di -p-toluenesulfonic acid salt (7 mmol). The reaction mixture is refluxed with azeotropic distillation for complete removal of water using a Dean-Stark trap. After cooling, the solvent is removed in vacuo to give N-[2-[4-(N-(5-(N-(l-iminoethyl)amino)-l- methoxycarbonylpentyl)imino)butyl)phenyl]ethyl]-N-methyl-6-(N-(l-iminoethyl)amino)- 2-(N-Boc-amino)hexanamide tri-p-toluenesulfonic acid salt. N-[2-[4-(N-(5-(N-(l-iminoethyl)amino)-l- methoxycarbonylpentyl)imino)butyl)phenyl]ethyl]-N-methyl-6-(N-(l-iminoethyl)amino)- 2-(N-Boc-amino)hexanamide tri-p-toluenesulfonic acid salt (6 mmol) is deprotected by allowing it to stand in 2N HCl and dioxane containing 6 mmol p-toluenesulfonic acid at 25°C for two hours. Concentrating in vacuo gives N-[2-[4-(N-(5-(N-(l- iminoethyl)amino)-l-methoxycarbonylpentyl)imino)butyl)phenyl]ethyl]-N-methyl-6-(N- (l-iminoethyl)amino)-2-aminohexanamide tetra-p-toluenesulfonic acid salt.
Figure imgf000216_0001
(28)
Example 28
EX-28a) 6-(N-(l-iminoethyl)amino)-2-(N-Boc-amino)hexanoic acid (10 mmol) and 2- (4,4-dimethoxycyclohexyl)ethanol (10 mmol) is dissolved in dry THF and acetonitrile and cooled in an ice bath. 1,3-Dicyclohexylcarbodiimide (10.5 mmol) in dry THF is added and the mixture is allowed to warm to room temperature. When the coupling is complete, the mixture is concentrated and is purified by chromatography to give 2-(4,4- dimethoxycyclohexyl)ethyl 6-(N-( 1 -iminoethyl)amino)-2-(N-Boc-amino)hexanoate.
EX-28b) 2-(4,4-dimethoxycyclohexyl)ethyl 6-(N-( 1 -iminoethyl)amino)-2-(N-Boc- amino)hexanoate (9 mmol) is stirred with p-toluenesulfonic acid (9 mmol), water (0.5 mmol), and 30 mL acetone until the ketal is hydrolyzed and transketalized. The reaction mixture is concentrated to dryness to give 2-(4-oxocyclohexyl)ethyl 6-(N-(l -iminoethyl) amino)-2-(N-Boc-amino)hexanoate p-toluenesulfonic acid salt. EX-28c) 2-(4-oxocyclohexyl)ethyl 6-(N-(l -iminoethyl) amino)-2-(N-Boc- amino)hexanoate p-toluenesulfonic acid salt and ethyl 6-(N-(l-iminoethyl)amino)-2- aminohexanoate di-p-toluenesulfonic acid salt are slurried in a mixture of 100 mL toluene and dimethylacetamide (19: 1) and refluxed azeotropically to remove water formed in the condensation. Concentrating in vacuo affords 2-[4-[N-(5-(N-(l-iminoethyl)amino)-l- ethoxycarbonylpentyl)imino] cyclohexyl]ethyl 6-(N-( 1 -iminoethyl)amino)-2-(N-Boc- amino)hexanoate tri-p-toluenesulfonic acid salt.
2-[4-[N-(5-(N-(l-iminoethyl)amino)-l-ethoxycarbonylpentyl) imino] cyclohexyl]ethyl 6- (N-(l-iminoethyl)amino)-2-(N-Boc-amino)hexanoate tri-p-toluenesulfonic acid salt is deprotected by allowing it to stand in 2N HCl and anhydrous dioxane containing one equivalent of p-toluenesulfonic acid at 25°C for two hours. Concentrating in vacuo affords 2-[4-[N-(5-(N-(l-iminoethyl)amino)-l-ethoxycarbonylpentyl)imino] cyclohexyl]ethyl 6-(N-( 1 -iminoethyl)amino)-2-aminohexanoate tetra-p-toluenesulfonic acid salt.
Figure imgf000217_0001
(29)
Example 29
Methyl 6-(N-(l-iminoethyl)amino)-2-aminohexanoate di-p-toluenesulfonic acid salt (20 mmol) is added to 25 ml of toluene and treated with p-toluenesulfonic acid (1 mmol) and di(ethyleneglycol) (10 mmol). The reaction mixture is heated to 80 °C with distillation for removal of methanol using a Dean-Stark trap. After cooling, the solvent is removed in vacuo to give 2-[2-[6-(N-(l-iminoethyl)amino)-2-aminohexanoyloxy]ethoxy]ethyl 6-(N- (l-iminoethyl)amino)-2-aminohexanoate tetra-p-toluenesulfonic acid salt.
Figure imgf000218_0001
(30)
Example 30
Methyl 6-(N-(l-iminoethyl)amino)-2-aminohexanoate di-p-toluenesulfonic acid (20 mmol) is added to 25 ml of toluene and treated p-toluenesulfonic acid (1 mmol) and 1,4- di(2-hydroxyethyl)benzene (10 mmol). The reaction mixture is heated to 80 °C with distillation for removal of methanol using a Dean-Stark trap. After cooling, the solvent is removed in vacuo to give 4-[2-[6-(N-(l-iminoethyl)amino)-2- aminohexanoyloxy]ethyl]phenethyl 6-(N-(l-iminoethyl)amino)-2-aminohexanoate tetra-p- toluenesulfonic acid salt.
Figure imgf000219_0001
(31)
Example 31 ; ;
EX-31a) 2,2,2-trichloroethyl N-(dichlorophosphinylmethyl)-N-Boc-glycinate (10 mmol) is dissolved in 25 ml of anhydrous THF and acetonitrile containing (42 mmol) triethylamine. After cooling in an ice bath, benzyl 6-(N-(l -iminoethyl) amino)-2- aminohexanoate dihyrochloride (20.5 mmol) is added to the mixture over 20 minutes. After warming to room temperature and standing for 2 hours, the reaction mixture is concentrated in vacuo, 50 ml of methylene chloride is added along with 20 ml of 10% sodium bicarbonate. The methylene chloride layer is separated, the water is extracted with methylene chloride three times, dried over MgSO concentrated, and chromatographed to afford 2,2,2-trichloroethyl N-[bis[N-(5-(N-(l-iminoethyl)amino)-l- (benzyloxycarbonyl)pentyl)amino] phosphinylmethyl]-N-Boc-glycinate.
EX-31b) 2,2,2-Trichloroethyl N- [bis [N-(5-(N-(l -iminoethyl) amino)-l- (benzyloxycarbonyl)pentyl)amino]phosphinylmethyl]-N-Boc-glycinate is dissolved in acetic acid (50 ml). Excess zinc dust is added until completion of removal of the trichloroethyl-function. The reaction mixture is concentrated in vacuo and the residue is neutralized with excess saturated aqueous sodium carbonate. The precipitate is removed by filtration. The residue is dissolved in 50% acetic acid and lyophilized. The crude product is purified by then adjusting the pH to 7.5 and poured onto a Dowex 50 cation exchange column. The column is washed with water. The Boc -protected product is then eluted with 10% aqueous pyridine and concentrated in vacuo to give N-[bis[N-(5-(N-(l- irninoethyl)armno)-l-rbenzyloxycarbonyl)pentyl)amino] phosphinylmethyl]-N-Boc- glycine.
EX-31c) N-[bis[N-(5-(N-(l-Iminoethyl)amino)-l- (benzyIoxycarbonyl)pentyl)amino]pl osphinylrnethyl]-N-Boc-glycJne (9 mmol) is dissolved in anhydrous THF, cooled in an ice bath and treated with ethyl chloroformate (9.1 mmol) and triethyl amine (30 mmol). The mixture is allowed to warm to room temperature. Upon completion, the mixture is again cooled in an ice bath and benzyl 3-(2- (N-(l -iminoethyl) amino)ethylthio)-2-aminopropanoate dihydrochloride (9.1 mmol) is added. The mixture is allowed to warm to room temperature. Upon completion the mixture is concentrated in vacuum. The resulting material is purified by chromatography giving benzyl 3-[2-(N-(l--jmnoemyl)amino)e ylthio]-2-[N-[bis[N-(5-(N-(l- iιr noeUιyl)amino)-l-(ben2yloxycarbonyl) pentyl)amino]phosphinylmethyl]-N-Boc- glycinamidojpropanoate.
EX-31d) BenzyJ 3-[2-(N-(l-iminoethyl)arnino)cthylthio]-2-[N-[bis[N-(5-(N-(l- irninoethyl)amino)-l-(beπzyloxycarbonyl) pentyl)amjno]phosphinylmethyl]-N-Boc- glycinamido]propanoate is dissolved in ethanol/acetic acid and is combined with a hydrogenation catalyst such as palladium on carbon and hydrogen. This reaction is shaken under pressure for an extended period of time in a standard Parr hydrogenation apparatus to remove the benzyl-function generating, after filtration and removal of solvent, 3-[2-(N- (l-iminoefJιyl) arr.ino)eΛylthio]-2-[N-^ carboxypentyl)arnino]phosphinylmemyl]-N-Boc-glycmamido] propanoic acid.
3-[2-(N-(l-Iι noethyl)aιnmo)cmylΛio]-2-[N-^ carboxypentyI)amino]phosphinylmemyl]-N-Boc-glycinarτndo]propanoic acid is deprotected by allowing it to stand in 2N HCl and dioxane at 25°C for two hours. Concentrating in vacuo affords 3-[2-(N-(l-imiπoethyl)amino) ethylthio]-2-[N-[bis[N-(5- (N-(l -iminoethyl)arnino)- 1 - carboxypentyl)amiπo]phosphmylmeιhyl]glycmamido]propanoic acid tetrahydrochloride.
Figure imgf000221_0001
(32)
Example 32
EX-32a) Benzyl 3-[2-(N-(l-iminoethyl)amino)ethylthio]-2-[N-[bis[N-(5-(N-(l- iminoethyl)amino)-l -(benzyloxycarbonyl) pentyl)amino]phosphinylmethyl]-N-Boc- glycinamidojpropanoate as prepared in EX-31c is then dissolved in 2N HCl and dioxane at 25°C for two hours until the t-butoxycarbonyl group is removed. The reaction mixture is then concentrated in vacuo to give benzyl 3-[2-(N-(l-iminoethyl)amino)ethylthio]-2-[N- [bis[N-(5-(N-( 1 -iminoethyl)amino)- 1 -(benzyloxycarbonyl) pentyl)amino]phosphinylmethyl]glycinamido]propanoate tetrahydrochloride.
EX -32b) 6-(N-(2-fluoro-l-iminoethyl)amino)-2-(N-Z- amino) hexanoic acid (10 mmol) is dissolved in anhydrous THF, cooled in an ice bath and treated with ethyl chloroformate (10.1 mmol) and triethyl amine (TEA) (11 mmol). The mixture is allowed to warm to room temperature. Upon completion, the mixture is again cooled in an ice bath, and then both 42 mmol triethylamine and benzyl 3-[2-(N-(l -iminoethyl) amino) ethylthio]-2-[N- [bis[N-(5-(N-( 1 -iminoethyl)amino)- 1 - (benzyloxycarbonyl)pentyl)amino]phosphinylmethyl] glycinamido]propanoate tetrahydrochloride (10.1 mmol) are added. After warming to room temperature and standing for 2 hours, the reaction mixture is concentrated in vacuo, 100 mL of methylene chloride is added along with 20 mL of aqueous 5% sodium carbonate. The methylene chloride layer is separated, the aqueous layer is extracted twice with methylene chloride (50 mL each), dried over MgSO_ι, and concentrated. The resulting material is purified chromatographically to yield benzyl 3-[2-(N-(l-iminoethyl)amino)ethylthio]-2-[N-[bis[N-(5-(N-(l-iminoethyl)amino)- l-(benzyloxycarbonyl)pentyl)amino] phosphinylmefhyl]-N-[6-(N-(2-fluoro-l- iminoethyl)amino)-2-(N-Z-amino)hexanoyl]glycinamido]propanoate.
Benzyl 3-[2-(N-(l-iminoethyl)amino)ethylthio]-2-[N-[bis[N-(5-(N-(l-iminoethyl)amino)- 1 -(benzyloxycarbonyl)pentyl)amino] phosphinylmethyl]-N- [6-(N-(2-fluoro- 1 - iminoethyl)amino)-2-(N-Z-amino)hexanoyl]glycinamido]propanoate is dissolved in ethanol and is combined with a hydrogenation catalyst such as palladium on carbon and hydrogen. This reaction is shaken under pressure for an extended period of time in a standard Parr hydrogenation apparatus to remove the protecting groups generating 3- [2- (N-( 1 -iminoethyl)amino)ethylthio] -2- [N- [bis [N-(5-(N-( 1 -iminoethyl)amino)- 1 - (benzyloxycarbonyl)pentyl) amino] phosphinylmethyl]-N-[6-(N-(2-fluoro-l-iminoethyl) amino)-2-(N-Z-amino)hexanoyl]glycinamido]propanoic acid.
Figure imgf000222_0001
(33)
Example 33 EX-33a) Tetraethylenepentamine (10 mmol) in THF is treated with phthalic anhydride (20.5 mmol) and heated to reflux until the protecting groups are completely reacted. The solvent is removed in vacuo, and the product is purified by chromatography to yield N-(2- phthalimidoethyl)-N'-[2-(N-(2-phthalimidoethyl)amino)ethyl]-l,2-ethanediamine.
EX -33b) 6-(N-(l-iminoethyl)amino)-2-(N-Z-amino)hexanoic acid (30 mmol) is dissolved in anhydrous THF, cooled in an ice bath and treated with ethyl chloroformate (30.5 mmol) and triethyl amine (TEA) (33 mmol). The mixture is allowed to warm to room temperature. Upon completion, the mixture is again cooled in an ice bath and is added to N-(2-phthalimidoethyl)-N ' - [2-(2-phthalimidoethylamino)ethyl]- 1 ,2-ethanediamine ( 10 mmol) cooled in an ice bath. After warming to room temperature and standing for 2 hours, the reaction mixture is concentrated in vacuo, 100 mL of methylene chloride is added along with 20 mL of aqueous 5% sodium carbonate. The methylene chloride layer is separated, the aqueous layer is extracted twice with methylene chloride (50 mL each), dried over MgSO and concentrated. The resulting material is purified chromatographically to yield N,N-bis[2-[N-(2-phthalimidoethyl)-6-(N-(l- iminoethyl)amino)-2-(N-Z-amino)hexanamido]ethyl]-6-[N-(l-iminoethyl)amino]-2-[N-Z- amino]hexanamide.
EX-33c) N,N-bis[2-[N-(2-phthalimidoethyl)-6-(N-(l-iminoethyl)amino)-2-(N-Z- amino)hexanamido]ethyl]-6-[N-(l-iminoethyl)amino]-2-[N-Z-amino]hexanamide (9 mmol) is dissolved in methanol/cyclohexane (1: 1) and treated with hydrazine (9.5 mmol). The mixture is heated to reflux. After complete removal of one phthaloyl protecting group, the reaction is filtered to removed phthaloyl hydrazide, the solvent is concentrated, and the reaction product purified by chromatography to give N-[2-[N-(2- phthalimidoethyl)-6-(N-(l-iminoethyl)amino)-2-(N-Z-amino)hexanamido]ethyl]-N-[2-[N- (2-aminoethyl)-6-(N-( 1 -iminoethyl)amino)-2-(N-Z-amino)hexanamido]ethyl]-6-[N-( 1 - iminoethyl)amino]-2-[N-Z-amino]hexan amide.
EX-33d) 3-(2-(N-(l-iminoethyl)amino)ethylthio)-2-(N-Z-amino)propanoic acid (8 mmol) is dissolved in anhydrous THF, cooled in an ice bath and treated with ethyl chloroformate (8.5 mmol) and triethyl amine (9 mmol). The mixture is allowed to warm to room temperature. Upon completion, the mixture is again cooled in an ice bath and is added to N-[2-[N-(2-phthalimidoethyl)-6-(N-(l-iminoethyl)amino)-2-(N-Z- amino)hexanamido]ethyl]-N-[2-[N-(2-aminoethyl)-6-(N-(l-iminoethyl)amino)-2-(N-Z- amino)hexanamido]ethyl]-6-[N-(l-iminoethyl)amino]-2-[N-Z-amino]hexanamide (8 mmol) cooled in an ice bath. After warming to room temperature and standing for 2 hours, the reaction mixture is concentrated in vacuo, 100 mL of methylene chloride is added along with 20 mL of aqueous 5% sodium carbonate. The methylene chloride layer is separated, the aqueous layer is extracted twice with methylene chloride (50 mL each), dried over MgSO and concentrated. The resulting material is purified chromatographically to yield N-[2-[N-(2-phthalimidoethyl)-6-(N-(l-iminoethyl)amino)-2- (N-Z-amino)hexanamido]ethyl]-N-[2-[N-[2-(3-(2-(N-(l-iminoethyl)amino)ethylthio)-2- (N-Z-amino)propanamido)ethyl]-6-(N-(l-iminoethyl)amino)-2-(N-Z- amino)hexanamido]ethyl]-6-[N-(l-iminoethyl)amino]-2-[N-Z-amino]hexanamide.
EX-33e N-[2-[N-(2-phthalimidoethyl)-6-(N-(l-iminoethyl)amino)-2-(N-Z- anuno)hexanamido]ethyl]-N-[2-[N-[2-(3-(2-(N-(l-iminoethyl)amino)ethylthio)-2-(N-Z- arrύno)propanamido)ethyl]-6-(N-(l-iminoethyl)amino)-2-(N-Z-amino)hexanamido]ethyl]- 6-[N-(l-iminoethyl)amino]-2-[N-Z-amino]hexanamide (7 mmol) is dissolved in methanol/cyclohexane (1: 1) and treated with hydrazine (7.5 mmol). The mixture is heated to reflux. After complete removal of one phthaloyl protecting group, the reaction is filtered to removed phthaloyl hydrazide, the solvent is concentrated, and the reaction product purified by chromatography to give N-[2-[N-(2-aminoethyl)-6-(N-(l- iminoethyl)amino)-2-(N-Z-amino)hexanamido]ethyl]-N-[2-[N-[2-(3-(2-(N-(l- iminoethyl)amino)ethylthio)-2-(N-Z-amino) propanamido)ethyl]-6-(N-(l- iminoethyl)amino)-2-(N-Z-amino) hexanamido]ethyl]-6-[N-(l-iminoethyl)amino]-2-[N-Z- amino] hexanamide.
EX-33f) 6-(N-(2-fluoro-l-iminoethyl)amino)-2-(N-Z-amino)hexanoic acid (6 mmol) is dissolved in anhydrous THF, cooled in an ice bath and treated with ethyl chloroformate
(6.5 mmol) and triethyl amine (TEA) (7 mmol). The mixture is allowed to warm to room temperature. Upon completion, the mixture is again cooled in an ice bath and is added to N-[2-[N-(2-aminoethyl) 6-(N-(l-iminoethyl)amino)-2-(N-Z-amino) hexanamido]ethyl]-N- [2-[N-[2-(3-(2-(N-(l-iminoethyl)amino) ethylthio)-2-(N-Z-amino)propanamido)ethyl]-6- (N-(l-iminoethyl)amino)-2-(N-Z-amino)hexanamido]ethyl]-6-[N-(l-iminoethyl)amino]-2-
[N-Z-amino]hexanamide (6 mmol) cooled in an ice bath. After warming to room temperature and standing for 2 hours, the reaction mixture is concentrated in vacuo, 100 mL of methylene chloride is added along with 20 mL of aqueous 5% sodium carbonate. The methylene chloride layer is separated, the aqueous layer is extracted twice with methylene chloride (50 mL each), dried over MgSU4, and concentrated. The resulting material is purified chromatographically to yield N-[2-[N-[2-(6-(N-(2-fluoro-l- iminoethyl)amino)-2-(N-Z-amino)hexanamido)ethyl]-6-(N-(l-iminoethyl)amino)-2-(N-Z- amino)hexanamido]ethyl]-N-[2-[N-[2-(3-(2-(N-(l-iminoethyl)amino)ethylthio)-2-(N-Z- amino) propanamido)ethyl]-6-(N-( 1 -iminoethyl)amino)-2-(N-Z- amino)hexanamido]ethyl]-6-[N-(l-iminoethyl)amino]-2-[N-Z-amino]hexanamide.
N-[2-[N-[2-(6-(N-(2-fluoro-l-iminoethyl)amino)-2-(N-Z-amino) hexanamido)ethyl]-6-(N- ( 1 -iminoethyl)amino)-2-(N-Z-amino) hexanamido]ethyl] -N- [2- [N- [2-(3-(2-(N-( 1 - iminoethyl)amino) ethylthio)-2-(N-Z-amino)propanamido)ethyl]-6-(N-( 1 - iminoethyl)amino)-2-(N-Z-amino)hexanamido]ethyl]-6-[N-(l-iminoethyl)amino]-2-[N-Z- amino] hexanamide is dissolved in ethanol/acetic acid and is combined with a hydrogenation catalyst such as palladium on carbon and hydrogen. This reaction is shaken under pressure for an extended period of time in a standard Parr hydrogenation apparatus to remove protecting groups, the catalyst is removed by filtration, and the solvent is removed generating the amino product N-[2-[N-[2-(6-(N-(2-fluoro-l-iminoethyl)amino)- 2-aminohexanamido) ethyl]-6-(N-(l-iminoethyl)amino)-2-aminohexanamido]ethyl]-N-[2- [N-[2-(3-(2-(N-( 1 -iminoethyl)amino)ethylthio)-2-aminopropanamido)ethyl]-6-(N-( 1 - iminoethyl)amino)-2-aminohexanamido]ethyl]-6-[N-(l-iminoethyl)amino]-2- aminohexan amide.
Biological Data
The subject compounds of Formula I are expected to be found to inhibit nitric oxide synthase and posses useful pharmacological properties as demonstrated in one or more of the following assays:
Citrulline Assay for Nitric Oxide Synthase
NOS activity can be measured by monitoring the conversion of L-[2,3- H]- arginine to L-[2,3--5H]-citrulline. Mouse inducible NOS (miNOS) can be prepared from an extract of LPS-treated mouse RAW 264.7 cells and rat brain constitutive NOS (rnNOS) can be prepared from an extract of rat cerebellum. Both preparations can be partially purified by DEAE-Sepharose chromatography. Enzyme (10 μL) can be added to 40 μL of 50 mM Tris (pH 7.6) and the reaction initiated by the addition of 50 μL of a solution containing 50 mM Tris (pH 7.6), 2.0 mg/mL bovine serum albumin, 2.0 mM DTT, 4.0 mM CaCl2, 20 μM FAD, 100 μM tetrahydrobiopterin, 2.0 mM NADPH and 60 μM L-
arginine containing 0.9 μCi of L-[2,3- H]-arginine. For constitutive NOS, calmodulin is included at a final concentration of 40 nM. Following incubation at 37°C for 15 minutes, the reaction can be terminated by addition of 300 μL cold buffer containing 10 mM
EGTA, 100 mM HEPES (pH 5.5) and 1.0 mM L-citrulline. The [3H]-citrulline can be separated by chromatography on Dowex 50W X-8 cation exchange resin and radioactivity quantified with a liquid scintillation counter.
Raw Cell Nitrite Assay
RAW 264.7 cells can be plated to confluency on a 96-well tissue culture plate grown overnight (17 h) in the presence of LPS to induce NOS. A row of 3-6 wells can be left untreated and served as controls for subtraction of nonspecific background. The media can be removed from each well and the cells washed twice with Kreb-Ringers- Hepes (25mM, pH 7.4) with 2 mg/ml glucose. The cells are then placed on ice and incubated with 50mL of buffer containing L-arginine (30mM) +/- inhibitors for 1 h. The assay can be initiated by warming the plate to 37°C in a water bath for 1 h. Production of nitrite by intracellular iNOS will be linear with time. To terminate the cellular assay, the plate of cells can be placed on ice and the nitrite-containing buffer removed and analyzed for nitrite using a previously published fluorescent determination for nitrite. T. P. Misko et al. Analytical Biochemistry. 214. 11-16 (1993).
In Vivo Assay
Rats can be treated with an intraperitoneal injection of lOmg/kg of endotoxin (LPS) with or without oral administration of the nitric oxide synthase inhibitors. Plasma nitrites can be measured 5 hours post-treatment. The results can be used to show that the administration of the nitric oxide synthase inhibitor decreases the rise in plasma nitrites, a reliable indicator of the production of nitric oxide induced by endotoxin. From the foregoing description, one skilled in the art can easily ascertain the essential characteristics of this invention, and without departing from the spirit and scope thereof, can make various changes and modifications of the invention to adapt it to various usages and conditions.

Claims

We Claim:
1. A compound having the Formula I:
[ Id B [ χb ] g
: ιc ] h
(I)
or a pharmaceutically acceptable salt thereof, wherein;
Ia, lb, Ic, and I,j are independently selected from a structure of Formula II:
Figure imgf000228_0001
(π)
wherein Formula (II) has a point of attachment for bonding to a linker B by replacement of a substituent group of Formula (II) independently selected from the group consisting of J ,
2 7
J , A-R , and a removable hydrogen from a substituent independently selected from the
1 2 3 4 7 8 group consisting of R , R , R , R , R and R ;
1 2 23 23
J and J are independently selected from the group consisting of OR , SR ,
24 24 25 26
NHR and N(R )R with the proviso that A is R ; 1 2
J and J can be taken together forming a group selected from the group consisting
28 28 28 28 24 28 24 26 of OR O, OR S, SR S, OR NR and SR NR with the proviso that A is R ;
1 2
J and J can be taken together forming J wherein J is connected to the carbon of
J1 and J2 by a covalent double bond and wherein J is independently selected from the
22 group consisting of O, NR and S with the proviso that A is selected from other than
26 R ;
G is independently selected from the group consisting of O, S, CH2, CHR ,
C(R15)2> NH, and NR15;
A is independently selected from the group consisting of O, N(R ), S and heterocyclyl;
A can be independently selected from the group consisting of O, N(R ) and S
1 2 connected to the point of attachment of any one of R and R by a spacer group selected from a linear moiety having a chain length of 1 to 6 atoms to form a heterocyclyl having from 5 to 10 members;
A can be independently selected from the group consisting of O, N(R ) and S
1 2 connected to the points of attachment of R and R by a spacer group selected from a linear moiety having a chain length of 1 to 6 to form a heterocyclyl having from 5 to 10 members;
A can be independently selected from the group consisting of O, N(R ) and S
3 connected to the point of attachment of R by a spacer group selected from a linear moiety having a chain length of 1 to 3 atoms to form a heterocyclyl having from 7 to 10 members; A can be independently selected from the group consisting of O, N(R ) and S
4 connected to the point of attachment of R by a spacer group selected from a linear moiety having a chain length of 1 to 4 atoms to form a heterocyclyl having from 6 to 10 members;
A can be independently selected from the group consisting of O, N(R ) and S connected to X by a substituent selected from hydroxyl, sulfhydryl, amino, carboxyl, and carbonyl substituents of group X by a spacer selected from the group consisting of a covalent bond and a linear moiety having a chain length of 1 to 4 atoms to form a heterocyclyl having from 5 to 10 members;
26 26
A can be R , wherein R is independently selected from the group consisting of hydrogen, formyl, hydroxyalkyl, alkenyl, alkynyl, acyl, aroyl, aralkanoyl, heteroaroyl, alkylsulfinylalkyl, alkylsulfonylalkyl, heteroaralkylthioalkyl, alkoxyalkyl, alkenyloxyalkyl, alkylthioalkyl, cycloalkylalkenyl, cycloalkenyl, haloalkyl, haloalkenyl, haloalkoxyalkyl, haloalkenyloxyalkyl, halocycloalkenyloxyalkyl, cyanoalkyl, carboxy, carboxamido, carboalkoxy, dicyanoalkyl, carboxamidoalkyl, dicarboxamidoalkyl, cyanocarboalkoxyalkyl, carboalkoxyalkyl, dicarboalkoxyalkyl, formylalkyl, and acylalkyl;
27 27
A can be R , wherein R is independently selected from the group consisting of
N(R5)OR7, N(R5)SR7, N(R5)N(R7)R25, N(R5)SO R13, N(R5)C(O)R15,
5 15 19 20 5 19 20
N(R )C(S)R , R (R )C=N-N(R ), R (R )C=N-O, natural amino acids, synthetic
amino acids, N(R5)P(O)(OR )ιR6 and N(R5)P(O)(QR13)2;
1 2 R and R are independently selected from the group consisting of hydrogen, hydroxyalkyl, aminoalkyl, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, haloalkyl,
13 haloalkenyl, cyanoalkyl, dicyanoalkyl, cyanocycloalkyl, dicyanocycloalkyl, S(O)R ,
SO R , C(O)R , CH2OC(O)R1 , hydroxyl, sulfhydryl, OR6, SR6, carboxamidoalkyl, dicarboxamidoalkyl, cyanocarboalkoxyalkyl, carboalkoxyalkyl, dicarboalkoxyalkyl, carboxamidocycloalkyl, dicarboxamidocycloalkyl, carboalkoxycyanocycloalkyl, carboalkoxycycloalkyl, dicarboalkoxycycloalkyl, formylalkyl, acylalkyl, CH2SO3 M ,
CH2CH2SO3" M+, CH PO3 "2 2M+, CH2CH2PO3"2 2M+, CH(OR6)CF3, P(O)R3°R31,
P(O)(R3°)2 R31, C(S)R15, CH2NR19C(O)R15, CH2NR19C(S)R15, CH2SC(O)R15,
CH SC(S)R15, CH2OC(O)GR15, CH2NR19C(O)GR15, CH2NR19C(S)GR15,
CH2OC(S)GR15, CH2SC(S)GR15, OSO2R13, OS(O)R13, OC(S)R15, SC(S)R15,
OC(S)GR15, SC(S)GR15, OC(O)R15, SC(O)R15, OC(O)GR15, SC(O)GR15, and
Figure imgf000231_0001
1 2 R and R can be taken together forming a group selected from the group
19 20 30 31 19 20 19 20 consisting of R (R )C=, D(C(R )(R ))ZD, and D((R )R C)eW(C(R )R ) D wherein z is 2 to 5, e is 1 to 2, k is 1 to 2, D is selected from the group consisting of
31 30 30 30 oxygen, C=O, C=S, S(O)m wherein m is 0 to 2, OP(OR )R , P(O)R , P(S)R and
19 20 Si(R )R and W is selected from the group consisting of oxygen, C=O, C=S, S(O)m,
30 30 19 19 20 S(O)m where m is 0 to 2, P(O)R , P(S)R , N(R ), and Si(R )R with the proviso that only one D can be oxygen or sulfur at any time;
1 2
R and R can be taken together forming a group selected from the group consisting of cycloalkyl radicals, cycloalkenyl radicals wherein said cycloalkyl radicals
30 31 and cycloalkenyl radicals may be optionally substituted with one or more R or R substituents, aryl radicals, heteroaryl radicals, saturated heterocyclic radicals and partially saturated heterocyclic radicals wherein said radicals are 1,2-disubstituted and said 1,2- 19 32 substitutents are independently selected from C=O, C=S, C(R )R , S(O), S(O)2,
31 30 30 30 19 20
OP(OR )R , P(O)R , P(S)R and Si(R )R ;
1 2
R and R can be taken together forming a group selected from the group consisting of cis- 1,2-disubstituted alkyls and cis- 1,2-disubstituted alkenyls wherein said
19 32 1,2-substitutents are independently selected from C=O, C=S, C(R )R , S(O), S(O)2,
31 30 30 30 19 20
OP(OR )R , P(O)R , P(S)R , and Si(R )R and said alkyl and alkenyl may be
30 31 optionally substituted with one or more R or R substituents;
3 4
R and R are independently selected from the group consisting of hydrogen,
hydroxyl, sulfhydryl, OR6, SR6, CH2SO3" M+, CH2CH2SO3" M+, CH2PO3 "2 2M+,
CH2CH2PO3" 2M , CH(OR )CF3, S(O)R , SO2R , P(O)R R , P(O)(R tøR ,
C(O)R15, C(S)R15, CH2OC(O)R15, CH2NR19C(O)R15, CH2NR19C(S)R15,
CH2SC(O)R15, CH2SC(S)R15, CH2OC(O)GR15, CH NR19C(O)GR15,
CH2NR19C(S)GR15, CH2OC(S)GR15, CH2SC(S)GR15, OSO2R13, OS(O)R13,
OC(S)R15, SC(S)R15, OC(S)GR15, SC(S)GR15, OC(O)R15, SC(O)R15, OC(O)GR15
and SC(O)GR15;
3 4
R and R can be taken together to form the group L-U-V wherein L is not identical to V, and L, U, and V are independently selected from the group consisting of O,
23 23 24
S, C(O), C(S), C(JH)2 wherein JH is independently selected from OR , SR , NHR ,
24 25 29 31 30 30 30 30 31 and N(R )R , CR , S(O), SO2, OP(OR )R , P(O)R , P(S)R , C(R )R ,
30 31 30 30 19 20 19 20 19 20 C=C(R )R , (O)2POP(O)2, R (O)POP(O)R , Si(R )R , Si(R )R Si(R )R , 19 20 19 20 19 20 19 20 19 20 19 20
Si(R )R OSi(R V , (R )R COC(R )R . (R )R CSC(R .
30 31 30 31 30 31 30 31
C(O)C(R )=C(R ), C(S)C(R )=C(R ), S(O)C(R )=C(R ), SO2C(R )=C(R ),
30 30 31 30 30 31 30 30 31
PR C(R )=C(R ), P(O)R C(R )=C(R ), P(S)R C(R )=C(R ),
30 31 DC(R )(R )D wherein D is selected from the group consisting of oxygen, C=O, C=S,
31 30 30 30 19 20 30 S(O)m wherein m is 0 to 2, OP(OR )R , P(O)R , P(S)R , Si(R )R and N(R ), and a covalent bond with the proviso that no more than any two of L, U and V are simultaneously covalent bonds and the heterocycle comprised of by L, U, and V is greater than a 4-membered ring;
3 4
R and R can be taken together to form the group L-U-V wherein L is not identical to V, and L, U, and V are independently selected from the group consisting of cycloalkyl radical, cycloalkenyl radical wherein said cycloalkyl radical and cycloalkenyl
30 31 radical may be optionally substituted with one or more R and R substituents, aryl radical, heteroaryl radical, saturated heterocyclic radical and partially saturated heterocyclic radical wherein said radicals are 1,2-disubstituted and said 1,2-substitutents
19 32 31 30 are independently selected from C=O, C=S, C(R )R , S(O), S(O)2, OP(OR )R ,
30 30 19 20
P(O)R , P(S)R and Si(R )R ;
3 4
R and R can be taken together to form the group L-U-V wherein L, U, and V are independently selected from the group consisting of cis- 1,2-disubstituted alkanyl and cis-
1 ,2-disubstituted alkenyl radicals wherein said 1,2-substitutents are independently selected
19 32 31 30 30 30 from C=O, C=S, C(R )R , S(O), S(O)2, OP(OR )R , P(O)R , P(S)R , and
19 20 Si(R )R and said alkanes and alkenes may be optionally substituted with one or more
«30 „31 , .
R or R substituents; R is independently selected from the group consisting of hydrogen, aryl, heteroaralkyl, hydroxy, alkyl, alkenyl, alkynyl, amino, cyanoalkyl, dicyanoalkyl, carboxamidoalkyl, hydroxyalkyl, dicarboxamidoalkyl, cyanocarboalkoxyalkyl, carboalkoxyalkyl, dicarboalkoxyalkyl, cyanocycloalkyl, dicyanocycloalkyl, carboxamidocycloalkyl, dicarboxamidocycloalkyl, carboalkoxycyanocycloalkyl,
13 carboalkoxycycloalkyl, dicarboalkoxycycloalkyl, formylalkyl, acylalkyl, S(O)R ,
13 30 31 30 31 15 15 15
SO2R , P(O)R R , P(O)(R )2R , C(O)R , C(S)R , CH2OC(O)R ,
CH2NR19C(O)R15, CH2NR19C(S)R15, CH2SC(O)R15, CH2SC(S)R15,
CH2OC(O)GR15, CH2NR19C(O)GR15, CH2NR19C(S)GR15, CH2OC(S)GR15,
15 CH2SC(S)GR , heteroaryloxyalkyl, aralkyl, aryloxyalkyl, aralkoxyalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl, aralkylthioalkyl, heteroaralkoxythioalkyl, alkoxyalkyl, heteroaryloxyalkyl, alkenyloxyalkyl, alkylthioalkyl, arylthioalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkenyl, cycloalkenylalkyl, haloalkyl, haloalkenyl, halocycloalkyl, aralkylsulfinylalkyl, aralkylsulfonylalkyl, carboxyalkyl, carboalkoxyalkyl, dialkoxyphosphonoalkyl, diaralkoxyphosphonoalkyl, phosphonoalkyl, dialkoxyphosphonoalkylamino, diaralkoxyphosphonoalkylamino, phosphonoalkylamino, dialkoxyphosphonoalkyl, diaralkoxyphosphonoalkyl, sulfonylalkyl, alkoxysulfonylalkyl, aralkoxysulfonylalkyl, alkoxysulfonylalkylamino, aralkoxysulfonylalkylamino and sulfonylalkylamino;
5 1 2 R , R and R can be taken together to form a spacer group consisting of a linear moiety having a chain length of 1 to 4 atoms to form a heterocyclyl having from 5 through 8 members;
5 R can be selected from a heterocyclyl radical in which there is at least one carbon in one ring and in which 1 to about 4 members of said ring are heteroatoms independently selected from oxygen, nitrogen and sulfur and said heterocyclyl radical may be optionally substituted with heteroarylamino, N-aryl-N-alkylamino, N-heteroarylamino-N-alkylamino, haloalkylthio, alkanoyloxy, alkoxy, heteroaralkoxy, cycloalkoxy, cycloalkenyloxy, hydroxy, amino, thio, nitro, lower alkylamino, alkylthio, alkylthioalkyl, arylamino, aralkylamino, arylthio, alkylsulfinyl, alkylsulfonyl, alkylsulfonamido, alkylaminosulfonyl, amidosulfonyl, monoalkyl amidosulfonyl, dialkyl amidosulfonyl, monoarylamidosulfonyl, arylsulfonamido, diarylamidosulfonyl, monoalkyl monoaryl amidosulfonyl, arylsulfinyl, arylsulfonyl, heteroarylthio, heteroarylsulfinyl, heteroarylsulfonyl, alkanoyl, alkenoyl, aroyl, heteroaroyl, aralkanoyl, heteroaralkanoyl, haloalkanoyl, alkyl, alkenyl, alkynyl, alkylenedioxy, haloalkylenedioxy, cycloalkyl, cycloalkenyl, lower cycloalkylalkyl, lower cycloalkenylalkyl, halo, haloalkyl, haloalkoxy, hydroxyhaloalkyl, hydroxyaralkyl, hydroxyalkyl, hydoxyheteroaralkyl, haloalkoxyalkyl, aryl, aralkyl, aryloxy, aralkoxy, aryloxyalkyl, saturated heterocyclyl, partially saturated heterocyclyl, heteroaryl, heteroaryloxy, heteroaryloxyalkyl, arylalkyl, heteroarylalkyl, arylalkenyl, heteroarylalkenyl, cyanoalkyl, dicyanoalkyl, carboxamidoalkyl, dicarboxamidoalkyl, cyanocarboalkoxyalkyl, carboalkoxyalkyl, dicarboalkoxyalkyl, cyanocycloalkyl, dicyanocycloalkyl, carboxamidocycloalkyl, dicarboxamidocycloalkyl, carboalkoxycyanocycloalkyl, carboalkoxycycloalkyl, dicarboalkoxycycloalkyl, formylalkyl, acylalkyl, dialkoxyphosphonoalkyl, diaralkoxyphosphonoalkyl, phosphonoalkyl, dialkoxyphosphonoalkoxy, diaralkoxyphosphonoalkoxy, phosphonoalkoxy, dialkoxyphosphonoalkylamino, diaralkoxyphosphonoalkylamino, phosphonoalkylamino, dialkoxyphosphonoalkyl, diaralkoxyphosphonoalkyl, guanidino, amidino, and acylamino;
6
R is independently selected from the group consisting of hydroxyalkyl, aminoalkyl, heteroaryloxyalkyl, alkyl, alkenyl, alkynyl, aryl, aralkyl, aryloxyalkyl, aralkoxyalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl, aralkylthioalkyl, heteroaralkoxythioalkyl, alkoxyalkyl, heteroaryloxyalkyl, alkenyloxyalkyl, alkylthioalkyl, arylthioalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkenyl, cycloalkenylalkyl, haloalkyl, haloalkenyl, halocycaralkylsulfinylalkyl, aralkylsulfonylalkyl, cyanoalkyl, dicyanoalkyl, carboxamidoalkyl, dicarboxamidoalkyl, cyanocarboalkoxyalkyl, carboalkoxyalkyl, dicarboalkoxyalkyl, cyanocycloalkyl, dicyanocycloalkyl, carboxamidocycloalkyl, dicarboxamidocycloalkyl, carboalkoxycyanocycloalkyl, carboalkoxycycloalkyl, dicarboalkoxycycloalkyl, formylalkyl, acylalkyl, dialkoxyphosphonoalkyl, diaralkoxyphosphonoalkyl, phosphonoalkyl, dialkoxyphosphonoalkylamino, diaralkoxyphosphonoalkylamino, phosphonoalkylamino, dialkoxyphosphonoalkyl, diaralkoxyphosphonoalkyl, sulfonylalkyl, alkoxysulfonylalkyl, aralkoxysulfonylalkyl, alkoxysulfonylalkylamino, aralkoxysulfonylalkylamino, sulfonylalkylamino, a natural amino acid, synthetic amino acid, and a polyhydroxy compound of carbon;
7 R is selected from the group consisting of hydrogen, aryl, heteroaralkyl, hydroxy, alkyl, alkenyl, alkynyl, amino, cyanoalkyl, dicyanoalkyl, carboxamidoalkyl, hydroxyalkyl, dicarboxamidoalkyl, cyanocarboalkoxyalkyl, carboalkoxyalkyl, dicarboalkoxyalkyl, cyanocycloalkyl, dicyanocycloalkyl, carboxamidocycloalkyl, dicarboxamidocycloalkyl, carboalkoxycyanocycloalkyl, carboalkoxycycloalkyl, dicarboalkoxycycloalkyl,
13 13 30 31 30 31 15 formylalkyl, acylalkyl, S(O)R , SO2R , P(O)R R , P(O)(R )2R , C(O)R ,
C(S)R15, CH2OC(O)R15, CH2NR19C(O)R15, CH2NR19C(S)R15, CH2SC(O)R15,
CH2SC(S)R15, CH2OC(O)GR15, CH2NR19C(O)GR15, CH2NR19C(S)GR15,
15 15
CH2OC(S)GR , CH2SC(S)GR , heteroaryloxyalkyl, aralkyl, aryloxyalkyl, aralkoxyalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl, aralkylthioalkyl, heteroaralkoxythioalkyl, alkoxyalkyl, heteroaryloxyalkyl, alkenyloxyalkyl, alkylthioalkyl, arylthioalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkenyl, cycloalkenylalkyl, haloalkyl, haloalkenyl, halocycloalkyl, aralkylsulfinylalkyl, aralkylsulfonylalkyl, carboxyalkyl, carboalkoxyalkyl, dialkoxyphosphonoalkyl, diaralkoxyphosphonoalkyl, phosphonoalkyl, dialkoxyphosphonoalkylamino, diaralkoxyphosphonoalkylamino, phosphonoalkylamino, dialkoxyphosphonoalkyl, diaralkoxyphosphonoalkyl, sulfonylalkyl, alkoxysulfonylalkyl, aralkoxysulfonylalkyl, alkoxysulfonylalkylamino, aralkoxysulfonylalkylamino and sulfonylalkylamino; 7 1 2
R , R and R can be taken together to form a spacer group selected from a linear moiety having a chain length of 1 to 4 atoms to form a heterocyclyl having from 5 to 8 members;
7 R can be selected from a heterocyclyl radical in which there is at least one carbon in one ring and in which 1 to about 4 members of said ring are heteroatoms independently selected from oxygen, nitrogen and sulfur and said heterocyclyl radical may be optionally substituted with heteroarylamino, N-aryl-N-alkylamino, N-heteroarylamino-N-alkylamino, haloalkylthio, alkanoyloxy, alkoxy, heteroaralkoxy, cycloalkoxy, cycloalkenyloxy, hydroxy, amino, thio, nitro, lower alkylamino, alkylthio, alkylthioalkyl, arylamino, aralkylamino, arylthio, alkylsulfmyl, alkylsulfonyl, alkylsulfonamido, alkylaminosulfonyl, amidosulfonyl, monoalkyl amidosulfonyl, dialkyl amidosulfonyl, monoarylamidosulfonyl, arylsulfonamido, diarylamidosulfonyl, monoalkyl monoaryl amidosulfonyl, arylsulfinyl, arylsulfonyl, heteroarylthio, heteroarylsulfinyl, heteroarylsulfonyl, alkanoyl, alkenoyl, aroyl, heteroaroyl, aralkanoyl, heteroaralkanoyl, haloalkanoyl, alkyl, alkenyl, alkynyl, alkylenedioxy, haloalkylenedioxy, cycloalkyl, cycloalkenyl, lower cycloalkylalkyl, lower cycloalkenylalkyl, halo, haloalkyl, haloalkoxy, hydroxyhaloalkyl, hydroxyaralkyl, hydroxyalkyl, hydoxyheteroaralkyl, haloalkoxyalkyl, aryl, aralkyl, aryloxy, aralkoxy, aryloxyalkyl, saturated heterocyclyl, partially saturated heterocyclyl, heteroaryl, heteroaryloxy, heteroaryloxyalkyl, arylalkyl, heteroarylalkyl, arylalkenyl, heteroarylalkenyl, cyanoalkyl, dicyanoalkyl, carboxamidoalkyl, dicarboxamidoalkyl, cyanocarboalkoxyalkyl, carboalkoxyalkyl, dicarboalkoxyalkyl, cyanocycloalkyl, dicyanocycloalkyl, carboxamidocycloalkyl, dicarboxamidocycloalkyl, carboalkoxycyanocycloalkyl, carboalkoxycycloalkyl, dicarboalkoxycycloalkyl, formylalkyl, acylalkyl, dialkoxyphosphonoalkyl, diaralkoxyphosphonoalkyl, phosphonoalkyl, dialkoxyphosphonoalkoxy, diaralkoxyphosphonoalkoxy, phosphonoalkoxy, dialkoxyphosphonoalkylamino, diaralkoxyphosphonoalkylamino, phosphonoalkylamino, dialkoxyphosphonoalkyl, diaralkoxyphosphonoalkyl, guanidino, amidino, and acylamino; R is selected from hydrogen, hydroxyalkyl, haloalkyl, alkyl, alkoxyalkyl, aminoalkyl, alkylaminoalkyl, alkylthioalkyl, cyanoalkyl, sulfhydrylalkyl, formyl, C(O)A- R7, C(S)A-R7, CH2OC(O)A-R7, CH2NR19C(O)A-R7, CH2NR19C(S)A-R7,
CH2SC(O)A-R7, CH2SC(S)A-R7, CH2OC(O)GR15, CH2NR19C(O)GR15,
CH2NR19C(S)GR15, CH2OC(S)GR15, CH2SC(S)GR15 and acyl;
g R may be taken together with X to form a carbocyclic or a heterocyclic ring having from 3 to 8 members;
13 R is independently selected from aryloxy, amino, alkylamino, dialkylamino, hydroxyalkyl, heteroaryloxyalkyl, alkoxy, alkylthio, arylthio, alkyl, alkenyl, alkynyl, aryl, aralkyl, aryloxyalkyl, aralkoxyalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl, aralkylthioalkyl, heteroaralkoxythioalkyl, alkoxyalkyl, heteroaryloxyalkyl, alkenyloxyalkyl, alkylthioalkyl, arylthioalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkenyl, cycloalkenylalkyl, haloalkyl, haloalkenyl, haloaralkylsulfinylalkyl, aralkylsulfonylalkyl, cyanoalkyl, dicyanoalkyl, carboxamidoalkyl, dicarboxamidoalkyl, cyanocarboalkoxyalkyl, carboalkoxyalkyl, dicarboalkoxyalkyl, cyanocycloalkyl, dicyanocycloalkyl, carboxamidocycloalkyl, dicarboxamidocycloalkyl, carboalkoxycyanocycloalkyl, carboalkoxycycloalkyl, dicarboalkoxycycloalkyl, formylalkyl, acylalkyl, dialkoxyphosphonoalkyl, diaralkoxyphosphonoalkyl, phosphonoalkyl, dialkoxyphosphonoalkoxy, diaralkoxyphosphonoalkoxy, phosphonoalkoxy, dialkoxyphosphonoalkylamino, diaralkoxyphosphonoalkylamino, phosphonoalkylamino, dialkoxyphosphonoalkyl, diaralkoxyphosphonoalkyl, sulfonylalkyl, alkoxysulfonylalkyl, aralkoxysulfonylalkyl, alkoxysulfonylalkoxy, aralkoxysulfonylalkoxy, sulfonylalkoxy, alkoxysulfonylalkylamino, aralkoxysulfonylalkylamino, sulfonylalkylamino, a natural amino acid, synthetic amino acid, and a polyhydroxy compound of carbon; R is independently selected from hydrido, aryloxy, amino, alkylamino, dialkylamino, hydroxyalkyl, heteroaryloxyalkyl, alkoxy, alkylthio, arylthio, alkyl, alkenyl, alkynyl, aryl, aralkyl, aryloxyalkyl, aralkoxyalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl, aralkylthioalkyl, heteroaralkoxythioalkyl, alkoxyalkyl, heteroaryloxyalkyl, alkenyloxyalkyl, alkylthioalkyl, arylthioalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkenyl, cycloalkenylalkyl, haloalkyl, haloalkenyl, haloaralkylsulfinylalkyl, aralkylsulfonylalkyl, carboxy, cyanoalkyl, dicyanoalkyl, carboxamidoalkyl, dicarboxamidoalkyl, cyanocarboalkoxyalkyl, carboalkoxyalkyl, dicarboalkoxyalkyl, cyanocycloalkyl, dicyanocycloalkyl, carboxamidocycloalkyl, dicarboxamidocycloalkyl, carboalkoxycyanocycloalkyl, carboalkoxycycloalkyl, dicarboalkoxycycloalkyl, formylalkyl, acylalkyl, dialkoxyphosphonoalkyl, diaralkoxyphosphonoalkyl, phosphonoalkyl, dialkoxyphosphonoalkoxy, diaralkoxyphosphonoalkoxy, phosphonoalkoxy, dialkoxyphosphonoalkylamino, diaralkoxyphosphonoalkylamino, phosphonoalkylamino, dialkoxyphosphonoalkyl, diaralkoxyphosphonoalkyl, sulfonylalkyl, alkoxysulfonylalkyl, aralkoxysulfonylalkyl, alkoxysulfonylalkoxy, aralkoxysulfonylalkoxy, sulfonylalkoxy, alkoxysulfonylalkylamino, aralkoxysulfonylalkylamino, sulfonylalkylamino, a natural amino acid, a synthetic amino acid, and a polyhydroxy compound of carbon;
M is a pharmaceutically acceptable cation;
X is selected from the group consisting of alkylene, alkenylene, alkynylene, -
(CH2)pQ(CH2)r- wherein p is 1 to 3, r is 1 to 3 and Q is selected from oxygen, C=O,
N(R12)SO2, SO2N(R12), S(O)t, Se(O)t wherein t is O to 2, P(O)R21, -(CH2)ST(CH )V- wherein s is O to 2, v is 0 to 2 and T is selected from 3 to 6 membered carbocyclic
12 radicals, aryl radicals and heterocyclyl radicals, and N(R ) wherein n is 1 to 2, wherein all positions on X may be optionally substituted with one or more selected from the group consisting of halogen, C I -CJO alkyl, Cj-Cio alkoxy, hydroxy, haloalkyl, nitro, cyano, and amino; 12 R is selected from hydrogen, hydroxyl, alkyl, hydroxyalkyl, aminoalkyl, alkylaminoalkyl, alkoxyalkyl, haloalkyl, aryl, aralkyl, cycloalkylalkyl, and heterocyclylalkyl ;
21 R is selected from hydroxyl and alkyl;
Y is selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxyalkyl, cycloalkyl, cycloalkenyl, cycloalkenyloxy, alkenyloxyalkyl, alkylthioalkyl,
9 10 9 10 alkylaminoalkyl and NR R wherein R and R are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, nitro, amino, hydroxy, alkoxy, aryl, heterocyclyl, and aralkyl;
9 10 R and R can be taken together to form a spacer group selected from a linear moiety having a chain length of 2 to 7 atoms to form a heterocyclyl having from 3 through 8 members;
19 20
R and R are independently selected from the group consisting of hydrogen, hydroxyalkyl, alkyl, alkenyl, alkynyl, aryl, aralkyl, aryloxyalkyl, acyl, aroyl, aralkanoyl, heteroaroyl, aralkoxyalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl, aralkylthioalkyl, heteroaralkylthioalkyl, alkoxyalkyl, heteroaryloxyalkyl, alkenyloxyalkyl, alkylthioalkyl, arylthioalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkenyl, cycloalkenylalkyl, haloalkyl, haloalkenyl, halocycloalkyl, halocycloalkenyl, haloalkoxyalkyl, haloalkenyloxyalkyl, halocycloalkoxy, halocycloalkoxyalkyl, halocycloalkenyloxyalkyl, perhaloaryl, perhaloaralkyl,' perhaloaryloxyalkyl, heteroaryl, heteroarylalkyl, heteroarylthioalkyl, heteroaralkylthioalkyl, cyanoalkyl, dicyanoalkyl, carboxamidoalkyl, dicarboxamidoalkyl, cyanocarboalkoxyalkyl, carboalkoxyalkyl, dicarboalkoxyalkyl, cyanocycloalkyl, dicyanocycloalkyl, carboxamidocycloalkyl, dicarboxamidocycloalkyl, carboalkoxycyanocycloalkyl, carboalkoxycycloalkyl, dicarboalkoxycycloalkyl, formylalkyl, acylalkyl, arylsulfinylalkyl, arylsulfonylalkyl, aralkylsulfinyl, cycloalkylsulfinylalkyl, cycloalkylsufonylalkyl, heteroarylsulfonylalkyl, heteroarylsulfinylalkyl, aralkylsulfinylalkyl, aralkylsulfonylalkyl, carboxy, dialkoxyphosphono, diaralkoxyphosphono, dialkoxyphosphonoalkyl and diaralkoxyphosphonoalkyl ;
19 20
R and R can be taken together to form a linear moiety spacer group having a chain length of 2 to 7 atoms and selected from the group consisting of a cycloalkyl having from 3 through 8 members, a cycloalkenyl having from 3 through 8 members, and a heterocyclyl having from 3 through 8 members;
22 23
R and R are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aralkyl, aryloxyalkyl, aralkoxyalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl, aralkylthioalkyl, heteroaralkylthioalkyl, alkoxyalkyl, heteroaryloxyalkyl, alkenyloxyalkyl, alkylthioalkyl, arylthioalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkenyl, cycloalkenylalkyl, haloalkyl, haloalkenyl, halocycloalkyl, halocycloalkenyl, haloalkoxyalkyl, haloalkenyloxyalkyl, halocycloalkoxyalkyl, halocycloalkenyloxyalkyl, perhaloaryloxyalkyl, heteroaryl, heteroarylalkyl, heteroarylthioalkyl, heteroaralkylthioalkyl, arylsulfinylalkyl, arylsulfonylalkyl, cycloalkylsulfinylalkyl, cycloalkylsufonylalkyl, heteroarylsulfonylalkyl, heteroarylsulfinylalkyl, aralkylsulfinylalkyl and aralkylsulfonylalkyl;
24 25
R and R are independently selected from the group consisting of hydrogen, hydroxyalkyl, alkyl, alkenyl, alkynyl, aryl, aralkyl, aryloxyalkyl, aralkoxyalkyl, alkoxy, alkylsulfinylalkyl, alkylsulfonylalkyl, aralkylthioalkyl, heteroaralkylthioalkyl, alkoxyalkyl, heteroaryloxyalkyl, alkenyloxyalkyl, alkylthioalkyl, arylthioalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkenyl, cycloalkenylalkyl, haloalkyl, haloalkenyl, halocycloalkyl, halocycloalkenyl, haloalkoxyalkyl, haloalkenyloxyalkyl, cycloalkoxy, halocycloalkoxyalkyl, halocycloalkenyloxyalkyl, perhaloaryl, perhaloaralkyl, perhaloaryloxyalkyl, heteroaryl, heteroarylalkyl, heteroarylthioalkyl, heteroaralkylthioalkyl, arylsulfinylalkyl, arylsulfonylalkyl, cycloalkylsulfinylalkyl, cycloalkylsufonylalkyl, heteroarylsulfonylalkyl, heteroarylsulfinylalkyl, aralkylsulfinylalkyl and aralkylsulfonylalkyl; 24 25
R and R can be taken to form a linear moiety spacer group having a chain length of 4 to 7 atoms to form a heterocyclyl having from 5 through 8 members;
R is independently selected from hydrogen, formyl, hydroxyalkyl, alkenyl, alkynyl, acyl, aroyl, aralkanoyl, heteroaroyl, alkylsulfinylalkyl, alkylsulfonylalkyl, heteroaralkylthioalkyl, alkoxyalkyl, alkenyloxyalkyl, alkylthioalkyl, cycloalkylalkenyl, cycloalkenyl, haloalkyl, haloalkenyl, haloalkoxyalkyl, haloalkenyloxyalkyl, halocycloalkenyloxyalkyl, cyanoalkyl, carboxy, carboxamido, carboalkoxy, dicyanoalkyl, carboxamidoalkyl, dicarboxamidoalkyl, cyanocarboalkoxyalkyl, carboalkoxyalkyl, dicarboalkoxyalkyl, formylalkyl and acylalkyl;
28 23 R is independently selected from a group consisting of CH(R )CH2,
23 23
CH(R )CH2CH2, CH2CH(R )CH2, cycloalkylene, and heterocyclylene;
30 31
R and R are independently selected from hydroxy, thiol, aryloxy, amino, alkylamino, dialkylamino, hydroxyalkyl, heteroaryloxyalkyl, alkoxy, alkylthio, arylthio, alkyl, alkenyl, alkynyl, aryl, aralkyl, aryloxyalkyl, aralkoxyalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl, aralkylthioalkyl, heteroaralkoxythioalkyl, alkoxyalkyl, heteroaryloxyalkyl, alkenyloxyalkyl, alkylthioalkyl, arylthioalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkenyl, cycloalkenylalkyl, haloalkyl, haloalkenyl, haloaralkylsulfinylalkyl, aralkylsulfonylalkyl, cyanoalkyl, dicyanoalkyl, carboxamidoalkyl, dicarboxamidoalkyl, cyanocarboalkoxyalkyl, carboalkoxyalkyl, dicarboalkoxyalkyl, cyanocycloalkyl, dicyanocycloalkyl, carboxamidocycloalkyl, dicarboxamidocycloalkyl, carboalkoxycyanocycloalkyl, carboalkoxycycloalkyl, dicarboalkoxycycloalkyl, formylalkyl, acylalkyl, dialkoxyphosphonoalkyl, diaralkoxyphosphonoalkyl, phosphonoalkyl, dialkoxyphosphonoalkoxy, diaralkoxyphosphonoalkoxy, phosphonoalkoxy, dialkoxyphosphonoalkylamino, diaralkoxyphosphonoalkylamino, phosphonoalkylamino, dialkoxyphosphonoalkyl, diaralkoxyphosphonoalkyl, sulfonylalkyl, alkoxysulfonylalkyl, aralkoxysulfonylalkyl, alkoxysulfonylalkoxy, aralkoxysulfonylalkoxy, sulfonylalkoxy, alkoxysulfonylalkylamino, acid, and polyhydroxy compound of carbon;
30 31
R and R can be taken to form a linear moiety spacer group having a chain length of 2 to 7 atoms to form a group selected from the group consisting of a cycloalkyl having from 3 through 8 members, a cycloalkenyl having from 3 through 8 members, and a heterocyclyl having from 3 through 8 members;
B is a linker selected from the group consisting of B\, B2, B3, B4, B5, Bg, B7, Bg,
B9, Bio. Bl 1. Bι2, B13, B14, and B15 wherein f, g, h, and i are integers independently selected from the group consisting of 0, 1, 2, 3, 4, and 5 representing the number of attachments to B, with the proviso that the sum of f, g, h, and i must be at least two;
B 1 is a linker connecting a first group independently selected from the group
consisting of Ia, lb, Ic, and 1^ through the point of bonding of a removable hydrogen of a
7 group selected independently from the group consisting of A and R to a second group
independently selected from the group consisting of Ia, lb, Ic, and
Figure imgf000243_0001
through the point of bonding of a removable hydrogen of a group selected independently from the group
7 consisting of A and R wherein said linker is selected from the group consisting of a
' covalent single bond with the proviso that only one A is simultaneously O and S,
CR1 W R1 V°)jC R1 V° CRY VV R7R20 (CR1 Y°)UQQ(C
19 20 7 20 7 20 19 20 19 20
Rl )w, (CR R )UQQ(CR R )w, (CH2)χT(CH2)y, (CR R )XT(CR R )y and
7 20 7 20 (CR R )XT(CR R )y wherein j is selected from an integer of 0 to 18, x and y are selected from an integer of 0 to 8, and u and w are selected from an integer of 1 to 8;
B2 is a linker connecting a first group independently selected from the group
7 consisting of Ia, lb, Ic, and Ij from the point of attachment of A-R to a second group independently selected from the group consisting of Ia, lb, Ic, and j from the point of
7 attachment of A-R wherein said
19 20 19 20 19 20 linker is selected from the group consisting of Hiink-CR R (CR R );CR R -Hijnk
, Hlink-CR7R20(CR7R20)jCR7R2°-Hlink, Hlink-(CH2)UQQ(CH2)W-Hiink, Hlink-
19 20 19 20 7 20 7 20 (CR R )UQQ(C R R )W-Hlink, Hlink-(CR R )UQQ(CR R )W-Hlink, Hlink-
(CH2)xT(CH2)y-Hlink, Hlink-(CR19R20)xT(CR19R20)y-Hlink, and Hlink-
7 20 7 20
(CR R )XT(CR R )y-Hijn wherein j is selected from an integer of 0 to 18, u and w are independently selected from an integer of 1 to 8, and x and y are independently selected from an integer of 0 to 8 with the proviso that only one Hijnk can be simultaneously a covalent single bond;
B2 can be a linker selected from the group consisting of natural amino acids and synthetic amino acids wherein said amino acids have two or more acylateable functional groups selected from the group consisting of primary amino, secondary amino, thiol, and hydroxy;
B3 is a linker connecting groups independently selected from the group consisting
7 of Ia, lb, Ic, and Ij from the point of attachment of A-R of said Ia, lb, Ic, and Ij groups wherein the number of groups attached to said linker from the point of attachment of A-
7 R is kk wherein kk is an integer selected from 2 to 20 wherein said integer represents the number of acylateable functions present on said linker with a range of from two to the maximum number of acylateable functions present on said linker with the proviso that no more than 5 each of Ia, lb, Ic, and
Figure imgf000244_0001
are simultaneously present on said linker and wherein said linker is selected from the group consisting of polyhydroxy compound of carbon selected from the group consisting of polyhydroxyalkanes, saccharides, disaccharides, polysaccharides, inositols, alditols, alditol acetals, alditol ketals, aldaric acids, aldonic acids, aldonic acid lactones, and hydroxyalkylamines having 2 to 20 acylateable hydroxy groups;
B3 can be a linker selected from the group consisting of polyamino compounds of carbon selected from the group consisting of diaminoalkanes, diaminocycloalkanes, diaminoaryls, diaminoheterocycyls, diaminoalkylamines, triaminoalkylamines, diaminoalkylaminoalkylamines, and triaminoalkylaminoalkylamines, wherein said polyamino compounds have two to twenty acylateable amino groups, and compounds of carbon having one to nineteen hydroxy functions, one to nineteen amino functions and zero to eighteen thiol functions;
B4 is a linker connecting a first group independently selected from the group
consisting of Ia, lb, Ic, and Ij through the point of bonding of a removable hydrogen of a
1 3 4 substituent independently selected from a group of substituents consisting of R , R , R
and R wherein R , R and R are independently selected from the group consisting of g hydrogen, hydroxy, and sulfhydryl and R is selected from the group consisting of hydroxyalkyl, aminoalkyl, alkylaminoalkyl and sulfhydrylalkyl to a second group independently selected from the group consisting of Ia, lb, Ic, and
Figure imgf000245_0001
through the point of bonding of a removable hydrogen of a substituent independently selected from a group of
• • , 1 r.3 4 8 , . 1 3 4 . , , , substituents consisting of R , R , R and R wherein R , R and R are independently
8 selected from the group consisting of hydrogen, hydroxy, and sulfhydryl and R is selected from the group consisting of hydroxyalkyl, aminoalkyl, alkylaminoalkyl and sulfhydrylalkyl wherein said linker is selected from the group consisting of C=O,
24 25 30 30
C(O)C(O), C=S, S=O, SO2, Si(R )(R ), P(O)R , P(S)R , (O)2POP(O)2,
R30(O)POP(O)R30 Si(R19)R2°Si(R19)R20 Sι(R19)R2°OSi(R19)R20; B4 can be a linker selected from the group consisting of Ajjnk-
1 20 19 20 19 20 7 20 7 20 7 70
CR R (CR R )jCR R -Alink, Alink-CR R (CR R )JCR 'R -Alink, Alink-
19 20 19 20 7 20 7 20
(CR R )UQQ(C R R )w-Alink, Alink-(CR R )UQQ(CR R )W-Alink, Alink-
19 20 19 20
(CH2)xT(CH2)y-Alink, Alink-(CR R )XT(CR R )y-Alink and Alink-
7 20 7 20 (CR R )XT(CR R )y-A]ink, wherein j is selected from an integer of 0 to 18, u and w are independently selected from an integer of 1 to 8 and x and y are independently selected from an integer of 0 to 8 with the proviso that only one Aijnk can be a covalent single bond;
B5 is a linker connecting a first group independently selected from the group
consisting of Ia, lb, Ic, and Ij through the point of bonding of a removable hydrogen of a
1 3' 4 substituent independently selected from a group of substituents consisting of R , R , R
and R wherein R , R and R are independently selected from the group consisting of g hydrogen, hydroxy, and sulfhydryl and R is selected from the group consisting of hydroxyalkyl, aminoalkyl, alkylaminoalkyl and sulfhydrylalkyl to a second group independently selected from the group consisting of Ia, lb, Ic, and Lj through the points of
1 2 1 2 bonding of both substituents R and R wherein R and R are both removable hydrogens
wherein said linker is selected from the group consisting of Dijnk-
^ 19 20, 19^20x „„ 19 20 A ^ ^7^20' 7 20 7 20
CR R (CR R )jCR R -Alink, Dlink-CR R (CR R )jCR R -Alink, Dliπk-
19 20 19 20 7 20 7 20
(CR R )UQQ(C R R )W-Alink, Dπnk-(CR R )UQQ(CR R )W-Alink, Dlink-
19 20 19 20 (CH2)xT(CH2)y-Alink, Dlink-(CR R )XT(CR R )y-Aιink, Dlink-
7 20 7 20 19 20
(CR R )XT(CR R )y-Aιink, Elink-T(CH2)y-Aιink, Eιink-T(CR R )y-Alink and Elink-
7 20 T(CR R )y-Ajink, wherein j is selected from an integer of 0 to 18, u and w are independently selected from an integer of 1 to 8, x and y are independently selected from an integer of 0 to 8, T is selected from the group consisting of a carbocyclic radical, aryl radical and a heterocyclyl radical, Dijnk is selected from a covalent single bond and
15 =C(R ), and Eijnk is selected from the group consisting of a covalent single bond and
covalent double bond with the provisos that only one of Aι k, Dijnk and Eijn can be simultaneously a covalent single bond and that only Dijnk and Eijn can bond to the points
1 2 of bonding of R and R ;
Bg is a linker connecting a first group independently selected from the group
consisting of Ia, lb, Ic, and j through the points of bonding of both substituents R and
2 1 2 R wherein R and R are both removeable hydrogens to a second group independently
selected from the group consisting of Ia, lb, Ic, and Lj through the points of bonding of
1 2 1 2 both substituents R and R wherein R and R are both removeable hydrogens wherein
19 20 19 20 19 20 said linker is selected from the group consisting of Fjjn -CR R (CR R )|CR R -
7 20 7 20 7 20 19 20 19 20
Flink, Flink-CR R (CR R )jCR R -Flink, Flink-(CR R )UQQ(C R R )W-Fιink.
7 20 7 20 19 20 19 20 Flink-(CR R )UQQ(CR R )W-Flink, Flink-(CR R )XT(CR R )y-Flink, F]ink-
7 20 7 20 19 20 7 20
(CR R )XT(CR R )y-Flink, Elink-T(CR R )y-Flink, Elink-T(CR R )y-Flink, Elink-
T-G]jnk and Gϋnk-T-Eunk wherein j is selected from an integer of 0 to 18, u and w are independently selected from an integer of 1 to 8, x and y are independently selected from an integer of 0 to 8, Ejjnk is selected from the group consisting of a covalent single bond
and covalent double bond, Fijnk is =C(R ), and Gι;nk is a covalent double bond;
B7 is an amide and ester forming linker connecting groups independently selected
from the group consisting of Ia, lb, Ic, and j through the point of bonding of a removable hydrogen of a substituent independently selected from a group of substituents consisting
1 3 4 8 1 3 4 of the group R , R , R and R wherein R , R and R are independently selected from g the group consisting of hydrogen, hydroxy, and sulfhydryl and R is selected from the group consisting of hydroxyalkyl, aminoalkyl, alkylaminoalkyl and sulfhydrylalkyl of said Ia, lb, Ic, and 1^ groups wherein the number of groups attached to said linker through the point of bonding of a removable hydrogen of a substituent independently selected from a
1 3 4 8 1 3 4 group of substituents consisting of R , R , R and R wherein R , R and R are independently selected from the group consisting of hydrogen, hydroxy, and sulfhydryl g and R is selected from the group consisting of hydroxyalkyl, aminoalkyl, alkylaminoalkyl and sulfhydrylalkyl is kk wherein kk is an integer selected from 2 to 20 wherein said integer represents the number of amide and ester forming functions present on said linker with a range of from two to the maximum number of amide and ester forming functions present on said linker with the proviso that no more than 5 each of Ia, lb, Ic, and Lj are connected by said amide and ester forming linker wherein said amide and ester forming linker is selected from the group consisting of carboxylic acid compounds of carbon selected from synthetic amino acids, natural amino acids, aldaric acids, citric acid cycle intermediates, alkylpolycarboxylic acids, arylpolycarboxylic acids and heteroarylpolycarboxylic acids wherein 2 to 20 acylating groups are present, said carboxylic acid compounds of carbon may be optionally substituted with one or more acylating substituents selected from the group consisting of phosphates, phosphonates, sulfonates, and sulfates, and said carboxylic acid compounds can be optionally substituted with acylateable substituents selected from the group consisting of amino, hydroxy, and sulfhydryl;
B7 can be an amide and ester forming linker selected from the group consisting of phosphoric acid compounds of carbon selected from the group consisting of phosphoric acid esters of saccharides, hydroxyaryls and heterocycles, phosphoric acid amides of amines, anilines, and aminoheterocycles wherein 2 to 20 acylating groups are present and said phosphoric acid compounds of carbon may be optionally substituted with acylating substituents selected from the group consisting of carboxylates, phosphonates, sulfonates, and sulfates and optionally substituted with one or more acylateable substituents selected from the group selected from amino, hydroxy, and sulfhydryl;
B7 can be an amide and ester forming linker selected from the group consisting of phosphonic acid compounds of carbon selected from the group consisting of multiply phosphonoalkylated ammonia, primary amines, primary and secondary diamines, primary and secondary triamines, primary and secondary tetramines, primary and secondary ethyleneimines, and primary and secondary propyleneiminines and multiphosphonated alkanes, alkenes, alcohols, carboxylic acids, arenes, heterocyclyl radicals, and amino acids wherein 2 to 20 acylating groups are present and said phosphonic acid compounds of carbon may be optionally substituted with one or more acylating substituents selected from the group consisting of carboxylates, phosphates, sulfonates, and sulfates and optionally substituted with one or more acylateable substituents selected from the group selected from amino, hydroxy, and sulfhydryl;
B7 can be an amide and ester forming linker selected from the group consisting of sulfonic acid compounds of carbon selected from the group consisting of multiply sulfonoalkylated ammonia, primary amines, primary and secondary diamines, primary and secondary triamines, primary and secondary tetramines, primary and secondary ethyleneimines, and primary and secondary propyleneiminines and multisulfonated alkanes, alkenes, alcohols, carboxylic acids, arenes, heterocyclyl radicals, and amino acids wherein 2 to 20 acylating groups are present and said sulfonic acid compounds of carbon may be optionally substituted with one or more acylating substituents selected from the group consisting of carboxylates, phosphates, phosphonates, and sulfates and optionally substituted with one or more acylateable substituents selected from the group selected from amino, hydroxy, and sulfhydryl;
B7 can be an amide and ester forming linker selected from the group consisting of sulfuric acid compounds of carbon selected from the group consisting of sulfuric acid esters of saccharides, hydroxy aryls and heterocycles, and sulfuric acid amides of amines, anilines, and aminoheterocycles wherein 2 to 20 acylating groups are present and said sulfuric acid compounds of carbon may be optionally substituted with one or more acylating substituents selected from the group consisting of carboxylates, phosphates, sulfonates, and phosphonates and optionally substituted with one or more acylateable substituents selected from the group selected from amino, hydroxy, and sulfhydryl;
Bg is a linker connecting a first group independently selected from the group
consisting of Ia, lb, Ic, and Lj through the point of bonding of a removable hydrogen of a
7 group selected independently from A and R to a second group independently selected
from the group consisting of Ia, lb, Ic, and lj through the point of bonding of a removable hydrogen of a substituent independently selected from a group of substituents consisting
1 3 4 1 3 4 of R , R and R wherein R , R and R are independently selected from hydrogen, hydroxy, and sulfhydryl wherein said linker is selected from the group consisting of a covalent single bond with the proviso that R is other than hydroxy and sulfhydryl,
19 20 19 20 19 20 7 20 7 20 7 20 19 20 CR R (CR R )jC R R , CR R (CR R )jC R R , (CR R )UQQ(C
19 20 7 20 7 20 19 20 19 20
R R )w, (CR R )UQQ(CR R )w , (CR R )XT(CR R )y and
7 20 7 20
(CR R )XT(CR R )y wherein j is selected from an integer of 0 to 18, u and w are independently selected from an integer of 1 to 8, and x and y are independently selected from an integer of 0 to 8;
Bg is a linker connecting a first group independently selected from the group
7 consisting of Ia, l , Ic, and j from the point of attachment of A-R to a second group
independently selected from the group consisting of Ia, lb, Ic, and Lj through the point of bonding of a removable hydrogen of a substituent independently selected from a group of
1 3 4 8 1 3 4 substituents consisting of R , R , R and R wherein R , R and R are independently g selected from the group consisting of hydrogen, hydroxy, and sulfhydryl and R is selected from the group consisting of hydroxyalkyl, aminoalkyl, alkylaminoalkyl and sulfhydrylalkyl and wherein said linker is selected from the group consisting of Hun -
19 20 19 20 1 20 7 20 7 20 7 20
CR R (CR R )jCR R -Alink, Hlink-CR R (CR R )jCR R -Alink, Hlink-
19 20 19 20 7 20 7 20 (CR R )UQQ(C R R )W-Alink, Hlink-(CR R )UQQ(CR R )W-Alink, Hlink-
19 20 19 20 7 20 7 20
(CR R )XT(CR R )y-Alink, and Hlink-(CR R )XT(CR R )y-Alink wherein j is selected from an integer of 0 to 18, u and w are independently selected from an integer of 1 to 8, and x and y are independently selected from an integer of 0 to 8 with the provisos that only one Aunk and Hunk can be simultaneously a covalent single bond, Aijnk is connected to the point of bonding of a removable hydrogen of a group of substituents consisting of R , R , R and R , and Hunk is connected only to the point of bonding of A-
R7;
B9 can be selected from the group consisting of bifunctional compounds of carbon wherein said compounds of carbon have one or more acylateable groups selected from the group consisting of primary amino, secondary amino, hydroxy, and sulfhydryl and one or more acylating groups selected from carboxy, thionocarboxy, sulfonyl, sulfate, sulfinyl, phosphate, and phosphonyl, wherein said compounds of carbon may e optionally
31 substituted with one or more R roups, wherein said acylateable group is connected to
7 the point of bonding of A-R and wherein said acylating group is connected to the point of
bonding of a removable hydrogen of a substituent group selected from R , R , R and R ;
B 10 is a linker connecting a first group independently selected from the group
consisting of Ia, lb, Ic, and j through the point of bonding of a removable hydrogen of a
7 group selected independently from A and R to a second group independently selected from the group consisting of Ia, lb, Ic, and j through the points of bonding of both
1 2 1 2 substituents R and R wherein R and R are both removable hydrogens and wherein
19 20 19 20 19 20 said linker is selected from the group consisting of CR R (CR R );CR R -Dijnk
7 20 7 20 7 20 19 20 19 20 and CR R (CR R )jC R R -Dlink, (CR R )UQQ(C R R )W-Dιink,
7 20 7 20 19 20 19 20 (CR R )UQQ(CR R )W-Dlink, (CR R )XT(CR R )y-Dlink,
7 20 7 20 19 20 7 20
(CR R )XT(CR R )y-Dlink, E]ink-T(CR R )y and Elink-T(CR R )y wherein j is selected from an integer of 0 to 18, u and w are independently selected from an integer of
1 to 8, x and y are independently selected from an integer of 0 to 8, Djjnk is selected from
a group consisting of a covalent single bond and =C(R ), and Eijnk is selected from a group consisting of a covalent single bond and a covalent double bond with the proviso
1 2 that only Dj jnk and Ejjn can bond to the points of bonding of R and R ;
B ] j is a linker connecting a first group independently selected from the group
7 consisting of Ia, lb, Ic, and j from the point of attachment of A-R to a second group
independently selected from the group consisting of Ia, lb, Ic, and Lj through the points of
1 2 1 2 bonding of both substituents R and R wherein R and R are both removable hydrogens
and wherein said linker is selected from the group consisting of Hijnk-
19 20 19 20 19 20 7 20 7 20 7 20
CR R (CR R )jCR R -Dlink, Hlink-CR R (CR R )jCR R -Dlink, Hlink-
19 20 19 20 7 20 7 20
(CR R )UQQ(C R R )w-Dlink, Hlink-(CR R )UQQ(CR R )W-Dlink, Hlink-
19 20 19 20 7 20 7 20
(CR R )XT(CR R )y-Dlink, HHnk-(CR R )XT(CR R )y-Dlink, Hlink-
19 20 7 20 (CR R )XT-E]jn and Hijnk-(CR R )XT-Eijnk wherein j is selected from an integer of
0 to 18, u and w are independently selected from an integer of 1 to 8, x and y are independently selected from an integer of 0 to 8, D]ink is selected from a covalent single bond and =C(R ) and E]jnk is selected from the group consisting of a covalent single
bond and covalent double bond with the provisos that only one Dijnk and Hijnk can be
simultaneously a covalent single bond, and Hijnk is connected only to the point of bonding
of A-R7;
B 12 is a linker connecting a first group independently selected from the group
7 consisting of Ia, lb, Ic, and Lj from the point of attachment of A-R to a second group
independently selected from the group consisting of Ia, lb, Ic, and lj through the point of bonding of a removable hydrogen of a group selected independently from the group
7 consisting of A and R wherein said linker is selected from the group consisting of
19 20 19 20 19 20 7 20 7 20 covalent single bond, Hιink-CR R (CR R )jC R R , Hlink-CR R (CR R )jC
7 20 19 20 19 20 7 20 7 20
R R , Hιink-(CR R )UQQ(C R R )w, Hlink-(CR R )UQQ(CR R )w, Hlink-
19 20 19 20 7 20 7 20
(CR R )XT(CR R )y and Hιink-(CR R )XT(CR R )y wherein j is selected from an integer of 0 to 18, u and w are independently selected from an integer of 1 to 8, and x and y are independently selected from an integer of 0 to 8 with the proviso that only Hjjnk
7 can be bonded to the point of attachment of A-R ;
B i3 is a linker connecting a first group independently selected from the group
7 1 consisting of Ia, lb, Ic, and Lj from the points of attachment of A-R and R to a second
group independently selected from the group consisting of Ia, lb, Ic, and lj from the point
7 1 of attachment of A-R and R wherein said linker consists of a single covalent bond
7 1 connecting A-R point of attachment of said first group to the point of attachment of R 7 of said second group and a single covalent bond connecting A-R point of attachment of
said second group to the point of attachment of R of said first group;
B i4 is a linker connecting a first group independently selected from the group
26 1 2 consisting of Ia, l , Ic, and Lj, wherein A is R , from the points of attachment of J , J ,
1 2 R and R to a second group independently selected from the group consisting of Ia, lb,
26 1 2 1 2
Ic, and Lj, wherein A is R , from the points of attachment of J , J , R and R wherein
said linker consists of a double covalent bond connecting the point of attachment of J and
2 1 2
J of said first group to the points of attachment of R and R of said second group and a
1 2 double covalent bond connecting the point of attachment of J and J of said second group
1 2 to the points of attachment of R and R of said first group;
B 5 is a linker connecting a first group independently selected from the group
7 1 2 consisting of Ia, lb, Ic, and lj from the points of attachment of A-R , R and R to a
second group independently selected from the group consisting of Ia, l , Ic, and Id,
wherein A is R , from the points of attachment of J , J and R where said linker
7 consists of a single covalent bond connecting A-R point of attachment of said first group
to the point of attachment of R of said second group and a double covalent bond
1 2 connecting the point of attachment of J and J of said second group to the points of
1 2 attachment of R and R of said first group; A]jnk is independently selected from the group consisting of covalent single bond,
24 25 30 30
C=O, C(O)C(O), C=S, S=O, SO2, S(O)2O, Si(R R )2, P(O)R , P(O)R O and
6 19 C(OR )(R );
H]jnk is independently selected from the group consisting of a covalent single
30 30 30 30 30 30 31 bond, O, S, N(R ), ON(R ), SN(R ), N(R )O, N(R )S, N(R )N(R ),
30 30 30 30 30 31
N(R )C(O), N(R )C(S), ON(R )C(O), ON(R )C(S), N(R )N(R )C(O),
30 31 30 31 31 30 30 31 30
N(R )N(R )C(S), N(R )N(R )P(OR )R , N(R )N(R )P(O)R ,
30 31 30 30 30 30 30 30 30
N(R )N(R )P(S)R , ON(R )P(O)R , ON(R )P(S)R , SN(R )P(O)R ,
30 30 30 30 30 30 30
SN(R )P(S)R , ON(R )C(O)O, ON(R )C(S)O, ON(R )C(O)N(R ), ON(R )C(S)
30 30 30 31 30 31 N(R ), ON(R )C(S)S, N(R )N(R )C(O)O, N(R )N(R )C(O)S,
30 31 31 30 31 30 31
N(R )N(R )C(O)N(R ), N(R )N(R )C(S)O, N(R )N(R )C(S)S,
30 31 31 30 31 31 30 30 31 30
N(R )N(R )C(S)N(R ), N(R )N(R )P(OR )R , N(R )N(R )P(O)R ,
30 31 30 30 31 30 30 31 30
N(R )N(R )P(S)R , N(R )N(R )P(O)R O, N(R )N(R )P(S)R O,
30 31 30 30 31 30 30 31 31 30 N(R )N(R )P(O)R S, N(R )N(R )P(S)R S, N(R )N(R )P(OR )R ,
31 30 31 30 31 30 31 30 N(R )P(O)R , N(R )P(S)R , N(R )P(O)R O, N(R )P(S)R O,
31 30 31 30 31 31 30 31 30
N(R )P(O)R S, N(R )P(S)R S, N(R )P(OR )R , N(R )P(O)R ,
31 30 30 30 30 30 30 30
N(R )P(S)R , ON(R )P(O)R , ON(R )P(S)R , SN(R )P(O)R ,
30 30 30 30 30
SN(R )P(S)R , ON(R )S(O)tt, SN(R )S(O)tt, and N(R )S(O)tt,
30 31 N(R )N(R )S(O)tt where tt is 1 to 2; 30 QQ is selected from the group consisting of O, ON(R ), C=O, C=S, S(O)t, Se(O)t
wherein t is 0 to 2, ON(R3°)S(O)tt, N(R3°)S(O)tt, N(R3°)Se(O)tt, ON(R3°)Se(O)tt
24 25 30 30 30 wherein tt is 1 to 2, Si(R R ) , N(R )n wherein n = 1 to 2, P(O)R and OP(O)(R ).
2. The compound as recited in Claim 1 or a pharmaceutically acceptable salt thereof, wherein;
Ia, lb, Ic and Id are independently selected from a structure of Formula II:
Figure imgf000256_0001
(π)
wherein Formula (II) has a point of attachment for bonding to a linker B by replacement of a substituent group of Formula (II) independently selected from the group consisting of J ,
2 7
J , A-R , and a removable hydrogen from a substituent independently selected from the
1 2 3 4 7 8 group consisting of R , R , R , R , R and R ;
1 2
J and J can be taken together forming J wherein J is connected to the carbon of J1 and J2 by a covalent double bond and wherein J is independently selected from the
22 group consisting of O, NR and S; G is independently selected from the group consisting of O, S, CH2, CHR ,
C(R15)2, NH, and NR15;
A is independently selected from the group consisting of O, N(R ), and S;
A can be independently selected from the group consisting of O, N(R ) and S
1 2 connected to the point of attachment of any one of R and R by a spacer group selected from a linear moiety having a chain length of 1 to 6 atoms to form a heterocyclyl having from 5 to 10 members;
A can be independently selected from the group consisting of O, N(R ) and S
1 2 connected to the points of attachment of R and R by a spacer group selected from a linear moiety having a chain length of 1 to 6 to form a heterocyclyl having from 5 to 10 members;
A can be independently selected from the group consisting of O, N(R ) and S
3 connected to the point of attachment of R by a spacer group selected from a linear moiety having a chain length of 1 to 3 atoms to form a heterocyclyl having from 7 to 10 members;
A can be independently selected from the group consisting of O, N(R ) and S
4 connected to the point of attachment of R by a spacer group selected from a linear moiety having a chain length of 1 to 4 atoms to form a heterocyclyl having from 6 to 10 members;
A can be independently selected from the group consisting of O, N(R ) and S connected to X by a substituent selected from hydroxyl, sulfhydryl, amino, carboxyl, and carbonyl substituents of group X by a spacer selected from the group consisting of a covalent bond and a linear moiety having a chain length of 1 to 4 atoms to form a heterocyclyl having from 5 to 10 members; 27 27
A can be R , wherein R is independently selected from the group consisting of
N(R5)OR?, N(R5)SR?, N(R5)N(R7)R25, N(R5)SO2R13, N(R5)C(O)R15,
5 15 19 20 5 19 20
N(R )C(S)R , R (R )C=N-N(R ), R (R )C=N-O, natural amino acids, synthetic
amino acids, N(R5)P(O)(OR13)!R6 and N(R5)P(O)(OR13)2;
1 2 R and R are independently selected from the group consisting of hydrogen, hydroxyalkyl, aminoalkyl, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, haloalkyl,
13 haloalkenyl, cyanoalkyl, dicyanoalkyl, cyanocycloalkyl, dicyanocycloalkyl, S(O)R ,
SO2R , C(O)R , CH2OC(O)R , hydroxyl, sulfhydryl, OR , SR , carboxamidoalkyl, dicarboxamidoalkyl, cyanocarboalkoxyalkyl, carboalkoxyalkyl, dicarboalkoxyalkyl, carboxamidocycloalkyl, dicarboxamidocycloalkyl, carboalkoxycyanocycloalkyl, carboalkoxycycloalkyl, dicarboalkoxycycloalkyl, formylalkyl, acylalkyl, CH2SO3 M ,
CH2CH2SO3 " M+, CH2PO "2 2M+, CH2CH2PO3 "2 2M+, CH(OR6)CF3, P(O)R3°R31,
P(O)(R3°)2 R31, C(S)R15, CH2NR19C(O)R15, CH NR19C(S)R15, CH2SC(O)R15,
CH SC(S)R15, CH2OC(O)GR15, CH2NR19C(O)GR15, CH NR19C(S)GR15,
CH2OC(S)GR15, CH2SC(S)GR15, OSO2R13, OS(O)R13, OC(S)R15, SC(S)R15,
OC(S)GR15, SC(S)GR15, OC(O)R15, SC(O)R15, OC(O)GR15, SC(O)GR15, and
19 20 R (R )CH;
1 2
R and R can be taken together forming a group selected from the group consisting of cycloalkyl radicals, cycloalkenyl radicals wherein said cycloalkyl radicals ■
30 31 and cycloalkenyl radicals may be optionally substituted with one or more R or R substituents, aryl radicals, heteroaryl radicals, saturated heterocyclic radicals and partially saturated heterocyclic radicals wherein said radicals are 1 ,2-disubstituted and said 1 ,2- 19 32 substitutents are independently selected from C=O, C=S, C(R )R , S(O), S(O)2,
31 30 30 30 19 20
OP(OR )R , P(O)R P(S)R and Si(R )R ;
1 2
R and R can be taken together forming a group selected from the group consisting of cis- 1,2-disubstituted alkyls and cis- 1,2-disubstituted alkenyls wherein said
19 32 1,2-substitutents are independently selected from C=O, C=S, C(R )R , S(O), S(O)2,
31 30 30 30 19 20
OP(OR )R , P(O)R , P(S)R , and Si(R )R and said alkyl and alkenyl may be 30 l , . optionally substituted with one or more R or R substituents;
3 4
R and R are independently selected from the group consisting of hydrogen,
hydroxyl, sulfhydryl, OR , SR , CH2SO3" M+, CH2CH2SO3" M+, CH2PO3" 2M ,
CH2CH2PO3" 2M
Figure imgf000259_0001
,
C(O)R15, C(S)R15, CH2OC(O)R15, CH2NR19C(O)R15, CH2NR19C(S)R15,
CH SC(O)R15, CH2SC(S)R15, CH2OC(O)GR15, CH2NR19C(O)GR15,
CH2NR19C(S)GR15, CH2OC(S)GR15, CH2SC(S)GR15, OSO2R13, OS(O)R13,
OC(S)R15, SC(S)R15, OC(S)GR15, SC(S)GR15, OC(O)R15, SC(O)R15, OC(O)GR15
15 and SC(O)GR ;
3 4
R and R can be taken together to form the i p L-V wherein L is not identical to V, and L and V are independently selected from the group consisting of O, S, and C(O);
5 R is independently selected from the group consisting of hydrogen, aryl, heteroaralkyl, hydroxy, alkyl, alkenyl, alkynyl, amino, cyanoalkyl, dicyanoalkyl, carboxamidoalkyl, hydroxyalkyl, dicarboxamidoalkyl, cyanocarboalkoxyalkyl, carboalkoxyalkyl, dicarboalkoxyalkyl, cyanocycloalkyl, dicyanocycloalkyl, carboxamidocycloalkyl, dicarboxamidocycloalkyl, carboalkoxycyanocycloalkyl,
13 carboalkoxycycloalkyl, dicarboalkoxycycloalkyl, formylalkyl, acylalkyl, S(O)R ,
13 30 31 30 31 15 15 15
SO2R , P(O)R R , P(O)(R )2R , C(O)R , C(S)R , CH2OC(O)R ,
CH2NR19C(O)R15, CH2NR19C(S)R15, CH2SC(O)R15, CH2SC(S)R15,
CH2OC(O)GR15, CH2NR19C(O)GR15, CH2NR19C(S)GR15, CH2OC(S)GR15,
15 CH2SC(S)GR , heteroaryloxyalkyl, aralkyl, aryloxyalkyl, aralkoxyalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl, aralkylthioalkyl, heteroaralkoxythioalkyl, alkoxyalkyl, heteroaryloxyalkyl, alkenyloxyalkyl, alkylthioalkyl, arylthioalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkenyl, cycloalkenylalkyl, haloalkyl, haloalkenyl, halocycloalkyl, aralkylsulfinylalkyl, aralkylsulfonylalkyl, carboxyalkyl, carboalkoxyalkyl, dialkoxyphosphonoalkyl, diaralkoxyphosphonoalkyl, phosphonoalkyl, dialkoxyphosphonoalkylamino, diaralkoxyphosphonoalkylamino, phosphonoalkylamino, dialkoxyphosphonoalkyl, diaralkoxyphosphonoalkyl, sulfonylalkyl, alkoxysulfonylalkyl, aralkoxysulfonylalkyl, alkoxysulfonylalkylamino, aralkoxysulfonylalkylamino and sulfonylalkylamino;
5 1 2
R , R and R can be taken together to form a spacer group consisting of a linear moiety having a chain length of 1 to 4 atoms to form a heterocyclyl having from 5 through 8 members;
R can be selected from a heterocyclyl radical in which there is at least one carbon in one ring and in which 1 to about 4 members of said "ring are heteroatoms independently selected from oxygen, nitrogen and sulfur and said heterocyclyl radical may be optionally substituted with heteroarylamino, N-aryl-N-alkylamino, N-heteroarylamino-N-alkylamino, haloalkylthio, alkanoyloxy, alkoxy, heteroaralkoxy, cycloalkoxy, cycloalkenyloxy, hydroxy, amino, thio, nitro, lower alkylamino, alkylthio, alkylthioalkyl, arylamino, aralkylamino, arylthio, alkylsulfmyl, alkylsulfonyl, alkylsulfonamido, alkylaminosulfonyl, amidosulfonyl, monoalkyl amidosulfonyl, dialkyl amidosulfonyl, monoarylamidosulfonyl, arylsulfonamido, diarylamidosulfonyl, monoalkyl monoaryl amidosulfonyl, arylsulfinyl, arylsulfonyl, heteroarylthio, heteroarylsulfinyl, heteroarylsulfonyl, alkanoyl, alkenoyl, aroyl, heteroaroyl, aralkanoyl, heteroaralkanoyl, haloalkanoyl, alkyl, alkenyl, alkynyl, alkylenedioxy, haloalkylenedioxy, cycloalkyl, cycloalkenyl, lower cycloalkylalkyl, lower cycloalkenylalkyl, halo, haloalkyl, haloalkoxy, hydroxyhaloalkyl, hydroxyaralkyl, hydroxyalkyl, hydoxyheteroaralkyl, haloalkoxyalkyl, aryl, aralkyl, aryloxy, aralkoxy, aryloxyalkyl, saturated heterocyclyl, partially saturated heterocyclyl, heteroaryl, heteroaryloxy, heteroaryloxyalkyl, arylalkyl, heteroarylalkyl, arylalkenyl, heteroarylalkenyl, cyanoalkyl, dicyanoalkyl, carboxamidoalkyl, dicarboxamidoalkyl, cyanocarboalkoxyalkyl, carboalkoxyalkyl, dicarboalkoxyalkyl, cyanocycloalkyl, dicyanocycloalkyl, carboxamidocycloalkyl, dicarboxamidocycloalkyl, carboalkoxycyanocycloalkyl, carboalkoxycycloalkyl, dicarboalkoxycycloalkyl, formylalkyl, acylalkyl, dialkoxyphosphonoalkyl, diaralkoxyphosphonoalkyl, phosphonoalkyl, dialkoxyphosphonoalkoxy, diaralkoxyphosphonoalkoxy, phosphonoalkoxy, dialkoxyphosphonoalkylamino, diaralkoxyphosphonoalkylamino, phosphonoalkylamino, dialkoxyphosphonoalkyl, diaralkoxyphosphonoalkyl, guanidino, amidino, and acylamino;
R is independently selected from the group consisting of hydroxyalkyl, aminoalkyl, heteroaryloxyalkyl, alkyl, alkenyl, alkynyl, aryl, aralkyl, aryloxyalkyl, aralkoxyalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl, aralkylthioalkyl, heteroaralkoxythioalkyl, alkoxyalkyl, heteroaryloxyalkyl, alkenyloxyalkyl, alkylthioalkyl, arylthioalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkenyl, cycloalkenylalkyl, haloalkyl, haloalkenyl, halocycaralkylsulfinylalkyl, aralkylsulfonylalkyl, cyanoalkyl, dicyanoalkyl, carboxamidoalkyl, dicarboxamidoalkyl, cyanocarboalkoxyalkyl, carboalkoxyalkyl, dicarboalkoxyalkyl, cyanocycloalkyl, dicyanocycloalkyl, carboxamidocycloalkyl, dicarboxamidocycloalkyl, carboalkoxycyanocycloalkyl, carboalkoxycycloalkyl, dicarboalkoxycycloalkyl, formylalkyl, acylalkyl, dialkoxyphosphonoalkyl, diaralkoxyphosphonoalkyl, phosphonoalkyl, dialkoxyphosphonoalkylamino, diaralkoxyphosphonoalkylamino, phosphonoalkylamino, dialkoχvnrιosphonoalkyl, diaralkoxyphosphonoalkyl, sulfonylalkyl, alkoxysulfonylalkyl, aralkoxysulfonylalkyl, alkoxysulfonylalkylamino, aralkoxysulfonylalkylamino, sulfonylalkylamino, a natural amino acid, synthetic amino acid, and a polyhydroxy compound of carbon;
7 R is selected from the group consisting of hydrogen, aryl, heteroaralkyl, hydroxy, alkyl, alkenyl, alkynyl, amino, cyanoalkyl, dicyanoalkyl, carboxamidoalkyl, hydroxyalkyl, dicarboxamidoalkyl, cyanocarboalkoxyalkyl, carboalkoxyalkyl, dicarboalkoxyalkyl, cyanocycloalkyl, dicyanocycloalkyl, carboxamidocycloalkyl, dicarboxamidocycloalkyl, carboalkoxycyanocycloalkyl, carboalkoxycycloalkyl, dicarboalkoxycycloalkyl,
13 13 30 31 30 31 15 formylalkyl, acylalkyl, S(O)R , SO R , P(O)R R , P(O)(R )2R , C(O)R ,
C(S)R15, CH2OC(O)R15, CH2NR19C(O)R15, CH2NR19C(S)R15, CH2SC(O)R15,
CH SC(S)R15, CH2OC(O)GR15, CH2NR19C(O)GR15, CH2NR19C(S)GR15,
15 15
CH2OC(S)GR , CH2SC(S)GR , heteroaryloxyalkyl, aralkyl, aryloxyalkyl, aralkoxyalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl, aralkylthioalkyl, heteroaralkoxythioalkyl, alkoxyalkyl, heteroaryloxyalkyl, alkenyloxyalkyl, alkylthioalkyl, arylthioalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkenyl, cycloalkenylalkyl, haloalkyl, haloalkenyl, halocycloalkyl, aralkylsulfinylalkyl, aralkylsulfonylalkyl, carboxyalkyl, carboalkoxyalkyl, dialkoxyphosphonoalkyl, diaralkoxyphosphonoalkyl, phosphonoalkyl, dialkoxyphosphonoalkylamino, diaralkoxyphosphonoalkylamino, phosphonoalkylamino, dialkoxyphosphonoalkyl, diaralkoxyphosphonoalkyl, sulfonylalkyl, alkoxysulfonylalkyl, aralkoxysulfonylalkyl, alkoxysulfonylalkylamino, aralkoxysulfonylalkylamino and sulfonylalkylamino;
7 1 2
R , R and R can be taken together to form a spacer group selected from a linear moiety having a chain length of 1 to 4 atoms to form a heterocyclyl having from 5 to 8 members;
7 R can be selected from a heterocyclyl radical in which there is at least one carbon in one ring and in which 1 to about 4 members of said ring are heteroatoms independently selected from oxygen, nitrogen and sulfur and said heterocyclyl radical may be optionally substituted with heteroarylamino, N-aryl-N-alkylamino, N-heteroarylamino-N-alkylamino, haloalkylthio, alkanoyloxy, alkoxy, heteroaralkoxy, cycloalkoxy, cycloalkenyloxy, hydroxy, amino, thio, nitro, lower alkylamino, alkylthio, alkylthioalkyl, arylamino, aralkylamino, arylthio, alkylsulfmyl, alkylsulfonyl, alkylsulfonamido, alkylaminosulfonyl, amidosulfonyl, monoalkyl amidosulfonyl, dialkyl amidosulfonyl, monoarylamidosulfonyl, arylsulfonamido, diarylamidosulfonyl, monoalkyl monoaryl amidosulfonyl, arylsulfinyl, arylsulfonyl, heteroarylthio, heteroarylsulfinyl, heteroarylsulfonyl, alkanoyl, alkenoyl, aroyl, heteroaroyl, aralkanoyl, heteroaralkanoyl, haloalkanoyl, alkyl, alkenyl, alkynyl, alkylenedioxy, haloalkylenedioxy, cycloalkyl, cycloalkenyl, lower cycloalkylalkyl, lower cycloalkenylalkyl, halo, haloalkyl, haloalkoxy, hydroxyhaloalkyl, hydroxy aralkyl, hydroxyalkyl, hydoxyheteroaralkyl, haloalkoxyalkyl, aryl, aralkyl, aryloxy, aralkoxy, aryloxyalkyl, saturated heterocyclyl, partially saturated heterocyclyl, heteroaryl, heteroaryloxy, heteroaryloxyalkyl, arylalkyl, heteroarylalkyl, arylalkenyl, heteroarylalkenyl, cyanoalkyl, dicyanoalkyl, carboxamidoalkyl, dicarboxamidoalkyl, cyanocarboalkoxyalkyl, carboalkoxyalkyl, dicarboalkoxyalkyl, cyanocycloalkyl, dicyanocycloalkyl, carboxamidocycloalkyl, dicarboxamidocycloalkyl, carboalkoxycyanocycloalkyl, carboalkoxycycloalkyl, dicarboalkoxycycloalkyl, formylalkyl, acylalkyl, dialkoxyphosphonoalkyl, diaralkoxyphosphonoalkyl, phosphonoalkyl, dialkoxyphosphonoalkoxy, diaralkoxyphosphonoalkoxy, phosphonoalkoxy, dialkoxyphosphonoalkylamino, diaralkoxyphosphonoalkylamino, phosphonoalkylamino, dialkoxyphosphonoalkyl, diaralkoxyphosphonoalkyl, guanidino, amidino, and acylamino;
8 R is selected from hydrogen, hydroxyalkyl, haloalkyl, alkyl, alkoxyalkyl, aminoalkyl, alkylaminoalkyl, alkylthioalkyl, cyanoalkyl, sulfhydrylalkyl, formyl, C(O)A-
R7, C(S)A-R?, CH2OC(O)A-R7, CH2NR19C(O)A-R?, CH2NR19C(S)A-R7,
CH2SC(O)A-R7, CH2SC(S)A-R7, CH2OC(O)GR15, CH NR19C(O)GR15,
19 15 15 15
CH2NR C(S)GR , CH2OC(S)GR , CH2SC(S)GR and acyl; g R may be taken together with X to form a carbocyclic or a heterocyclic ring having from 3 to 8 members;
13 R is independently selected from aryloxy, amino, alkylamino, dialkylamino, hydroxyalkyl, heteroaryloxyalkyl, alkoxy, alkylthio, arylthio, alkyl, alkenyl, alkynyl, aryl, aralkyl, aryloxyalkyl, aralkoxyalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl, aralkylthioalkyl, heteroaralkoxythioalkyl, alkoxyalkyl, heteroaryloxyalkyl, alkenyloxyalkyl, alkylthioalkyl, arylthioalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkenyl, cycloalkenylalkyl, haloalkyl, haloalkenyl, haloaralkylsulfinylalkyl, aralkylsulfonylalkyl, cyanoalkyl, dicyanoalkyl, carboxamidoalkyl, dicarboxamidoalkyl, cyanocarboalkoxyalkyl, carboalkoxyalkyl, dicarboalkoxyalkyl, cyanocycloalkyl, dicyanocycloalkyl, carboxamidocycloalkyl, dicarboxamidocycloalkyl, carboalkoxycyanocycloalkyl, carboalkoxycycloalkyl, dicarboalkoxycycloalkyl, formylalkyl, acylalkyl, dialkoxyphosphonoalkyl, diaralkoxyphosphonoalkyl, phosphonoalkyl, dialkoxyphosphonoalkoxy, diaralkoxyphosphonoalkoxy, phosphonoalkoxy, dialkoxyphosphonoalkylamino, diaralkoxyphosphonoalkylamino, phosphonoalkylamino, dialkoxyphosphonoalkyl , diaralkoxyphosphonoalkyl, sulfonylalkyl, alkoxysulfonylalkyl, aralkoxysulfonylalkyl, alkoxysulfonylalkoxy, aralkoxysulfonylalkoxy, sulfonylalkoxy, alkoxysulfonylalkylamino, aralkoxysulfonylalkylamino, sulfonylalkylamino, a natural amino acid, synthetic amino acid, and a polyhydroxy compound of carbon;
15 R is independently selected from hydrido, aryloxy, amino, alkylamino, dialkylamino, hydroxyalkyl, heteroaryloxyalkyl, alkoxy, alkylthio, arylthio, alkyl, alkenyl, alkynyl, aryl, aralkyl, aryloxyalkyl, aralkoxyalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl, aralkylthioalkyl, heteroaralkoxythioalkyl, alkoxyalkyl, heteroaryloxyalkyl, alkenyloxyalkyl, alkylthioalkyl, arylthioalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkenyl, cycloalkenylalkyl, haloalkyl, haloalkenyl, haloaralkylsulfinylalkyl, aralkylsulfonylalkyl, carboxy, cyanoalkyl, dicyanoalkyl, carboxamidoalkyl, dicarboxamidoalkyl, cyanocarboalkoxyalkyl, carboalkoxyalkyl, dicarboalkoxyalkyl, cyanocycloalkyl, dicyanocycloalkyl, carboxamidocycloalkyl, dicarboxamidocycloalkyl, carboalkoxycyanocycloalkyl, carboalkoxycycloalkyl, dicarboalkoxycycloalkyl, formylalkyl, acylalkyl, dialkoxyphosphonoalkyl, diaralkoxyphosphonoalkyl, phosphonoalkyl, dialkoxyphosphonoalkoxy, diaralkoxyphosphonoalkoxy, phosphonoalkoxy, dialkoxyphosphonoalkylamino, diaralkoxyphosphonoalkylamino, phosphonoalkylamino, dialkoxyphosphonoalkyl, diaralkoxyphosphonoalkyl, sulfonylalkyl, alkoxysulfonylalkyl, aralkoxysulfonylalkyl, alkoxysulfonylalkoxy, aralkoxysulfonylalkoxy, sulfonylalkoxy, alkoxysulfonylalkylamino, aralkoxysulfonylalkylamino, sulfonylalkylamino, a natural amino acid, a synthetic amino acid, and a polyhydroxy compound of carbon;
M is a pharmaceutically acceptable cation;
X is selected from the group consisting of alkylene, alkenylene, alkynylene, - (CH2)nQ(CH2) wherein p is 1 to 3, r is 1 to 3 and Q is selected from oxygen, C=O,
N(R12)SO2, SO N(R12), S(O)t, Se(O)t wherein t is 0 to 2, P(O)R21, -(CH2)sT(CH2)v- wherein s is O to 2, v is 0 to 2 and T is selected from 3 to 6 membered carbocyclic
12 radicals, aryl radicals and heterocyclyl radicals, and N(R ) wherein n is 1 to 2, wherein all positions on X may be optionally substituted with one or more selected from the group consisting of halogen, Cj-C o alkyl, Cj-C o alkoxy, hydroxy, haloalkyl, nitro, cyano, and amino;
12 R is selected from hydrogen, hydroxyl, alkyl, hydroxyalkyl, aminoalkyl, alkylaminoalkyl, alkoxyalkyl, haloalkyl, aryl, aralkyl, cycloalkylalkyl, and heterocy clylalkyl ;
21 R is selected from hydroxyl and alkyl;
Y is selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxyalkyl, cycloalkyl, cycloalkenyl, cycloalkenyloxy, alkenyloxyalkyl, alkylthioalkyl, 9 10 9 10 alkylaminoalkyl and NR R wherein R and R are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, nitro, amino, hydroxy, alkoxy, aryl, heterocyclyl, and aralkyl;
9 10
R and R can be taken together to form a spacer group selected from a linear moiety having a chain length of 2 to 7 atoms to form a heterocyclyl having from 3 through 8 members;
19 20
R and R are independently selected from the group consisting of hydrogen, hydroxyalkyl, alkyl, alkenyl, alkynyl, aryl, aralkyl, aryloxyalkyl, acyl, aroyl, aralkanoyl, heteroaroyl, aralkoxyalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl, aralkylthioalkyl, heteroaralkylthioalkyl, alkoxyalkyl, heteroaryloxyalkyl, alkenyloxyalkyl, alkylthioalkyl, arylthioalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkenyl, cycloalkenylalkyl, haloalkyl, haloalkenyl, halocycloalkyl, halocycloalkenyl, haloalkoxyalkyl, haloalkenyloxyalkyl, halocycloalkoxy, halocycloalkoxyalkyl, halocycloalkenyloxyalkyl, perhaloaryl, perhaloaralkyl, perhaloaryloxyalkyl, heteroaryl, heteroarylalkyl, heteroarylthioalkyl, heteroaralkylthioalkyl, cyanoalkyl, dicyanoalkyl, carboxamidoalkyl, dicarboxamidoalkyl, cyanocarboalkoxyalkyl, carboalkoxyalkyl, dicarboalkoxyalkyl, cyanocycloalkyl, dicyanocycloalkyl, carboxamidocycloalkyl, dicarboxamidocycloalkyl, carboalkoxycyanocycloalkyl, carboalkoxycycloalkyl, dicarboalkoxycycloalkyl, formylalkyl, acylalkyl, arylsulfinylalkyl, arylsulfonylalkyl, aralkylsulfinyl, cycloalkylsulfinylalkyl, cycloalkylsufonylalkyl, heteroarylsulfonylalkyl, heteroarylsulfinylalkyl, aralkylsulfinylalkyl, aralkylsulfonylalkyl, carboxy, dialkoxyphosphono, diaralkoxyphosphono, dialkoxyphosphonoalkyl and diaralkoxyphosphonoalkyl;
19 20
R and R can be taken together to form a linear moiety spacer group having a chain length of 2 to 7 atoms and selected from the group consisting of a cycloalkyl having from 3 through 8 members, a cycloalkenyl having from 3 through 8 members, and a heterocyclyl having from 3 through 8 members; 22 R is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aralkyl, aryloxyalkyl, aralkoxyalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl, aralkylthioalkyl, heteroaralkylthioalkyl, alkoxyalkyl, heteroaryloxyalkyl, alkenyloxyalkyl, alkylthioalkyl, arylthioalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkenyl, cycloalkenylalkyl, haloalkyl, haloalkenyl, halocycloalkyl, halocycloalkenyl, haloalkoxyalkyl, haloalkenyloxyalkyl, halocycloalkoxyalkyl, halocycloalkenyloxyalkyl, perhaloaryloxyalkyl, heteroaryl, heteroarylalkyl, heteroarylthioalkyl, heteroaralkylthioalkyl, arylsulfinylalkyl, arylsulfonylalkyl, cycloalkylsulfinylalkyl, cycloalkylsufonylalkyl, heteroarylsulfonylalkyl, heteroarylsulfinylalkyl, aralkylsulfinylalkyl and aralkylsulfonylalkyl;
24 25
R and R are independently selected from the group consisting of hydrogen, hydroxyalkyl, alkyl, alkenyl, alkynyl, aryl, aralkyl, aryloxyalkyl, aralkoxyalkyl, alkoxy, alkylsulfinylalkyl, alkylsulfonylalkyl, aralkylthioalkyl, heteroaralkylthioalkyl, alkoxyalkyl, heteroaryloxyalkyl, alkenyloxyalkyl, alkylthioalkyl, arylthioalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkenyl, cycloalkenylalkyl, haloalkyl, haloalkenyl, halocycloalkyl, halocycloalkenyl, haloalkoxyalkyl, haloalkenyloxyalkyl, cycloalkoxy, halocycloalkoxyalkyl, halocycloalkenyloxyalkyl, perhaloaryl, perhaloaralkyl, perhaloaryloxyalkyl, heteroaryl, heteroarylalkyl, heteroarylthioalkyl, heteroaralkylthioalkyl, arylsulfinylalkyl, arylsulfonylalkyl, cycloalkylsulfinylalkyl, cycloalkylsufonylalkyl, heteroarylsulfonylalkyl, heteroarylsulfinylalkyl, aralkylsulfinylalkyl and aralkylsulfonylalkyl;
24 25
R and R can be taken to form a linear moiety spacer group having a chain length of 4 to 7 atoms to form a heterocyclyl having from 5 through 8 members;
30 31
R and R are independently selected from hydroxy, thiol, aryloxy, amino, alkylamino, dialkylamino, hydroxyalkyl, heteroaryloxyalkyl, alkoxy, alkylthio, arylthio, alkyl, alkenyl, alkynyl, aryl, aralkyl, aryloxyalkyl, aralkoxyalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl, aralkylthioalkyl, heteroaralkoxythioalkyl, alkoxyalkyl, heteroaryloxyalkyl, alkenyloxyalkyl, alkylthioalkyl, arylthioalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkenyl, cycloalkenylalkyl, haloalkyl, haloalkenyl, haloaralkylsulfinylalkyl, aralkylsulfonylalkyl, cyanoalkyl, dicyanoalkyl, carboxamidoalkyl, dicarboxamidoalkyl, cyanocarboalkoxyalkyl, carboalkoxyalkyl, dicarboalkoxyalkyl, cyanocycloalkyl, dicyanocycloalkyl, carboxamidocycloalkyl, dicarboxamidocycloalkyl, carboalkoxycyanocycloalkyl, carboalkoxycycloalkyl, dicarboalkoxycycloalkyl, formylalkyl, acylalkyl, dialkoxyphosphonoalkyl, diaralkoxyphosphonoalkyl, phosphonoalkyl, dialkoxyphosphonoalkoxy, diaralkoxyphosphonoalkoxy, phosphonoalkoxy, dialkoxyphosphonoalkylamino, diaralkoxyphosphonoalkylamino, phosphonoalkylamino, dialkoxyphosphonoalkyl, diaralkoxyphosphonoalkyl, sulfonylalkyl, alkoxysulfonylalkyl, aralkoxysulfonylalkyl, alkoxysulfonylalkoxy, aralkoxysulfonylalkoxy, sulfonylalkoxy, alkoxysulfonylalkylamino, aralkoxysulfonylalkylamino, sulfonylalkylamino, a natural amino acid, a synthetic amino acid, and polyhydroxy compound of carbon;
30 31 R and R can be taken to form a linear moiety spacer group having a chain length of 2 to 7 atoms to form a group selected from the group consisting of a cycloalkyl having from 3 through 8 members, a cycloalkenyl having from 3 through 8 members, and a heterocyclyl having from 3 through 8 members;
B is a linker selected from the group consisting of B\, B2, B3, B4, B5, B6, B7, Bg, B9, Bio, Bι ι, B]2, B 3, B14, and B 15, wherein f is an integer selected from 2 to 5, and g, h, and i are each the integer zero;
B 1 is a linker connecting a first group Ia through the point of bonding of a removable hydrogen of a group selected independently from the group consisting of A and
7 R to a second group Ia through the point of bonding of a removable hydrogen of a group
7 selected independently from the group consisting of A and R wherein said linker is selected from the group consisting of a covalent single bond with the proviso that only one 19 20 19 20 19 20 7 ?0 7 20
A is simultaneously O and S, CR R (CR R )jC R R , CR R (CR R )jC
7 20 19 20 19 20 7 20 7 20
R R , (CR R )UQQ(C R R )w, (CR R )UQQ(CR R )w> (CH2)xT(CH2)y,
19 20 19 20 7 20 7 20
(CR R )XT(CR R )y and (CR R )XT(CR R )y wherein j is selected from an integer of 0 to 18, x and y are selected from an integer of 0 to 8, and u and w are selected from an integer of 1 to 8;
7 B2 is a linker connecting a first group Ia from the point of attachment of A-R to a
7 second group Ia from the point of attachment of A-R wherein said linker is selected from
19 20 19 20 19 20 the group consisting of Hjjnk-CR R (CR R )jCR R -Hunk , H]jnk-
CR7R2°(CR7R20)jCR7R20-Hιink) Hlink-(CH2)uQQ(CH2)w-Hιink, HUnk-
19 20 19 20 7 20 7 20 (CR R )UQQ(C R R )w-HHnk, Hlink-(CR R )UQQ(CR R )W-Hlink> Hlink-
(CH2)xT(CH2)y-Hιink, Hιink-(CR19R2°)xT(CR19R20)y-Hιink, and Hlink-
7 20 7 20
(CR R )xT(CR R )y-Hijnk wherein j is selected from an integer of 0 to 18, u and w are independently selected from an integer of 1 to 8, and x and y are independently selected from an integer of 0 to 8 with the proviso that only one Hϋnk can be simultaneously a covalent single bond;
B2 can be a linker selected from the group consisting of natural amino acids and synthetic amino acids wherein said amino acids have two or more acylateable functional groups selected from the group consisting of primary amino, secondary amino, thiol, and hydroxy;
7 B3 is a linker connecting group Ia from the point of attachment of A-R of said Ia wherein the number of groups attached to said linker from the point of attachment of A-
7 R is kk wherein kk is an integer selected from 2 to 5 wherein said integer represents the number of acylateable functions present on said linker with a range of from two to the maximum number of acylateable functions present on said linker with the proviso that no more than 5 each of Ia are simultaneously present on said linker and wherein said linker is selected from the group consisting of polyhydroxy compound of carbon selected from the group consisting of polyhydroxyalkanes, saccharides, disaccharides, polysaccharides, inositols, alditols, alditol acetals, alditol ketals, aldaric acids, aldonic acids, aldonic acid lactones, and hydroxyalkylamines having 2 to 5 acylateable hydroxy groups;
B3 can be a linker selected from the group consisting of polyamino compounds of carbon selected from the group consisting of diaminoalkanes, diaminocycloalkanes, diaminoaryls, diaminoheterocycyls, diaminoalkylamines, triaminoalkylamines, diaminoalkylaminoalkylamines, and triaminoalkylaminoalkylamines, wherein said polyamino compounds have two to twenty acylateable amino groups, and compounds of carbon having one to nineteen hydroxy functions, one to nineteen amino functions and zero to eighteen thiol functions;
B4 is a linker connecting a first group Ia through the point of bonding of a removable hydrogen of a substituent independently selected from a group of substituents
1 3 4 8 1 3 4 consisting of R , R , R and R wherein R , R and R are independently selected from
the group consisting of hydrogen, hydroxy, and sulfhydryl and R is selected from the group consisting of hydroxyalkyl, aminoalkyl, alkylaminoalkyl and sulfhydrylalkyl to a second group Ia through the point of bonding of a removable hydrogen of a substituent
independently selected from a group of substituents consisting of R , R , R and R
1 3 4 wherein R , R and R are independently selected from the group consisting of hydrogen, o hydroxy, and sulfhydryl and R is selected from the group consisting of hydroxyalkyl, aminoalkyl, alkylaminoalkyl and sulfhydrylalkyl wherein said linker is selected from the
24 25 30 30 group consisting of C=O, C(O)C(O), C=S, S=O, SO2, Si(R )(R ), P(O)R , P(S)R ,
30 30 19 20 19 20 19 20 1 20 (O)2POP(O)2, R (O)POP(O)R Si(R )R Si(R )R , Si(R )R OSi(R )R ; B4 can be a linker selected from the group consisting of A]jnk-
19 20 19 20 19 20 7 20 7 20 7 20
CR R (CR R )jCR R -Alink, Alink-CR R (CR R )jCR R -Alink, Alink-
19 20 19 20 7 20 7 20
(CR R )UQQ(C R R )W-Alink, Aιink-(CR R )UQQ(CR R )W-Alink, Alink-
(CH2)xT(CH2)y-A,ink, Alink-(CR19R2°)xT(CR19R20)y-Alink and AHnk-
7 20 7 20
(CR R )XT(CR R )y-A]jnk, wherein j is selected from an integer of 0 to 18, u and w are independently selected from an integer of 1 to 8 and x and y are independently selected from an integer of 0 to 8 with the proviso that only one Aιjnk can be a covalent single bond;
B5 is a linker connecting Ia through the point of bonding of a removable hydrogen
1 3 of a substituent independently selected from a group of substituents consisting of R , R ,
4 8 1 3 4
R and R wherein R , R and R are independently selected from the group consisting of g hydrogen, hydroxy, and sulfhydryl and R is selected from the group consisting of
hydroxyalkyl, aminoalkyl, alkylaminoalkyl and sulfhydrylalkyl to a second Ia through the
1 2 1 2 points of bonding of both substituents R and R wherein R and R are both removable
hydrogens wherein said linker is selected from the group consisting of Dijn - 19 r, 20„_„ 19^ 20 ^ 19„ 20 4 ^ „n ln 20„___, 7^ 20 m 7^ 20 A
CR R (CR R )jCR R -Alink, Dlink-CR R (CR R )jCR R -Alink, Dlink-
19 20 19 20 7 20 7 20
(CR R )UQQ(C R R )W-Alink, Dlink-(CR R )UQQ(CR R )W-Alink, Dlink-
19 20 19 20
(CH2)xT(CH2)y- Aiink, Dlink-(CR R )χT(CR R )y-Alink, Dlink-
7 20 7 20 19 20
(CR R )xT(CR R )y-Alink, Elink-T(CH2)y-Alink, Elink-T(CR R )y-Ahnk and Elink-
7 20 T(CR R )y-Aijn , wherein j is selected from an integer of 0 to 18, u and w are independently selected from an integer of 1 to 8, x and y are independently selected from an integer of 0 to 8, T is selected from the group consisting of a carbocyclic radical, aryl radical and a heterocyclyl radical, Dijnk is selected from a covalent single bond and
15 =C(R ), and Eijnk is selected from the group consisting of a covalent single bond and
covalent double bond with the provisos that only one of A]jnk, Dijnk and Eijnk can be
simultaneously a covalent single bond and that only Dπnk and E]jnk can bond to the points
1 2 of bonding of R and R ;
B6 is a linker connecting Ia through the points of bonding of both substituents R
2 1 2 and R wherein R and R are both removeable hydrogens to Ia through the points of
1 2 1 2 bonding of both substituents R and R wherein R and R are both removeable
hydrogens wherein said linker is selected from the group consisting of Fijnk-
19 20 19 20 19 20 7 20 7 20 7 20 CR R (CR R )jCR R -Flink, F,ink-CR R (CR R )jCR R -Flink, Flink-
19 20 19 20 7 20 7 20
(CR R )UQQ(C R R )W-Flink, Flink-(CR R )UQQ(CR R )W-Fιink, Flink-
19 20 19 20 7 20 7 20
(CR R )XT(CR R )y-Fιink, Flink-(CR R )XT(CR R )y-FHnk, Elink-
19 20 7 20
T(CR R )y-Flink, Elink-T(CR R )y-FHnk, Eιink-T-Glink and Glink-T-Elink wherein j is selected from an integer of 0 to 18, u and w are independently selected from an integer of 1 to 8, x and y are independently selected from an integer of 0 to 8, Ejjnk is selected from
the group consisting of a covalent single bond and covalent double bond, Fijnk is
15 =C(R ), and Gunk is a covalent double bond;
B7 is an amide and ester forming linker connecting Ia through the point of bonding of a removable hydrogen of a substituent independently selected from a group of
1 3 4 8 1 3 4 substituents consisting of the group R , R , R and R wherein R , R and R are independently selected from the group consisting of hydrogen, hydroxy, and sulfhydryl g and R is selected from the group consisting of hydroxyalkyl, aminoalkyl, alkylaminoalkyl
and sulfhydrylalkyl of said Ia groups wherein the number of groups attached to said linker through the point of bonding of a removable hydrogen of a substituent independently selected from a group of substituents consisting of R , R , R and R wherein R , R and
4 R are independently selected from the group consisting of hydrogen, hydroxy, and
8 sulfhydryl and R is selected from the group consisting of hydroxyalkyl, aminoalkyl, alkylaminoalkyl and sulfhydrylalkyl is kk wherein kk is an integer selected from 2 to 5 wherein said integer represents the number of amide and ester forming functions present on said linker with a range of from two to the maximum number of amide and ester forming functions present on said linker with the proviso that no more than 5 of Ia are connected by said amide and ester forming linker wherein said amide and ester forming linker is selected from the group consisting of carboxylic acid compounds of carbon selected from synthetic amino acids, natural amino acids, aldaric acids, citric acid cycle intermediates, alkylpolycarboxylic acids, arylpolycarboxylic acids and heteroarylpolycarboxylic acids wherein 2 to 5 acylating groups are present, said carboxylic acid compounds of carbon may be optionally substituted with one or more acylating substituents selected from the group consisting of phosphates, phosphonates, sulfonates, and sulfates, and said carboxylic acid compounds can be optionally substituted with acylateable substituents selected from the group consisting of amino, hydroxy, and sulfhydryl;
B7 can be an amide and ester forming linker selected from the group consisting of phosphoric acid compounds of carbon selected from the group consisting of phosphoric acid esters of saccharides, hydroxyaryls and heterocycles, phosphoric acid amides of amines, anilines, and aminoheterocycles wherein 2 to 5 acylating groups are present and said phosphoric acid compounds of carbon may be optionally substituted with acylating substituents selected from the group consisting of carboxylates, phosphonates, sulfonates, and sulfates and optionally substituted with one or more acylateable substituents selected from the group selected from amino, hydroxy, and sulfhydryl;
B7 can be an amide and ester forming linker selected from the group consisting of phosphonic acid compounds of carbon selected from the group consisting of multiply phosphonoalkylated ammonia, primary amines, primary and secondary diamines, primary and secondary triamines, primary and secondary tetramines, primary and secondary ethyleneimines, and primary and secondary propyleneiminines and multiphosphonated alkanes, alkenes, alcohols, carboxylic acids, arenes, heterocyclyl radicals, and amino acids wherein 2 to 5 acylating groups are present and said phosphonic acid compounds of carbon may be optionally substituted with one or more acylating substituents selected from the group consisting of carboxylates, phosphates, sulfonates, and sulfates and optionally substituted with one or more acylateable substituents selected from the group selected from amino, hydroxy, and sulfhydryl;
B7 can be an amide and ester forming linker selected from the group consisting of sulfonic acid compounds of carbon selected from the group consisting of multiply sulfonoalkylated ammonia, primary amines, primary and secondary diamines, primary and secondary triamines, primary and secondary tetramines, primary and secondary ethyleneimines, and primary and secondary propyleneiminines and multisulfonated alkanes, alkenes, alcohols, carboxylic acids, arenes, heterocyclyl radicals, and amino acids wherein 2 to 5 acylating groups are present and said sulfonic acid compounds of carbon may be optionally substituted with one or more acylating substituents selected from the group consisting of carboxylates, phosphates, phosphonates, and sulfates and optionally substituted with one or more acylateable substituents selected from the group selected from amino, hydroxy, and sulfhydryl;
B7 can be an amide and ester forming linker selected from the group consisting of sulfuric acid compounds of carbon selected from the group consisting of sulfuric acid esters of saccharides, hydroxy aryls and heterocycles, and sulfuric acid amides of amines, anilines, and aminoheterocycles wherein 2 to 5 acylating groups are present and said sulfuric acid compounds of carbon may be optionally substituted with one or more acylating substituents selected from the group consisting of carboxylates, phosphates, sulfonates, and phosphonates and optionally substituted with one or more acylateable substituents selected from the group selected from amino, hydroxy, and sulfhydryl;
Bg is a linker connecting Ia through the point of bonding of a removable hydrogen
7 of a group selected independently from A and R to a second group Ia through the point of bonding of a removable hydrogen of a substituent independently selected from a group of
1 3 4 1 3 4 substituents consisting of R , R and R wherein R , R and R are independently selected from hydrogen, hydroxy, and sulfhydryl wherein said linker is selected from the group consisting of a covalent single bond with the proviso that R is other than hydroxy
19 20 19 20 19 20 7 20 7 20 7 20 and sulfhydryl, CR R (CR R )jC R R , CR R (CR R )jC R R ,
19 20 19 20 7 20 7 20 19 20 19 20
(CR R )UQQ(C R R )W, (CR R )UQQ(CR R )w , (CR R )XT(CR R )y
7 20 7 20 and (CR R )XT(CR R )y wherein j is selected from an integer of 0 to 18, u and w are independently selected from an integer of 1 to 8, and x and y are independently selected from an integer of 0 to 8 ;
7 B9 is a linker connecting a first group Ia from the point of attachment of A-R to a
second group Ia through the point of bonding of a removable hydrogen of a substituent
1 3 4 8 independently selected from a group of substituents consisting of R , R , R and R
1 3 4 wherein R , R and R are independently selected from the group consisting of hydrogen, g hydroxy, and sulfhydryl and R is selected from the group consisting of hydroxyalkyl, aminoalkyl, alkylaminoalkyl and sulfhydrylalkyl and wherein said linker is selected from
19 20 19 20 19 20 the group consisting of Hiink-CR R (CR R )jCR R -Annk, Hnnk-
7 20 7 20 7 20 19 20 19 ?Ω
CR R (CR R )jCR R -Aiink, Hιink-(CR R )UQQ(C R *R )W-Alink, Hlink- 7 20 7 20 19 20 19 20
(CR R )UQQ(CR R )W-Alink, Hlink-(CR R )XT(CR R )y-AIink, and Hlink-
7 20 7 20
(CR R )XT(CR R )y-A)jnk wherein j is selected from an integer of 0 to 18, u and w are independently selected from an integer of 1 to 8, and x and y are independently selected from an integer of 0 to 8 with the provisos that only one Aunk and Hnn can be simultaneously a covalent single bond, Aunk is connected to the point of bonding of a
removable hydrogen of a group of substituents consisting of R , R , R and R , and Hijnk
7 is connected only to the point of bonding of A-R ;
B9 can be selected from the group consisting of bifunctional compounds of carbon wherein said compounds of carbon have one or more acylateable groups selected from the group consisting of primary amino, secondary amino, hydroxy, and sulfhydryl and one or more acylating groups selected from carboxy, thionocarboxy, sulfonyl, sulfate, sulfinyl, phosphate, and phosphonyl, wherein said compounds of carbon may be optionally
31 substituted with one or more R groups, wherein said acylateable group is connected to
7 the point of bonding of A-R and wherein said acylating group is connected to the point of
1 3 4 8 bonding of a removable hydrogen of a substituent group selected from R , R , R and R ;
Bio is a linker connecting a first group Ia through the point of bonding of a
7 removable hydrogen of a group selected independently from A and R to a second group
1 2 1 2
Ia through the points of bonding of both substituents R and R wherein R and R are both removable hydrogens and wherein said linker is selected from the group consisting of
19 20 19 20 19 20 7 20 7 20 7 20 CR R (CR R )jCR R -Dlink and CR R (CR R )jC R R -Dlink,
19 20 19 20 7 20 7 20
(CR R )UQQ(C R R )W-Dlink, (CR R )UQQ(CR R )w-DHnk,
19 20 19 20 7 20 7 20 19 20
(CR R )XT(CR R )y-Dlink, (CR R )XT(CR R )y-Dιink, Eιink-T(CR R )y and 7 20 Elink"T(CR R )y wherein j is selected from an integer of 0 to 18, u and w are independently selected from an integer of 1 to 8, x and y are independently selected from an integer of 0 to 8, Djjnk is selected from a group consisting of a covalent single bond and
=C(R ), and Eϋnk is selected from a group consisting of a covalent single bond and a
covalent double bond with the proviso that only Dnnk and Eijnk can bond to the points of
1 2 bonding of R and R ;
7 B j j is a linker connecting a first group Ia from the point of attachment of A-R to
1 2 a second group Ia through the points of bonding of both substituents R and R wherein
1 2
R and R are both removable hydrogens and wherein said linker is selected from the
19 20 19 20 19 20 group consisting of Hiink-CR R (CR R )jCR R -Dijnk, Hnnk-
7 20 7 20 7 20 19 20 19 20
CR R (CR R )jCR R -Dιink, Hιink-(CR R )UQQ(C R R )W-Dlink, Hlink-
7 20 7 20 19 20 19 20
(CR R )UQQ(CR R )w-DHnk, Hiink-(CR R )XT(CR R )y-Dlink, Hlink-
7 20 7 20 19 20 7 20
(CR R )XT(CR R )y-Dlink, Hlink-(CR R )XT-Elink and Hlink-(CR R )XT-Elink wherein j is selected from an integer of 0 to 18, u and w are independently selected from an integer of 1 to 8, x and y are independently selected from an integer of 0 to 8, Dijnk is
selected from a covalent single bond and =C(R ) and Eunk is selected from the group consisting of a covalent single bond and covalent double bond with the provisos that only one Djjnk and Hϋnk can be simultaneously a covalent single bond, and Hϋn is connected
7 only to the point of bonding of A-R ;
7 B i2 is a linker connecting a first group Ia from the point of attachment of A-R to
a second group Ia through the point of bonding of a removable hydrogen of a group 7 selected independently from the group consisting of A and R wherein said linker is
19 20 19 20 selected from the group consisting of covalent single bond, Hjjnk-CR R (CR R )jC
19 20 7 90 7 20 7 20 19 20 19 20
R R , Hiink-CR R (CR R )jC R R , Hlink-(CR R )UQQ(C R R )w, Hlink-
7 20 7 20 19 20 19 20
(CR R )UQQ(CR R )w, HHnk-(CR R )XT(CR R )y and HIink-
7 20 7 20 (CR R )XT(CR R )y wherein j is selected from an integer of 0 to 18, u and w are independently selected from an integer of 1 to 8, and x and y are independently selected from an integer of 0 to 8 with the proviso that only Hi,nk can be bonded to the point of
7 attachment of A-R ;
7 B i3 is a linker connecting a first group Ia from the points of attachment of A-R
1 7 1 and R to a second group Ia from the point of attachment of A-R and R wherein said
7 linker consists of a single covalent bond connecting A-R point of attachment of said first
group to the point of attachment of R of said second group and a single covalent bond
7 connecting A-R point of attachment of said second group to the point of attachment of
R of said first group;
26 B14 is a linker connecting a first group Ia wherein A is R ;
Ajjnk is independently selected from the group'consisting of covalent single bond,
24 25 30 30
C=O, C(O)C(O), C=S, S=O, SO2, S(O)2O, Si(R R )2, P(O)R , P(O)R O and
6 19 C(OR )(R );
Hjjnk is independently selected from the group consisting of a covalent single
30 30 30 30 30 30 31 bond, O, S, N(R ), ON(R ), SN(R ), N(R )O, N(R )S, N(R )N(R ), 30 30 30 30 30 31
N(R )C(O), N(R )C(S), ON(R )C(O), ON(R )C(S), N(R )N(R )C(O),
30 31 30 31 31 30 30 31 30
N(R )N(R )C(S), N(R )N(R )P(OR )R , N(R )N(R )P(O)R ,
30 31 30 30 30 30 30 30 30
N(R )N(R )P(S)R , ON(R )P(O)R , ON(R )P(S)R , SN(R )P(O)R ,
30 30 30 30 30 30 30 SN(R )P(S)R , ON(R )C(O)O, ON(R )C(S)O, ON(R )C(O)N(R ), ON(R )C(S)
30 30 30 31 30 31 N(R ), ON(R )C(S)S, N(R )N(R )C(O)O, N(R )N(R )C(O)S,
30 31 31 30 31 30 31
N(R )N(R )C(O)N(R ), N(R )N(R )C(S)O, N(R )N(R )C(S)S,
30 31 31 30 31 31 30 30 31 30
N(R )N(R )C(S)N(R ), N(R )N(R )P(OR )R , N(R )N(R )P(O)R ,
30 31 30 30 31 30 30 31 30
N(R )N(R )P(S)R , N(R )N(R )P(O)R O, N(R )N(R )P(S)R O,
30 31 30 30 31 30 30 31 31 30 N(R )N(R )P(O)R S, N(R )N(R )P(S)R S, N(R )N(R )P(OR )R ,
31 30 31 30 31 30 31 30 N(R )P(O)R , N(R )P(S)R , N(R )P(O)R O, N(R )P(S)R O,
31 30 31 30 31 31 30 31 30
N(R )P(O)R S, N(R )P(S)R S, N(R )P(OR )R , N(R )P(O)R ,
31 30 30 30 30 30 30 30
N(R )P(S)R , ON(R )P(O)R , ON(R )P(S)R , SN(R )P(O)R ,
30 30 30 30 30
SN(R )P(S)R , ON(R )S(O)tt, SN(R )S(O)tt, and N(R )S(O)tt,
N(R30)N(R31)S(O)tt where tt is 1 to 2;
30 QQ is selected from the group consisting of O, ON(R ), C=O, C=S, S(O)t, Se(O)t
30 30 30 30 wherein t is 0 to 2, ON(R )S(O)tt, N(R )S(O)tt, N(R )Se(O)tt, ON(R )Se(O)tt
24 25 30 30 30 wherein tt is 1 to 2, Si(R R )2, N(R )n wherein n = 1 to 2, P(O)R and OP(O)(R ).
3. The compound as recited in Claim 2 or a pharmaceutical salt thereof, wherein; B is a linker selected from the group consisting of B2, B3, B4, B7, and B9 wherein f is an integer selected from 2 through 5 and g, h, and i are each the integer zero;
7 B2 is a linker connecting a first Ia group from the point of attachment of A-R to a
7 second Ia group from the point of attachment of A-R wherein said
19 20 19 20 19 20 linker is selected from the group consisting of Hjink-CR R (CR R )jCR R -H nk
7 20 7 20 7 20 and Hπnk-CR R (CR R );CR R -H]jnk, wherein j is an integer selected from 0
through 4 and Hϋnk is O and S;
B2 can be a linker selected from the group consisting of natural amino acids and synthetic amino acids wherein said amino acids have two or more acylateable functional groups selected from the group consisting of primary amino, secondary amino, thiol, and hydroxy;
7 B3 is a linker connecting Ia groups from the point of attachment of each A-R of
said Ia groups wherein the number of groups attached to said linker from the point of
7 attachment of A-R is kk wherein kk is an integer selected from 2 to 5 wherein said integer can be any number of acylateable functions present on said linker with a range of from two to five of the maximum number of acylateable functions present on said linker with the proviso that no more than 5 Ia groups are simultaneously present on said linker and wherein said linker is selected from the group consisting of polyhydroxy compound of carbon selected from the group consisting of poly hydroxy alkanes, saccharides, disaccharides, polysaccharides, inositols, alditols, alditol acetals, alditol ketals, aldaric acids, aldonic acids, aldonic acid lactones, and hydroxyalkylamines;
B4 is a linker, connecting a first Ia group through the point of bonding of a removable hydrogen of a substituent independently selected from a group of substituents 1 3 4 1 3 4 consisting of R , R , and R wherein R , R and R are independently selected from the group consisting of hydrogen, hydroxy, and sulfhydryl, to a second Ia group through the point of bonding of a removable hydrogen of a substituent independently selected from a
1 3 4 1 3 4 group of substituents consisting of R , R , and R wherein R , R and R are independently selected from the group consisting of hydrogen, hydroxy, and sulfhydryl and wherein said linker is selected from the group consisting of C=O, S(O), SO2,
P(O)R30, and (O)2POP(O)2;
B4 can be a linker selected from the group consisting of Aϋnk- 19„ 20^„ 19„ 20, ^„ 19 20 A A ^ 7^ 20„___17„ 20, „n 7„ 20 A
CR R (CR R )jCR R -Alink, Aιink-CR R (CR R )jCR R -Aιink, Alink-
19 20 19 20 7 20 7 20 (CR R )UQQ(C R R )W-Aιink, and Aιink-(CR R )UQQ(CR R )W-Alink, wherein j is selected from an integer of 0 to 4, QQ is selected from the group consisting of O, NH,
30 and S, and Aiink is selected from the group consisting of C(O) and P(O)R ;
B7 is an amide and ester forming linker connecting Ia groups through the point of bonding of a removable hydrogen of a substituent independently selected from a group of
1 3 4 1 3 4 substituents consisting of the group R , R , and R wherein R , R and R are independently selected from the group consisting of hydrogen, hydroxy, and sulfhydryl of said Ia group wherein the number of Ia groups attached to said linker through the point of bonding of a removable hydrogen of a substituent independently selected from said group
1 3 4 of substituents consisting of R , R , and R is kk wherein kk is an integer selected from 2 through 5 wherein the number of amide and ester forming functions present on said linker ranges from two through six wherein said amide and ester forming linker is selected from the group consisting of carboxylic acid compounds of carbon selected from synthetic amino acids, natural amino acids, aldaric acids, citric acid cycle intermediates, and alkylpolycarboxylic acids wherein 2 to 6 acylating groups are present; 7 B9 is a linker connecting a first Ia group from the point of attachment of A-R to a
second Ia group through the point of bonding of a removable hydrogen of a substituent of
said second Ia group independently selected from a group of substituents consisting of R ,
3 4 1 3 4
R , and R wherein R , R and R are independently selected from the group consisting of hydrogen, hydroxy, and sulfhydryl wherein said linker is selected from the group consisting of
19 20 19 20 19 20 Hlink-CR R (CR R )jCR R -Aπnk and
7 20 7 20 7 20 Hjink-CR R (CR R )jCR R -A]jnk wherein j is selected from an integer of 0 to 4,
Aiink is connected to the point of bonding of a removable hydrogen of a group of
1 3 4 substituents consisting of R , R , and R , Hunk is independently selected from the group
7 consisting of O and S, and Hnnk is connected only to the point of bonding of A-R ;
B9 can be selected from the group consisting of bifunctional compounds of carbon wherein said compounds of carbon have one or more acylateable groups selected from the group consisting of primary amino, secondary amino, hydroxy, and sulfhydryl and one or more acylating groups selected from carboxy and phosphoryl, wherein said acylateable
7 group is connected to the point of bonding of A-R and said acylating group is connected
to the point of bonding of a removable hydrogen of a substituent group selected from R ,
R , and R ;
J and J are taken together forming J wherein J is connected to the carbon of J1 and J by a covalent double bond and wherein J is independently selected from the group
22 consisting of O, NR and S; A is independently selected from the group consisting of O, N(R ), and S;
1 2
R and R are independently selected from the group consisting of hydrogen,
hydroxyl, sulfhydryl, OR , and SR ;
3 4
R and R are independently selected from the group consisting of hydrogen,
hydroxyl, sulfhydryl, OR , and SR ;
R is independently selected from the group consisting of hydrogen, aryl, heteroaralkyl, hydroxy, alkyl, alkenyl, alkynyl, amino, cyanoalkyl, dicyanoalkyl, carboxamidoalkyl, hydroxyalkyl, dicarboxamidoalkyl, cyanocarboalkoxyalkyl, carboalkoxyalkyl, dicarboalkoxyalkyl, cyanocycloalkyl, dicyanocycloalkyl, carboxamidocycloalkyl, dicarboxamidocycloalkyl, carboalkoxycyanocycloalkyl,
13 carboalkoxycycloalkyl, dicarboalkoxycycloalkyl, formylalkyl, acylalkyl, S(O)R ,
13 30 31 30 31 15 15 15
SO2R , P(O)R R , P(O)(R )2R , C(O)R , C(S)R , CH2OC(O)R ,
CH2NR19C(O)R15, CH2NR19C(S)R15, CH2SC(O)R15, CH2SC(S)R15, heteroaryloxyalkyl, aralkyl, aryloxyalkyl, aralkoxyalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl, aralkylthioalkyl, heteroaralkoxythioalkyl, alkoxyalkyl, heteroaryloxyalkyl, alkenyloxyalkyl, alkylthioalkyl, arylthioalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkenyl, cycloalkenylalkyl, haloalkyl, haloalkenyl, halocycloalkyl, aralkylsulfinylalkyl, aralkylsulfonylalkyl, carboxyalkyl, carboalkoxyalkyl, dialkoxyphosphonoalkyl, diaralkoxyphosphonoalkyl, phosphonoalkyl, dialkoxyphosphonoalkylamino, diaralkoxyphosphonoalkylamino, phosphonoalkylamino, dialkoxyphosphonoalkyl, diaralkoxyphosphonoalkyl, sulfonylalkyl, alkoxysulfonylalkyl, aralkoxysulfonylalkyl, alkoxysulfonylalkylamino, aralkoxysulfonylalkylamino and sulfonylalkylamino; 5 R can be selected from a heterocyclyl radical in which there is at least one carbon in one ring and in which 1 to about 4 members of said ring are heteroatoms independently selected from oxygen, nitrogen and sulfur and said heterocyclyl radical may be optionally substituted with heteroarylamino, N-aryl-N-alkylamino, N-heteroarylamino-N-alkylamino, haloalkylthio, alkanoyloxy, alkoxy, heteroaralkoxy, cycloalkoxy, cycloalkenyloxy, hydroxy, amino, thio, nitro, lower alkylamino, alkylthio, alkylthioalkyl, arylamino, aralkylamino, arylthio, alkylsulfinyl, alkylsulfonyl, alkylsulfonamido, alkylaminosulfonyl, amidosulfonyl, monoalkyl amidosulfonyl, dialkyl amidosulfonyl, monoarylamidosulfonyl, arylsulfonamido, diarylamidosulfonyl, monoalkyl monoaryl amidosulfonyl, arylsulfinyl, arylsulfonyl, heteroarylthio, heteroarylsulfinyl, heteroarylsulfonyl, alkanoyl, alkenoyl, aroyl, heteroaroyl, aralkanoyl, heteroaralkanoyl, haloalkanoyl, alkyl, alkenyl, alkynyl, alkylenedioxy, haloalkylenedioxy, cycloalkyl, cycloalkenyl, lower cycloalkylalkyl, lower cycloalkenylalkyl, halo, haloalkyl, haloalkoxy, hydroxyhaloalkyl, hydroxy aralkyl, hydroxyalkyl, hydoxyheteroaralkyl, haloalkoxyalkyl, aryl, aralkyl, aryloxy, aralkoxy, aryloxyalkyl, saturated heterocyclyl, partially saturated heterocyclyl, heteroaryl, heteroaryloxy, heteroaryloxyalkyl, arylalkyl, heteroarylalkyl, arylalkenyl, heteroarylalkenyl, cyanoalkyl, dicyanoalkyl, carboxamidoalkyl, dicarboxamidoalkyl, cyanocarboalkoxyalkyl, carboalkoxyalkyl, dicarboalkoxyalkyl, cyanocycloalkyl, dicyanocycloalkyl, carboxamidocycloalkyl, dicarboxamidocycloalkyl, carboalkoxycyanocycloalkyl, carboalkoxycycloalkyl, dicarboalkoxycycloalkyl, formylalkyl, acylalkyl, dialkoxyphosphonoalkyl, diaralkoxyphosphonoalkyl, phosphonoalkyl, dialkoxyphosphonoalkoxy, diaralkoxyphosphonoalkoxy, phosphonoalkoxy, dialkoxyphosphonoalkylamino, diaralkoxyphosphonoalkylamino, phosphonoalkylamino, dialkoxyphosphonoalkyl, diaralkoxyphosphonoalkyl, guanidino, amidino, and acylamino;
6
R is alkyl;
7 R is selected from the group consisting of hydrogen, aryl, heteroaralkyl, hydroxy, alkyl, alkenyl, alkynyl, amino, cyanoalkyl, dicyanoalkyl, carboxamidoalkyl, hydroxyalkyl, dicarboxamidoalkyl, cyanocarboalkoxyalkyl, carboalkoxyalkyl, dicarboalkoxyalkyl, cyanocycloalkyl, dicyanocycloalkyl, carboxamidocycloalkyl, dicarboxamidocycloalkyl, carboalkoxycyanocycloalkyl, carboalkoxycycloalkyl, dicarboalkoxycycloalkyl,
13 13 30 31 30 31 15 formylalkyl, acylalkyl, S(O)R , SO2R , P(O)R R , P(O)(R )2R , C(O)R ,
C(S)R15, CH OC(O)R15, CH2NR19C(O)R15, CH2NR19C(S)R15, CH2SC(O)R15,
CH2SC(S)R , heteroaryloxyalkyl, aralkyl, aryloxyalkyl, aralkoxyalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl, aralkylthioalkyl, heteroaralkoxythioalkyl, alkoxyalkyl, heteroaryloxyalkyl, alkenyloxyalkyl, alkylthioalkyl, arylthioalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkenyl, cycloalkenylalkyl, haloalkyl, haloalkenyl, halocycloalkyl, aralkylsulfinylalkyl, aralkylsulfonylalkyl, carboxyalkyl, carboalkoxyalkyl, dialkoxyphosphonoalkyl, diaralkoxyphosphonoalkyl, phosphonoalkyl, dialkoxyphosphonoalkylamino, diaralkoxyphosphonoalkylamino, phosphonoalkylamino, dialkoxyphosphonoalkyl, diaralkoxyphosphonoalkyl, sulfonylalkyl, alkoxysulfonylalkyl, aralkoxysulfonylalkyl, alkoxysulfonylalkylamino, aralkoxysulfonylalkylamino and sulfonylalkylamino;
7 R can be selected from a heterocyclyl radical in which there is at least one carbon in one ring and in which 1 to about 4 members of said ring are heteroatoms independently selected from oxygen, nitrogen and sulfur and said heterocyclyl radical may be optionally substituted with heteroarylamino, N-aryl-N-alkylamino, N-heteroarylamino-N-alkylamino, haloalkylthio, alkanoyloxy, alkoxy, heteroaralkoxy, cycloalkoxy, cycloalkenyloxy, hydroxy, amino, thio, nitro, lower alkylamino, alkylthio, alkylthioalkyl, arylamino, aralkylamino, arylthio, alkylsulfinyl, alkylsulfonyl, alkylsulfonamido, alkylaminosulfonyl, amidosulfonyl, monoalkyl amidosulfonyl, dialkyl amidosulfonyl, monoarylamidosulfonyl, arylsulfonamido, diarylamidosulfonyl, monoalkyl monoaryl amidosulfonyl, arylsulfinyl, arylsulfonyl, heteroarylthio, heteroarylsulfinyl, heteroarylsulfonyl, alkanoyl, alkenoyl, aroyl, heteroaroyl, aralkanoyl, heteroaralkanoyl, haloalkanoyl, alkyl, alkenyl, alkynyl, alkylenedioxy, haloalkylenedioxy, cycloalkyl, cycloalkenyl, lower cycloalkylalkyl, lower cycloalkenylalkyl, halo, haloalkyl, haloalkoxy, hydroxyhaloalkyl, hydroxyaralkyl, hydroxyalkyl, hydoxyheteroaralkyl, haloalkoxyalkyl, aryl, aralkyl, aryloxy, aralkoxy, aryloxyalkyl, saturated heterocyclyl, partially saturated heterocyclyl, heteroaryl, heteroaryloxy, heteroaryloxyalkyl, arylalkyl, heteroarylalkyl, arylalkenyl, heteroarylalkenyl, cyanoalkyl, dicyanoalkyl, carboxamidoalkyl, dicarboxamidoalkyl, cyanocarboalkoxyalkyl, carboalkoxyalkyl, dicarboalkoxyalkyl, cyanocycloalkyl, dicyanocycloalkyl, carboxamidocycloalkyl, dicarboxamidocycloalkyl, carboalkoxycyanocycloalkyl, carboalkoxycycloalkyl, dicarboalkoxycycloalkyl, formylalkyl, acylalkyl, dialkoxyphosphonoalkyl, diaralkoxyphosphonoalkyl, phosphonoalkyl, dialkoxyphosphonoalkoxy, diaralkoxyphosphonoalkoxy, phosphonoalkoxy, dialkoxyphosphonoalkylamino, diaralkoxyphosphonoalkylamino, phosphonoalkylamino, dialkoxyphosphonoalkyl, diaralkoxyphosphonoalkyl, guanidino, amidino, and acylamino;
8 R is selected from hydrogen, hydroxyalkyl, haloalkyl, alkyl, alkoxyalkyl, aminoalkyl, alkylaminoalkyl, alkylthioalkyl, cyanoalkyl, sulfhydrylalkyl; g R may be taken together with X to form a carbocyclic or a heterocyclic ring having from 3 to 6 members;
13 R is independently selected from aryloxy, amino, alkylamino, dialkylamino, hydroxyalkyl, heteroaryloxyalkyl, alkoxy, alkylthio, arylthio, alkyl, alkenyl, alkynyl, aryl, aralkyl, aryloxyalkyl, aralkoxyalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl, aralkylthioalkyl, heteroaralkoxythioalkyl, alkoxyalkyl, heteroaryloxyalkyl, alkenyloxyalkyl, alkylthioalkyl, arylthioalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkenyl, cycloalkenylalkyl, haloalkyl, haloalkenyl, haloaralkylsulfinylalkyl, aralkylsulfonylalkyl, cyanoalkyl, dicyanoalkyl, carboxamidoalkyl, dicarboxamidoalkyl, cyanocarboalkoxyalkyl, carboalkoxyalkyl, dicarboalkoxyalkyl, cyanocycloalkyl, dicyanocycloalkyl, carboxamidocycloalkyl, dicarboxamidocycloalkyl, carboalkoxycyanocycloalkyl, carboalkoxycycloalkyl, dicarboalkoxycycloalkyl, formylalkyl, acylalkyl, dialkoxyphosphonoalkyl, diaralkoxyphosphonoalkyl, phosphonoalkyl, dialkoxyphosphonoalkoxy, diaralkoxyphosphonoalkoxy, phosphonoalkoxy, dialkoxyphosphonoalkylamino, diaralkoxyphosphonoalkylamino, phosphonoalkylamino, dialkoxyphosphonoalkyl, diaralkoxyphosphonoalkyl, sulfonylalkyl, alkoxysulfonylalkyl, aralkoxysulfonylalkyl, alkoxysulfonylalkoxy, aralkoxysulfonylalkoxy, sulfonylalkoxy, alkoxysulfonylalkylamino, aralkoxysulfonylalkylamino, sulfonylalkylamino, a natural amino acid, synthetic amino acid, and a polyhydroxy compound of carbon;
R is independently selected from hydrido, aryloxy, amino, alkylamino, dialkylamino, hydroxyalkyl, heteroaryloxyalkyl, alkoxy, alkylthio, arylthio, alkyl, alkenyl, alkynyl, aryl, aralkyl, aryloxyalkyl, aralkoxyalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl, aralkylthioalkyl, heteroaralkoxythioalkyl, alkoxyalkyl, heteroaryloxyalkyl, alkenyloxyalkyl, alkylthioalkyl, arylthioalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkenyl, cycloalkenylalkyl, haloalkyl, haloalkenyl, haloaralkylsulfinylalkyl, aralkylsulfonylalkyl, carboxy, cyanoalkyl, dicyanoalkyl, carboxamidoalkyl, dicarboxamidoalkyl, cyanocarboalkoxyalkyl, carboalkoxyalkyl, dicarboalkoxyalkyl, cyanocycloalkyl, dicyanocycloalkyl, carboxamidocycloalkyl, dicarboxamidocycloalkyl, carboalkoxycyanocycloalkyl, carboalkoxycycloalkyl, dicarboalkoxycycloalkyl, formylalkyl, acylalkyl, dialkoxyphosphonoalkyl, diaralkoxyphosphonoalkyl, phosphonoalkyl, dialkoxyphosphonoalkoxy, diaralkoxyphosphonoalkoxy, phosphonoalkoxy, dialkoxyphosphonoalkylamino, diaralkoxyphosphonoalkylamino, phosphonoalkylamino, dialkoxyphosphonoalkyl, diaralkoxyphosphonoalkyl, sulfonylalkyl, alkoxysulfonylalkyl, aralkoxysulfonylalkyl, alkoxysulfonylalkoxy, aralkoxysulfonylalkoxy, sulfonylalkoxy, alkoxysulfonylalkylamino, aralkoxysulfonylalkylamino, sulfonylalkylamino, a natural amino acid, a synthetic amino acid, and a polyhydroxy compound of carbon;
X is selected from the group consisting of alkylene, alkenylene, alkynylene, -
(CH2)pQ(CH2)r- wherein p is 1 to 3, r is 1 to 3 and Q is selected from oxygen, C=O,
N(R12)SO2, SO2N(R12), S(O)t, wherein t is 0 to 2, -(CH2)ST(CH2)V- wherein s is O to 2, v is 0 to 2 and T is selected from 3 to 6 membered carbocyclic radicals, aryl radicals and 12 heterocyclyl radicals, and N(R ) wherein n is 1 to 2, wherein all positions on X may be
optionally substituted with one or more selected from the group consisting of halogen, C\-
C o alkyl, Cj-Cio alkoxy, hydroxy, haloalkyl, nitro, cyano, and amino;
12 R is selected from hydrogen, hydroxyl, alkyl, hydroxyalkyl, aminoalkyl, alkylaminoalkyl, alkoxyalkyl, haloalkyl, aryl, aralkyl, cycloalkylalkyl, and heterocyclylalkyl;
Y is selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxyalkyl, cycloalkyl, cycloalkenyl, cycloalkenyloxy, alkenyloxyalkyl, alkylthioalkyl, and alkylaminoalkyl;
19 20 R and R are independently selected from the group consisting of hydrogen, hydroxyalkyl, alkyl, alkenyl, alkynyl, aryl, aralkyl, aryloxyalkyl, acyl, aroyl, aralkanoyl, heteroaroyl, aralkoxyalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl, aralkylthioalkyl, heteroaralkylthioalkyl, alkoxyalkyl, heteroaryloxyalkyl, alkenyloxyalkyl, alkylthioalkyl, arylthioalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkenyl, cycloalkenylalkyl, haloalkyl, haloalkenyl, halocycloalkyl, halocycloalkenyl, haloalkoxyalkyl, haloalkenyloxyalkyl, halocycloalkoxy, halocycloalkoxyalkyl, halocycloalkenyloxyalkyl, perhaloaryl, perhaloaralkyl, perhaloaryloxyalkyl, heteroaryl, heteroarylalkyl, heteroarylthioalkyl, heteroaralkylthioalkyl, cyanoalkyl, dicyanoalkyl, carboxamidoalkyl, dicarboxamidoalkyl, cyanocarboalkoxyalkyl, carboalkoxyalkyl, dicarboalkoxyalkyl, cyanocycloalkyl, dicyanocycloalkyl, carboxamidocycloalkyl, dicarboxamidocycloalkyl, carboalkoxycyanocycloalkyl, carboalkoxycycloalkyl, dicarboalkoxycycloalkyl, formylalkyl, acylalkyl, arylsulfinylalkyl, arylsulfonylalkyl, aralkylsulfinyl, cycloalkylsulfinylalkyl, cycloalkylsufonylalkyl, heteroarylsulfonylalkyl, heteroarylsulfinylalkyl, aralkylsulfinylalkyl, aralkylsulfonylalkyl, carboxy, dialkoxyphosphono, diaralkoxyphosphono, dialkoxyphosphonoalkyl and diaralkoxyphosphonoalkyl; 22 R is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aralkyl, aryloxyalkyl, aralkoxyalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl, aralkylthioalkyl, heteroaralkylthioalkyl, alkoxyalkyl, heteroaryloxyalkyl, alkenyloxyalkyl, alkylthioalkyl, arylthioalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkenyl, cycloalkenylalkyl, haloalkyl, haloalkenyl, halocycloalkyl, halocycloalkenyl, haloalkoxyalkyl, haloalkenyloxyalkyl, halocycloalkoxyalkyl, halocycloalkenyloxyalkyl, perhaloaryloxyalkyl, heteroaryl, heteroarylalkyl, heteroarylthioalkyl, heteroaralkylthioalkyl, arylsulfinylalkyl, arylsulfonylalkyl, cycloalkylsulfinylalkyl, cycloalkylsufonylalkyl, heteroarylsulfonylalkyl, heteroarylsulfinylalkyl, aralkylsulfinylalkyl and aralkylsulfonylalkyl;
24 25
R and R are independently selected from the group consisting of hydrogen, hydroxyalkyl, alkyl, alkenyl, alkynyl, aryl, aralkyl, aryloxyalkyl, aralkoxyalkyl, alkoxy, alkylsulfinylalkyl, alkylsulfonylalkyl, aralkylthioalkyl, heteroaralkylthioalkyl, alkoxyalkyl, heteroaryloxyalkyl, alkenyloxyalkyl, alkylthioalkyl, arylthioalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkenyl, cycloalkenylalkyl, haloalkyl, haloalkenyl, halocycloalkyl, halocycloalkenyl, haloalkoxyalkyl, haloalkenyloxyalkyl, cycloalkoxy, halocycloalkoxyalkyl, halocycloalkenyloxyalkyl, perhaloaryl, perhaloaralkyl, perhaloaryloxyalkyl, heteroaryl, heteroarylalkyl, heteroarylthioalkyl, heteroaralkylthioalkyl, arylsulfinylalkyl, arylsulfonylalkyl, cycloalkylsulfinylalkyl, cycloalkylsufonylalkyl, heteroarylsulfonylalkyl, heteroarylsulfinylalkyl, aralkylsulfinylalkyl and aralkylsulfonylalkyl;
30 31
R and R are independently selected from hydroxy, thiol, aryloxy, amino, alkylamino, dialkylamino, hydroxyalkyl, heteroaryloxyalkyl, alkoxy, alkylthio, arylthio, alkyl, alkenyl, alkynyl, aryl, aralkyl, aryloxyalkyl, aralkoxyalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl, aralkylthioalkyl, heteroaralkoxythioalkyl, alkoxyalkyl, heteroaryloxyalkyl, alkenyloxyalkyl, alkylthioalkyl, arylthioalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkenyl, cycloalkenylalkyl, haloalkyl, haloalkenyl, haloaralkylsulfinylalkyl, aralkylsulfonylalkyl, cyanoalkyl, dicyanoalkyl, carboxamidoalkyl, dicarboxamidoalkyl, cyanocarboalkoxyalkyl, carboalkoxyalkyl, dicarboalkoxyalkyl, cyanocycloalkyl, dicyanocycloalkyl, carboxamidocycloalkyl, dicarboxamidocycloalkyl, carboalkoxycyanocycloalkyl, carboalkoxycycloalkyl, dicarboalkoxycycloalkyl, formylalkyl, acylalkyl, dialkoxyphosphonoalkyl, diaralkoxyphosphonoalkyl, phosphonoalkyl, dialkoxyphosphonoalkoxy, diaralkoxyphosphonoalkoxy, phosphonoalkoxy, dialkoxyphosphonoalkylamino, diaralkoxyphosphonoalkylamino, phosphonoalkylamino, dialkoxyphosphonoalkyl, diaralkoxyphosphonoalkyl, sulfonylalkyl, alkoxysulfonylalkyl, aralkoxysulfonylalkyl, alkoxysulfonylalkoxy, aralkoxysulfonylalkoxy, sulfonylalkoxy, alkoxysulfonylalkylamino, aralkoxysulfonylalkylamino, sulfonylalkylamino, a natural amino acid, a synthetic amino acid, and polyhydroxy compound of carbon.
4. The compound as recited in Claim 3 or a pharmaceutical salt thereof, wherein;
B is a linker selected from the group consisting of B2, B3, B4, B7, and B9 wherein f is the integer 2 and g, h, and i are each the integer zero;
7 B2 is a linker connecting a first Ia group from the point of attachment of A-R to a
7 second Ia group from the point of attachment of A-R wherein said
19 20 19 20 19 20 linker is selected from the group consisting of Hunk-CR R (CR R );CR R -Hijnk
7 20 7 20 7 20 and Hiink-CR R (CR R )jCR R -Hunk, wherein j is an integer selected from 0
7 through 4, R , when part of B2 linker, is selected from the group consisting of hydrogen,
19 20 hydroxy, alkyl, and hydroxyalkyl, R and R are, when part of B2 linker, independently selected from the group consisting of hydrogen, hydroxyalkyl, alkyl, and carboxy, and
Hlink i selected from the group consisting of O and S; B2 can be a linker selected from the group consisting of natural amino acids and synthetic amino acids wherein said amino acids have two or more acylateable functional groups selected from the group consisting of primary amino, secondary amino, thiol, and hydroxy;
7 B3 is a linker connecting Ia groups from the point of attachment of each A-R of
said Ia groups wherein the number of groups attached to said linker from the point of
7 attachment of A-R is kk wherein kk is the integer 2 wherein the number of acylateable
functions present on said linker are at least two with the proviso that no more than 2 Ia groups are simultaneously present on said linker and wherein said linker is selected from the group consisting of a polyhydroxy compound of carbon selected from the group consisting of polyhydroxyalkanes, saccharides, disaccharides, polysaccharides, inositols, alditols, alditol acetals, alditol ketals, aldaric acids, aldonic acids, and aldonic acid lactones;
B4 is a linker, connecting a first Ia group through the point of bonding of a removable hydrogen of a substituent independently selected from a group of substituents
1 3 4 1 3 4 consisting of R , R , and R wherein R , R and R are independently selected from the group consisting of hydrogen, hydroxy, and sulfhydryl, to a second Ia group through the point of bonding of a removable hydrogen of a substituent independently selected from a
1 3 4 1 3 4 group of substituents consisting of R , R , and R wherein R , R and R are independently selected from the group consisting of hydrogen, hydroxy, and sulfhydryl and wherein said linker is selected from the group consisting of C=O, S(O), SO2,
P(O)R3° and (O)2POP(O)2;
B4 can be a linker selected from the group consisting of Aunk-
19 20 19 20 19 20 7 20 7 20 7 20
CR R (CR R )jCR R -Alink, Aιink-CR R (CR R )jCR R -Aιink, and 19 20 19 20 7 20 7 20
AHnk-(CR R )UQQ(C R R )W-Alink, Aιink-(CR R )UQQ(CR R )W-Alink, wherein j is selected from an integer of 0 to 4, QQ is selected from the group consisting of
7 O, NH, and S, R , when part of B4 linker, is selected from the group consisting of
19 20 hydrogen, hydroxy, alkyl, and hydroxyalkyl, R and R are, when part of B4 linker, independently selected from the group consisting of hydrogen, hydroxyalkyl, alkyl, and
30 carboxy, and Aunk is selected from the group consisting of C(O) and P(O)R ;
B7 is an amide and ester forming linker connecting Ia groups through the point of bonding of a removable hydrogen of a substituent independently selected from a group of
1 3 4 1 3 4 substituents consisting of the group R , R , and R wherein R , R and R are independently selected from the group consisting of hydrogen, hydroxy, and sulfhydryl of said Ia group wherein the number of Ia groups attached to said linker through the point of bonding of a removable hydrogen of a substituent independently selected from said group
1 3 4 of substituents consisting of R , R , and R is kk wherein kk is the integer 2 wherein the number of amide and ester forming functions present on said linker can range from two through three wherein said amide and ester forming linker is selected from the group consisting of carboxylic acid compounds of carbon selected from synthetic amino acids, natural amino acids, aldaric acids, citric acid cycle intermediates, and alkylpolycarboxylic acids wherein 2 to 6 acylating groups are present;
7 B9 is a linker connecting a first Ia group from the point of attachment of A-R to a
second Ia group through the point of bonding of a removable hydrogen of a substituent of
said second Ia group independently selected from a group of substituents consisting of R ,
3 4 1 3 4
R , and R wherein R , R and R are independently selected from the group consisting of hydrogen, hydroxy, and sulfhydryl wherein said linker is selected from the group consisting of 19 20 1 20 19 20
Hiink-CR R (CR R )jCR R -Alink and
7 20 7 20 7 20 Hlink-CR R (CR R )jCR R -A]jnk wherein j is selected from an integer of 0 to 4,
7 R , when part of B9 linker, is selected from the group consisting of hydrogen, hydroxy,
19 20 alkyl, and hydroxyalkyl, R and R are, when part of B9 linker, independently selected from the group consisting of hydrogen, hydroxyalkyl, alkyl, and carboxy,
Aiink is connected to the point of bonding of a removable hydrogen of a group of
1 3 4 substituents consisting of R , R , and R , and Hunk is connected only to the point of
7 bonding of A-R ;
B9 can be selected from the group consisting of bifunctional compounds of carbon wherein said compounds of carbon have from one through five acylateable groups selected from the group consisting of primary amino, secondary amino, hydroxy, and sulfhydryl and wherein said compounds have from one through four acylating groups selected from carboxy and phosphoryl, wherein said acylateable group is connected to the point of bonding of
7 A-R and said acylating group is connected to the point of bonding of a removable
1 3 4 hydrogen of a substituent group selected from R , R , and R ;
1 2
J and J can be taken together forming J wherein J is connected to the carbon of
J1 and J2 by a covalent double bond and wherein J is O;
A is independently selected from the group consisting of O, N(R ), and S;
1 2 R and R are hydrogen; 3 4
R and R are independently selected from the group consisting of hydrogen,
hydroxyl, sulfhydryl, OR , and SR ;
R is independently selected from the group consisting of hydrogen, aryl, heteroaralkyl, hydroxy, alkyl, alkenyl, alkynyl, amino, cyanoalkyl, dicyanoalkyl, carboxamidoalkyl, hydroxyalkyl, dicarboxamidoalkyl, cyanocarboalkoxyalkyl, carboalkoxyalkyl, dicarboalkoxyalkyl, cyanocycloalkyl, dicyanocycloalkyl, carboxamidocycloalkyl, dicarboxamidocycloalkyl, carboalkoxycyanocycloalkyl,
13 carboalkoxycycloalkyl, dicarboalkoxycycloalkyl, formylalkyl, acylalkyl, S(O)R ,
13 SO2R , heteroaryloxyalkyl, aralkyl, aryloxyalkyl, aralkoxyalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl, aralkylthioalkyl, heteroaralkoxythioalkyl, alkoxyalkyl, heteroaryloxyalkyl, alkenyloxyalkyl, alkylthioalkyl, arylthioalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkenyl, cycloalkenylalkyl, haloalkyl, haloalkenyl, halocycloalkyl, aralkylsulfinylalkyl, aralkylsulfonylalkyl, carboxyalkyl, carboalkoxyalkyl, dialkoxyphosphonoalkyl, diaralkoxyphosphonoalkyl, phosphonoalkyl, dialkoxyphosphonoalkylamino, diaralkoxyphosphonoalkylamino, phosphonoalkylamino, dialkoxyphosphonoalkyl, diaralkoxyphosphonoalkyl, sulfonylalkyl, alkoxysulfonylalkyl, aralkoxysulfonylalkyl, alkoxysulfonylalkylamino, aralkoxysulfonylalkylamino and sulfonylalkylamino;
5 R can be selected from a heterocyclyl radical in which there is at least one carbon in one ring and in which 1 to about 4 members of said ring are heteroatoms independently selected from oxygen, nitrogen and sulfur and said heterocyclyl radical may be optionally substituted with heteroarylamino, N-aryl-N-alkylamino, N-heteroarylamino-N-alkylamino, haloalkylthio, alkanoyloxy, alkoxy, heteroaralkoxy, cycloalkoxy, cycloalkenyloxy, hydroxy, amino, thio, nitro, lower alkylamino, alkylthio, alkylthioalkyl, arylamino, aralkylamino, arylthio, alkylsulfinyl, alkylsulfonyl, alkylsulfonamido, alkylaminosulfonyl, amidosulfonyl, monoalkyl amidosulfonyl, dialkyl amidosulfonyl, monoarylamidosulfonyl, arylsulfonamido, diarylamidosulfonyl, monoalkyl monoaryl amidosulfonyl, arylsulfinyl, arylsulfonyl, heteroarylthio, heteroarylsulfinyl, heteroarylsulfonyl, alkanoyl, alkenoyl, aroyl, heteroaroyl, aralkanoyl, heteroaralkanoyl, haloalkanoyl, alkyl, alkenyl, alkynyl, alkylenedioxy, haloalkylenedioxy, cycloalkyl, cycloalkenyl, lower cycloalkylalkyl, lower cycloalkenylalkyl, halo, haloalkyl, haloalkoxy, hydroxyhaloalkyl, hydroxyaralkyl, hydroxyalkyl, hydoxyheteroaralkyl, haloalkoxyalkyl, aryl, aralkyl, aryloxy, aralkoxy, aryloxyalkyl, saturated heterocyclyl, partially saturated heterocyclyl, heteroaryl, heteroaryloxy, heteroaryloxyalkyl, arylalkyl, heteroarylalkyl, arylalkenyl, heteroarylalkenyl, cyanoalkyl, dicyanoalkyl, carboxamidoalkyl, dicarboxamidoalkyl, cyanocarboalkoxyalkyl, carboalkoxyalkyl, dicarboalkoxyalkyl, cyanocycloalkyl, dicyanocycloalkyl, carboxamidocycloalkyl, dicarboxamidocycloalkyl, carboalkoxycyanocycloalkyl, carboalkoxycycloalkyl, dicarboalkoxycycloalkyl, formylalkyl, acylalkyl, dialkoxyphosphonoalkyl, diaralkoxyphosphonoalkyl, phosphonoalkyl, dialkoxyphosphonoalkoxy, diaralkoxyphosphonoalkoxy, phosphonoalkoxy, dialkoxyphosphonoalkylamino, diaralkoxyphosphonoalkylamino, phosphonoalkylamino, dialkoxyphosphonoalkyl, diaralkoxyphosphonoalkyl, guanidino, amidino, and acylamino;
6 R is alkyl;
7 R is selected from the group consisting of hydrogen, aryl, heteroaralkyl, hydroxy, alkyl, alkenyl, alkynyl, amino, cyanoalkyl, dicyanoalkyl, carboxamidoalkyl, hydroxyalkyl, dicarboxamidoalkyl, cyanocarboalkoxyalkyl, carboalkoxyalkyl, dicarboalkoxyalkyl, cyanocycloalkyl, dicyanocycloalkyl, carboxamidocycloalkyl, dicarboxamidocycloalkyl, carboalkoxycyanocycloalkyl, carboalkoxycycloalkyl, dicarboalkoxycycloalkyl,
13 13 formylalkyl, acylalkyl, S(O)R , SO2R , heteroaryloxyalkyl, aralkyl, aryloxyalkyl, aralkoxyalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl, aralkylthioalkyl, heteroaralkoxythioalkyl, alkoxyalkyl, heteroaryloxyalkyl, alkenyloxyalkyl, alkylthioalkyl, arylthioalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkenyl, cycloalkenylalkyl, haloalkyl, haloalkenyl, halocycloalkyl, aralkylsulfinylalkyl, aralkylsulfonylalkyl, carboxyalkyl, carboalkoxyalkyl, dialkoxyphosphonoalkyl, diaralkoxyphosphonoalkyl, phosphonoalkyl, dialkoxyphosphonoalkylamino, diaralkoxyphosphonoalkylamino, phosphonoalkylamino, dialkoxyphosphonoalkyl, diaralkoxyphosphonoalkyl, sulfonylalkyl, alkoxysulfonylalkyl, aralkoxysulfonylalkyl, alkoxysulfonylalkylamino, aralkoxysulfonylalkylamino and sulfonylalkylamino;
7 R can be selected from a heterocyclyl radical in which there is at least one carbon in one ring and in which 1 to about 4 members of said ring are heteroatoms independently selected from oxygen, nitrogen and sulfur and said heterocyclyl radical may be optionally substituted with heteroarylamino, N-aryl-N-alkylamino, N-heteroarylamino-N-alkylamino, haloalkylthio, alkanoyloxy, alkoxy, heteroaralkoxy, cycloalkoxy, cycloalkenyloxy, hydroxy, amino, thio, nitro, lower alkylamino, alkylthio, alkylthioalkyl, arylamino, aralkylamino, arylthio, alkylsulfinyl, alkylsulfonyl, alkylsulfonamido, alkylaminosulfonyl, amidosulfonyl, monoalkyl amidosulfonyl, dialkyl amidosulfonyl, monoarylamidosulfonyl, arylsulfonamido, diarylamidosulfonyl, monoalkyl monoaryl amidosulfonyl, arylsulfinyl, arylsulfonyl, heteroarylthio, heteroarylsulfinyl, heteroarylsulfonyl, alkanoyl, alkenoyl, aroyl, heteroaroyl, aralkanoyl, heteroaralkanoyl, haloalkanoyl, alkyl, alkenyl, alkynyl, alkylenedioxy, haloalkylenedioxy, cycloalkyl, cycloalkenyl, lower cycloalkylalkyl, lower cycloalkenylalkyl, halo, haloalkyl, haloalkoxy, hydroxyhaloalkyl, hydroxyaralkyl, hydroxyalkyl, hydoxyheteroaralkyl, haloalkoxyalkyl, aryl, aralkyl, aryloxy, aralkoxy, aryloxyalkyl, saturated heterocyclyl, partially saturated heterocyclyl, heteroaryl, heteroaryloxy, heteroaryloxyalkyl, arylalkyl, heteroarylalkyl, arylalkenyl, heteroarylalkenyl, cyanoalkyl, dicyanoalkyl, carboxamidoalkyl, dicarboxamidoalkyl, cyanocarboalkoxyalkyl, carboalkoxyalkyl, dicarboalkoxyalkyl, cyanocycloalkyl, dicyanocycloalkyl, carboxamidocycloalkyl, dicarboxamidocycloalkyl, carboalkoxycyanocycloalkyl, carboalkoxycycloalkyl, dicarboalkoxycycloalkyl, formylalkyl, acylalkyl, dialkoxyphosphonoalkyl, diaralkoxyphosphonoalkyl, phosphonoalkyl, dialkoxyphosphonoalkoxy, diaralkoxyphosphonoalkoxy, phosphonoalkoxy, dialkoxyphosphonoalkylamino, diaralkoxyphosphonoalkylamino, phosphonoalkylamino, dialkoxyphosphonoalkyl, diaralkoxyphosphonoalkyl, guanidino, amidino, and acylamino; g
R is selected from hydrogen, hydroxyalkyl, alkyl, and alkoxyalkyl;
13 R is independently selected from aryloxy, amino, alkylamino, dialkylamino, hydroxyalkyl, heteroaryloxyalkyl, alkoxy, alkylthio, arylthio, alkyl, alkenyl, alkynyl, aryl, aralkyl, aryloxyalkyl, aralkoxyalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl, aralkylthioalkyl, heteroaralkoxythioalkyl, alkoxyalkyl, heteroaryloxyalkyl, alkenyloxyalkyl, alkylthioalkyl, arylthioalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkenyl, cycloalkenylalkyl, haloalkyl, haloalkenyl, haloaralkylsulfinylalkyl, aralkylsulfonylalkyl, cyanoalkyl, dicyanoalkyl, carboxamidoalkyl, dicarboxamidoalkyl, cyanocarboalkoxyalkyl, carboalkoxyalkyl, dicarboalkoxyalkyl, cyanocycloalkyl, dicyanocycloalkyl, carboxamidocycloalkyl, dicarboxamidocycloalkyl, carboalkoxycyanocycloalkyl, carboalkoxycycloalkyl, dicarboalkoxycycloalkyl, formylalkyl, acylalkyl, dialkoxyphosphonoalkyl, diaralkoxyphosphonoalkyl, phosphonoalkyl, dialkoxyphosphonoalkoxy, diaralkoxyphosphonoalkoxy, phosphonoalkoxy, dialkoxyphosphonoalkylamino, diaralkoxyphosphonoalkylamino, phosphonoalkylamino, dialkoxyphosphonoalkyl, diaralkoxyphosphonoalkyl, sulfonylalkyl, alkoxysulfonylalkyl, aralkoxysulfonylalkyl, alkoxysulfonylalkoxy, aralkoxysulfonylalkoxy, sulfonylalkoxy, alkoxysulfonylalkylamino, aralkoxysulfonylalkylamino, sulfonylalkylamino, a natural amino acid, synthetic amino acid, and a polyhydroxy compound of carbon;
X is selected from the group consisting of alkylene, alkenylene, alkynylene, -
(CH2)pQ(CH2)r- wherein p is 1 to 3, r is 1 to 3 and Q is selected from oxygen, S(O)t,
wherein t is 0 to 2, -(CH2)ST(CH2)V- wherein s is O to 2, v is 0 to 2 and T is a heterocyclyl radical, wherein all positions on X may be optionally substituted with one or more selected from the group consisting of halogen, Ci- o alkyl, C\-C\Q alkoxy, hydroxy, haloalkyl, nitro, cyano, and amino;
Y is selected from the group consisting of alkyl, alkenyl, alkynyl, and alkylaminoalkyl.
5. The compound as recited in Claim 4 or a pharmaceutically acceptable salt thereof, wherein;
B is B2 wherein f is the integer 2 and g, h, and i are each the integer zero;
7 B2 is a linker connecting a first Ia group from the point of attachment of A-R to a
7 second Ia group from the point of attachment of A-R wherein said
linker is selected from the group of radicals consisting of -OCH(COOH)CH(COOH)O-, - OCH2CH(O-)(CH(OH)) COOH,
-OCH2CH(OH)CH(O-)(CH(OH))2COOH, -OCH2CH(O-)CH2(OH),
-OCH2(CH(OH))2CH(O-)CH(OH)COOH, -OCH2CH(OH)CH (O-),
-OCH2(CH(OH))3CH(O-)COOH, and -OCH2CH(O-)CH3 ;
B2 can be a linker selected from the group of radicals consisting of natural amino acids and synthetic amino acids wherein said amino acid radicals have two or more acylateable functional groups are selected from the group consisting of -SCH2CH(NH-
)COOH, -OCH2CH(NH-)COOH,
HOOCCH(NH-)CH2S-SCH CH(NH-)COOH, -O(CH.3)CHCH(NH-)COOH,
-NHC(=NH)NHCH2CH2CH2CH(NH-)COOH, -NHCH2CH2CH2CH CH(NH-)COOH,
and (4-(-O)C6H4)CH2CH(NH-)COOH.
6. The compound as recited in Claim 4 or a pharmaceutically acceptable salt thereof, wherein; B is B2 wherein f is the integer 2 and g, h, and i are each the integer zero;
7 B2 is linker connecting a first Ia group from the point of attachment of A-R to a
7 second Ia group from the point of attachment of A-R wherein said linker is selected from a group compounds consisting of tartaric acid, propylene glycol, gluconic acid, glycerin, cysteine, cystine, arginine, lysine, serine, threonine, and tyrosine.
7. The compound as recited in Claim 4 or a pharmaceutically acceptable salt thereof, wherein;
B is B3 wherein f is the integer 2 and g, h, and i are each the integer zero;
7 B3 is a linker connecting Ia groups from the point of attachment of each A-R of
said Ia groups wherein the number of groups attached to said linker from the point of
7 attachment of A-R is kk wherein kk is the integer 2 wherein the number of acylateable
functions present on said linker are at least two with the proviso that no more than two Ia groups are simultaneously present on said linker and wherein said linker is selected from the group consisting of a polyhydroxy compound of carbon selected from the group consisting of polyhydroxyalkanes, saccharides, disaccharides, polysaccharides, inositols, alditols, alditol acetals, alditol ketals, aldaric acids, aldonic acids, and aldonic acid lactones.
8. The compound as recited in Claim 4 or a pharmaceutically acceptable salt thereof, wherein;
B is B3 wherein f is the integer 2 and g, h, and i are each the integer zero; 7 B3 is linker connecting a first Ia group from the point of attachment of A-R to a
7 second Ia group from the point of attachment of A-R wherein said linker is selected from a group compounds consisting of tartaric acid, propylene glycol, gluconic acid, glycerin, glycerol monostearate, methyl cellulose, ascorbic acid, erythrobic acid, inositol, mannitol, and sorbitol.
9. The compound as recited in Claim 4 or a pharmaceutically acceptable salt thereof, wherein;
B is B4 wherein f is the integer 2 and g, h, and i are each the integer zero;
B4 is a linker, connecting a first Ia group through the point of bonding of a removable hydrogen of a substituent independently selected from a group of substituents
1 3 4 1 3 4 consisting of R , R , and R wherein R , R and R are independently selected from the group consisting of hydrogen, hydroxy, and sulfhydryl, to a second Ia group through the point of bonding of a removable hydrogen of a substituent of said second Ia group
1 3 4 independently selected from a group of substituents consisting of R , R , and R wherein
1 3 4
R , R and R are independently selected from the group consisting of hydrogen, hydroxy, and sulfhydryl and wherein said linker is selected from the group of radicals
30 consisting of C=O, SO2, P(O)R , -(O)C(CH2)2C(O)-,
-(O)C(CH2)4C(O)-, -(O)CCH(OH)CH(OH)C(O)-,
-(O)CCH C(OH)(COOH)CH2C(O)-, -(O)CCH C(OH)(C(O)-)CH2COOH, and -
(O)C(CH2)2S(CH2)2C(O)-.
10. The compound as recited in Claim 4 or a pharmaceutically acceptable salt thereof, wherein;
B is B4 wherein f is the integer 2 and g, h, and i are each the integer zero;
B4 is a linker, connecting a first Ia group through the point of bonding of a removable hydrogen of a substituent independently selected from a group of substituents
1 3 4 consisting of R , R , and R to a second Ia group through the point of bonding of a removable hydrogen of a substituent of said second Ia group independently selected from
1 3 4 a group of substituents consisting of R , R , and R wherein said linker is selected from a group compounds consisting of adipic acid, citric acid, phosphoric acid, tartaric acid, succinic acid, sulfuric acid, carbonic acid, and thiodipropionic acid.
11. The compound as recited in Claim 4 or a pharmaceutically acceptable salt thereof, wherein;
B is B7 wherein f is the integer 2 and g, h, and i are each the integer zero;
B 7 is an amide and ester forming linker connecting an Ia group through the point of bonding of a removable hydrogen of a substituent independently selected from a group
1 3 4 1 3 4 of substituents consisting of the group R , R , and R wherein R , R and R are independently selected from the group consisting of hydrogen, hydroxy, and sulfhydryl of said Ia group to a second Ia group attached to said linker through the point of bonding of a
removable hydrogen of a substituent independently selected from said second Ia group of 1 3 4 1 3 4 substituents consisting of R , R , and R wherein R , R and R are independently
selected from the group consisting of hydrogen, hydroxy, and sulfhydryl of said second Ia group wherein said linker is selected from the group of radicals consisting of - (O)C(CH2)2C(O)-, -(O)C(CH2)4C(O)-,
-(O)CCH(OH)CH(OH)C(O)-, -(O)CCH2C(OH)(COOH)CH2C(O)-,
-(O)CCH2C(OH)(C(O)-)CH2COOH, -(O)CCH2CH(NH2)C(O)-,
and -(O)CCH2CH2CH(NH2)C(O)-.
12. The compound as recited in Claim 4 or a pharmaceutically acceptable salt thereof, wherein;
B is B7 wherein f is the integer 2 and g, h, and i are each the integer zero;
B7 is a linker, connecting a first Ia group through the point of bonding of a removable hydrogen of a substituent independently selected from a group of substituents
1 3 4 consisting of R , R , and R to a second Ia group through the point of bonding of a removable hydrogen of a substituent independently selected from a group of substituents
1 3 4 of said second Ia group consisting of R , R , and R wherein said linker is selected from a group compounds consisting of adipic acid, citric acid, tartaric acid, succinic acid, aspartic acid, and glutamic acid.
13. The compound as recited in Claim 4 or a pharmaceutically acceptable salt thereof, wherein;
B is B9 wherein f is the integer 2 and g, h, and i are each the integer zero; 7 B9 is a linker connecting a first Ia group from the point of attachment of A-R to a
second Ia group through the point of bonding of a removable hydrogen of a substituent of
said second Ia group independently selected from a group of substituents consisting of R ,
3 4 1 3 4
R , and R wherein R , R and R are independently selected from the group consisting of hydrogen, hydroxy, and sulfhydryl wherein said linker is selected from the group of radicals consisting of
HOOCCH(OH)CH(O-)C(O)-, -(O)CCH(OH)CH(O-)COOH,
HOOCCH2C(O-)(COOH)CH2C(O)-, CH3CH(O-)C(O)-,
HOOCCH2C(O-)(C(O)-)CH2COOH, -(O)CCH2CH(NH-)COOH,
-(O)CCH2CH2CH(NH-)COOH, HOOCCH2CH2CH(NH-)C(O)-,
HOOCCH2CH(NH-)C(O)-, -(O)CCH2CH(O-)COOH, HOOCCH2CH(O-)C(O)-,
CH2(NH-)C(O)-, CH CH(NH-)C(O)-, HSCH2CH(NH-)C(O)-,
-SCH2CH(NH2)C(O)-, HOOCCH(NH2)CH2S-SCH2CH(NH-)C(O)-,
NH2C(=NH)NHCH2CH2CH2CH(NH-)C(O)-,
-NHC(=NH)NHCH2CH2CH2CH(NH2)C(O)-,
4-imidazolylCH2CH(NH-)C(O)-, NH2CH2CH2CH2CH2CH(NH-)C(O)-, -NHCH CH2CH2CH2CH(NH )C(O)-, CH CH2CH(CH3)CH(NH-)C(O)-,
(CH3)2CHCH2CH(NH-)C(O)-, CH3)2CHCH(NH-)C(O)-, CH3SCH2CH2CH(NH-)C(O)-
, CH3SCH2CH2CH(O-)C(O)-, (C6H5)CH2CH(NH-)C(O)-, -OCH2CH(OH)POH(O)-,
CH2(OH)CH(O-)POH(O)-, HOCH CH(NH-)C(O)-, -OCH2CH(NH2)C(O)-, (4-
HOC6H4)CH2CH(NH-)C(O)-, (4-(-O)C6H4)CH2CH(NH2)C(O)-,
3-IndolylCH2CH(NH-)C(O)-, HO(CH3)CHCH(NH-)C(O)-,
-O(CH3)CHCH(NH2)C(O)-, and
Figure imgf000304_0001
14. The compound as recited in Claim 4 or a pharmaceutically acceptable salt thereof, wherein:
B is B9 wherein f is the integer 2 and g, h, and i are each the integer zero;
7 B9 is a linker connecting a first Ia group from the point of attachment of A-R to a
second Ia group through the point of bonding of a removable hydrogen of a substituent of
said second Ia group independently selected from a group of substituents consisting of R ,
3 4 1 3 4 R , and R wherein R , R and R are independently selected from the group consisting of hydrogen, hydroxy, and sulfhydryl wherein said linker is selected from the group of acids consisting of citric acid, lactic acid, malic acid, tartaric acid, gluconic acid, glutamic acid, glutamine, carboxymethylcellulose, aspartic acid, asparagine, glycine, alanine, arginine, cysteine, cystine, histidine, isoleucine, leucine, lysine, methionine, methionine hydroxy analog, phenylalanine, glycerolphosphoric acid, serine, proline, threonine, tryptophan, tyrosine, and valine.
15. The compound or a pharmaceutically acceptable salt of a compound Claim 1 wherein the compound is selected from the group consisting of : l,5-Bis-[6-(N-(l- iminoethyl)amino)-2-amino-2-methylhexanamido]pentane tetrahydrochloride; 4-[6-(N-( 1 -iminoethyl)amino)-2-amino-2-methylhexanamido] - 1 - [6-(N-( 1 - oximinoethyl)amino)-2-amino-2-methylhexanamido]butane tetrahydrochloride; l,5-bis[3-(2-(N-(l-iminoethyl)amino)ethylthio)-2-aminopropanamido]-pent-3-one tetrahydrochloride; a,a'-Bis[N-ethyl-6-(N-(l-oximinoethyl)amino)-2-amino-2-methylhexanamido]-m-xylene; 3-[N-methyl-6-(N-(l-oximinoethyl)amino)-2-amino-2-methylhexanamidomethyl]-benzyl 6-(N-(l-oximinoethyl)amino)-2-amino-2-methylhexanoate tetrahydrochloride; 2-[2-[N-Methyl-6-(N-(l-oximinoethyl)amino)-2-amino-2-methylhexanamido]ethoxy]ethyl 6-(N-(l-oximinoethyl)amino)-2-amino-2-methylhexanoate tetrahydrochloride; N,N-bis[4-[N-(3-(2-(N-( 1 -oximoethyl)amino)ethylthio)- 1 -(N- tetrazolylamidocarbonyl)propyl)imino]butyl] -N-methylamine penta-p-toluenesulfonic acid salt; l,3-bis[2-[N-(5-(N-(l-iminoethyl) amino)- l-carboxypentyl)iminopropyl]benzene tetra-p- toluenesulfonic acid salt;
6-(N-( 1 -iminoethyl)amino)-2-[3- [2-(N-(5-(N-( 1 -iminoethyl)amino)- 1 - carboxypentyl)imino)propyl]phenylacetamido]-hexanoic acid tri-p-toluenesulfonic acid salt; 6-(N-(l-iminoethyl)amino)-2-[4-[4-(N-(5-(N-(l-iminoethyl)amino)-l- carboxypentyl)imino)pentylthio]butanamido]-hexanoate tri-p-toluenesulfonic acid salt; N,N'-bis[5-(N-(l-iminoethyl)amino)-l-carboxypentyl]oxamide dihydrochloride;
6-[N-[l-[N-(2-(6-(N-(l-iminoethyl)amino)-2- aminohexanamido)acetoxy)imino]ethyl]amino]-2-aminohexanoic acid tetrahydrochloride; N,N'-bis(5-amino-5-carboxypentyl)-N,N'-bis(l-iminoethyl)glutar amide tetrahydrochloride ;
6- [N-( 1 -iminoethyl) amino] -2- [4- [N-(5-amino-5-carboxypentyl)-N-( 1 -iminoethyl))- amidocarbonylmethyl]phenylacetamido]hexanoic acid trihydrochloride; 2,5-bis(4-(N-(l-iminoethyl)amino)butyl)-2,5-dihydropyrazine tetrahydrochloride; give 2,5-bis[4-(N-(l-iminoethyl)amino)butyl]-2,3,4,5-tetrahydro-3-oxopyrazine trihydrochloride;
3-methyl-3,6-bis(4-(N-(l-iminoethyl)amino)butyl)-2,5-dioxopiperazine; 2,5-bis[6-(N-(2-fluoro-l-iminoethyl)amino)-2-aminohexanamido]pentanoic acid;
2,4-dihydroxy-3- [6-(N-( 1 -iminoethyl)amino)-2-aminohexanoyloxy ]butyl 6-(N-(2-fluoro- l-iminoethyl)amino)-2-aminohexanoate tetra-p-toluenesulfonic acid salt; 2-[3-(2-(N-(l-iminoethyl)amino) ethylthio)-2-aminopropanoyloxy]-3-[6-(N-(l- iminoethyl)amino)-2-aminohexanoyloxy]-4-[6-(N-(l-oxyiminoethyl)amino)-2- aminohexanoyloxy]butyl 6-(N-(2-fluoro- 1 -iminoethyl)amino)-2-aminohexanoate octyl-p- toluenesulfonic acid salt; l-[N-[5-(N-(l-iminoethyl)amino)-l-carboxypentyl]amidocarbonyl]-4-[N-[5-(N-(2-fluoro- l-iminoethyl)amino)-l-carboxypentyl]amidocarbonyl]-2,3-butanedicarboxylic acid;
1 - [N- [5-(N-( 1 -iminoethyl)amino)- 1 -carboxypentyl] amidocarbonyl] -2- [N- [5-(N-( 1 - oximinoethyl)amino)-l-carboxypentyl]amidocarbonyl]-3-[N-[2-(2-(N-(l- iminoethyl)amino)ethylthio)- 1 -carboxyethyl] amidocarbonyl] -4- [N- [5-(N-(2-fluoro- 1 - iminoethyl)amino)- 1 -carboxypentyl]amidocarbonyl]butane;
N-[5-(N-( 1 -iminoethyl)amino)- 1 -methyl- 1 -carboxypentyl]-2-[6-(N-( 1 -iminoethyl)amino)- 2-aminohexanoyloxy]acetamide tri-p-toluenesulfonic acid salt;
6-(N-(2-fluoro-l-iminoethyl)amino)-2-[2-(6-(N-(l-iminoethyl) amino)-2- aminohexanoyloxy)acetamidomethyl]-2-aminohexanoic acid tetra-p-toluenesulfonic acid salt;
2-[N-[6-(N-(l-iminoethyl)amino)-l-carboethoxypentyl]imino]propyl 6-(N-(l- iminoethyl)amino)-2-aminohexanoate tetra-p-toluenesulfonic acid salt; N-[2-[2-[3-(5-(N-(l-Iminoethyl)amino)-l-ethoxycarbonylpentyl)imino]propoxy]ethyl]-6- (N-(l -iminoethyl) amino)-2-aminohexanamide tetra-p-toluenesulfonic acid salt; N-[2-[4-(N-(5-(N-( 1 -iminoethyl)amino)- 1 - methoxycarbonylpentyl)imino)butyl)phenyl]ethyl]-N-methyl-6-(N-(l-iminoethyl)amino)- 2-aminohexanamide tetra-p-toluenesulfonic acid salt;
2- [4- [N-(5-(N-( 1 -iminoethyl)amino)- 1 -ethoxycarbonylpentyl)imino] cyclohexyl]ethyl 6- (N-(l-iminoethyl)amino)-2-aminohexanoate tetra-p-toluenesulfonic acid salt;
2- [2- [6-(N-( 1 -iminoethyl)amino)-2-aminohexanoyloxy]ethoxy]ethyl 6-(N-( 1 - iminoethyl)amino)-2-aminohexanoate tetra-p-toluenesulfonic acid salt; 4-[2-[6-(N-(l-iminoethyl)amino)-2-aminohexanoyloxy]ethyl]phenethyl 6-(N-(l- iminoethyl)amino)-2-aminohexanoate tetra-p-toluenesulfonic acid salt; 3-[2-(N-(l-iminoethyl)amino) ethylthio]-2-[N-[bis[N-(5-(N-(l-iminoethyl)amino)-l- carboxypentyl)amino]phosphinylmethyl]glycinamido]propanoic acid tetrahydrochloride;
3- [2-(N-( 1 -iminoethyl)amino)ethylthio] -2- [N- [bis [N-(5-(N-( 1 -iminoethyl)amino)- 1 - (benzyloxycarbonyl)pentyl) amino] phosphinylmethyl]-N-[6-(N-(2-fluoro-l-iminoethyl) amino)-2-(N-Z-amino)hexanoyl]glycinamido]propanoic acid;
N-[2- [N- [2-(6-(N-(2-fluoro- 1 -iminoethyl)amino)-2-aminohexanamido) ethyl] -6-(N-( 1 - iminoethyl)amino)-2-aminohexanamido]ethyl]-N-[2-[N-[2-(3-(2-(N-(l- iminoethyl)amino)ethyltWo)-2-aminopropanamido)ethyl]-6-(N-(l-iminoethyl)amino)-2- aminohexanamido]ethyl]-6-[N-(l-iminoethyl)amino]-2-aminohexanamide.
16. A method of inhibiting nitric oxide synthesis in a subject in need of such inhibition by administering a therapeutically effective amount of a compound of any of claims 1 through 15.
17. A method of selectively inhibiting nitric oxide synthesis produced by inducible NO synthase over nitric oxide produced by the constitutive forms of NO synthase in a subject in need of such selective inhibition by administering a therapeutically effective amount of a compound of any of claims 1 through 15.
18. A method of lowering nitric oxide levels in a subject in need of such by administering a therapeutically effective amount of a compound of anyone of claims 1 through 15.
19. A pharmaceutical composition comprising a compound of anyone of claims 1 through 15 together with one or more pharmaceutically acceptable carriers.
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