WO2001005748A1 - Derives oligomeriques d'acides amines utilises comme inhibiteurs de l'oxyde nitrique synthase - Google Patents

Derives oligomeriques d'acides amines utilises comme inhibiteurs de l'oxyde nitrique synthase Download PDF

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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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R. Keith Webber
Melvin L. Reuppel
Donald W. Hansen, Jr.
E. Ann Hallinan
Timothy J. Hagen
Barnett S. Pitzele
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Monsanto Company
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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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    • C07C323/57—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 the carbon skeleton being further substituted by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C323/58—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 the carbon skeleton being further substituted by nitrogen atoms, not being part of nitro or nitroso groups with amino groups bound to the carbon skeleton
    • C07C323/59—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 the carbon skeleton being further substituted by nitrogen atoms, not being part of nitro or nitroso groups with amino groups bound to the carbon skeleton with acylated amino groups bound to the carbon skeleton
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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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    • C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
    • 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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    • C07D257/00—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms
    • C07D257/02—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D257/04—Five-membered rings
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    • C07F9/02—Phosphorus compounds
    • C07F9/28—Phosphorus compounds with one or more P—C bonds
    • C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
    • 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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    • C07F9/28—Phosphorus compounds with one or more P—C bonds
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    • C07F9/44—Amides thereof
    • C07F9/4461—Amides thereof the amide moiety containing a substituent or a structure which is considered as characteristic
    • C07F9/4465—Amides thereof the amide moiety containing a substituent or a structure which is considered as characteristic of aliphatic amines
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    • C07F9/6581—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
    • 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
    • C07F9/65844—Cyclic amide derivatives of acids of phosphorus, in which one nitrogen atom belongs to the ring the phosphorus atom being part of a five-membered ring which may be condensed with another ring system
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    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
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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

La présente invention concerne de nouveaux dérivés oligomériques d'amidino aminocarboxylate utilisés comme inhibiteurs de l'oxyde nitrique synthase.
PCT/US2000/019373 1999-07-15 2000-07-14 Derives oligomeriques d'acides amines utilises comme inhibiteurs de l'oxyde nitrique synthase WO2001005748A1 (fr)

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WO2003097050A2 (fr) * 2002-05-16 2003-11-27 Pharmacia Corporation Methodes de traitement de maladies et de troubles respiratoires avec un inhibiteur inos selectif et un inhibiteur pde et compositions a cet effet

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WO1995025717A1 (fr) * 1994-03-24 1995-09-28 G.D. Searle & Co. Derives amidino utiles comme inhibiteurs de la synthase d'oxyde nitrique
WO1996015120A1 (fr) * 1994-11-09 1996-05-23 G.D. Searle & Co. Derives d'aminotetrazole utiles en tant qu'inhibiteurs de la monoxyde d'azote synthetase

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WO1995025717A1 (fr) * 1994-03-24 1995-09-28 G.D. Searle & Co. Derives amidino utiles comme inhibiteurs de la synthase d'oxyde nitrique
WO1996015120A1 (fr) * 1994-11-09 1996-05-23 G.D. Searle & Co. Derives d'aminotetrazole utiles en tant qu'inhibiteurs de la monoxyde d'azote synthetase

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003097050A2 (fr) * 2002-05-16 2003-11-27 Pharmacia Corporation Methodes de traitement de maladies et de troubles respiratoires avec un inhibiteur inos selectif et un inhibiteur pde et compositions a cet effet
WO2003097050A3 (fr) * 2002-05-16 2004-06-17 Pharmacia Corp Methodes de traitement de maladies et de troubles respiratoires avec un inhibiteur inos selectif et un inhibiteur pde et compositions a cet effet

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