WO2000044731A1 - Novel hydroxyamidino carboxylate derivatives useful as nitric oxide synthase inhibitors - Google Patents

Novel hydroxyamidino carboxylate derivatives useful as nitric oxide synthase inhibitors Download PDF

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Publication number
WO2000044731A1
WO2000044731A1 PCT/US2000/000491 US0000491W WO0044731A1 WO 2000044731 A1 WO2000044731 A1 WO 2000044731A1 US 0000491 W US0000491 W US 0000491W WO 0044731 A1 WO0044731 A1 WO 0044731A1
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group
amino
alkyl
heteroaryloxyalkyl
diaralkoxyphosphonoalkyl
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PCT/US2000/000491
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French (fr)
Inventor
R. Keith Webber
Melvin L. Rueppel
Donald W. Hansen, Jr.
E. Ann Hallinan
Timothy J. Hagen
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G.D. Searle & Co.
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Priority to AU28472/00A priority Critical patent/AU2847200A/en
Publication of WO2000044731A1 publication Critical patent/WO2000044731A1/en

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    • C07D209/44—Iso-indoles; Hydrogenated iso-indoles
    • C07D209/48—Iso-indoles; Hydrogenated iso-indoles with oxygen atoms in positions 1 and 3, e.g. phthalimide
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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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    • C07D263/30—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
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    • C07D265/34—1,4-Oxazines; Hydrogenated 1,4-oxazines condensed with carbocyclic rings
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    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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Definitions

  • the present invention relates to novel hydroxamidino carboxylate derivatives and their use in therapy, in particular their use as nitric oxide synthase inhibitors.
  • endothelium- derived relaxing factor a labile humoral factor termed endothelium- derived relaxing factor (EDRF) .
  • EDRF endothelium- derived relaxing factor
  • NO nitric oxide
  • amylnitrite, glyceryltrinitrate and other nitrovasodilators have 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.
  • NO is involved in a number of biological 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 therapy with certain cytokines (Kerwin et al . , J. Medicinal Chemistry, 38, 4343- 4362, 1995).
  • L-arginine analogue L-N-monomethyl-arginine
  • L-NMMA L-N-monomethyl-arginine
  • 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.
  • 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
  • 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
  • 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) .
  • 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.
  • 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.
  • 29 J is selected from the group consisting of 0, NR and S ; 29 . 29 J can be R , wherein R is a group selected from
  • 23 23 J 1 and J 2 are independently selected from OR , SR
  • 15 15 G is selected from O, S, CH2 , CHR , C(R ) 2 , NH and
  • A is selected from the group consisting of O, N(R ), S and heterocyclyl with the proviso that J is selected from other than 0 and A is selected from other than O, S and
  • C(R 15 )2, NH, and NR 15 and R 15 is selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl and heteroaryl;
  • A is selected from the group consisting of 0, N(R )
  • C(0)R 15 can represent natural and synthetic amino acids and where R ⁇ s selected from substituted dihydropyridyl , alkyl, alkylthio, alkoxy, amino
  • R is selected from other than H, alkanoyl
  • R is selected from other than hydrogen, hydroxyalkyl, alkoxyalkyl, alkyl and haloalkyl;
  • A can be selected from the group selected from 0,
  • N(R ) and S connected to the point of attachment of R by a spacer group selected from a group consisting of a covalent bond and a linear moiety having a chain length of 1 to 4 atoms to form C6 to CIO heterocyclyl provided that the linear moiety is selected from other than 0 and S;
  • A can be selected from the group selected from 0,
  • R and R by a spacer group selected from a linear moiety having a chain length of 1 to 6 atoms to form C5 to
  • R is selected from other than H, S(0)R 13 , SO2R 13 , CH2 ⁇ C(0)R 15 and C(0)R-'-5 where C(0)R-'- ⁇ may represent natural and synthetic amino acids and where R!5 j_ s selected from substituted dihydropyridyl, alkyl, alkylthio, alkoxy, amino
  • R is selected from other than H
  • alkanoyl and aroyl or R is selected from other than hydrogen, hydroxyalkyl, alkoxyalkyl, alkyl and haloalkyl;
  • A can be selected from the group consisting of O,
  • N(R ) and S connected to the points of attachment of R and 2 R by a spacer group selected from a linear moiety having a chain length of 1 to 6 to form C5 to CIO heterocyclyl;
  • A can be selected from the group consisting of 0,
  • A can be R with the proviso that when R is H, R is
  • R is selected from other than hydrogen, or R is selected from other than H, S(0)R 13 , S02R 13 , CH2 ⁇ C(0)R 15 and C(0)R 15 wherein C(0)R-'- ⁇ can represent natural and synthetic amino acids and wherein R ⁇ i ⁇ selected from substituted
  • R is selected from other than H, alkanoyl and aroyl, or J is selected from other than O;
  • A can be R , wherein R is selected from the group
  • 5 7 , 5 7 25 5 13 consisting of N(R ) OR , N(R )N(R )R , N(R ) SO2R ,
  • R and R are independently selected from the group
  • 6 6 consisting of hydrogen, hydroxyl, sulfhydryl, OR , SR , cyanoalkyl , dicyanoalkyl , carboxamidoalkyl , dicarboxamidoalkyl , cyanocarboalkoxyalkyl, carboalkoxyalkyl, dicarboalkoxyalkyl , cyanocycloalkyl, dicyanocycloalkyl , carboxamidocycloalkyl , dicarboxamidocycloalkyl , carboalkoxycyanocycloalkyl , carboalkoxycycloalkyl , dicarboalkoxycycloalkyl , formylalkyl, acylalkyl , CH2SO3- M + , CH 2 CH 2 S03 ⁇ M+ , CH2PO3 "
  • OC(0)GR , SC(0)GR and R (R )CH provided that R is selected from other than H, S(0)R 13 , SO2R 13 , CH2 ⁇ C(0)-R 15 and C(0)R where C(0)R-'- ⁇ can represent natural and synthetic amino acids and where R ⁇ is selected from substituted dihydropyridyl, alkyl, alkylthio, alkoxy, amino
  • J is selected from NR , R and S,
  • R is selected from other than H, alkanoyl and aroyl, R is
  • A is R , or R is selected from other than hydrogen, hydroxyalkyl, alkoxyalkyl, alkyl and haloalkyl or
  • R is selected from other than H, alkanoyl
  • C(0)R 15 can represent natural and synthetic amino acids where R15 i s selected from substituted dihydropyridyl, alkyl, alkylthio,
  • J is selected from NR , R
  • R is present, A is R , or R is selected from other than hydrogen, hydroxyalkyl, alkoxyalkyl, alkyl or haloalkyl;
  • R or R substituents one or more R or R substituents, aryl radicals, heteroaryl radicals, saturated heterocyclic radicals and partially saturated heterocyclic radicals where said radicals are 1, 2-disubstituted and said 1, 2-substitutents are independently selected from the group consisting of
  • R or R substituents 3 4 R and R are independently selected from the group
  • R is present, A is R , or R is selected from other than hydrogen, hydroxyalkyl, alkoxyalkyl, alkyl and haloalkyl;
  • 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 , formylalkyl, acylalkyl, heteroaryl polyhydroxyalkyl, 13 13 30 31 polyacycloalkyl, carboalkoxy, S(0)R , SO2R , P(0)
  • R is selected from other than the group consisting of hydrogen, alkyl, alkenyl, aryl, heteroaryl, aralkyl, heteroaralkyl, hydroxyalkyl, polyhydroxyalkyl, amino, hydroxy, polyacyloxyalkyl,
  • G is independently selected from 0, S, CH2 , CHR 15 , C(R 15 )2, NH, and NR 15 and where R ⁇ 5 is selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl and heteroaryl
  • J is selected from NR , R and S, R and R are
  • R is present, A is R , or R is selected from other than hydrogen, hydroxyalkyl, alkoxyalkyl, alkyl and haloalkyl;
  • 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 C5 to C8 heterocyclyl;
  • R can be 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 the group consisting of oxygen, nitrogen and sulfur and said heterocyclyl radical may be optionally substituted with heteroarylamino, N-aryl-N-alkylamino,
  • 5 1 is selected from other than H when A is N(R ) unless R and
  • R is selected from the group selected from hydrogen, heterocyclic, heteroaryl, hydroxyalkyl, minoalkyl, heteroaryloxyalkyl, alkyl, alkenyl, alkynyl, aryl, aralkyl, aryloxyalkyl, aralkoxyalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl , aralkylthioalkyl , heteroaralkoxythioalkyl, alkoxyalkyl, heteroaryloxyalkyl, alkenyloxyalkyl, alkylthioalkyl, arylthioalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkyl, cycloalkylalkenyl , cycloalkenyl, cycloalkenylalkyl, haloalkyl, haloalkenyl, halocycaralkylsul
  • A is R , R and R are taken together, or R is selected from other than hydrogen, hydroxyalkyl, alkoxyalkyl, alkyl and haloalkyl;
  • 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,
  • R is selected from other than the group consisting of hydrogen, alkyl, alkenyl, aryl, heteroaryl, aralkyl, heteroaralkyl, hydroxyalkyl, polyhydroxyalkyl, amino, hydroxy,
  • G is selected from the group consisting of 0, S, CH2 , CHR 15 , C(R 15 )2 NH, and NR 15 and wherein R 15 is selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl and heteroaryl unless J is selected
  • R is selected from other than hydrogen, hydroxyalkyl, alkoxyalkyl, alkyl and haloalkyl; or
  • R 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 C5 to C8 heterocyclyl;
  • heterocyclyl radical 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, monoalkyl
  • R and S or J 1 and J 2 are selected from two groups 23 23 24 independently selected from OR , SR NHR and
  • N(R )R , R and R are taken together when A is R , or
  • R is selected from other than H when A is
  • R is selected from hydrogen, hydroxyalkyl, haloalkyl, alkyl, alkoxyalkyl, aminoalkyl, alkylaminoalkyl, alkylthioalkyl, cyanoalkyl, sulfhydrylalkyl, formyl, C(0)A-
  • R is selected from other than hydrogen, hydroxyalkyl, haloalkyl, alkyl, alkoxyalkyl
  • J 1 and J 2 are selected from NR , R and S, R is , 2 , , . 27 present, R and R are taken together, or A is R
  • R is independently selected from aryloxy, ammo, 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,
  • 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, haloalky
  • + M is a pharmaceutically acceptable cation
  • X is selected from the group consisting of alkylene, alkenylene, and alkynylene groups which may be optionally substituted from the group consisting of alkyl, alkoxy, hydroxy, sulfhydryl, halogen, trifluoromethyl, nitro, cyano and amino; or
  • 21 21 t is 0 to 2
  • P(0)R wherein R is hydroxyl or alkyl which may be optionally substituted with one of the group consisting of alkyl, alkoxy, hydroxy, halogen,
  • n 1 to 2 and R is selected from the group consisting of hydrogen, oxy, hydroxyl and alkyl which may be optionally substituted from the group consisting of alkyl, alkoxy, hydroxy, halogen, trifluoromethyl , nitro, cyano and amino ;
  • X can be - (CH 2 ) S T (CH 2 ) v _ wherein s is O to 2, v is 0 to
  • T is selected from a 3 to 6 membered carbocyclic radical, aryl radical and a heterocyclyl radical where all said radicals may be optionally substituted with alkyl, alkoxy, hydroxy, halogen, trifluoromethyl, nitro, cyano and amino;
  • Y is selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxyalkyl, cycloalkyl, cycloalkenyl, cycloalkenyloxy, alkenyloxyalkyl, alkylthioalkyl,
  • R and R are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, nitro, amino, hydroxy, alkoxy, aryl, heterocyclyl, and aralkyl;
  • 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 C3 to C8 heterocyclyl;
  • 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, halocyclo
  • R and R can be taken together to form a linear moiety spacer group having a chain length of 2 to 7 atoms to form a group consisting of C3 to C8 cycloalkyl, C3 to C8 cycloalkenyl and C3 to C8 heterocyclyl;
  • 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, halocycloalkyl, halocycloalkenyl, haloalkoxyalky
  • 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, halocycloalkyl, halocycloal
  • R and R can be taken together to form a spacer group independently selected from a linear moiety having a chain length of 4 to 7 atoms to form C5 to C8 heterocyclyl;
  • 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 , carboalkoxy
  • R is other than hydrogen; 28 R is independently selected from a group consisting of
  • R and R independently selected from the group 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, cycloalkenyl, cycloalkenylalky
  • 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 are also included in the family of compounds of Formula I and II.
  • 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 1 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-hydroxybenzoic, phenylacetic, mandelic, embonic (pamoic), methanesulfonic, ethylsulfonic, benzenesulfonic, sulfanilic, stearic, cyclohexylaminosulfonic, algenic, galacturonic acid.
  • Suitable pharmaceutically-acceptable base addition salts of compounds of Formula 1 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 1 by reacting, for example, the appropriate acid or base with the compound of Formula 1.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula (1) 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 iacceptable ⁇ 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 (1) 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 active 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 and II 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.
  • 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.
  • hydrodo 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 (— CH— > , or two hydrido radicals may be attached to a carbon atom to form a "methylene" (-CH 2 -) 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 .
  • alkoxy radicals may be further substituted with one or more halo atoms, such as fluoro, chloro or bromo, to provide "haloalkoxy" radicals.
  • haloalkoxy radicals include fluoromethoxy, chloromethoxy, trifluoromethoxy, 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 .
  • Said "aryl” group may 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, alkylsulfinyl, alkylsulfonyl , alkylsulfonamido, alkylaminosulfonyl, amidosulfonyl , monoalkyl amidosulfonyl , dialkyl amidosulfonyl , monoarylamidosulfonyl, arylsulfonamido, diarylamidos
  • 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 above.
  • 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 .
  • unsaturated heterocyclic radicals also termed “heteroaryl” radicals
  • unsaturated heterocyclic radicals include unsaturated 5 to 6 membered heteromonocyclyl group containing 1 to 4 nitrogen atoms, for example, pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, triazolyl [e.g., 4H- 1,2, 4-triazolyl, 1H-1 , 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 [1 , 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.
  • thiazolyl, thiadiazolyl unsaturated 5 to 6-membered heteromonocyclic group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms
  • thiazolyl, thiadiazolyl e.g., 1,2,4- thiadiazolyl , 1,3,4- thiadia
  • heterocyclyl group may have 1 to 3 substituents as defined below.
  • 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.
  • 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,
  • Said "heterocyclyl” group may 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, alkylsulfinyl, alkylsulfonyl, alkylsulfonamido, alkylaminosulfonyl , amidosulfonyl, monoalkyl amidosulfonyl , dialkyl amidosulfonyl , monoarylamidosulfonyl , arylsulfonamido, diarylam
  • alkylsulfonyl denotes respectively divalent radicals -S0 2 -.
  • 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.
  • alkylsulfinyl embraces alkyl radicals attached to a sulfinyl radical, where alkyl is defined as above.
  • Alkylsulfinylalkyl embraces alkylsulfinyl 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 aryl in said aralkyl may have additional 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, alkylsulfinyl , alkylsulfonyl, alkylsulfonamido, alkylaminosulfonyl, amidosulfonyl, monoalkyl amidosulfonyl , dialkyl amidosulfonyl, monoarylamidosulfonyl , arylsulfonamido , diarylam
  • 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.
  • Alkylsulfinyl embraces aralkyl radicals attached to a sulfinyl radical, where aralkyl is defined as above.
  • Alkylsulfinylalkyl 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.
  • 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.
  • radicals examples 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.
  • 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 (CH 3 -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.
  • the aryl in said aryloxy may be additionally 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 amidos
  • aroyl embraces aryl radicals, as defined above, attached to an carbonyl radical as defined above. Examples of such radicals include benzoyl and toluoyl .
  • the aroyl in said aroyl may be additionally substituted with heteroarylamino, N-aryl-N-alkylamino, N- heteroarylamino-N-alkylamino, haloalkyl hio, alkanoyloxy, alkoxy, heteroaralkoxy, cycloalkoxy, cycloalkenyloxy, hydroxy, amino, thio, nitro, lower alkylamino, alkylthio, alkylthioalkyl , arylamino, aralkylamino, arylthio, alkylsulfinyl, alkylsulfonyl, alkylsulfonamido, alkylaminosulfonyl, amidosulfonyl, monoalkyl amidosul
  • aralkanoyl embraces aralkyl radicals, as defined herein, attached to an carbonyl radical as defined above. Examples of such radicals include, for example, phenylacetyl .
  • the aryl in said aralalkanoyl may be additionally 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 ,
  • 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 aryl in said aralkoxy radicals may be additionally 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 , diarylamidosulf
  • aryloxyalkyl embraces aryloxy radicals, as defined above, attached to an alkyl group. Examples of such radicals include phenoxymethyl .
  • the aryl in said aryloxyalkyl may be additionally 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 amidosulfony
  • 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.
  • the heteroaryl in said heteroaryloxy may be additionally 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 , diarylamidosulfon
  • heteroaroyl embraces heteroaryl radicals, as defined above, attached to an carbonyl radical as defined above. Examples of such radicals include furoyl and nicotinyl.
  • the heteroaryl in said heteroaroyl may be additionally 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,
  • 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 .
  • heteroaryl in said heteroaralalkanoyl may be additionally 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, diaryl
  • heteroaralkoxy embraces oxy-containing heteroaralkyl radicals attached through an oxygen atom to other radicals. More preferred heteroaralkoxy radicals are "lower heteroaralkoxy” radicals having heteroaryl radicals attached to lower alkoxy radical as described above.
  • heteroaryl in said heteroaralkoxy radicals may be additionally 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, diarylamidos
  • heteroaryloxyalkyl embraces heteroaryloxy radicals, as defined above, attached to an alkyl group. Examples of such radicals include pyridyloxymethyl .
  • the heteroaryl in said heteroaryloxyalkyl may be additionally 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, monoalky
  • arylthio embraces aryl radicals, as defined above, attached to an sulfur atom. Examples of such radicals include phenylthio.
  • the aryl in said arylthio may be additionally 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,
  • arylthioalkyl embraces arylthio radicals, as defined above, attached to an alkyl group. Examples of such radicals include phenylthiomethyl .
  • the aryl in said arylthioalkyl may be additionally 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 , monoal
  • 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 methoxymethyl .
  • 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.
  • carboxyalkoxy 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 .
  • the alkanoyl in said haloalkanoyl may be additionally substituted with hydroxy, amino, thio, 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, alkeno
  • 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 .
  • 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.
  • the chain may be constituted of one or more radicals selected from: lower alkylene, lower alkenyl,
  • 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, alkylsulfinyl , alkylsulfonyl , alkylsulfonamido, alkylaminosulfonyl, amidosulfonyl, monoalkyl amidosulfonyl , dialkyl amidosulfonyl,
  • 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.
  • 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.
  • DCC represents 1,3- dicyclohexylcarbodiimide
  • DIBAH represents diisobutylaluminum hydride
  • DIPEA represents diisopropylethylamine
  • DF represents dimethylformamide
  • DMSO represents dimethylsulfoxide
  • Fmoc represents 9- fluorenylmethoxycarbonyl
  • LDA lithium diisopropylamide
  • PHTH represents a phthaloyl group
  • pnZ represents 4-nitrobenzyloxycarbonyl
  • PTC represents a phase transfer catalyst
  • p-TsOH represents paratoluenesulfonic acid
  • TBTU represents 2-(lH- benzotriozole-1-yl) -1,1,3, 3-tetramethyl uronium tetrafluoroborate
  • TAA represents triethylamine
  • THF represents tetrahydrofuran
  • Z represents benzyloxycarbonyl .
  • 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 8 -reagent such as RR -Br, R°-OTs, R° -oxirane
  • N- (2-cyanoethyl) -N- (2-thiazolyl) -e-Z-a-Boc-2- methyl-L-Lysinamide 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-function generating the amino product N- (2-cyanoethyl) -N- (2-thiazolyl) -a-Boc-2-methyl-L- Lysinamide .
  • 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. After concentrating, the product produced in Ex-2c is deprotected by allowing it to stand in 2N HCl at 25°C for two hours. Concentrating in vacuo afforded L-N-(2- dimethylamino) -N- (2-pyridyl) - e-N- (iminoethyl) -2 -methyl-L- lysinamide tetrahydrochloride .
  • N- (2-hydroxyethyl) -N- (2-thiazolyl) -a-Z-S- (N-Boc-2- aminoethyl) -2-methyl-L-Cysteinamide is then dissolved in trifluoroacetic acid and allowed to stand at room temperature until the t-butoxycarbonyl group is removed. The reaction mixture is then concentrated in vacuo to give N- (2-hydroxyethyl) -N- (2-thiazolyl) -a-Z- S- (2-aminoethyl) -2- methyl-L-Cysteinamide trifluoroacetate .
  • N- (2-hydroxyethyl) -N- (2-thiazolyl) -a-Z- S-(2-(N- oximinoethyl) amino) ethyl) -2-methyl-L-Cysteinamide is dissolved in 25 ml of acetic anhydride containing a 0.1 g pyridine. After standing at room temperature for 2 hours, the reaction mixture is concentrated in vacuo to give N-(2- acetoxyethyl) -N- (2-thiazolyl) -a-Z-S- (2- (N- (2- acetoxyiminoethyl) amino) ethyl) -2-methyl-L-Cysteinamide .
  • N- (2-acetoxyethyl) -N- (2-thiazolyl) -a-Z-S- (2- (N- (2- acetoxyiminoethyl) amino) ethyl) -2-methyl-L-Cysteinamide is dissolved in 30% HBr in acetic acid to remove the Z- function generating the amino product N- (2-acetoxyethyl) -N- (2-thiazolyl) -S- (2- (N- (2-acetoxyiminoethyl ) amino) ethyl) -2- methyl-L-Cysteinamide .
  • N- (4-pyridyl) - a-Z-S- (N-Boc-2-aminoethyl) -2-methyl- L-Cysteinamide is then dissolved in trifluoroacetic acid and allowed to stand at room temperature until the t- butoxycarbonyl group is removed. The reaction mixture is then concentrated in vacuo to give N- (4-pyridyl) - a-Z-S- (2- aminoethyl) -2-methyl-L-Cysteinamide trifluoroacetate .
  • 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 Z-protected product is then eluted with 10% aqueous pyridine.
  • N- (4-pyridyl) -a-Z-S- (2- (N- (N-Z- iminoethyl) amino) ethyl) -2-methyl-L-Cysteinamide (0.005 mol) is thoroughly dried and dissolved in 25 ml of anhydrous THF.
  • THF solution cooled to -78 °C is added 1.1 equivalents of diisopropylamine followed by 1 equivalent on n-butyl lithium in hexane. Subsequently, 1.1 equivalents of acetyl chloride is added.
  • N-acetyl-N- (4-pyridyl) -a-Z-S- (2- (N- (N-Z- iminoethyl) amino) ethyl) -2-methyl-L-Cysteinamide 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 N-acetyl-N- (4- pyridyl) -S- (2- (N- (iminoethyl) amino) ethyl) -2-methyl-L- Cysteinamide .
  • N- (phenyl) -N- (2-imidazolyl) -a-Z-e-Boc-2-methyl-L- Lysinamide is then dissolved in trifluoroacetic acid and allowed to stand at room temperature until the t- butoxycarbonyl group is removed. The reaction mixture is then concentrated in vacuo to give N- (phenyl) -N- (2- imidazolyl) -a-Z-2-methyl-L-Lysinamide trifluoroacetate .
  • 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 N- (phenyl) -N- (2- imidazolyl) -a-Z-e- (1-iminoethyl) -2-methyl-L-Lysinamide dihydrochloride is then eluted with 10% aqueous pyridine.
  • N- (phenyl) -N- (2-imidazolyl) -a-Z-e- (N-Boc-1- iminoethyl) -2-methyl-L-Lysinamide 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-function generating the amino product N- (phenyl) -N- (2-imidazolyl) -e- (N-Boc-1-iminoethyl) -2-methyl-L-Lysinamide .
  • N- (phenyl) -N- (2-imidazolyl) -e- (N-Boc-1-iminoethyl) -2- methyl-L-Lysinamide is dissolved in ethanol. The solution is cooled in an ice bath. Triethylamine (TEA) (1 mL) is added, followed by 1, 1-dicyanoethene . The reaction is allowed to warm to room temperature. Upon completion, the reaction mixture is concentrated in vacuum.
  • TAA Triethylamine
  • N-methoxy-N- (5-tetrazoyl) -e- (N-Boc-amino) -a-hydroxy hexanamide (2.32 g, 8 mmol) is dissolved in DMSO and treated with 1, 3-dicyclohexylcarbodimide (DCC) (1.6 g, 8 mmol) and phosphoric acid. The reaction is stirred at room temperature. Upon completion, 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 MgS0 , filtered and solvents removed in vacuo. The product is passed through a reverse phase chromatographic column, giving N-methoxy-N- (5-tetrazoyl) -e- (N-Boc-amino) -2-oxohexanamide .
  • DCC 1, 3-dicyclohexylcarbodimide
  • N-methoxy-N- (5-tetrazoyl) -e- (N-Boc-amino) -2- oxohexanamide (2.22 g, 8 mmol) is dissolved in ethanol and treated with hydroxylamine hydrochloride (0.6 g, 8 mmol) and sodium carbonate (1 g) .
  • the reaction mixture is filtered and concentrated in vacuum, giving crude N- methoxy-N- (5-tetrazoyl) -e- (N-Boc-amino) -2- oximinohexanamide .
  • N-methoxy-N- (5-tetrazoyl) -e- (N-Boc-amino) -2-oximino hexanamide is cooled in an ice bath and 1.0M borane- tetrahydrofuran complex (8.5 mL) added dropwise. When addition is complete, the reaction is allowed to warm to room temperature. Upon complete reduction 1 mL of water is added. The reaction is concentrated at reduced pressure. 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. N-methoxy-N- ( 5- tetrazoyl) -e- (N-Boc-amino) -2-oxaminohexanamide is then eluted with 10% aqueous pyridine.
  • N-methoxy-N- (5-tetrazoyl) -e- (N-Boc-amino) - a- (N- hydroxy-N-acetamido) hexanamide is deprotected by allowing it to stand in dioxane and 2N HCl at 25°C for two hours. Concentrating in vacuo affords N-methoxy-N- (5-tetrazoyl) -e- amino- a- (N-hydroxy-N-acetamido) hexanamide hydrochloride.
  • 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 N-methoxy-N- (5-tetrazoyl) -e- (N- ( 1- iminoethyl) ) amino- a- (N-hydroxy-N-acetamido) hexanamide is then eluted with 10% aqueous pyridine and solvents removed and compound dried.
  • N- (2-Thiazolyl) -e- (N-Boc-amino) -a- (acetoxy) hexanamide (3.5 g, 10 mmol) is dissolved in ethanol and treated with sodium hydroxide (4.0 g, 10 mmol) .
  • sodium hydroxide 4.0 g, 10 mmol
  • the mixture is concentrated in vacuum and passed through a reverse phase chromatographic column, giving N- (2-thiazolyl) -e- (N-Boc- amino) -a- (hydroxy) hexanamide .
  • N- (2-Thiazolyl) -e- (N-Boc-amino) -a- (hydroxy) hexanamide (3.0 g, 9 mmol) is dissolved in DMSO and treated with 1, 3-dicyclohexylcarbodimide (DCC) (1.8 g, 9 mmol) and phosphoric acid. The reaction is stirred at room temperature . Upon completion, 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 MgS0 4 , filtered and solvents removed in vacuo. The product is passed through a reverse phase chromatographic column, giving N- (2-thiazolyl) -e- (N- Boc-amino) -2-oxohexanamide .
  • DCC 3-dicyclohexylcarbodimide
  • N- (2-Thiazolyl) -e- (N-Boc-amino) -2-oxohexanamide (2.8 g, 9 mmol) is dissolved in ethanol and treated with methoxyamine hydrochloride (0.78 g, 9 mmol) and sodium carbonate (1 g) . Upon completion, the reaction mixture is filtered and concentrated in vacuum, giving crude N-(2- thiazolyl) -e- (N-Boc-amino) -2-methoxyiminohexanamide .
  • N- (2-Thiazolyl) -e- (N-Boc-amino) -2- methoxyiminohexanamide (prepared in example 9) is cooled in an ice bath and 1.0M borane-tetrahydrofuran complex (9.5 mL) added dropwise. When addition is complete, the reaction is allowed to warm to room temperature. Upon complete reduction 1 mL of water is added. The reaction is concentrated in vacuum. 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 . N- (2-thiazolyl) -e- (N-Boc-amino) -2- methoxyaminohexanamide is then eluted with 10% aqueous pyridine .
  • N- (2-Thiazolyl) -e- (N-Boc-amino) -a- (N-methoxy-N- acetamido) hexanamide is deprotected by allowing it to stand in dioxane and 2N HCl at 25°C for two hours. Concentrating in vacuo affords N- (2-thiazolyl) -e- (amino) -a- (N- methoxyacetamido) hexanamide hydrochloride .
  • N- (2 -Imidazolyl) - a- (N-Boc) -S- (N-Z-2-aminoethyl) - 2-methyl-D, L-homocysteinamide is then dissolved in trifluoroacetic acid and allowed to stand at room temperature until the t-butoxycarbonyl group is removed. The reaction mixture is then concentrated in vacuo to give N- (2-imidazolyl) -S- (N-Z-2-aminoethyl) -2-methyl-D, L- Homocysteinamide trifluoroacetate .
  • N- (2-imidazolyl) -S- (N-Z-2-aminoethyl) -a-N- (4- morpholmomethylbenzoyl) -2-methyl-D, L-homocysteinamide 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-function generating the amino product N-(2- imidazolyl) -S- (2-aminoethyl) - a-N- (4- morpholinomethylbenzoyl) -2-methyl-D, L-homocysteinamide .
  • the l-chloro-2-fluoroacetaldoxime is isolated after three hours by extracting into diethyl ether and washing with aqueous NaCl. Drying with MgSO ⁇ , filtration and concentration under 30°C affords l-chloro-2-fluoro acetaldoxime as a pale yellow oil.
  • N- (3-Quiniclidinyl) - d-Z-a- (N-Boc) -D, L- 2 , 5dimethylornithinamide is then dissolved in trifluoroacetic acid and allowed to stand at room temperature until the t-butoxycarbonyl group is removed. The reaction mixture is then concentrated in vacuo to give N- (3-quiniclidinyl) - d-Z-D, L-2 , 5-dimethylornithinamide trifluoroacetate .
  • N- (3-Quiniclidinyl) - d-Z-a- (N-methoxyformyl ) -D, L- 2 , 5-dimethylornithinamide 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-function generating the amino product N- (3-quiniclidinyl) -a- (N-methoxyformyl ) - D, L-2 , 5-dimethylornithinamide .
  • 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. N- (3-quiniclidinyl) - d-N-(l- imino-1-cyclopropylmethyl) -a- (N-methoxyformyl) -D, L-2 , 5- dimethylornithinamide is then eluted with 10% aqueous pyridine and solvents removed and compound dried.
  • the resulting material is passed through a reverse phase chromatographic column, giving N- ( 2-g-butyrolactone) -a- (N-methansulfonyl) -ortho- (N-Z-aminomethyl) -2-methylphenylalanmamide .
  • N- ( 2-g-Butyrolactone) -a- (N-methansulfonyl ) -ortho- (N-Z-aminomethyl) -2-methylphenylalanmamide 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- function generating the amino product N- ( 2-g- butyrolactone) -a- (N-methansulfonyl) -ortho- (aminomethyl) -2- methylphenylalaninamide .
  • N- (2-pyrimidinyl) - 3-(5-(N-Z- Aminomethyl) thiophenyl) -2- (N-Boc-amino) -2- methylpropionamide is then dissolved in trifluoroacetic acid and allowed to stand at room temperature until the t- butoxycarbonyl group is removed. The reaction mixture is then concentrated in vacuo to give N- (2-pyrimidinyl) - 3- (5- (N-Z-Aminomethyl) thiophenyl) -2-amino-2-methylpropionamide trifluoroacetate .
  • N- (2-pyrimidinyl) - 3-(5-(N-Z- Aminomethyl) thiophenyl) -2-acetamido-2-methylpropionamide 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-function generating the amino product N-(2- pyrimidinyl) - 3- (5- (aminomethyl) thiophenyl) -2-acetamido-2- methylpropionamide .
  • 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 product N- (2-pyrimidinyl) - 3-(5-(N-(l- iminoethyl) amino) methyl) thiophenyl) -2-acetamido-2- methylpropionamide is then eluted with 10% aqueous pyridine and solvents removed and compound dried.
  • N-methyl-N- (2-pyridyl) - ⁇ -Boc-O- (2- (N-Z- amino) ethyl) -2-methyl-L-serinamide 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-function generating the amino product N-methyl-N- (2-pyridyl) - ⁇ -Boc- 0- (2-aminoethyl) -2-methyl-L-serinamide.
  • 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 .
  • N-methyl-N- (2-pyridyl) - ⁇ -Boc-O- (2- (N- (1- iminoethyl) amino) ethyl) -2-methyl-L-serinamide (1.97 g, 0.005 mol) is added to 50 ml of THF containing 1.01 grams of triethylamine.
  • Carbobenzoxy chloride (Z-Cl; 1.03 g,
  • N-methyl-N- (2-pyridyl) - ⁇ -Boc-O- (2- (N- (N-Z-l- iminoethyl) amino) ethyl) -2-methyl-L-serinamide is then dissolved in trifluoroacetic acid and allowed to stand at room temperature with spectroscopic monitoring until the t- butoxycarbonyl group is removed.
  • the reaction mixture is then concentrated in vacuo to give N-methyl-N- (2-pyridyl) - O- (2- (N- (N-Z-iminoethyl) amino) ethyl) -2-methyl-L-serinamide trifluoroacetate .
  • N-methyl-N- (2-pyridyl) - ⁇ - (N-cyclopentylene) -0- (2- (N- (N-Z-1-iminoethyl) amino) ethyl) -L-serinamide is placed in a mixture with anhydrous toluene, 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 reduce the imine and remove the Z-function generating the p-toluenesulfonate salt of the amino product N-methyl-N- (2-pyridyl) - ⁇ - (N- cyclopentyl) -O- (2- (N- (1-iminoethyl) amino) ethyl) -2-methyl-L- serinamide .
  • N-methyl-N- (4-imidazolyl) - ⁇ -Z-O- (2- (N-Boc- amino) ethyl) -2-methyl-L-serinamide is dissolved in trifluoroacetic acid and allowed to stand at room temperature with spectroscopic monitoring until the t- butoxycarbonyl group is removed. The reaction mixture is then concentrated in vacuo to give the amino product N- methyl-N- (4-imidazolyl) - ⁇ -Z-O- (2-aminoethyl) -2-methyl-L- serinamide trifluoroacetate .
  • N-methyl-N- (4-imidazolyl) - ⁇ -Z-O- (2- (N- (1- oximinoethyl) amino) ethyl) -2-methyl-L-serinamide (2.12 g, 0.005 mol) is added to 50 ml of THF containing 1.01 grams of triethylamine.
  • Methyl chloroformate (0.567 g, 0.006 mol) is added and stirred at room temperature for 24 hours. The reaction mixture is concentrated in vacuo to remove THF and slurried with 50 ml. methylene chloride.
  • N-methyl-N- (4-imidazolyl) - ⁇ -Z-O- (2- (N- (1- (0- (methoxycarbonyl) oximino) ethyl) amino) ethyl) -2-methyl-L- serinamide is then 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 give N-methyl-N- (4-imidazolyl) -O- (2- (N- (1- (0- (methoxycarbonyl) oximino) ethyl) amino) ethyl) -2-methyl-L- serinamide .
  • This reaction is shaken under pressure for an extended period of time in a standard Parr hydrogenation apparatus to reduce the imine generating the p-toluenesulfonate salt of the amino product N-methyl- N- (4-imidazolyl) - ⁇ - (N- (1-pyrrolylethylenyl) ) -O- (2- (N- (1- (0- (methoxycarbonyl) oximino) ethyl) amino) ethyl) -2-methyl-L- serinamide.
  • N-methyl-N- (4-imidazolyl) - ⁇ - (N- ( 1-pyrrolylethylenyl) )-0-(2-(N-(l-(0- (methoxycarbonyl) oximino) ethyl) amino) ethyl) -2-methyl-L-serinamide (0.003 mol) is placed in 20 ml of anhydrous THF containing 1.01 grams of triethylamine. After cooling to -78 °C, ethanesulfonyl chloride (0.412 g, 0.0032 mol) in 10 ml anhydrous THF is added over 20 minutes.
  • N-methyl-N- (4-thiazolyl) - ⁇ -Z-O- (2-aminoethyl) -2- methyl-L-serinamide is converted to N-methyl-N- (4- thiazolyl) - ⁇ -Z-O- (2- (N- (2-fluoro-1-iminoethyl) amino) ethyl) - 2-methyl-L-serinamide using methyl 2-fluoroacetimidate hydrochloride as described in Ex-2c.
  • N-methyl-N- (4-thiazolyl) - ⁇ -Z-O- (2- (N- (2-fluoro-1- iminoethyl) amino) ethyl) -2-methyl-L-serinamide is then 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 give N- methyl-N- (4-thiazolyl) -O- (2- (N- (2-fluoro-1- iminoethyl) amino) ethyl) -2-methyl-L-serinamide .
  • N-methyl-N- (4-thiazolyl) -0- (2- (N- (2-fluoro-1- iminoethyl) amino) ethyl) -2-methyl-L-serinamide (1.25 g, 0.004 mol) is reacted with sodium hydroxymethylsulfonate in aqueous solution at a pH of 10 using a procedure described by L. Maier (Phosphorus, Sulfur, Silicon Related Elements (1990), vol.
  • N-Methyl-N- (3-oxacycloheptyl) - a-Boc -e-N-(l- imino-3 -butenyl) -2-methyl-L-Lysinamide is then subjected to conditions to remove the Boc protecting group as described in Ex-2d to give N-methyl-N- (3-oxacycloheptyl) -e-N- (1- imino-3 -butenyl) -2-methyl-L-Lysinamide .
  • N-Methyl-N- (3-oxacycloheptyl) -e-N- (l-imino-3- butenyl) -2-methyl-L-Lysinamide (3.57 g, 11 mmol) is treated with one equivalent 2 , 2 , 2-trichloroethyl chloroformate (2.22 g, 11 mmol) and sodium carbonate in aqueous tetrahydrofuran under the conditions described by D.
  • the product N-methyl-N- (3- oxacycloheptyl) -e-N- (l-imino-3 -butenyl) -2-methyl-L- thionolysinamide is cooled in an ice bath and treated with one equivalent of 2-furanylacetyl chloride (1.4 g, 10 mmol) and stirred at room temperature for 24 hours.
  • the reaction mixture is concentrated in vacuo and slurried with 50 ml methylene chloride.
  • N-ethyl-N- (4- (1,2, 3-triazolyl) ) -e- (N-Z-amino) -a- (N-Boc-amino) -2-methylhex-4-enamide is then subject to conditions to remove the Z protecting group as described in Ex-lb to N-ethyl-N- (4- (1, 2 , 3-triazolyl) ) -e-amino-a- (N-Boc- amino) -2-methylhex-4-enamide .
  • N-ethyl-N- (4- (1, 2 , 3-triazolyl) ) -e-N- (1- (2- fluorocyclopropyl) oximinomethyl) amino-a- (N-Boc-amino) -2- methylhex-4-enamide is then subject to conditions to remove the Boc protecting group as described in Ex-Id to give N- ethyl-N- (4- (1, 2 , 3-triazolyl) ) -e-N-(l-(2- fluorocyclopropyl ) oximinomethyl ) amino-2-amino-2-methylhex- 4-enamide .
  • N-ethyl-N- (4- (1, 2 , 3-triazolyl) ) -e-N- (1- (2- fluorocyclopropyl ) oximinomethyl ) amino-2-N- (2,2,2- trichloroethoxyformyl) amino-2-methylhex-4-enamide (6.29 g) is treated with Lawesson's Reagent under the conditions described in Chem.
  • N-ethyl-N- (4- (1,2, 3-triazolyl) ) -e-N- (1- (2- fluorocyclopropyl) oximinomethyl) amino-2-N- (2,2,2- trichloroethoxythionoformyl) amino-2-methyl-thionohex-4- enamide (5.40g, 10 mmol) is dissolved in acetic acid and treated with zinc dust (0.65g, 10 mmol). After stirring two hours, saturated aqueous sodium carbonate is added.
  • the solids are removed by filtration.
  • 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 N-ethyl-N- (4- (1, 2 , 3-triazolyl) ) - e-N- (1- (2-fluorocyclopropyl) oximinomethyl) amino-2-amino-2- methyl-thionohex-4-enamide is then eluted with 10% aqueous pyridine .
  • N-ethyl-N- (4- (1, 2, 3-triazolyl) ) -e-N- (1- (2- fluorocyclopropyl) oximinomethyl) amino-2-amino-2-methyl- thionohex-4-enamide (3.32 g, 9 mmol) is added to 50 mL of toluene in 100 mL reaction flask. After adding 1.71 g of p-toluenesulfonic acid and 2.17 g (14 mmol) 3-cyclopentenyl (thiomethyl) methyl ketone, the reaction mixture is refluxed with azeotropic distillation for complete removal of water using a Dean-Stark trap.
  • N-ethyl-N- (4- (1,2, 3-triazolyl) ) -e-N- (1- (2- fluorocyclopropyl ) oximinomethyl ) amino-2-N- ( 1- ( 1- cyclopentyl-2-methylthioethenyl ) ) amino-2-methyl-thionohex- 4-enamide toluenesulfonate salt is dissolved in methanol and treated with 1.
  • N-Ethyl-N- (4- (1, 2 , 3-triazolyl ) ) -e-N- (1- (2- fluorocyclopropyl) oximinomethyl) amino-2 -N- (1- (1- cyclopentyl-2-methylthioethyl ) ) amino-2-methyl-thionohex-4- enamide (3.94g, 0.008 mol) is place in 20 ml of anhydrous THF containing 1.01 grams of triethylamine. After cooling in an ice bath, 2-cyanopropionyl chloride (0.99 g, 8.5 mmol) in 10 ml anhydrous THF is added over 20 minutes.
  • N- (5-Tetrazolyl) -e- (N-Z-amino) -a- (N-Boc-amino) -2- methylpent-3-ynamide is then subject to conditions to remove the Z protecting group as described in Ex-lb to give N- (5-tetrazolyl) -e-amino-a- (N-Boc-amino) -2-methylpent- 3 -ynamide .
  • N- (5-tetrazolyl) -e-N- (1-oximinoethyl) amino-a- (N- Boc-amino) -2-methylpent-3 -ynamide is dissolved in 30 mL of propionic anhydride containing 0.1 g of pyridine. After standing at room temperature for 2 hours, the reaction mixture is concentrated in vacuo to give N- (5-tetrazolyl) - e-N- (1- (O-propionyloximino) ethyl) amino-a- (N-Boc-amino) -2- methylpent-3 -ynamide .
  • N- (5-tetrazolyl) -e-N- (1- (O- propionyloximino) ethyl) amino-a- (N-Boc-amino) -2-methylpent- 3 -ynamide (4.10 g, 10 mmol) is dissolved in THF and cooled to -78°C.
  • Two equivalents of lithium diisopropylamine (LDA) 2.0M solution (10 mL) is added dropwise over a period of 20 minutes.
  • Phosgene (.998 g, 10.1 mmol) is added through a gas inlet tube over 30 minutes. After the mixture is allowed to warm to room temperature, 1 mL of water is added.
  • 3-N- (5-tetrazolyl) -5- (3- (N- (1- (0- propionyloximino) ethyl) amino) prop-1-ynyl) -5-methyl-l- (N- Boc) -hydantoin is then dissolved in trifluoroacetic acid and allowed to stand at room temperature until the t- butoxycarbonyl group is removed. The reaction mixture is then concentrated in vacuo to give 3-N- (5-tetrazolyl) -5- (3- (N- (1- (O-propionyloximino) ethyl) amino) prop-1-ynyl) -5- methyl-hydantoin trifluoroacetate .
  • Example 21 Ex-21a) a- (N-Boc) -0- (N-Z-2-aminoethyl) -2-methyl-L-serine (4.21 g, 11 mmol) is reacted with 2-aminoimidazole (0.95 g, 11.5 mmol) using the process described in Ex-2a to yield N- (2-imidazolyl) -a- (N-boc) -0- (N-Z-2-aminoethyl) -2-methyl-L- serinamide.
  • N- (2-Imidazolyl) -a- (N-Boc) -O- (N-Z-2-aminoethyl) -2- methyl-L-serinamide is then subjected to conditions to remove the Z protecting group as described in Ex-2b to give N- (2-imidazolyl) -a- (N-Boc) -O- (2-aminoethyl) -2-methyl-L- serinamide.
  • N- (2-imidazolyl) -a- (N-boc) -O- (2- (N- (1- iminoethyl) amino) ethyl) -2-methyl-L-serinamide (3.68 g, 10 mmol) is dissolved in THF and cooled to -78°C. To the cooled mixture is added one equivalent of 2.0M lithium diisopropylamide solution (5 mL) over 30 minutes. One equivalent of 2-bromo-l , l-dimethoxy-4-thiomethylbutane (2.43 g, 10 mmol) dissolved in THF is added to the cooled mixture over 20 minutes. The mixture is allowed to warm to room temperature and 1 mL of water is added.
  • N- (l-dimethoxy-4-thiomethyl-2-butyl) -N- (2-imidazolyl) -a- (N- boc) -0- (2- (N- (1-iminoethyl) amino) ethyl) -2-methyl-L- serinamide (5 mmol) is then placed in 50 ml of aqueous 2N HCl.
  • N-Methyl-N- (5-tetrazolyl) -a- (N-Boc) -S- (N-Z- aminoethyl ) -2-methyl-L-cysteinamide is then subject to conditions to remove the Z protecting group as described in Ex-2b to give N-methyl-N- (5-tetrazolyl ) -a- (N-Boc ) -S- (aminoethyl) -2-methyl-L-cysteinamide .
  • N-methyl-N- (5- tetrazolyl) -a- (N-Boc) -S- (2- (N- phosphonomethyleneamino) ethyl) -2-methyl-L-cysteinamide by addition of 10 mmol of disodium formylphosphonate while maintaining a pH of 6-7, 50 ml of methanol is added.
  • the reaction mixture is treated with 1.0M sodium cyanoborohydride in THF (40 L) .
  • N-methyl-N- (5-tetrazolyl) -a- (N-Boc) -S- (2- (N- phosphonomethy1amino) ethyl) -2-methyl-L-cysteinamide (8 mmol) is reacted with methyl acetimidate hydrochloride (1.75 g) using the process described in Ex-2c to yield N- methyl-N- (5-tetrazolyl) -a- (N-Boc) -S- (2- (N-phosphonomethyl- N- (1-iminoethyl) amino) ethyl) -2-methyl-L-cysteinamide .
  • N-methyl-N- (5-tetrazolyl) -a- (N-Boc) -S- (2- (N- phosphonomethyl-N- (1-iminoethyl) amino) ethyl) -2-methyl-L- cysteinamide is then placed in 50 ml of aqueous 2N HCl. After standing at room temperature until the t- butoxycarbonyl group is removed, the reaction mixture is then concentrated in vacuo to give N-methyl-N- (5- tetrazolyl) -S- (2- (N-phosphonomethyl-N- (1- iminoethyl) amino) ethyl) -2-methyl-L-cysteinamide hydrochloride .
  • N-methyl-N- (5-tetrazolyl) -S- (2- (N-phosphonomethyl-N- (1- iminoethyl) amino) ethyl) -2-methyl-L-cysteinamide hydrochloride (5 mmol) is placed in 50 ml water and stirred vigorously with a mixture of 5mmol of N,N- dimethyloctadecylamine in 75 ml of toluene.
  • the aqueous layer is separated and two equivalents of NaOH (10 mmol) is added to generate the disodium salt of N-methyl-N- (5- tetrazolyl) -S- (2- (N-phosphonomethyl-N- (1- i inoethyl) amino) ethyl) -2-methyl-L-cysteinamide .
  • N-Methyl-N- (5-tetrazolyl) -e- (N-Z-amino) -a- (N-Boc- amino) -2-methylhexanamide is then subject to conditions to remove the Z protecting group as described in Ex-lb to yield N-methyl-N- (5-tetrazolyl) -e- (amino) -a- (N-Boc-amino) - 2-methylhexanamide .
  • N-methyl-N- (5-tetrazolyl) -e- (N- (1- iminoethyl) amino) -a- (N-Boc-amino) -2-methylhexanamide is then subject to conditions to remove the Boc protecting group as described in Ex-2d to give N-methyl-N- (5- tetrazolyl ) -e- (N- (1-iminoethyl ) amino) -2-amino-2- methylhexanamide .
  • N-methyl-N- (5-tetrazolyl) -e- (N- (1- iminoethyl) amino) -2 -amino-2-methylhexanamide (3.05 g, 11 mmol) is treated with one equivalent trichloroethyl chloroformate (2.29 g) and sodium carbonate in aqueous tetrahydrofuran under the conditions described by D.
  • N-methyl-N- (5-tetrazolyl) -e- (N- (1- iminoethyl ) amino ) -2- (N- (2,2,2- trichloroethoxythionoformyl) ) amino-2-methyl- thionohexanamide (4.84 g, 10 mmol) is dissolved in acetic acid and treated with zinc dust (0.65g, 10 mmol) . After stirring two hours, saturated aqueous sodium carbonate is added. The solids are removed by filtration. 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.
  • N-methyl-N- (5-tetrazolyl) - e- (N- (1-iminoethyl) amino) -2 -amino-2 -methyl-thionohexanamide is then eluted with 10% aqueous pyridine.
  • N-methyl-N- (5-tetrazolyl) -e- (N- (1-iminoethyl) amino) -2- amino-2-methyl-thionohexanamide (2.65 g, 9 mmol) is place in 20 ml of anhydrous THF containing 1.01 grams of triethylamine. After cooling to -78 °C, ethyl chloroformate (0.98 g, 9 mmol) in 10 ml anhydrous THF is added over 20 minutes. After warming to room temperature, the solvent is removed in vacuo, 50 ml methylene chloride added along with 20 ml of water.
  • N-Methyl-N- (5-tetrazolyl) -e- (N-Z-amino) -a- (N-Boc- amino) -2-methylhexanamide is then subject to conditions to remove the Z protecting group as described in Ex-2b to give N-methyl-N- (5-tetrazolyl) -e- (amino) -a- (N-Boc-amino) -2- methylhexanamide .
  • N-methyl-N- (5-tetrazolyl) -e- (N- (l-imino-2- fluoroethyl) amino) -a- (N-Boc-amino) -2-methylhexanamide is then subject to conditions to remove the Boc protecting group as described in Ex-2d to N-methyl-N- (5-tetrazolyl) -e- (N- (l-imino-2-fluoroethyl) amino) -2-amino-2 - methylhexanamide .
  • N-methyl-N- (5-tetrazolyl) -e- (N- (l-imino-2- fluoroethyl) amino) -2-amino-2-methylhexanamide (3.09 g, 10 mmol) is placed in 20 mL of anhydrous THF containing 1.01 grams of triethylamine. After cooling to -78°C, trifluoroacetic anhydride (2.17 g, 10.3 mmol) in 10 mL anhydrous THF is added over 20 minutes.
  • N-methyl-N- (5-tetrazolyl) -e- (N- (l-imino-2- fluoroethyl ) amino ) -2-trifluoroacetamido-2 -methylhexanamide trifluoroacetate 9 mmol is dissolved in ethanol and treated with two equivalents of sodium borohydride (0.74 g, 20 mmol). After stirring several hours, the ethanol is removed in vacuo. Upon completion, 50 mL methylene chloride is added along with 20 mL of water.
  • N-methyl-N- (5-tetrazolyl) -a- (N-Z) -S- (2- (1- (N- (benzoyloxymethyl) imino) ethyl) -N-hydroxy) aminoethyl) -2- methyl-L-cysteinamide is then subject to conditions to remove the Z protecting group as described in Ex-2b to give N-methyl-N- (5-tetrazolyl) -S- (2- (1- (N-
  • N-methyl-N- (5-tetrazolyl) -a- (N-Z) -e- (N-Boc) -2- methyl-L-Lysine is then subject to conditions to remove the Boc protecting group as described in Ex-3b to give N- methyl-N- (5-tetrazolyl ) -a- (N-Z) -2-methyl-L-Lysine .
  • N-Methyl-N- (5-tetrazolyl) -a- (N-Z) -2-methyl-L- Lysine (3.51 g, 10 mmol) is added to 50 mL of toluene in 100 mL reaction flask. After adding 1.89 g of p- toluenesulfonic acid and 0.93 g (16 mmol) propionaldehyde the reaction mixture is refluxed with azeotropic distillation for complete removal of water using a Dean- Stark trap.
  • N-methyl-N- (5-tetrazolyl) -a- (N-Z) -e-N- (1- propylene) -2-methyl-L-Lysine p-toluenesulfonate (9 mmol) is dissolved in methanol and treated with 1.0M sodium cyanoborohydride in THF (19 mL) and potassium hydroxide using the conditions and work-up described by R. F. Borch in Organic Synthesis, 52, 124, 1972 to give the product, N- methyl-N- (5-tetrazolyl) -a- (N-Z) -e-N- (1-propyl) -2-methyl-L- Lysine .
  • N-methyl-N- (5-tetrazolyl) -a- (N-Z) -e-N- (1-propyl) - 2-methyl-L-Lysine (3.38 g, 8 mmol) is treated with methyl (N- (benzoyloxymethyl) acetimidate hydrochloride (3.70 g) as described in Ex-2c to give N-methyl-N- (5-tetrazolyl) -a- (N- Z) -e-N- (2- (1- (N- (benzoyloxymethyl) imino) ethyl) ) - e-N- (1- propyl) -2-methyl-L-Lysine .
  • N-methyl-N- (5-tetrazolyl) -a- (N-Z) -e-N- (2- (1- (N- (benzoyloxymethyl) imino) ethyl) ) - e-N- (1-propyl) -2-methyl-L- Lysine is then subject to conditions to remove the Z protecting group as in Ex-2b to give N-methyl-N- ( 5- tetrazolyl) -e-N- (2- (1- (N- (benzoyloxymethyl) imino) ethyl) ) - e-N- (1-propyl) -2-methyl-L-Lysine.
  • N-methyl-N- (5- (4-nitrobenzyloxymethyl) tetrazolyl) - ⁇ -pnZ- ⁇ -Boc-2-methyl-L-Lysinamide is then dissolved in 25 mL. anhydrous trifluoroacetic acid and allowed to stand at room temperature until the t-butoxycarbonyl group is removed.
  • the reaction mixture is concentrated to dryness in vacuo, aqueous sodium carbonate added to neutralize residual acid, and the aqueous solution extracted with methylene chloride to yield N-methyl-N- (5- (4- nitrobenzyloxymethyl) tetrazolyl) - ⁇ -pnZ-2-methyl-L- Lysinamide.
  • N-methyl-N- (5- (4-nitrobenzyloxymethyl) tetrazolyl) - ⁇ -pnZ-2-methyl-L-Lysinamide (4.68 g, 8.0 mmol) is placed in admixture with tetrahydrofuran (50 mL) and phthalic anhydride (1.19 g, 8.0 mmol) and heated at reflux until the reaction is complete. Removal of the tetrahydrofuran afforded the phthalimide of N-methyl-N- (5- (4- nitrobenzyloxymethyl) tetrazolyl) - ⁇ -pnZ-2-methyl-L- Lysinamide .
  • Phthalimide is thoroughly dried and dissolved in 25 mL of anhydrous THF. To the THF solution cooled to -78
  • N-methyl-N- (5- (tetrazolyl) - ⁇ -N-phthaloyl- ⁇ -N- (2-fluoro-1- iminoethyl ) - ⁇ -N- (N, N'N' -trimethylureido-N-methylene) -2- methyl-L-Lysinamide (1.64 g, 0.003 mol) is dissolved in 25 mL methanol and hydrazine (0.96 g, 0.003 mol) added. After refluxing for 6 hours, the methanol is removed, aqueous 10 % hydrochloric acid added to the residue in an ice bath until the pH was 3 to 4, and the precipitated hydrazide removed by filtration.
  • the aqueous solution is concentrated in vacuo to give the dihydrochloride of N- methyl-N- (5- (tetrazolyl) - ⁇ -N- (2-fluoro-1-iminoethyl) - ⁇ -N- (N,N'N' -trimethylureido-N-methylene) -2-methyl-L-Lysinamide.
  • N-methyl-N- (5- (4-nitrobenzyloxymethyl) tetrazolyl) - ⁇ -Boc- ⁇ -pnZ-2-methyl-L-Lysinamide is then dissolved in 25 mL. anhydrous trifluoroacetic acid and allowed to stand at room temperature until the t-butoxycarbonyl group is removed.
  • the reaction mixture is concentrated to dryness in vacuo, aqueous sodium carbonate added to neutralize residual acid, and the aqueous solution extracted with methylene chloride to yield N-methyl-N- (5- (4- nitrobenzyloxymethyl) tetrazolyl) - ⁇ -pnZ-2-methyl-L- Lysinamide .
  • N-methyl-N- (5- (4-nitrobenzyloxymethyl) tetrazolyl) - ⁇ -pnZ-2-methyl-L-Lysinamide (4.68 g, 8.0 mmol) is placed in admixture with tetrahydrofuran (50 mL) and phthalic anhydride (1.19 g, 8.0 mmol) and heated at reflux until the reaction is complete. Removal of the tetrahydrofuran affords the phthalimide of N-methyl-N- (5- ( 4- nitrobenzyloxymethyl) tetrazolyl) - ⁇ -pnZ-2-methyl-L- Lysinamide.
  • Phthalimide is thoroughly dried and dissolved in 25 mL of anhydrous THF.
  • THF solution cooled to -78 °C.
  • 1.1 equivalents of diisopropylamine followed by 1 equivalent on n-butyl lithium in hexane.
  • 1.1 equivalents of N-chloromethyl-N,N'N' -trimethylurea is added.
  • N-methyl-N- (5- (4-nitrobenzyloxymethyl) tetrazolyl) - ⁇ -N-phthaloyl- ⁇ -pnZ- ⁇ -N- (N,N'N' -trimethylureido-N- methylene) -2-methyl-L-Lysinamide is dissolved in 25 mL methanol and one equivalent of hydrazine added. After refluxing for 6 hours, the methanol is removed, aqueous 10 % hydrochloric acid added to the residue in an ice bath until the pH is 7, and the precipitated hydrazide removed by filtration.
  • N-methyl-N- (5- (4-nitrobenzyloxymethyl) tetrazolyl) - ⁇ -pnZ- ⁇ -N- (2-fluoro-1-iminoethyl) - ⁇ -N- (N,N'N' -trimethylureido-N- methylene) -2-methyl-L-Lysinamide is dissolved in ethanol and is combined with a hydrogenation catalyst such as palladium on carbon and hydrogen.
  • N-methyl-N- (5-tetrazolyl) -e- (N- (l-imino-2- fluoroethyl) amino) -a- (N-Boc-amino) -2-methylhexanamide is then subject to conditions to remove the Boc protecting group as described in Ex-2d to give N-methyl-N- (5- tetrazolyl) -e- (N- ( l-imino-2-fluoroethyl) amino) -2-amino-2- methylhexanamide .
  • N-methyl-N- (5-tetrazolyl) -e- (N- (l-imino-2- fluoroethyl) amino) -2- (N- (N-Boc-phenylalaninyl) amino) -2- methylhexanamide is then subject to conditions to remove the Boc protecting group as described in Ex-2d to give in Example 2 to give N-methyl-N- (5-tetrazolyl) -e- (N- (1-imino- 2 -fluoroethyl) amino) -2- (N- (phenylalaninyl) amino) -2- methylhexanamide .
  • EXAMPLE 30 Ex-30a) ⁇ -Boc- ⁇ -pnZ-2-methyl-L-Lysine (4.64 g, 10.0 mmol) and 1- (4-nitrobenzyloxymethyl) aminotetrazole (2.62 g, 10.5 mmol) is converted to N-(5-(4- nitrobenzyloxymethyl) tetrazolyl) - ⁇ -Boc- ⁇ -pnZ-2-methyl-L- Lysinamide analogous to that described in Example 28.
  • N-acetoxymethyl-N- (5- (4- nitrobenzyloxymethyl) tetrazolyl) - ⁇ -N-phthaloyl- ⁇ -pnZ-2- methyl-L-Lysinamide is converted to N-acetoxymethyl-N- ( 5- (4-nitrobenzyloxymethyl) tetrazolyl) - ⁇ -pnZ-2-methyl-L- Lysinamide analogous to that described in Example 28.
  • N-acetoxymethyl-N- (5- (4-nitrobenzyloxymethyl) tetrazolyl) - ⁇ - pnZ- ⁇ -N- (iminoethyl) -2-methyl-L-Lysinamide 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 pnZ- functions generating the amino product N-acetoxymethyl-N- ( 5-tetrazolyl) - ⁇ -N- (iminoethyl) -2-methyl-L-Lysinamide .
  • 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 e- (N- (1-Iminoethyl) amino) - a- (N-Boc-amino) -2- (cyanomethyl) hexanoic acid is then eluted with 10% aqueous pyridine and thoroughly dried.
  • This product is refluxed in toluene and sodium carbonate (3 equivalents) to give the cyclized product 3-(4-(N-(l- iminoethyl) amino) butyl) -3-cyanomethyl-6-methylmorpholine- 2 , 5-dione .
  • 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 e- (N- (1-Iminoethyl) amino) - a- (N-Boc-amino) -2- (2-methylthioethyl) hexanoic acid is then eluted with 10% aqueous pyridine.
  • 6- (N-Boc-amino) -2-phthalimido-hex-4-enol (2.7 g, 8 mmol) is dissolved in DMSO and treated with 1,3- dicyclohexylcarbodimide (DCC) (1.6 g, 8 mmol) and phosphoric acid. The reaction is stirred at room temperature . Upon completion, 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 MgS0 , filtered and solvents removed in vacuo. The product is passed through a reverse phase chromatographic column, giving 6- (N-Boc-amino) -2- phthalimido-hex-4-enal .
  • DCC 1,3- dicyclohexylcarbodimide
  • Phenyl 2- (4- (N-Boc-amino) but-2-enyl) -2-phthalimido- 3- (2- (1, 3-dioxanyl) ) acetate is dissolved in anhydrous trifluoroacetic acid to remove the Boc-function generating the amino product, phenyl 2- (4-aminobut-2-enyl) -2- phthalimido-3- (2- (1 , 3-dioxanyl) ) acetate trifluoroacetate, after removal of solvent.
  • Phenyl 2- (4-aminobut-2-enyl) -2 -phthalimido-3- (2- (1, 3- dioxanyl) ) acetate (2.38 g, 5 mmol) is dissolved in methanol and 0.5 g hydrazine monohydrate. After complete removal of the phthaloyl protecting group and filtering to remove the phthaloylhydrazide, the methanolic solution is then concentrated to dryness to give the product.
  • Ethyl 6-phthalimido-2-cyano-2- (N-Boc- amino) hexanoate (4.29 g, 10 mmol) is dissolved in methanol and 1.0 g hydrazine monohydrate. The mixture is heated to reflux. After complete removal of the phthaloyl protecting group and filtering to remove the phthaloylhydrazide, the methanolic solution is then concentrated to dryness in an ice bath to give the product ethyl 6-amino-2-cyano-2- (N- Boc-amino) hexanoate .
  • Ethyl 6- (N- (1-iminoethyl) amino) -2 -cyano-2- (N-Boc- amino) hexanoate (2.73 g, 8 mmol) is dissolved in methylene chloride and 10 mL anhydrous ethanol is added. The mixture is cooled to -10°C and (1.2 g) HCl gas is added by gas inlet tube. The reaction is allowed to warm to room temperature. When the reaction is completed, the solvent is removed in vacuo to yield ethyl 6-(N-(l- iminoethyl) amino) -2- (ethoxyiminomethyl) -2-aminohexanoate trihydrochloride .
  • Ethyl 6- (N- ( 1-iminoethyl) amino) -2-cyano-2- (N-Boc- amino) hexanoate (Ex-41c) (3.41 g, 10 mmol) is dissolved in ethanol and treated with one equivalent of sodium hydroxide (0.37 g, 10 mmol) . When the ester group is removed, p- toluenesulfonic acid (10 mmol) is added. The mixture is concentrated in vacuum. The residue is dissolved in 60 mL of DMF. 5-methylaminotetrazole hydrochloride (1.40 g, 10.5 mmol) and 1-hydroxybenzotriazole hydrate (1.46 g, 10.5 mmol) are added.
  • N-Methyl-N- (5-tetrazolyl) -6- (N- (1-iminoethyl) amino) -2- cyano-2- (N-Boc-amino) hexanamide (3.15 g, 8 mmol) is dissolved in methylene chloride and (0.26 g, 8 mmol) methanol is added. The mixture is cooled to -10°C and (1.9 g) HCl gas is added by gas inlet tube. The reaction is allowed to warm to room temperature.
  • 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 product tert-Butyl 6- (N- (1-iminoethyl) amino) -2-cyano-2- phthalimidohexanoate is then eluted with a solvent of 10% pyridine, 50% methanol and 40% water and taken to dryness in vacuo .
  • the resulting material is passed through a reverse phase chromatographic column, giving tert-butyl 6-(N-(l- iminoethyl ) amino) -2- (N- (N-Boc-glycyl ) ) aminomethyl-2- phthalimidohexanoate .
  • tert-Butyl 6- (N- (1-iminoethyl) amino) -2- (N- (N-Boc- glycyl) ) aminomethyl-2-phthalimidohexanoate (7 mmol) is dissolved in methanol and 0.5 g hydrazine monohydrate. The mixture is heated to reflux. After complete removal of the phthaloyl protecting group, cooling and filtering to remove the phthaloylhydrazide, the methanolic solution is then concentrated to dryness . The product is taken up and allowed to stand in 2N HCl and dioxane at 25 °C for two hours.
  • This reaction is shaken under pressure for an extended period of time in a standard Parr hydrogenation apparatus to remove the benzyl group generating, after filtering to remove catalyst and concentration in vacuo, N- methyl-N- (N- (5-tetrazoyl) amino) - 2-phthalimido-2- (2- hydroxyethyl) -6- (N- ( 1-iminoethyl) amino) hexanamide .
  • N-Methyl-N- (N- ( 5- ⁇ etrazoyl) amino) - 2-phthalimido-2- (2- hydroxyethyl) -6- (N- (1-iminoethyl) amino) hexanamide (2.29 g, 5 mmol) is dissolved in methanol and 0.5 g hydrazine monohydrate. The mixture is heated to reflux.
  • N- (2-amino-2- (2-cyanoethyl) -6- (N- (1- iminoethyl) amino) hexanoyl) aminoacetate is allowed to stand in 2N HCl and dioxane at 25°C for two hours. The solution is then concentrated to dryness to give N- (2-amino-2- (2- cyanoethyl) -6- (N- (1-iminoethyl) amino) hexanoyl) aminoacetic acid hydrochloride.
  • N-methylsulfonylmethyl-N- (5-tetrazolyl) -2-cyanomethyl-2- phthalimido-6- (N- (1-iminoethyl) amino) hexanamide (3.61 g, 7 mmol) is dissolved in methanol and 0.5 g hydrazine monohydrate. The mixture is heated to reflux.
  • N-Methanesulfonylmethyl-N- (O-methoxymethoxy) -2 -cyanomethyl- 2-phthalimido-6- (N- (1-iminoethyl) amino) hexanamide (2.54 g, 5 mmol) is dissolved in methanol and 0.5 g hydrazine monohydrate. The mixture is heated to reflux.

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Abstract

The current invention discloses novel hydroxyamidino carboxylate derivatives useful as nitric oxide synthase inhibitors. Compounds of particular interest are defined by Formula (I) wherein X, Y, A, J, R?1, R2 R3, R4, R7 and R8¿ are as described in the specification.

Description

NOVEL HYDROXYAMIDINO CARBOXYLATE DERIVATIVES USEFUL AS
NITRIC OXIDE SYNTHASE INHIBITORS
Background of the Invention
Field of the Invention
The present invention relates to novel hydroxamidino carboxylate derivatives and their use in therapy, in particular their use as nitric oxide synthase inhibitors.
Related Art
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 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 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 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, W094/12165, 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 Formula I and II:
Figure imgf000007_0001
II
and pharmaceutically acceptable salts thereof, wherein;
22
J is selected from the group consisting of 0, NR and S ; 29 . 29 J can be R , wherein R is a group selected from
28 28 28 28 24 , 28 24 . .
OR 0, OR S, SR S, OR NR and SR NR provided that A
26 is R
23 23 J1 and J2 are independently selected from OR , SR
NHR and N(R )R provided that A is R
15 15 G is selected from O, S, CH2 , CHR , C(R ) 2 , NH and
15 NR ;
A is selected from the group consisting of O, N(R ), S and heterocyclyl with the proviso that J is selected from other than 0 and A is selected from other than O, S and
8 heterocyclyl unless R is other than hydrogen,
7 hydroxyalkyl, alkoxyalkyl , alkyl and haloalkyl, or R is selected from other than aryl, heteroaryl, aralkyl, heteroaralkyl, H, alkyl, alkenyl, CH2OC (=0) GR15, hydroxyalkyl, polyhydroxyalkyl, amino, hydroxy, (poly) acyloxyalkyl and carboxyalkyl where G is selected from the group consisting from 0, S, CH2 , CHR-'--',
C(R15)2, NH, and NR15 and R15 is selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl and heteroaryl;
A is selected from the group consisting of 0, N(R )
3 and S connected to the point of attachment of R by a spacer selected from a group consisting of a covalent bond and a linear moiety having a chain length of 1 to 3 atoms to form C7 to CIO heterocyclyl with the proviso that when J
1 . is selected from 0 and A is selected from O and S, R is selected from other than H, S(0)R13, SO2R13 , CH2θC(0)R15 and C(0)R15 where C(0)R15 can represent natural and synthetic amino acids and where R^ s selected from substituted dihydropyridyl , alkyl, alkylthio, alkoxy, amino
2 and cycloalkoxy, R is selected from other than H, alkanoyl
8 and aroyl, or R is selected from other than hydrogen, hydroxyalkyl, alkoxyalkyl, alkyl and haloalkyl;
A can be selected from the group selected from 0,
5 4
N(R ) and S connected to the point of attachment of R by a spacer group selected from a group consisting of a covalent bond and a linear moiety having a chain length of 1 to 4 atoms to form C6 to CIO heterocyclyl provided that the linear moiety is selected from other than 0 and S;
A can be selected from the group selected from 0,
5 N(R ) and S connected to the point of attachment of any one
1 2 of R and R by a spacer group selected from a linear moiety having a chain length of 1 to 6 atoms to form C5 to
5 1 CIO heterocyclyl provided that, when A is N(R ), R is selected from other than H, S(0)R13, SO2R13 , CH2θC(0)R15 and C(0)R-'-5 where C(0)R-'-^ may represent natural and synthetic amino acids and where R!5 j_s selected from substituted dihydropyridyl, alkyl, alkylthio, alkoxy, amino
2 and cycloalkoxy, or R is selected from other than H,
8 alkanoyl and aroyl or R is selected from other than hydrogen, hydroxyalkyl, alkoxyalkyl, alkyl and haloalkyl;
A can be selected from the group consisting of O,
5 1
N(R ) and S connected to the points of attachment of R and 2 R by a spacer group selected from a linear moiety having a chain length of 1 to 6 to form C5 to CIO heterocyclyl;
A can be selected from the group consisting of 0,
N(R ) and S connected to X through substituent selected from hydroxyl, sulfhydryl, amino, carboxy1 , and carbonyl substituents of group X by a spacer selected from a covalent bond and a linear moiety having a chain length of 1 to 4 atoms to form C5 to CIO heterocyclyl;
26 . , . 26 . 8 . A can be R with the proviso that when R is H, R is
selected from other than hydrogen, or R is selected from other than H, S(0)R13, S02R13 , CH2θC(0)R15 and C(0)R15 wherein C(0)R-'-^ can represent natural and synthetic amino acids and wherein R^ iΞ selected from substituted
2 dihydropyridyl, alkyl, alkylthio and alkoxy, or R is selected from other than H, alkanoyl and aroyl, or J is selected from other than O;
27 27
A can be R , wherein R is selected from the group
, 5 7 , 5 7 25 5 13 consisting of N(R ) OR , N(R )N(R )R , N(R ) SO2R ,
5 15 5 15 19 20 5 19 20 N(R )C(0)R , N(R )C(S)R , R (R )C=N-N(R ), R (R ) C=N-
5 13 6 0, natural and synthetic ammo acids, N(R )P(0) (OR ) ι_R and
N(R )P(0) (OR )2;
1 2 R and R are independently selected from the group
6 6 consisting of hydrogen, hydroxyl, sulfhydryl, OR , SR , cyanoalkyl , dicyanoalkyl , carboxamidoalkyl , dicarboxamidoalkyl , cyanocarboalkoxyalkyl, carboalkoxyalkyl, dicarboalkoxyalkyl , cyanocycloalkyl, dicyanocycloalkyl , carboxamidocycloalkyl , dicarboxamidocycloalkyl , carboalkoxycyanocycloalkyl , carboalkoxycycloalkyl , dicarboalkoxycycloalkyl , formylalkyl, acylalkyl , CH2SO3- M+ , CH2CH2S03~ M+ , CH2PO3"
+ _2 + 6 13 13 2M , CH2CH2PO3 2M , CH(OR ) CF3 , S(0)R , SO2R ,
30 31 30 31 15 15 15
P(0)R R , P(O) (R )2 , C(0)R , C(S)R , CH2OC(0)R ,
19 , 15 19 , 15 , 15 15
CH2NR C(0)R , CH2NR C(S)R , CH2SC(0)R , CH2SC(S)R ,
15 19 , 15 19 15 CH2θC(0)GR , CH2NR C(0)GR , CH2NR C(S)GR ,
CH2OC(S)GR , CH2SC(S)GR , 0S02R , 0S(0)R , 0C(S)R ,
15 15 15 15 15 SC(S)R , OC(S)GR , SC(S)GR , OC(0)R , SC(0)R ,
15 , 15 . 19 20 . 1 .
OC(0)GR , SC(0)GR and R (R )CH, provided that R is selected from other than H, S(0)R13, SO2R13, CH2θC(0)-R15 and C(0)R where C(0)R-'-^ can represent natural and synthetic amino acids and where R^ is selected from substituted dihydropyridyl, alkyl, alkylthio, alkoxy, amino
22 29 and cycloalkoxy, unless J is selected from NR , R and S,
2 26
R is selected from other than H, alkanoyl and aroyl, R is
"?7 8 present, A is R , or R is selected from other than hydrogen, hydroxyalkyl, alkoxyalkyl, alkyl and haloalkyl or
2 provided that R is selected from other than H, alkanoyl
1 . and aroyl, unless R is selected from other than H,
S(0)R13, SO2R13, CH20C(O)R15 and C(0)R15 where C(0)R15 can represent natural and synthetic amino acids where R15 is selected from substituted dihydropyridyl, alkyl, alkylthio,
22 29 alkoxy, amino and cycloalkoxy, J is selected from NR , R
26 . . 27 8 . and S, R is present, A is R , or R is selected from other than hydrogen, hydroxyalkyl, alkoxyalkyl, alkyl or haloalkyl;
1 2 R and R can be taken together forming group selected r 19, 20 30 31 from a group consisting of R (R )C=, D(C(R ) (R ) ) ZD where z is 2 to 5 and D is selected from the group consisting of oxygen, C=0, C=S, S(0)m where m is 0 to 2 ,
31 30 , , 30 30 . 19 20 OP(OR )R , P(0)R , P(S)R and Si (R )R
19 20 , , 19 20 D((R )R C)eW(C(R )R )kD where e is 1 to 2, k is 1 to 2, with the proviso that only one D can be oxygen or sulfur at any time, and W is selected from the group consisting of oxygen, C=0, C=S, S(0)m, Se(0)m where m is 0 to 2 , P (0) R ,
30 19 ., 19 20 P(S)R , N(R ), and Sι(R )R , cycloalkyl radicals, cycloalkenyl radicals wherein said cycloalkyl radicals and cycloalkenyl radicals may be optionally substituted with
30 31 one or more R or R substituents, aryl radicals, heteroaryl radicals, saturated heterocyclic radicals and partially saturated heterocyclic radicals where said radicals are 1, 2-disubstituted and said 1, 2-substitutents are independently selected from the group consisting of
19 32 31 30 30 C=0, C=S, C(R )R , S(O), S(0)2, OP(OR )R , P(0)R ,
30 19 20
P(S)R , and Sι(R )R , cιs-1 , 2-dιsubstιtuted alkanes and cis-1, 2-disubstituted alkenes where said 1, 2-substitutents
19 32 are independently selected from C=0, C=S, C(R )R , S(0),
31 30 , v 30 30 19 20
S(0)2, OP(OR )R , P(0)R , P(S)R , and Si(R )R and said alkyl and alkenyl may be optionally substituted with
30 31 one or more R or R substituents; 3 4 R and R are independently selected from the group
6 6 consisting of hydrogen, hydroxyl, sulfhydryl, OR , SR ,
+ - _2 + _2 +
CH2SO3 M , CH2CH2Sθ3 M+, CH2PO3 2M , CH2CH2PO3 2M ,
, 6 , , 13 13 30 31 30 31 CH(OR )CF3, S(0)R , S02R , P(0)R R , P(0) (R ) 2R ,
15 15 15 19 15 C(0)R , C(S)R , CH2θC(0)R , CH2NR C(0)R ,
19 , % 15 , , 15 15 15
CH2NR C(S)R , CH2SC(0)R , CH2SC(S)R , CH2OC(0)GR ,
19 15 19 15 15
CH2NR C(0)GR , CH2NR C(S)GR , CH2OC(S)GR ,
15 13 13 15 15 CH2SC(S)GR , OS02R , OS(0)R , OC(S)R , SC(S)R ,
15 15 15 15 15
OC(S)GR , SC(S)GR , OC(0)R , SC(0)R , OC(0)GR and
15 3 4 SC(0)GR with the proviso that R and R are selected from other than H, OH, SH, OR6, SR6, OC(=0)R15, SC(=0)R15, CH20C(=0)GR15, OC(=0)GR15, SC(=0)GR15, OS02R13 and OS(0)R13 wherein R6 , R^3 and R^-5 are independently selected from the group selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl and heteroaryl unless J is
22 29 1 2 selected from NR , R and S, R and R are taken together,
26 . . 27 8 .
R is present, A is R , or R is selected from other than hydrogen, hydroxyalkyl, alkoxyalkyl, alkyl and haloalkyl;
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 , formylalkyl, acylalkyl, heteroaryl polyhydroxyalkyl, 13 13 30 31 polyacycloalkyl, carboalkoxy, S(0)R , SO2R , P(0)R R
30 31 15 15 15
P(O) (R )2R , C(0)R , C(S)R , CH2OC(0)R ,
19 15 19 15 15 15
CH NR C(0)R , CH2NR C(S)R , CH2SC(0)R , CH2SC(S)R ,
, 15 19 , 15 19 15 CH OC(0)GR , CH2NR C(0)GR , CH2NR C(S)GR ,
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;
5 with the proviso that R is selected from other than the group consisting of hydrogen, alkyl, alkenyl, aryl, heteroaryl, aralkyl, heteroaralkyl, hydroxyalkyl, polyhydroxyalkyl, amino, hydroxy, polyacyloxyalkyl,
15 carboalkoxy and CH2OC(0)GR where G is independently selected from 0, S, CH2 , CHR15, C(R15)2, NH, and NR15 and where R^5 is selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl and heteroaryl
22 1 2 unless J is selected from NR , R and S, R and R are
26 27 8 . taken together, R is present, A is R , or R is selected from other than hydrogen, hydroxyalkyl, alkoxyalkyl, alkyl and haloalkyl;
5 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 C5 to C8 heterocyclyl;
5 R can be 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 the group consisting of 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, loweralkylamino, 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 , o guanidino, amidino and acylamino with the proviso that R
5 1 is selected from other than H when A is N(R ) unless R and
2 R are taken together;
6 R is selected from the group selected from hydrogen, heterocyclic, heteroaryl, hydroxyalkyl, minoalkyl, 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, natural and synthetic amino acids and polyhydroxy compounds of carbon with the proviso that R6 is selected from other than hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl and heteroaryl unless J is
00 n Q f, selected from the group consisting of NR , R and S, R
27 1 2 8 is present, A is R , R and R are taken together, or R is selected from other than hydrogen, hydroxyalkyl, alkoxyalkyl, alkyl and haloalkyl;
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 formylalkyl, acylalkyl, S(0)R , SO2R , P(0)R R ,
30 31 15 15 15
P(0)(R ) R , C(0)R , C(S)R , CH2OC(0)R ,
19 , 15 19 15 15 , 15
CH2NR C(0)R , CH2NR C(S)R , CH2SC(0)R , CH2SC(S)R ,
, v 15 19 , 15 19 15 CH2OC(0)GR , CH2NR C(0)GR , CH2NR C(S)GR ,
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
7 sulfonylalkylamino with the proviso that R is selected from other than the group consisting of hydrogen, alkyl, alkenyl, aryl, heteroaryl, aralkyl, heteroaralkyl, hydroxyalkyl, polyhydroxyalkyl, amino, hydroxy,
15 polyacyloxyalkyl, carboalkoxy and CH2θC(0)GR where G is selected from the group consisting of 0, S, CH2 , CHR15, C(R15)2 NH, and NR15 and wherein R15 is selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl and heteroaryl unless J is selected
22 29 26 . . 27 1 ., 2 from NR , R and S, R is present, A is R , R and R
8 are taken together, or R is selected from other than hydrogen, hydroxyalkyl, alkoxyalkyl, alkyl and haloalkyl; or
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 C5 to C8 heterocyclyl;
7 R can be a heterocyclyl radical 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 with the proviso that A is selected from other than 0 and S unless J is selected from
22 29 NR , R and S or J1 and J2 are selected from two groups 23 23 24 independently selected from OR , SR NHR and
24 25 1 . 2 n . 26
N(R )R , R and R are taken together when A is R , or
8 . provided that R is selected from other than H when A is
N(R ) ;
R is selected from hydrogen, hydroxyalkyl, haloalkyl, alkyl, alkoxyalkyl, aminoalkyl, alkylaminoalkyl, alkylthioalkyl, cyanoalkyl, sulfhydrylalkyl, formyl, C(0)A-
7 7 7 19 7 19
R , C(S)A-R , CH2OC(0)A-R , CH2NR C(0)A-R , CH2NR C(S)A-
7 7 7 15
R , CH2SC(0)A-R , CH2SC(S)A-R , CH2OC(0)GR ,
19 15 19 15 15 15 CH NR C(0)GR , CH2NR C(S)GR , CH2OC(S)GR , CH2SC(S)GR
and acyl with the proviso that R is selected from other than hydrogen, hydroxyalkyl, haloalkyl, alkyl, alkoxyalkyl
22 29 26 unless J1 and J2 are selected from NR , R and S, R is , 2 , , . 27 present, R and R are taken together, or A is R
13 R is independently selected from aryloxy, ammo, 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, natural and synthetic amino acids and polyhydroxy compounds 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 , icarboalkoxycycloalkyl , formylalkyl, acylalkyl, dialkoxyphosphonoalkyl , diaralkoxyphosphonoalkyl , phosphonoalkyl , dialkoxyphosphonoalkoxy, diaralkoxyphosphonoalkoxy, phosphonoalkoxy, dialkoxyphosphonoalkylamino , diaralkoxyphosphonoalkylamino , phosphonoalkylamino , dialkoxyphosphonoalkyl , diaralkoxyphosphonoalkyl , sulfonylalkyl , alkoxysulfonylalkyl , aralkoxysulfonylalkyl , alkoxysulfonylalkoxy, aralkoxysulfonylalkoxy, sulfonylalkoxy, alkoxysulfonylalkylamino, aralkoxysulfonylalkylamino, sulfonylalkylamino, natural and synthetic amino acids and polyhydroxy compounds of carbon;
+ M is a pharmaceutically acceptable cation;
X is selected from the group consisting of alkylene, alkenylene, and alkynylene groups which may be optionally substituted from the group consisting of alkyl, alkoxy, hydroxy, sulfhydryl, halogen, trifluoromethyl, nitro, cyano and amino; or
X can be - (CH2 )pQ (CH2 ) r- wherein p is 1 to 3 , r is 1 to 3 and Q is selected from oxygen, C=0, S(0)t, Se(0)t wherein
21 21 t is 0 to 2, P(0)R wherein R is hydroxyl or alkyl which may be optionally substituted with one of the group consisting of alkyl, alkoxy, hydroxy, halogen,
12 trifluoromethyl, nitro, cyano, am o, carboxy, and N(R )n
12 where n is 1 to 2 and R is selected from the group consisting of hydrogen, oxy, hydroxyl and alkyl which may be optionally substituted from the group consisting of alkyl, alkoxy, hydroxy, halogen, trifluoromethyl , nitro, cyano and amino ;
X can be - (CH2 ) ST (CH2 ) v _ wherein s is O to 2, v is 0 to
2 and T is selected from a 3 to 6 membered carbocyclic radical, aryl radical and a heterocyclyl radical where all said radicals may be optionally substituted with alkyl, alkoxy, hydroxy, halogen, trifluoromethyl, nitro, cyano and amino;
Y is selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxyalkyl, cycloalkyl, cycloalkenyl, cycloalkenyloxy, alkenyloxyalkyl, alkylthioalkyl,
9 10 9 10 alkylammoalkyl and NR R where 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 C3 to C8 heterocyclyl;
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 with
19 20 . the proviso that only one of R and R is hydrogen;
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 to form a group consisting of C3 to C8 cycloalkyl, C3 to C8 cycloalkenyl and C3 to C8 heterocyclyl;
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 together to form a spacer group independently selected from a linear moiety having a chain length of 4 to 7 atoms to form C5 to C8 heterocyclyl;
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 with the proviso that J is selected from other
8 . than 0 unless R is other than hydrogen; 28 R is independently selected from a group consisting
23 23 23 of CH(R )CH2, CH(R ) CH2CH2 , CH2CH(R ) CH2 , cycloalkylene and heterocyclylene;
30 31 R and R independently selected from the group 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, natural and synthetic amino acids, and polyhydroxy compounds of carbon; 30 , 31 R and R can be together to form a linear moiety spacer group having a chain length of 2 to 7 atoms selected from the group consisting of C3 to C8 cycloalkyl, C3 to C8 cycloalkenyl, and C3 to C8 heterocyclyl substituted independently and optionally with one or more alkyl, haloalkyl, aryl, heteroaryl, alkoxyalkyl, alkoxy, haloalkoxy, cyano, carboalkoxy, hydroxy, hydroxyalkyl, and halo groups .
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 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 and II 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 1 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-hydroxybenzoic, phenylacetic, mandelic, embonic (pamoic), methanesulfonic, ethylsulfonic, benzenesulfonic, sulfanilic, stearic, cyclohexylaminosulfonic, algenic, galacturonic acid. Suitable pharmaceutically-acceptable base addition salts of compounds of Formula 1 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 1 by reacting, for example, the appropriate acid or base with the compound of Formula 1.
While it may be possible for the compounds of formula (1) 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 (1) 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 iacceptableϊ 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 (1) 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 active 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 and II 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 (— CH— > , 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, trifluoromethoxy, 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 . Said "aryl" group may 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, 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, he eroaryloxy, heteroaryloxyalkyl, arylalkyl, heteroarylalkyl, arylalkenyl, heteroarylalkenyl, carboalkoxy, carboaralkoxy, cyano, and carbohaloalkoxy .
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 above.
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, pyrazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, triazolyl [e.g., 4H- 1,2, 4-triazolyl, 1H-1 , 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 [1 , 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. Said "heterocyclyl" group may have 1 to 3 substituents as defined below. 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. 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.
Said "heterocyclyl" group may 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, 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 , carboalkoxy, carboaralkoxy, cyano, and carbohaloalkoxy .
The term "sulfonyl", whether used alone or linked to other terms such as alkylsulfonyl , denotes respectively divalent radicals -S02-. "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 alkylsulfinyl, denotes respectively divalent radicals -S(O)-. "Alkylsulfinyl" , embraces alkyl radicals attached to a sulfinyl radical, where alkyl is defined as above. "Alkylsulfinylalkyl " , embraces alkylsulfinyl 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 aryl in said aralkyl may have additional 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, 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, carboalkoxy, carboaralkoxy, cyano, and carbohaloalkoxy . 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 "alkylsulfinyl " embraces radicals containing a linear or branched alkyl radical, of one to ten carbon atoms, attached to a divalent - S(=0)- 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(=0)- 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(=0)- 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 aryl in said aryloxy may be additionally 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, carboalkoxy, carboaralkoxy, cyano, and carbohaloalkoxy .
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 aroyl in said aroyl may be additionally substituted with heteroarylamino, N-aryl-N-alkylamino, N- heteroarylamino-N-alkylamino, haloalkyl hio, 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, carboalkoxy, carboaralkoxy, cyano, and carbohaloalkoxy .
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 aryl in said aralalkanoyl may be additionally 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, carboalkoxy, carboaralkoxy, cyano, and carbohaloalkoxy. 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 aryl in said aralkoxy radicals may be additionally 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, carboalkoxy, carboaralkoxy, cyano, and carbohaloalkoxy.
The term "aryloxyalkyl" embraces aryloxy radicals, as defined above, attached to an alkyl group. Examples of such radicals include phenoxymethyl . The aryl in said aryloxyalkyl may be additionally 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, diaryla idosulfonyl, 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 "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 heteroaryl in said heteroaryloxy may be additionally 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, carboalkoxy, carboaralkoxy, cyano, and carbohaloalkoxy.
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 heteroaryl in said heteroaroyl may be additionally 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, carboalkoxy, carboaralkoxy, cyano, and carbohaloalkoxy.
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 heteroaryl in said heteroaralalkanoyl may be additionally 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, carboalkoxy, carboaralkoxy, cyano, and carbohaloalkoxy.
The term "heteroaralkoxy" embraces oxy-containing heteroaralkyl radicals attached through an oxygen atom to other radicals. More preferred heteroaralkoxy radicals are "lower heteroaralkoxy" radicals having heteroaryl radicals attached to lower alkoxy radical as described above. The heteroaryl in said heteroaralkoxy radicals may be additionally 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, carboalkoxy, carboaralkoxy, cyano, and carbohaloalkoxy. The term "heteroaryloxyalkyl" embraces heteroaryloxy radicals, as defined above, attached to an alkyl group. Examples of such radicals include pyridyloxymethyl . The heteroaryl in said heteroaryloxyalkyl may be additionally 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, hydroxyal yl, 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 "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 aryl in said arylthio may be additionally 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, carboalkoxy, carboaralkoxy, cyano, and carbohaloalkoxy. The term "arylthioalkyl" embraces arylthio radicals, as defined above, attached to an alkyl group. Examples of such radicals include phenylthiomethyl . The aryl in said arylthioalkyl may be additionally 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, carboalkoxy, carboaralkoxy, cyano, and carbohaloalkoxy.
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 methoxymethyl . 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 alkanoyl in said haloalkanoyl may be additionally substituted with hydroxy, amino, thio, 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, carboalkoxy, carboaralkoxy, cyano, and carbohaloalkoxy.
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 thionoformyl 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.
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(R )-, -0-, -S-, -S(O)-, - 6 6
S ( 0 ) 2 - , -NH- , -N ( R ) - , -N= , -CH ( OH ) - , =C ( OH ) - , -CH ( OR ) - ,
=C(OR )-, 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,
-0-, -0-CH2-, -S-CH2-, -CH2CH2-, ethenyl, -CH=CH(OH)-, -
6 6
OCH20-, -0(CH2)2θ-, -NHCH2-, -OCH(R ) 0- , -0(CH2CHR ) O- , -
OCF20-, -0(CF2)2θ-, -S-, -S(O)-, -S(0)2-, -N(H)-, -N(H)0-, -N(R )0-, -N(R )-, -C(O)-, -C(0)NH-, -C(0)NR -, -N=, -0CH2-,
6 -SCH2-, S(0)CH2-, -CH2C(0)-, -CH(OH)-, =C(0H)-, -CH(OR )-,
6 6
=C(OR )-, S(0)2CH2-, and -NR CH2- 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, 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, 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. 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-
Cl" represents a chloromethylation or bromomethylation
15 19 15 reagent such as Cl-CH2θC(0)R , CI-CH2NR C(0)R , Cl-
CH2NR C(S)R , C1-CH2SC(0)R , C1-CH2SC(S)R , Cl-
15 19 15 19 15
CH2OC(0)GR , C1-CH2NR C(0)GR , Cl-CH2NR C(S)GR , Cl-
15 15 CH2OC(S)GR , or CI-CH2SC ( S) GR , "DCC" represents 1,3- dicyclohexylcarbodiimide, "DIBAH" represents diisobutylaluminum hydride, "DIPEA" represents diisopropylethylamine, "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, "p-TsOH" represents paratoluenesulfonic acid, "TBTU" represents 2-(lH- benzotriozole-1-yl) -1,1,3, 3-tetramethyl uronium tetrafluoroborate, "TEA" represents triethylamine, "THF" represents tetrahydrofuran, and "Z" represents benzyloxycarbonyl .
Disclosed are fifty-three synthetic processes useful in the preparation of 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 imgf000063_0001
(a) R -NH2 (aa) N-chlorosuccimide, DMF
(b) BOP, DIPEA, DMF
(c) Pd, H2 , Ethanol/Acetic Acid
(d) H20, pH 9-10
(e) HCl, dioxane or trifluoroacetic acid. Scheme 2
Figure imgf000064_0001
(a) HCl, Methanol
(b) BOP, DIPEA, DMF
(c) Pd, ≡2 ' Ethanol/Acetic Acid
(d) TEA, DMF
(e) HCl, dioxane or trifluoroacetic acid
Figure imgf000065_0001
(a) R3 -NH2 (aa) N-chlorosuccimide, DMF
(b) BOP, DIPEA, DMF
(c) HCl, dioxane or trifluoroacetic acid
(d) H20, pH 9-10 (e) Pd, H , Ethanol/Acetic Acid Scheme 4
Figure imgf000066_0001
(a) HCl, Methanol
(b) BOP, DIPEA, DMF
(c) HCl, dioxane or trifluoroacetic acid
(d) TEA, DMF
(e) Pd, H2, Ethanol/Acetic Acid
Figure imgf000067_0001
(a) t-Butoxycarbonyl azide, H2O, dioxane, MgO
(b) Pd, H2, Ethanol/Acetic Acid
(c) TEA, 0-80 °C
Figure imgf000068_0001
(a) TEA, 0-80 °C
(b) HCl, dioxane
Figure imgf000069_0001
(R1^ hydroxyl, sulfhydryl, OR 6 or SR 6 )
(a) 1. t-butoxycarbonylazide, H 2°- dioxane, MgO
2. acetic anhydride, TEA (b) BOP, DIPEA, DMF
(c) 1 equiv. NaOH, ethanol (d) DMSO, DCC, H 3PO4
(e) R1-NH9, ethanol, sodium carbonate Scheme 8
Figure imgf000070_0001
( R1 ^ hydroxyl , sulfhydryl , OR6 or SR6 ) ( a ) BH3 , THF
2
(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) HCl, dioxane or trifluoroacetic acid
(d) H20, pH 9-10 with (2) or TEA, DMF with (2b) Scheme 9
H
Figure imgf000071_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, OR 6 or SR6 ethanol, sodium carbonate Scheme 10
Figure imgf000072_0001
(R = hydroxyl, sulfhydryl, ORD or SR° ) (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) HCl, dioxane or trifluoroacetic acid
(d) H20, pH 9-10 with (2) or TEA, DMF with (2b)
Figure imgf000073_0001
(a) RJ-NH2 (aa) N-chlorosuccimide, DMF
(b) HCl, 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) H2O, pH 9-10
Figure imgf000074_0001
(a) HCl, Methanol
(b) HCl, dioxane or trifluoroacetic acid ι
(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 imgf000075_0001
(a) R -NH2 (aa) N-chlorosuccimide, DMF
(b) HCl, dioxane or trifluoroacetic acid
2
(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, B.2 ' Ethanol/Acetic Acid
(e) H20, pH 9-10
Figure imgf000076_0001
(a) HCl, methanol
(b) HCl, dioxane or trifluoroacetic acid
(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 imgf000077_0001
(a) Benzyl chloroformate, Na 2 03, THF, Water
(b) HCl, dioxane or trifluoroacetic acid
(c) catalytic p-TsOH, hexane or toluene, azeotropic distillation (d) Pd, H 2 > Ethanol/Acetic Acid (e) Acylation with R 1 or R 2 : carboxylic acid choride or anhydride, chloroformate, isocyanate, sulfonyl chloride or sulfinyl chloride with standard conditions.
Figure imgf000078_0001
(a) catalytic p-TsOH, hexane or toluene, azeotropic distillation
(b) Pd, H2, Ethanol/Acetic Acid
(c) Acylation with R 1or R2 : carboxylic acid choride or anhydride, chloroformate, isocyanate, sulfonyl chloride or sulfinyl chloride with standard conditions.
Figure imgf000079_0001
(a) Naθ3SCH2OH, pH 10-11 [see L. 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 imgf000080_0001
(a) Trichloroethyl chloroformate, Na 2C03' H 2θ, 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 2 03' 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 with (d) -conditions .
Figure imgf000081_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 imgf000082_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) Na2C03, toluene, heat
Figure imgf000083_0001
(c) Lithium Diisopropylamide, THF, then dialkyl acetal of a bromoalkanone
Figure imgf000084_0001
(a) R -NH2 (aa) N-chlorosuccimide, DMF
(b) an aldehyde or ketone precursor to R , 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 imgf000085_0001
(a) Na2Cθ3 , aqueous dioxane; Acylation with a carboxylic acid choride or anhydride
(b) Na2C03 , aqueous dioxane; sulfonation with a sulfonyl chloride or sulfinyl chloride with standard conditions
Figure imgf000086_0001
(a) Na2C03, aqueous dioxane; Acylation with carboxylic acid choride or anhydride
(b) N 2Cθ3, aqueous dioxane; sulfonation with sulfonyl chloride or sulfinyl chloride with standard conditions
(c) trifluoroacetic acid anhydride
(d) NaBH4, R6-OH, aprotic polar solvent
Figure imgf000087_0001
(b) benzyl chloroformate, Na2Cθ3, dioxane, water
(c) NaOH, H20
(d) BOP, DIPEA, DMF
(e) DMF, heat
(f) Pd, H2, Ethanol
Figure imgf000088_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 imgf000089_0001
(a) Phthalic anhydride, THF at reflux
(b) LDA, THF, then Alkylation with a chloromethylation reagent (CMR-Cl)
(c) Pd, B-2 ' Ethanol
(d) H20, pH 9-10
(e) Hydrazine, methanol, reflux.
Figure imgf000090_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 imgf000091_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, H2, Ethanol
(d) HCl, dioxane, H2O
Figure imgf000092_0001
(a) LDA, THF Alkylation with a chloromethylation reagent (CMR-Cl)
(b) Hydrazine, methanol, reflux
(c) H20, pH 9-10
(d) Pd, H2, Ethanol
Figure imgf000093_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 imgf000094_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) Na2Cθ3, toluene, heat
Figure imgf000095_0001
(b) HCl, d oxane or tr fluoroacetic acid
(c) Lithium Diisopropylamide, THF, then dialkyl acetal of a bromoalkanone
Figure imgf000096_0001
(c) Lithium Diisopropylamide, THF, then dialkyl acetal of a bromoalkanone
Figure imgf000097_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, R23-OH, hexane, heat
(f) BF3 etherate with an R23-OH or R23 -SH in an aprotic solvent
(g) 1. Aqueous a2Cθ3 wash, 2. thoroughly dry, then 3. HCl in dioxane
Figure imgf000098_0001
(a) H20, pH 9-10
(b) Hydrazine, methanol, reflux
Figure imgf000099_0001
(a) BF3 etherate with H0R 2'8O,0H,
Figure imgf000099_0002
HOR28NR24H, or HSR28NR24H in an aprotic solvent or, with HOR28OH, p-TsOH, R23-OH, hexane, heat
(b) HCl, dixoane or trifluoroacetic acid
(c) H2O, pH 9-10 (d) Hydrazine, methanol, reflux
Figure imgf000100_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 7
(e) BF3 etherate with an R23-OH or R23 -SH in an aprotic solvent
Figure imgf000101_0001
(a) Pd, Hp, ethanol/acetic acid
(b) H2O, pH 9-10
(c) Hydrazine, methanol, reflux Scheme 40
Figure imgf000102_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, H 0
(d) R7-SH, CH2C12, -10 °C, HCl
(e) R7-OH, CH2C12, -10 °C, HCl Scheme 40
Figure imgf000103_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-OH, CH2C12, -10 °C , HCl Scheme 41
Figure imgf000104_0001
(a) Hydrazine, ethanol, reflux
(b) Intermediate (2) or (2b), pH 9-10, H20
(c) R7-SH, CH2C12, -10 °C, HCl
(d) R7-OH, CH2C12, -10 °C, HCl
Scheme 42
Figure imgf000105_0001
(a) H-NR ,5π R7 , toluene, reflux
(b) R7-OH, CH2C12, -10 °C, HCl
(c) R7-SH, CH2Cl2, -10 °C, HCl
(d) 1. 1 equivalent NaOH in ethanol, 2. 1 equivalent of HCl, 3. BOP, DIPEA, DMF, H-NR5R7
Figure imgf000106_0001
(a) Pd, H2, Ethanol/Acetic Acid
(b) Intermediate (2) or (2b), pH 9-10, H20
(c) H2 Pt, Acetic acid
(d) C1-C(0)R15, triethylamine
(e) 1. Hydrazine, methanol, reflux, 2. HCl, dioxane Scheme 44
Figure imgf000107_0001
(a) 1. 1 equivalent LDA/THF at -78 °C, 2. bromoacetal (166)
(b) 1. 1 equivalent LDA/THF at -78 °C, 2. Br-CH2CH20-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 imgf000108_0001
(a) Intermediate (2) or (2b) , pH 9-10, H 2°
(b) HCl/Acetic acid
(c) 1. BOP, DIPEA, DMF, 2. H-A-R
(d) Pd, H2, Ethanol/Acetic Acid
(e) Hydrazine, methanol, reflux
Figure imgf000109_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 imgf000110_0001
(a) 1. HCl, dioxane, 2. BOP, DIPEA, DMF, 3. H0CH2CC13
(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) 3
Figure imgf000111_0001
(a) Intermediate (2) or (2b) , pH 9-10, H 20
(b) Zinc dust/THF
(c) 1. BOP, DIPEA, DMF, 2. H-A-R7
(d) Hydrazine, methanol, reflux
Figure imgf000112_0001
(a) 1. 1 equivalent LDA/THF at -78 °C, 2. alkylation with an R 8-reagent such as R8 -Br, R8 -OTs, R8 -oxirane, thiirane, or aziridine, or CMR-Cl
(b) catalytic p-TsOH, H20, 0-5 °C
(c) H2N-R4 , NaCNBH3, methanol, KOH
(d) Intermediate (2) or (2b), pH 9-10, H20
Figure imgf000113_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 ) S02R13 , HN (R22 ) C (0) R 15
HN(R 22 C (S)R 15 HN(R22 )P(0) (OR13 )nR6
Figure imgf000114_0001
(a) 1. BOP, DIPEA, DMF,
2. t-butyl ester of amino acid with t-butoxycarbonyl protected OH or SH group (H N-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 imgf000115_0001
(c) R 8 -reagent such as RR -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 R 23 -SH
(g) BF3 etherate with HOR 28OH, HOR28SH, HSR28SH, HOR28NR24H, or HSR28NR 4H
(h) H2 , Pd/C, Ammonium Formate
Figure imgf000116_0001
(a) t-Butoxycarbonyl azide, H2O, dioxane, MgO
(b) H2O, phosphoric acid
22
(c) R -NH2 , catalytic p-TsOH, toluene, azeotropic distillation (d) N-chlorosuccinimide, DMF (e) R7-OH, toluene, reflux (f) HCl, dioxane
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. It should also be noted that some numerical measurements (e.g. molarity, time temperature, mass etc.) in the Examples may be estimates, therefore minor experimentation is contemplated for exact values.
All experiments are performed under either dry nitrogen or argon. All solvents and reagents are 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 is extracted n times (x) with the indicated organic solvent. The combined organic extracts is washed n times (x) with the indicated aqueous solutions, dried over anhydrous Na S04, filtered, concentrated in vacuo, and purified as indicated. Separations by column chromatography are 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 are made from IN HCl, HCl in ethanol (EtOH) , 2 N in MeOH, or 6 N HCl in dioxane. Thin layer chromatograms are run on 0.25 mm EM precoated plates of silica gel 60 F254. High performance liquid chromatograms (HPLC) are obtained from C-8 or C-18 reverse phase columns which are obtained from several vendors . Analytical samples are dried in an Abderhalden apparatus at either 56°C or 78°C. !H NMR spectra are obtained from either General Electric QE-300 or Varian VXR 400 MHz spectrometer. 13C NMR spectra is obtained from a Varian spectrometer at 125.8 MHz.
Figure imgf000118_0001
EXAMPLE 1
Ex-la) To a stirring DMF solution of e-Z-a-Boc-2-methyl-L- Lysine (3.94 g, 10.0 mmol), N- (2-cyanoethyl) -2-aminothiazole (1.46 g, 10.5 mmol), and 1-hydroxybenzotriazole hydrate (1.45 g, 10.5 mmol) in 75 mL of dimethylformamide (DMF) cooled in an ice bath is added [ (N, -dimethylamino) propyl] ethylcarbodiimide hydrochloride (1.93 g, 10.5 mmol). After stirring 55 h at ambient temperature, the reaction mixture is concentrated in vacuum. The resulting material is dissolved in aqueous acetonitrile and passed through a reverse phase chromatographic column, giving N- (2-cyanoethyl) -N- (2-thiazolyl) -e-Z-a-Boc-2- methyl-L-Lysinamide .
Ex-lb) N- (2-cyanoethyl) -N- (2-thiazolyl) -e-Z-a-Boc-2- methyl-L-Lysinamide 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-function generating the amino product N- (2-cyanoethyl) -N- (2-thiazolyl) -a-Boc-2-methyl-L- Lysinamide .
Ex-lc) To a 125 mL flask is added 2.60 g (0.01 mol) of N- (2-cyanoethyl) -N- (2-thiazolyl) -a-Boc-2-methyl-L-Lysinamide 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, 2.15 g of O-methyl chloroacetaldoxime which is prepared immediately prior to use by the reaction of
5.38 g (0.05 mol) of O-methyl acetaldoxime with 8 g (0.060 mol) of N-chlorosuccinimide in 65 mL of N,N- dimethylformamide at 0°C. The O-methyl chloroacetaldoxime is isolated after three hours by extracting into diethyl ether and washing with aqueous NaCl. Drying with MgS04 , filtration and concentration under 30°C affords the 0- methyl chloroacetaldoxime as a pale yellow oil. During the O-methyl 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 produced in Ex-lc is deprotected by allowing it to stand in 2N HCl at 25°C for two hours. Concentrating in vacuo affords L-N-(2- cyanoethyl) -N- (2-thiazolyl) - e-N- (methoxyiminoethyl) -2- methyllysinamide dihydrochloride .
Figure imgf000119_0001
EXAMPLE 2 Ex-2a) To a stirring DMF solution of e-Z-a-Boc-2-methyl-L- Lysine (3.94 g, 10.0 mmol), N, -dimethyl-N' - (2- pyridyl) hydrazine dihydrochloride (2.31 g, 10.5 mmol), 2.53 g triethylamine (0.025 mol) and 1-hydroxybenzotriazole hydrate (1.45 g, 10.5 mmol) in 75 mL of dimethylformamide (DMF) cooled in an ice bath is added [(N,N- dimethylamino)propyl] ethylcarbodiimide hydrochloride (1.93 g, 10.5 mmol). After stirring 55 h at ambient temperature, the reaction mixture is concentrated in vacuum. The resulting material is dissolved in aqueous acetonitrile and passed through a reverse phase chromatographic column, giving N- (2-dimethylamino) -N- (2-pyridyl) -e-Z-a-Boc-2- methyl-L-Lysinamide .
Ex-2b) N- (2-dimethylamino) -N- (2-pyridyl) -e-Z-a-Boc-2- methyl-L-Lysinamide 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-function generating the amino product N- (2-dimethylamino) -N- (2-pyridyl) -a-Boc-2-methyl-L- Lysinamide .
Ex-2c) To a 125 mL flask is added 2.60 g (0.01 mol) of N- ( 2-dimethylamino) -N- (2-pyridyl) -a-Boc-2-methyl-L-Lysinamide and 70mL of DMF. To this solution is added 2.19 g of methyl acetimidate hydrochloride. Triethylamine (TEA) (3.04 g, 0.03 mol) was 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. After concentrating, the product produced in Ex-2c is deprotected by allowing it to stand in 2N HCl at 25°C for two hours. Concentrating in vacuo afforded L-N-(2- dimethylamino) -N- (2-pyridyl) - e-N- (iminoethyl) -2 -methyl-L- lysinamide tetrahydrochloride .
Figure imgf000121_0001
EXAMPLE 3
Ex-3a) To a stirring DMF solution of a-Z-S- (N-Boc-2- aminoethyl) -2-methyl-L-Cysteine (4.12 g, 10.0 mmol), N-(2- hydroxyethyl) -N- (2-thiazolyl) amine (1.39 g, 10.5 mmol), and 1-hydroxybenzotriazole hydrate (1.45 g, 10.5 mmol) in 75 mL of dimethylformamide (DMF) cooled in an ice bath is added [ (N,N-dimethylamino)propyl] ethylcarbodiimide hydrochloride (1.93 g, 10.5 mmol) . After stirring 55 h at ambient temperature, the reaction mixture is concentrated in vacuum. The resulting material is dissolved in aqueous acetonitrile and passed through a reverse phase chromatographic column, giving N- (2-hydroxyethyl) -N- (2- thiazolyl) -a-Z-S- (N-Boc-2-aminoethyl) -2-methyl-L- Cysteinamide .
Ex-3b) N- (2-hydroxyethyl) -N- (2-thiazolyl) -a-Z-S- (N-Boc-2- aminoethyl) -2-methyl-L-Cysteinamide is then dissolved in trifluoroacetic acid and allowed to stand at room temperature until the t-butoxycarbonyl group is removed. The reaction mixture is then concentrated in vacuo to give N- (2-hydroxyethyl) -N- (2-thiazolyl) -a-Z- S- (2-aminoethyl) -2- methyl-L-Cysteinamide trifluoroacetate .
Ex-3c) To a 125 mL flask is added (10 mmol) of N-(2- hydroxyethyl) -N- (2-thiazolyl) -a-Z- S- (2-aminoethyl) -2- methyl-L-Cysteinamide 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, 2.34 g of chloroacetaldoxime which is prepared immediately prior to use by the reaction of 3.55 g (0.06 mol) of acetaldoxime with 10.4 g (0.078 mol) of N-chlorosuccinimide in 65 mL of
N,N-dimethylformamide at 0°C. The chloroacetaldoxime is isolated after three hours by extracting into diethyl ether and washing with aqueous NaCl. Drying with MgSO^ , filtration and concentration under 30°C affords the chloroacetaldoxime as a pale yellow oil . 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 Z-protected product is then eluted with 10% aqueous pyridine and lyophilized to remove solvent.
Ex-3d) N- (2-hydroxyethyl) -N- (2-thiazolyl) -a-Z- S-(2-(N- oximinoethyl) amino) ethyl) -2-methyl-L-Cysteinamide is dissolved in 25 ml of acetic anhydride containing a 0.1 g pyridine. After standing at room temperature for 2 hours, the reaction mixture is concentrated in vacuo to give N-(2- acetoxyethyl) -N- (2-thiazolyl) -a-Z-S- (2- (N- (2- acetoxyiminoethyl) amino) ethyl) -2-methyl-L-Cysteinamide .
N- (2-acetoxyethyl) -N- (2-thiazolyl) -a-Z-S- (2- (N- (2- acetoxyiminoethyl) amino) ethyl) -2-methyl-L-Cysteinamide is dissolved in 30% HBr in acetic acid to remove the Z- function generating the amino product N- (2-acetoxyethyl) -N- (2-thiazolyl) -S- (2- (N- (2-acetoxyiminoethyl ) amino) ethyl) -2- methyl-L-Cysteinamide .
Figure imgf000123_0001
EXAMPLE 4
Ex-4a) To a stirring DMF solution of a-Z-S- (N-Boc-2- aminoethyl) -2 -methyl-L-Cysteine (4.12 g, 10.0 mmol), 4- aminopyridine (1.00 g, 10.5 mmol), and 1- hydroxybenzotriazole hydrate (1.45 g, 10.5 mmol) in 75 L of dimethylformamide (DMF) cooled in an ice bath is added [ (N, -dimethylamino) propyl] ethylcarbodiimide hydrochloride (1.93 g, 10.5 mmol) . After stirring 55 h at ambient temperature, the reaction mixture is concentrated in vacuum. The resulting material is dissolved in aqueous acetonitrile and passed through a reverse phase chromatographic column, giving N- (4-pyridyl) - a-Z-S- (N-Boc- 2-aminoethyl) -2-methyl-L-Cysteinamide .
Ex-4b) N- (4-pyridyl) - a-Z-S- (N-Boc-2-aminoethyl) -2-methyl- L-Cysteinamide is then dissolved in trifluoroacetic acid and allowed to stand at room temperature until the t- butoxycarbonyl group is removed. The reaction mixture is then concentrated in vacuo to give N- (4-pyridyl) - a-Z-S- (2- aminoethyl) -2-methyl-L-Cysteinamide trifluoroacetate .
Ex-4c) To a 125 mL flask is added (10 mmol) of N-(4- pyridyl)- a-Z-S- (2-aminoethyl) -2-methyl-L-Cysteinamide and 70mL of DMF. To this solution is added 4.14 g of methyl N- Z-acetimidate. Triethylamine (TEA) (3.04 g, 0.03 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 Z-protected product is then eluted with 10% aqueous pyridine.
Ex-4d) N- (4-pyridyl) -a-Z-S- (2- (N- (N-Z- iminoethyl) amino) ethyl) -2-methyl-L-Cysteinamide (0.005 mol) 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 on n-butyl lithium in hexane. Subsequently, 1.1 equivalents of acetyl chloride is added. After warming to room temperature, the reaction mixture is filterd to remove the precipitant and concentrated in vacuo to give N-acetyl-N- (4-pyridyl) -a-Z-S- (2- (N- (N-Z-iminoethyl ) amino) ethyl ) -2- methyl-L-Cysteinamide .
N-acetyl-N- (4-pyridyl) -a-Z-S- (2- (N- (N-Z- iminoethyl) amino) ethyl) -2-methyl-L-Cysteinamide 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 N-acetyl-N- (4- pyridyl) -S- (2- (N- (iminoethyl) amino) ethyl) -2-methyl-L- Cysteinamide .
Figure imgf000125_0001
Example 5
Ex-5a) To a stirring DMF solution of a-Z-e-Boc-2-methyl-L- Lysine (3.94 g, 10.0 mmol), N- (phenyl) -2-aminoimidazole (1.67 g, 10.5 mmol), and 1-hydroxybenzotriazole hydrate (1.45 g, 10.5 mmol) in 75 mL of dimethylformamide (DMF) cooled in an ice bath is added [ (N, N-dimethylamino) propyl] ethylcarbodiimide hydrochloride (1.93 g, 10.5 mmol). After stirring 55 h at ambient temperature, the reaction mixture is concentrated in vacuum. The resulting material is dissolved in aqueous acetonitrile and passed through a reverse phase chromatographic column, giving N- (phenyl) -N- (2 -imidazolyl) -a-Z-e-Boc-2-methyl-L-Lysinamide .
Ex-5b) N- (phenyl) -N- (2-imidazolyl) -a-Z-e-Boc-2-methyl-L- Lysinamide is then dissolved in trifluoroacetic acid and allowed to stand at room temperature until the t- butoxycarbonyl group is removed. The reaction mixture is then concentrated in vacuo to give N- (phenyl) -N- (2- imidazolyl) -a-Z-2-methyl-L-Lysinamide trifluoroacetate .
To a 125 mL flask is added (10 mmol) of N- (phenyl) -N- (2- imidazolyl) -a-Z-2-methyl-L-Lysinamide and 70mL of DMF. To this solution is added 1.50g of methyl acetimidate hydrochloride. Triethylamine (TEA) (3.04 g, 0.03 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 N- (phenyl) -N- (2- imidazolyl) -a-Z-e- (1-iminoethyl) -2-methyl-L-Lysinamide dihydrochloride is then eluted with 10% aqueous pyridine.
Ex-5c) A Boc protecting group is added to N- (phenyl) -N- (2- imidazolyl) -a-Z-e- (1-iminoethyl) -2-methyl-L-Lysinamide dihydrochloride using BOC-ON and the conditions in Fieser and Fieser (volume 6, page 91) to give N- (phenyl) * - (2- imidazolyl) -a-Z-e- (N-Boc-1-iminoethyl) -2-methyl-L- lysinamide.
Ex-5d) N- (phenyl) -N- (2-imidazolyl) -a-Z-e- (N-Boc-1- iminoethyl) -2-methyl-L-Lysinamide 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-function generating the amino product N- (phenyl) -N- (2-imidazolyl) -e- (N-Boc-1-iminoethyl) -2-methyl-L-Lysinamide .
N- (phenyl) -N- (2-imidazolyl) -e- (N-Boc-1-iminoethyl) -2- methyl-L-Lysinamide is dissolved in ethanol. The solution is cooled in an ice bath. Triethylamine (TEA) (1 mL) is added, followed by 1, 1-dicyanoethene . The reaction is allowed to warm to room temperature. Upon completion, the reaction mixture is concentrated in vacuum. The resulting material is dissolved in aqueous acetonitrile and passed through a reverse phase chromatographic column giving, N- (phenyl) -N- (2-imidazolyl) -a-N- (2 , 2-dicyanoethyl) -e- (N-Boc- 1-iminoethyl) -2-methyl-L-Lysinamide . This material is used in example 6.
Figure imgf000127_0001
Example 6
After concentrating, N- (phenyl) -N- (2-imidazolyl) -a-N- (2 , 2- dicyanoethyl) -e- (N-Boc-1-iminoethyl) -2-methyl-L-Lysinamide
(prepared in example 5) is deprotected by allowing it to stand in dioxane and 2N HCl at 25°C for three hours. The reaction mixture is then concentrated in vacuo to give N-
(phenyl) -N- (2-imidazolyl) -a-N- (2 , 2-dicyanoethyl) -e- (1- iminoethyl) -2-methyl-L-lysinamide trihydrochloride .
H3
Figure imgf000127_0002
Example 8
Ex-8a) e-Amino-a-hydroxyhexanoic acid (1.47 g, 10 mmol) is allowed to stir with t-butoxycarbonylazide (1.49 g, 10.5 mmol) and MgO (0.47 g, 10.5 mmol) in dioxane/water solution. Upon completion, the magnesium salts are removed by filtration. The e- (N-Boc-amino) -a-hydroxy hexanoic acid solution is cooled in an ice bath and treated with acetic anhydride (1.07 g, 10.5 mmol) and triethyl amine (TEA) (1.06 g, 10.5 mmol) and stirred. Upon completion the mixture is concentrated in vacuum. The resulting material is passed through a reverse phase chromatographic column, giving e- (N-Boc-amino) -a- (acetoxy) hexanoic acid.
Ex-8b) To a stirring DMF solution of e- (N-Boc-amino) -a- (acetoxy) hexanoic acid (2.68 g, 9 mmol), N-5-tetrazoyl-N- methoxyamine hydrochloride (1.53 g, 9.5 mmol), and 1- hydroxybenzotriazole hydrate (1.31 g, 9.5 mmol) in 75 mL of dimethylformamide (DMF) cooled in an ice bath is added [ (N, N-dimethylamino) propyl] ethylcarbodiimide hydrochloride (1.74 g, 9.5 mmol). After stirring 55 h at ambient temperature, the reaction mixture is concentrated in vacuum. The resulting material is dissolved in aqueous acetonitrile and passed through a reverse phase chromatographic column, giving N-methoxy-N- (5-tetrazoyl) -e- (N-Boc-amino) -a- (acetoxy) hexanamide .
Ex-8c) N-methoxy-N- (5-tetrazoyl) -e- (N-Boc-amino) -a- (acetoxy) hexanamide (2.82 g, 8 mmol) is dissolved in ethanol and treated with sodium hydroxide (0.3 g, 8 mmol) . When the acetyl group is removed the mixture is concentrated in vacuum and passed through a reverse phase chromatographic column, giving N-methoxy-N- (5-tetrazoyl) -e- (N-Boc-amino) -a-hydroxyhexanamide .
Ex-8d) N-methoxy-N- (5-tetrazoyl) -e- (N-Boc-amino) -a-hydroxy hexanamide (2.32 g, 8 mmol) is dissolved in DMSO and treated with 1, 3-dicyclohexylcarbodimide (DCC) (1.6 g, 8 mmol) and phosphoric acid. The reaction is stirred at room temperature. Upon completion, 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 MgS0 , filtered and solvents removed in vacuo. The product is passed through a reverse phase chromatographic column, giving N-methoxy-N- (5-tetrazoyl) -e- (N-Boc-amino) -2-oxohexanamide .
Ex-8e) N-methoxy-N- (5-tetrazoyl) -e- (N-Boc-amino) -2- oxohexanamide (2.22 g, 8 mmol) is dissolved in ethanol and treated with hydroxylamine hydrochloride (0.6 g, 8 mmol) and sodium carbonate (1 g) . The reaction mixture is filtered and concentrated in vacuum, giving crude N- methoxy-N- (5-tetrazoyl) -e- (N-Boc-amino) -2- oximinohexanamide .
Ex-8f) N-methoxy-N- (5-tetrazoyl) -e- (N-Boc-amino) -2-oximino hexanamide is cooled in an ice bath and 1.0M borane- tetrahydrofuran complex (8.5 mL) added dropwise. When addition is complete, the reaction is allowed to warm to room temperature. Upon complete reduction 1 mL of water is added. The reaction is concentrated at reduced pressure. 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. N-methoxy-N- ( 5- tetrazoyl) -e- (N-Boc-amino) -2-oxaminohexanamide is then eluted with 10% aqueous pyridine.
Ex-8g) After concentrating, the product is treated with one equivalent of acetic anhydride (0.82 g, 8 mmol) and triethyl amine (TEA) (0.80 g, 8 mmol) and stirred. Upon completion the mixture is concentrated in vacuum. The resulting material is passed through a reverse phase chromatographic column, giving N-methoxy-N- (5-tetrazoyl) -e- (N-Boc-amino) -a- (N-hydroxy-N-acetamido) hexanamide.
Ex-8h) N-methoxy-N- (5-tetrazoyl) -e- (N-Boc-amino) - a- (N- hydroxy-N-acetamido) hexanamide is deprotected by allowing it to stand in dioxane and 2N HCl at 25°C for two hours. Concentrating in vacuo affords N-methoxy-N- (5-tetrazoyl) -e- amino- a- (N-hydroxy-N-acetamido) hexanamide hydrochloride. To a 125 mL flask is added 2.08 g (7 mmol) N-methoxy-N- ( 5 tetrazoyl) -e-amino- a- (N-hydroxy-N-acetamido) hexanamide hydrochloride and 50 mL of DMF. To this solution is added 1.05 g of methyl acetimidate hydrochloride. Triethylamine (TEA) (2.03 g, 20 mmol) 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 N-methoxy-N- (5-tetrazoyl) -e- (N- ( 1- iminoethyl) ) amino- a- (N-hydroxy-N-acetamido) hexanamide is then eluted with 10% aqueous pyridine and solvents removed and compound dried.
Figure imgf000130_0001
Example 10
e- (N-Boc-amino) -a- (acetoxy) hexanoic acid is prepared as in example 8.
Ex-lOa) To a stirring DMF solution of e- (N-Boc-amino) -a- (acetoxy) hexanoic acid (2.97 g, 10 mmol), 2-aminothiazole (1.05 g, 10.5 mmol), and 1-hydroxybenzotriazole hydrate (1.45 g, 10.5 mmol) in 75 mL of dimethylformamide (DMF) cooled in an ice bath is added [ (N,N-dimethylamino) propyl] ethylcarbodiimide hydrochloride (1.93 g, 10.5 mmol). After stirring 55 h at ambient temperature, the reaction mixture is concentrated in vacuum. The resulting material is dissolved in aqueous acetonitrile and passed through a reverse phase chromatographic column, giving N-(2- thiazolyl) -e- (N-Boc-amino) -a- (acetoxy) hexanamide .
Ex-lOb) N- (2-Thiazolyl) -e- (N-Boc-amino) -a- (acetoxy) hexanamide (3.5 g, 10 mmol) is dissolved in ethanol and treated with sodium hydroxide (4.0 g, 10 mmol) . When the acetyl group is removed, the mixture is concentrated in vacuum and passed through a reverse phase chromatographic column, giving N- (2-thiazolyl) -e- (N-Boc- amino) -a- (hydroxy) hexanamide .
Ex-lOc) N- (2-Thiazolyl) -e- (N-Boc-amino) -a- (hydroxy) hexanamide (3.0 g, 9 mmol) is dissolved in DMSO and treated with 1, 3-dicyclohexylcarbodimide (DCC) (1.8 g, 9 mmol) and phosphoric acid. The reaction is stirred at room temperature . Upon completion, 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 MgS04, filtered and solvents removed in vacuo. The product is passed through a reverse phase chromatographic column, giving N- (2-thiazolyl) -e- (N- Boc-amino) -2-oxohexanamide .
Ex-lOd) N- (2-Thiazolyl) -e- (N-Boc-amino) -2-oxohexanamide (2.8 g, 9 mmol) is dissolved in ethanol and treated with methoxyamine hydrochloride (0.78 g, 9 mmol) and sodium carbonate (1 g) . Upon completion, the reaction mixture is filtered and concentrated in vacuum, giving crude N-(2- thiazolyl) -e- (N-Boc-amino) -2-methoxyiminohexanamide .
Ex-lOe) N- (2-Thiazolyl) -e- (N-Boc-amino) -2- methoxyiminohexanamide (prepared in example 9) is cooled in an ice bath and 1.0M borane-tetrahydrofuran complex (9.5 mL) added dropwise. When addition is complete, the reaction is allowed to warm to room temperature. Upon complete reduction 1 mL of water is added. The reaction is concentrated in vacuum. 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 . N- (2-thiazolyl) -e- (N-Boc-amino) -2- methoxyaminohexanamide is then eluted with 10% aqueous pyridine .
Ex-lOf) After concentrating, the product is cooled in an ice bath, treated with one equivalent of acetic anhydride (0.92 g, 9 mmol) and triethyl amine (TEA) (0.90 g, 9 mmol), stirred, and 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 N- (2-thiazolyl) -e- (N-Boc- amino) -a- (N-methoxyacetamido) hexanamide .
Ex-lOg) N- (2-Thiazolyl) -e- (N-Boc-amino) -a- (N-methoxy-N- acetamido) hexanamide is deprotected by allowing it to stand in dioxane and 2N HCl at 25°C for two hours. Concentrating in vacuo affords N- (2-thiazolyl) -e- (amino) -a- (N- methoxyacetamido) hexanamide hydrochloride .
To a 125 mL flask is added 3.01 g (8 mmol) of afforded N- (2-thiazolyl) -e- (amino) -a- (N-methoxyacetamido) hexanamide hydrochloride 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 by the reaction of 5.38 g
(0.05 mol) of acetaldoxime with 8 g (0.060 mol) of N- chlorosuccinimide in 65 mL of N,N-dimethylformamide at 0°C. The chloroacetaldoxime is isolated after three hours by extracting into diethyl ether and washing with aqueous NaCl. Drying with MgS0 , filtration and concentration under
30°C afforded the chloroacetaldoxime as a pale yellow oil. 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 product N-(2- thiazolyl) -e- (N- (1-oximinoethyl) amino) -a- (N- methoxyacetamido) hexanamide is then eluted with 10% aqueous pyridine. The solvents are removed, and the compound dried.
Figure imgf000133_0001
Example 11
Ex-lla) a-(N-Boc) -S- (N-Z-2-aminoethyl) -2-methyl-D, L- Homocysteine (4.55 g, 11 mmol) is coupled with 2- aminoimidazole (0.95 g, 11.5 mmol) following the procedure used in Ex-la. The result is N- (2-imidazolyl) - a- (N-Boc) - S- (N-Z-2-aminoethyl) -2-methyl-D, L-Homocysteinamide .
Ex-llb) N- (2 -Imidazolyl) - a- (N-Boc) -S- (N-Z-2-aminoethyl) - 2-methyl-D, L-homocysteinamide is then dissolved in trifluoroacetic acid and allowed to stand at room temperature until the t-butoxycarbonyl group is removed. The reaction mixture is then concentrated in vacuo to give N- (2-imidazolyl) -S- (N-Z-2-aminoethyl) -2-methyl-D, L- Homocysteinamide trifluoroacetate .
Ex-llc) N- (2 -Imidazolyl) -S- (N-Z-2-aminoethyl ) -2 -methyl- D, L-homocysteinamide (10 mmol) is cooled in an ice bath and treated with 4-morpholmomethylbenzoyl chloride (2.50 g, 10.5 mmol) and triethyl amine (TEA) (2.1 g, 21 mmol) and stirred. 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 N-(2- imidazolyl) -S- (N-Z-2-aminoethyl) -a-N- (4- morpholinomethylbenzoyl) -2-methyl-D, L-homocysteinamide .
Ex-lld) N- (2-imidazolyl) -S- (N-Z-2-aminoethyl) -a-N- (4- morpholmomethylbenzoyl) -2-methyl-D, L-homocysteinamide 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-function generating the amino product N-(2- imidazolyl) -S- (2-aminoethyl) - a-N- (4- morpholinomethylbenzoyl) -2-methyl-D, L-homocysteinamide .
To a 125 mL flask is added 4.43 g (10 mmol) of afforded N- (2-imidazolyl) -S- (2-aminoethyl) - a-N- (4- morpholmomethylbenzoyl) -2-methyl-D, L-homocysteinamide 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, 2.23 g of l-chloro-2-fluoroacetaldoxime which is prepared immediately prior to use by the reaction of 5.38 g (0.05 mol) of 2-fluoroacetaldoxime with 8 g (0.060 mol) of
N-chlorosuccinimide in 65 mL of N, -dimethylformamide at
0°C. The l-chloro-2-fluoroacetaldoxime is isolated after three hours by extracting into diethyl ether and washing with aqueous NaCl. Drying with MgSO^ , filtration and concentration under 30°C affords l-chloro-2-fluoro acetaldoxime as a pale yellow oil. During l-chloro-2- fluoroacetaldoxime 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 product N- (2-imidazolyl) - S- (2- (N- (2-fluoro-1-oximinoethyl) amino) ethyl) - a-N- (4- morpholinomethylbenzoyl) -2-methyl-D, L-homocysteinamide is then eluted with 10% aqueous pyridine. The solvents are removed, and the compound dried.
Figure imgf000135_0001
Example 12
Ex-12a) d-Z-a- (N-Boc) -D,L-2, 5-Dimethylornithine (4.19 g, 11 mmol) is coupled with 3-aminoquiniclidine (1.45 g, 11.5 mmol) following the procedure used in Ex-la. The result is N- (3-quiniclidinyl) - d-Z-a- (N Boc) -D, L-2 , 5- dimethylornithinamide .
Ex-12b) N- (3-Quiniclidinyl) - d-Z-a- (N-Boc) -D, L- 2 , 5dimethylornithinamide is then dissolved in trifluoroacetic acid and allowed to stand at room temperature until the t-butoxycarbonyl group is removed. The reaction mixture is then concentrated in vacuo to give N- (3-quiniclidinyl) - d-Z-D, L-2 , 5-dimethylornithinamide trifluoroacetate .
Ex-12c) The product N- (3-quiniclidinyl) - d-Z-D, L-2, 5- dimethylornithinamide (10 mmol) is cooled in an ice bath and treated with methylchloroformate (0.97 g, 10.5 mmol) and triethyl amine (TEA) (2.1 g, 21 mmol) . 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 N- (3-quiniclidinyl) - d-Z-a- (N-methoxyformyl) -D, L- 2 , 5-dimethylornithinamide .
Ex-12d) N- (3-Quiniclidinyl) - d-Z-a- (N-methoxyformyl ) -D, L- 2 , 5-dimethylornithinamide 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-function generating the amino product N- (3-quiniclidinyl) -a- (N-methoxyformyl ) - D, L-2 , 5-dimethylornithinamide .
To a 125 mL flask is added 3.02 g (9 mmol) N-(3- quiniclidinyl) -a- (N-methoxyformyl) -D, L-2 , 5- dimethylornithinamide) and 50 mL of DMF. To this solution is added 2.57 g of methyl cyclopropylformimidate hydrochloride. Triethylamine (TEA) (1.82 g, 18 mmol) 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. N- (3-quiniclidinyl) - d-N-(l- imino-1-cyclopropylmethyl) -a- (N-methoxyformyl) -D, L-2 , 5- dimethylornithinamide is then eluted with 10% aqueous pyridine and solvents removed and compound dried.
Figure imgf000137_0001
Example 13
Ex-13a) a- (N-Boc) -ortho- (N-Z-aminomethyl) -2- methylphenylalanine (4.70 g, 11 mmol) is coupled with a- amino-g-butyrolactone hydrobromide (2.07 g, 11.5 mmol) following the procedure used in Ex-la. The result is N- ( 2-g-butyrolactone) - a- (N-Boc) -ortho- (N-Z-aminomethyl) -2- methylphenylalaninamide .
Ex-13b) N- ( 2-g-Butyrolactone) - a- (N-Boc) -ortho- (N-Z- aminomethyl) -2-methylphenylalaninamide is then dissolved in trifluoroacetic acid and allowed to stand at room temperature until the t-butoxycarbonyl group is removed.
The reaction mixture is then concentrated in vacuo to give N- ( 2-g-butyrolactone) -ortho- (N-Z-aminomethyl) -2- methylphenylalaninamide trifluoroacetate .
Ex-13c) N- ( 2-g-Butyrolactone) -ortho- (N-Z-aminomethyl) -2- methylphenylalanmamide (10 mmol) is cooled to -78°C and treated with methanesulfonyl chloride (1.20 g, 10.5 mmol) and triethyl amine (TEA) (2.1 g, 21 mmol) . 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 N- ( 2-g-butyrolactone) -a- (N-methansulfonyl) -ortho- (N-Z-aminomethyl) -2-methylphenylalanmamide .
Ex-13d) N- ( 2-g-Butyrolactone) -a- (N-methansulfonyl ) -ortho- (N-Z-aminomethyl) -2-methylphenylalanmamide 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- function generating the amino product N- ( 2-g- butyrolactone) -a- (N-methansulfonyl) -ortho- (aminomethyl) -2- methylphenylalaninamide .
To a 125 mL flask is added 3.68 g (10 mmol) of afforded N- ( 2-g-butyrolactone) -a- (N-methansulfonyl) -ortho- (aminomethyl) -2-methylphenylalanmamide 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, 2.34 g of chloroacetaldoxime which is prepared immediately prior to use by the reaction of 3.55 g (0.06 mol) of acetaldoxime with 10.4 g (0.078 mol) of N-chlorosuccinimide in 65 mL of
N,N-dimethylformamide at 0°C. The chloroacetaldoxime is isolated after three hours by extracting into diethyl ether and washing with aqueous NaCl. Drying with MgSO^ , filtration and concentration under 30°C affords chloroacetaldoxime as a pale yellow oil. During 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 product N- ( 2-g- butyrolactone) -a- (N-methansulfonyl) -ortho- (N- (1- oximinoethyl) ) aminomethyl) -2 -methylphenylalanmamide is then eluted with 10% aqueous pyridine. The solvents are removed, and the compound dried.
Figure imgf000139_0001
Example 14
Ex-14a) 3- (5- (N-Z-Aminomethyl) thiophenyl) -2- (N-Boc-amino) - 2-methylpropionic acid (4.78 g, 11 mmol) is coupled with 2- aminopyrimidine (1.09 g, 11.5 mmol) following the procedure used in Ex-la. The result is N- (2-pyrimidinyl) - 3-(5-(N-Z- Aminomethyl) thiophenyl) -2- (N-Boc-amino) -2- methylpropionamide .
Ex-14b) N- (2-pyrimidinyl) - 3-(5-(N-Z- Aminomethyl) thiophenyl) -2- (N-Boc-amino) -2- methylpropionamide is then dissolved in trifluoroacetic acid and allowed to stand at room temperature until the t- butoxycarbonyl group is removed. The reaction mixture is then concentrated in vacuo to give N- (2-pyrimidinyl) - 3- (5- (N-Z-Aminomethyl) thiophenyl) -2-amino-2-methylpropionamide trifluoroacetate .
Ex-14c) The product N- (2-pyrimidinyl) - 3-(5-(N-Z- Aminomethyl ) thiophenyl ) -2-amino-2-methylpropionamide trifluoroacetate is cooled in an ice bath and treated with methyoxyacetyl chloride (1.14 g, 10.5 mmol) and triethyl amine (TEA) (2.1 g, 21 mmol) . 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 The product N- (2-pyrimidinyl) - 3-(5-(N-Z-
Aminomethyl) thiophenyl) -2-acetamido-2-methylpropionamide .
Ex-14d) N- (2-pyrimidinyl) - 3-(5-(N-Z- Aminomethyl) thiophenyl) -2-acetamido-2-methylpropionamide 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-function generating the amino product N-(2- pyrimidinyl) - 3- (5- (aminomethyl) thiophenyl) -2-acetamido-2- methylpropionamide .
To a 125 mL flask is added 3.02 g (9 mmol) N-(2- pyrimidinyl) - 3- (5- (aminomethyl) thiophenyl) -2-acetamido-2 - methylpropionamide and 50 mL of DMF. To this solution is added 1.97 g of methyl acetimidate hydrochloride. Triethylamine (TEA) (2.74 g, 27 mmol) 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 product N- (2-pyrimidinyl) - 3-(5-(N-(l- iminoethyl) amino) methyl) thiophenyl) -2-acetamido-2- methylpropionamide is then eluted with 10% aqueous pyridine and solvents removed and compound dried.
Figure imgf000141_0001
EXAMPLE 15
Ex-15a) To a stirring DMF solution of α-Boc-O- (2- (N-Z- amino) ethyl) -2-methyl-L-serine (3.96 g, 10.0 mmol), 2- methylaminopyridine (1.14 g, 10.5 mmol), and 1- hydroxybenzotriazole hydrate (1.45 g, 10.5 mmol) in 75 mL of dimethylformamide (DMF) cooled in an ice bath is added t (N,N-dimethylamino) propyl] ethylcarbodiimide hydrochloride (1.93 g, 10.5 mmol) . After stirring 55 h at ambient temperature, the reaction mixture is concentrated in vacuum. The resulting material is dissolved in aqueous acetonitrile and passed through a reverse phase chromatographic column, giving N-methyl-N- (2-pyridyl) -α- Boc-O- (2- (N-Z-amino) ethyl) - 2-methyl-L-serinamide .
Ex-15b) N-methyl-N- (2-pyridyl) -α-Boc-O- (2- (N-Z- amino) ethyl) -2-methyl-L-serinamide 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-function generating the amino product N-methyl-N- (2-pyridyl) -α-Boc- 0- (2-aminoethyl) -2-methyl-L-serinamide.
Ex-15c) To a 125 mL flask was added 2.83 g (0.008 mol) of N-methyl-N- (2-pyridyl) -α-Boc-O- (2-aminoethyl) -2-methyl-L- serinamide and 70mL of DMF. To this solution was added 4.14 g of methyl N-Z-acetimidate . Triethylamine (TEA) (3.04 g, 0.03 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 .
Ex-15d) N-methyl-N- (2-pyridyl) -α-Boc-O- (2- (N- (1- iminoethyl) amino) ethyl) -2-methyl-L-serinamide (1.97 g, 0.005 mol) is added to 50 ml of THF containing 1.01 grams of triethylamine. Carbobenzoxy chloride (Z-Cl; 1.03 g,
0.006 mol) is added and stirred at room temperature for 24 hours . The reaction mixture is concentrated in vacuo to remove THF and slurried with 50 ml. methylene chloride. The methylene chloride is washed with water, concentrated in vacuo at 50 °C, and residue purified by chromatography to afford N-methyl-N- (2-pyridyl) -α-Boc-O- (2- (N- (N-Z-l- iminoethyl) amino) ethyl) -2-methyl-L-serinamide.
Ex-15e) N-methyl-N- (2-pyridyl) -α-Boc-O- (2- (N- (N-Z-l- iminoethyl) amino) ethyl) -2-methyl-L-serinamide is then dissolved in trifluoroacetic acid and allowed to stand at room temperature with spectroscopic monitoring until the t- butoxycarbonyl group is removed. The reaction mixture is then concentrated in vacuo to give N-methyl-N- (2-pyridyl) - O- (2- (N- (N-Z-iminoethyl) amino) ethyl) -2-methyl-L-serinamide trifluoroacetate .
Ex-15f) N-methyl-N- (2-pyridyl) -O- (2- (N- (N-Z- iminoethyl) amino) ethyl) -2-methyl-L-serinamide trifluoroacetate is added to 50 ml of toluene in 100 ml. reaction flask. After adding 0.761 g of p-toluenesulfonic acid and 0.504 g (0.006 mol) cyclopentanone, the reaction mixture is refluxed with azeotropic distillation complete removal of water using a Dean-Stark trap. After cooling, the solvent and excess cyclopentanone is removed in vacuo to give an essentially quantitative yield of the imine N- methyl-N- (2-pyridyl) -α- (N-cyclopentylene) -O- (2- (N- (N-Z-l- iminoethyl) amino) ethyl) -2-methyl-L-serinamide toluenesulfonate salt.
Ex-15g) N-methyl-N- (2-pyridyl) -α- (N-cyclopentylene) -0- (2- (N- (N-Z-1-iminoethyl) amino) ethyl) -L-serinamide is placed in a mixture with anhydrous toluene, 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 reduce the imine and remove the Z-function generating the p-toluenesulfonate salt of the amino product N-methyl-N- (2-pyridyl) -α- (N- cyclopentyl) -O- (2- (N- (1-iminoethyl) amino) ethyl) -2-methyl-L- serinamide .
The p-toluenesulfonate salt of N-methyl-N- (2-pyridyl) -α- (N- cyclopentyl) -O- (2- (N- (1-iminoethyl) amino) ethyl) -2-methyl-L- serinamide (0.003 mol) is placed in 20 ml of anhydrous THF containing 1.01 grams of triethylamine. After cooling to - 78 °C, 3 , 3, 3-trifluoropropanoic anhydride (0.762g, 0.0032 mol) in 10 ml anhydrous THF is added over 20 minutes. After warming to room temperature, the solvent is removed in vacuo, 50 ml methylene chloride added along with 20 ml of water. The methylene chloride layer is separated, back washed with water, and concentrated to afford N-methyl-N- ( 2-pyridyl) -α- (N-cyclopentyl) -α-N- (3,3,3- trifluoropropanoyl) -O- (2- (N- (1-iminoethyl) amino) ethyl) -2- methyl-L-serinamide which can be purified if needed chromatographically .
Figure imgf000144_0001
EXAMPLE 16
Ex-16a) To a stirring DMF solution of α-Z-O- (2- (N-Boc- amino) ethyl) -2-methyl-L-serine (3.96 g, 10.0 mmol), 4- methylaminoimidazole (1.01 g, 10.5 mmol), and 1- hydroxybenzotriazole hydrate (1.45 g, 10.5 mmol) in 75 mL of dimethylformamide (DMF) cooled in an ice bath is added [ (N,N-dimethylamino) propyl] ethylcarbodiimide hydrochloride (1.93 g, 10.5 mmol) . After stirring 55 h at ambient temperature, the reaction mixture is concentrated in vacuum. The resulting material is dissolved in aqueous acetonitrile and passed through a reverse phase chromatographic column, giving N-methyl-N- (4-imidazolyl) -α- Z-O- (2- (N-Boc-amino) ethyl) -2-methyl-L-serinamide.
Ex-16b) N-methyl-N- (4-imidazolyl) -α-Z-O- (2- (N-Boc- amino) ethyl) -2-methyl-L-serinamide is dissolved in trifluoroacetic acid and allowed to stand at room temperature with spectroscopic monitoring until the t- butoxycarbonyl group is removed. The reaction mixture is then concentrated in vacuo to give the amino product N- methyl-N- (4-imidazolyl) -α-Z-O- (2-aminoethyl) -2-methyl-L- serinamide trifluoroacetate . Ex-16c) N-methyl-N- (4-imidazolyl) -α-Z-O- (2-aminoethyl) -2- methyl-L-serinamide is converted to N-methyl-N- (4- imidazolyl) -α-Z-O- (2- (N- (1-oximinoethyl) ) amino) ethyl) -2- methyl-L-serinamide as described for the conversion of product of Ex-2b to product of Ex-2c .
Ex-16d) N-methyl-N- (4-imidazolyl) -α-Z-O- (2- (N- (1- oximinoethyl) amino) ethyl) -2-methyl-L-serinamide (2.12 g, 0.005 mol) is added to 50 ml of THF containing 1.01 grams of triethylamine. Methyl chloroformate (0.567 g, 0.006 mol) is added and stirred at room temperature for 24 hours. The reaction mixture is concentrated in vacuo to remove THF and slurried with 50 ml. methylene chloride. The methylene chloride is washed with water, concentrated in vacuo at 50 °C, and residue purified by chromatography to afford N- methyl-N- (4-imidazolyl) -α-Z-O- (2- (N- (1- (0-
(methoxycarbonyl) oximino) ethyl) amino) ethyl) -2-methyl-L- serinamide .
Ex-16e) N-methyl-N- (4-imidazolyl) -α-Z-O- (2- (N- (1- (0- (methoxycarbonyl) oximino) ethyl) amino) ethyl) -2-methyl-L- serinamide is then 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 give N-methyl-N- (4-imidazolyl) -O- (2- (N- (1- (0- (methoxycarbonyl) oximino) ethyl) amino) ethyl) -2-methyl-L- serinamide .
Ex-16f ) N-methyl-N- (4-imidazolyl) -O- (2- (N- (1- (O- (methoxycarbonyl) oximino) ethyl) amino) ethyl) -2-methyl-L- serinamide (1.40 g, 0.004 mol) is added to 50 ml of toluene in 100 ml. reaction flask. After adding 0.761 g of p- toluenesulfonic acid and 0.546 g (0.005 mol) 2- acetylpyrrole, the reaction mixture is refluxed with azeotropic distillation complete removal of water using a Dean-Stark trap. After cooling, the solvent is removed in vacuo to give an essentially quantitative yield of the imine N-methyl-N- (4-imidazolyl) -α- (N- (1- pyrrolylethylenyl) ) -0- (2- (N- (1- (O- (methoxycarbonyl) oximino) ethyl) amino) ethyl) -2-methyl-L-serinamide toluenesulfonate salt.
Ex-16g) N-methyl-N- (4-imidazolyl) -α- (N- (1- pyrrolylethylenyl) ) -0-(2-(N-(l- (0-
( ethoxycarbonyl) oximino) ethyl) amino) ethyl) -2-methyl-L- serinamide toluenesulfonate salt is placed in a mixture with anhydrous toluene, 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 reduce the imine generating the p-toluenesulfonate salt of the amino product N-methyl- N- (4-imidazolyl) -α- (N- (1-pyrrolylethylenyl) ) -O- (2- (N- (1- (0- (methoxycarbonyl) oximino) ethyl) amino) ethyl) -2-methyl-L- serinamide.
The p-toluenesulfonate salt N-methyl-N- (4-imidazolyl) -α- (N- ( 1-pyrrolylethylenyl) )-0-(2-(N-(l-(0- (methoxycarbonyl) oximino) ethyl) amino) ethyl) -2-methyl-L-serinamide (0.003 mol) is placed in 20 ml of anhydrous THF containing 1.01 grams of triethylamine. After cooling to -78 °C, ethanesulfonyl chloride (0.412 g, 0.0032 mol) in 10 ml anhydrous THF is added over 20 minutes. After warming to room temperature, the solvent is removed in vacuo, 50 ml methylene chloride added along with 20 ml of water. The methylene chloride layer is separated, back washed with water, and concentrated to afford N-methyl-N- (4- imidazolyl) -α- (N- (1-pyrrolylethylenyl) ) -0- (2- (N- (1- (O- (methoxycarbonyl) oximino) ethyl) amino) ethyl) -α- (N- ethanesulfonyl) -2-methyl-L-serinamide which can be purified if needed chromatographically .
Figure imgf000147_0001
EXAMPLE 17
Ex-17a) α-Z-O- (2- (N-Boc-amino) ethyl) -2-methyl-L-serine (3.96 g, 10.0 mmol) is reacted with 4-methylaminothiazole (1.20 g, 10.5 mmol) as described in Example 16 to yield N- methyl-N- (4-thiazolyl) -α-Z-O- (2- (N-Boc-amino) ethyl) -2- methyl-L-serinamide .
Ex-17b) N- (4-thiazolyl) -α-Z-O- (2- (N-Boc-amino) ethyl) -2- methyl-L-serinamide is converted to N-methyl-N- (4- thiazolyl) -α-Z-O- (2-aminoethyl) -2-methyl-L-serinamide as described in Example 16.
Ex-17c) N-methyl-N- (4-thiazolyl) -α-Z-O- (2-aminoethyl) -2- methyl-L-serinamide is converted to N-methyl-N- (4- thiazolyl) -α-Z-O- (2- (N- (2-fluoro-1-iminoethyl) amino) ethyl) - 2-methyl-L-serinamide using methyl 2-fluoroacetimidate hydrochloride as described in Ex-2c.
Ex-17d) N-methyl-N- (4-thiazolyl) -α-Z-O- (2- (N- (2-fluoro-1- iminoethyl) amino) ethyl) -2-methyl-L-serinamide is then 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 give N- methyl-N- (4-thiazolyl) -O- (2- (N- (2-fluoro-1- iminoethyl) amino) ethyl) -2-methyl-L-serinamide . N-methyl-N- (4-thiazolyl) -0- (2- (N- (2-fluoro-1- iminoethyl) amino) ethyl) -2-methyl-L-serinamide (1.25 g, 0.004 mol) is reacted with sodium hydroxymethylsulfonate in aqueous solution at a pH of 10 using a procedure described by L. Maier (Phosphorus, Sulfur, Silicon Related Elements (1990), vol. 47, pages 43-46) to form sodium α-N- (N-methyl- N- (4-thiazolyl) -0- (2- (N- (2-fluoro-1- iminoethyl) amino) ethyl) - 2-methyl-L- serinamido)methanesulfonate .
Figure imgf000148_0001
Example 18
Ex-18a) e-Z-a-Boc-2-methyl-L-Lysine (4.56 g, 12 mmol) is reacted with 3 (N-methylamino) oxacycloheptane (1,61 g, 12.5 mmol) as described in Ex-2a to yield N-methyl-N- (3- oxacycloheptyl) -e-Z-a-Boc-2-methyl-L-Lysinamide .
Ex-18b) N-Methyl-N- (3-oxacycloheptyl) -e-Z-a-Boc-2-methyl- L-Lysinamide is then subjected to conditions to remove the Z protecting group as described in Ex-2b to give N-methyl- N- (3-oxacycloheptyl) -a-Boc-2-methyl-L-Lysinamide .
Ex-18c) The resulting N-methyl-N- (3-oxacycloheptyl) -a-Boc- 2-methyl-L-Lysinamide (3.93 g, 11 mmol) is reacted with methyl but-3-eneimidate hydrochloride (2.90 g) as described in Ex-2c in Example 2 to yield N-methyl-N- (3- oxacycloheptyl) - a-Boc -e-N- (l-imino-3 -butenyl) -2-methyl-L- Lysinamide.
Ex-18d) N-Methyl-N- (3-oxacycloheptyl) - a-Boc -e-N-(l- imino-3 -butenyl) -2-methyl-L-Lysinamide is then subjected to conditions to remove the Boc protecting group as described in Ex-2d to give N-methyl-N- (3-oxacycloheptyl) -e-N- (1- imino-3 -butenyl) -2-methyl-L-Lysinamide .
Ex-18e) N-Methyl-N- (3-oxacycloheptyl) -e-N- (l-imino-3- butenyl) -2-methyl-L-Lysinamide (3.57 g, 11 mmol) is treated with one equivalent 2 , 2 , 2-trichloroethyl chloroformate (2.22 g, 11 mmol) and sodium carbonate in aqueous tetrahydrofuran under the conditions described by D. Gravel in Canadian Journal of Chemistry, 50, 3846, 1972 to give N- methyl-N- (3-oxacycloheptyl) -a-N- (2,2,2- trichloroethoxyformyl) -e-N- (l-imino-3 -butenyl) -2-methyl-L- Lysinamide .
Ex-18f) N-Methyl-N- (3-oxacycloheptyl) -a-N- (2,2,2- trichloroethoxyformyl) -e-N- (l-imino-3-butenyl) -2-methyl-L- Lysinamide (5.24 g, 10 mmol) is treated with Lawesson's Reagent under the conditions described in Chem. Reviews, 84, 17-30, 1984 and references cited therein. To yield N- methyl-N- (3-oxacycloheptyl) -a-N- (2,2,2- trichloroethoxythioformyl) -e-N- (l-imino-3 -butenyl) -2- methyl-L-thionolysinamide .
Ex-18g) N-Methyl-N- (3-oxacycloheptyl) -a-N- (2,2,2- trichloroethoxythioformyl) -e-N- (l-imino-3 -butenyl) -2- methyl-L-thionolysinamide (5.03 g, 10 mmol) is dissolved in acetic acid and treated with zinc dust (0.65g, 10 mmol) . After stirring two hours, saturated aqueous sodium carbonate is added. The solids are removed by filtration. 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 product N- methyl-N- (3-oxacycloheptyl) -e-N- (l-imino-3-butenyl) -2- methyl-L-thionolysmamide is then eluted with 10% aqueous pyridine .
After concentration, the product N-methyl-N- (3- oxacycloheptyl) -e-N- (l-imino-3 -butenyl) -2-methyl-L- thionolysinamide is cooled in an ice bath and treated with one equivalent of 2-furanylacetyl chloride (1.4 g, 10 mmol) and stirred at room temperature for 24 hours. The reaction mixture is concentrated in vacuo and slurried with 50 ml methylene chloride. The methylene chloride is washed with water, concentrated in vacuo at 50 °C, and residue purified by chromatography to afford N-methyl-N- (3-oxacycloheptyl) - a-N- (2-furanylacetyl) -e-N- (l-imino-3 -butenyl) -2-methyl-L- thionolysinamide .
Figure imgf000150_0001
Example 19
Ex-19a) e- (N-Z-Amino) -a- (N-boc-amino) -2-methylhex-4-ene- oic acid (4.54 g, 12 mmol) is reacted with 4- (N- ethylamino) -1, 2 , 3-triazole (1.40 g, 12.5 mmol) using the conditions to prepare as describe in Ex-la in Example 1 to yield N-ethyl-N- (4- (1,2, 3-triazolyl) ) -e- (N-Z-amino) -a- (N- Boc-amino) -2-methylhex-4-enamide .
Ex-19b) N-ethyl-N- (4- (1,2, 3-triazolyl) ) -e- (N-Z-amino) -a- (N-Boc-amino) -2-methylhex-4-enamide is then subject to conditions to remove the Z protecting group as described in Ex-lb to N-ethyl-N- (4- (1, 2 , 3-triazolyl) ) -e-amino-a- (N-Boc- amino) -2-methylhex-4-enamide .
Ex-19c) The resulting N-ethyl-N- (4- (1, 2 , 3-triazolyl) ) -e- amino-a- (N-Boc-amino) -2-methylhex-4-enamide (3.95 g, 11 mmol) is reacted with chloro l-(2- fluorocyclopropyl) formaldoxime (3.08 g) using the process described in Ex-lc to yield N-ethyl-N- (4- (1, 2 , 3- triazolyl) ) -e-N- (1- (2- fluorocyclopropyl) oximinomethyl) amino-a- (N-Boc-amino) -2- methylhex-4-enamide.
Ex-19d) N-ethyl-N- (4- (1, 2 , 3-triazolyl) ) -e-N- (1- (2- fluorocyclopropyl) oximinomethyl) amino-a- (N-Boc-amino) -2- methylhex-4-enamide is then subject to conditions to remove the Boc protecting group as described in Ex-Id to give N- ethyl-N- (4- (1, 2 , 3-triazolyl) ) -e-N-(l-(2- fluorocyclopropyl ) oximinomethyl ) amino-2-amino-2-methylhex- 4-enamide .
Ex-19e) N-ethyl-N- (4- ( 1 , 2 , 3-triazolyl) ) -e-N-(l- (2- fluorocyclopropyl) oximinomethyl) amino-2 -amino-2-methylhex- 4-enamide (4.87 g, 11 mmol) is treated with one equivalent trichloroethyl chloroformate (2.29 g, 11 mmol) and sodium carbonate in aqueous tetrahydrofuran under the conditions described by D. Gravel in Canadian Journal of Chemistry, 50, 3846, 1972 to give N-ethyl-N- (4- (1, 2 , 3-triazolyl) ) -e-N- (1- (2-fluorocyclopropyl) oximinomethyl) amino-2-N- (2,2,2- trichloroethoxyformyl) amino-2-methylhex-4-enamide . Ex-19f) N-ethyl-N- (4- (1, 2 , 3-triazolyl) ) -e-N- (1- (2- fluorocyclopropyl ) oximinomethyl ) amino-2-N- (2,2,2- trichloroethoxyformyl) amino-2-methylhex-4-enamide (6.29 g) is treated with Lawesson's Reagent under the conditions described in Chem. Reviews, 84, 17-30, 1984 and references cited therein, to yield N-ethyl-N- (4- (1, 2 , 3-triazolyl) ) -e- N- (1- (2-fluorocyclopropyl) oximinomethyl) amino-2-N- (2,2,2- trichloroethoxythionoformyl) amino-2-methyl-thionohex-4- ena ide .
Ex-19g) N-ethyl-N- (4- (1,2, 3-triazolyl) ) -e-N- (1- (2- fluorocyclopropyl) oximinomethyl) amino-2-N- (2,2,2- trichloroethoxythionoformyl) amino-2-methyl-thionohex-4- enamide (5.40g, 10 mmol) is dissolved in acetic acid and treated with zinc dust (0.65g, 10 mmol). After stirring two hours, saturated aqueous sodium carbonate is added.
The solids are removed by filtration. 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 N-ethyl-N- (4- (1, 2 , 3-triazolyl) ) - e-N- (1- (2-fluorocyclopropyl) oximinomethyl) amino-2-amino-2- methyl-thionohex-4-enamide is then eluted with 10% aqueous pyridine .
Ex-19h) N-ethyl-N- (4- (1, 2, 3-triazolyl) ) -e-N- (1- (2- fluorocyclopropyl) oximinomethyl) amino-2-amino-2-methyl- thionohex-4-enamide (3.32 g, 9 mmol) is added to 50 mL of toluene in 100 mL reaction flask. After adding 1.71 g of p-toluenesulfonic acid and 2.17 g (14 mmol) 3-cyclopentenyl (thiomethyl) methyl ketone, the reaction mixture is refluxed with azeotropic distillation for complete removal of water using a Dean-Stark trap. After cooling, the solvent and excess 3-cyclopentenyl methoxymethyl ketone are removed in vacuo to give an essentially quantitative yield of the imine N-ethyl-N- (4- (1, 2 , 3-triazolyl) ) -e-N- (1- (2- fluorocyclopropyl) oximinomethyl) amino-2-N- (l-cyclopentyl-2- methylthioethenyl) amino-2-methyl-thionohex-4-enamide toluenesulfonate salt. Ex-19i) N-ethyl-N- (4- (1,2, 3-triazolyl) ) -e-N- (1- (2- fluorocyclopropyl ) oximinomethyl ) amino-2-N- ( 1- ( 1- cyclopentyl-2-methylthioethenyl ) ) amino-2-methyl-thionohex- 4-enamide toluenesulfonate salt is dissolved in methanol and treated with 1. OM sodium cyanoborohydride in THF (9.1 mL) and potassium hydroxide using the conditions described by R. F. Borch in Organic Synthesis, 52, 124, 1972 to give, the product N-ethyl-N- (4- (1 , 2 , 3-triazolyl) ) -e-N- (1- (2- fluorocyclopropyl) oximinomethyl) amino-2-N- (1- (1- cyclopentyl-2-methylthioethyl) ) amino-2-methyl-thionohex-4- enamide .
N-Ethyl-N- (4- (1, 2 , 3-triazolyl ) ) -e-N- (1- (2- fluorocyclopropyl) oximinomethyl) amino-2 -N- (1- (1- cyclopentyl-2-methylthioethyl ) ) amino-2-methyl-thionohex-4- enamide (3.94g, 0.008 mol) is place in 20 ml of anhydrous THF containing 1.01 grams of triethylamine. After cooling in an ice bath, 2-cyanopropionyl chloride (0.99 g, 8.5 mmol) in 10 ml anhydrous THF is added over 20 minutes. After warming to room temperature, the solvent is removed in vacuo, 50 ml methylene chloride added along with 20 ml of water. The methylene chloride layer is separated, back washed with water, and concentrated to afford N-Ethyl-N- (4- (1,2, 3-triazolyl) ) -e-N- (1- (2- fluorocyclopropyl) oximinomethyl) amino-2-N- (1- (1- cyclopentyl-2-methylthioethyl) ) -2-cyanopropanamido-2- methyl-thionohex-4-enamide which can be purified if needed chromatographically .
Figure imgf000154_0001
Example 20
Ex-20a) e- (N-Z-Amino) -a- (N-Boc-amino) -2-methylpent-3 - ynoic acid (3.99g, 11 mmol) is reacted with 5- aminotetrazole hydrochloride (1.40 g, 11.5 mmol) using the processed described in Ex-la to yield N- (5-tetrazolyl) -e- (N-Z-amino) -a- (N-Boc-amino) -2-methylpent-3-ynamide .
Ex-20b) N- (5-Tetrazolyl) -e- (N-Z-amino) -a- (N-Boc-amino) -2- methylpent-3-ynamide is then subject to conditions to remove the Z protecting group as described in Ex-lb to give N- (5-tetrazolyl) -e-amino-a- (N-Boc-amino) -2-methylpent- 3 -ynamide .
Ex-20c) The resulting N- (5-tetrazolyl) -e-amino-a- (N-Boc- amino) -2 -methylpent-3 -ynamide (3.24 g, 10 mmol) is reacted with chloroacetaldoxime (1.63 g) using the processed described in Ex-lc to yield N- (5-tetrazolyl) -e-N- (1- oximinoethyl) amino-a- (N-Boc-amino) -2 -methylpent-3 -ynamide .
Ex-20d) N- (5-tetrazolyl) -e-N- (1-oximinoethyl) amino-a- (N- Boc-amino) -2-methylpent-3 -ynamide is dissolved in 30 mL of propionic anhydride containing 0.1 g of pyridine. After standing at room temperature for 2 hours, the reaction mixture is concentrated in vacuo to give N- (5-tetrazolyl) - e-N- (1- (O-propionyloximino) ethyl) amino-a- (N-Boc-amino) -2- methylpent-3 -ynamide . Ex-20e) N- (5-tetrazolyl) -e-N- (1- (O- propionyloximino) ethyl) amino-a- (N-Boc-amino) -2-methylpent- 3 -ynamide (4.10 g, 10 mmol) is dissolved in THF and cooled to -78°C. Two equivalents of lithium diisopropylamine (LDA) 2.0M solution (10 mL) is added dropwise over a period of 20 minutes. Phosgene (.998 g, 10.1 mmol) is added through a gas inlet tube over 30 minutes. After the mixture is allowed to warm to room temperature, 1 mL of water is added. The solvents are removed in vacuo and the product purified by chromatography to give 3-N- (5- tetrazolyl) -5- (3- (N- (1- (O- propionyloximino) ethyl) amino) prop-1-ynyl) -5-methyl-l- (N- Boc ) -hydantoin .
3-N- (5-tetrazolyl) -5- (3- (N- (1- (0- propionyloximino) ethyl) amino) prop-1-ynyl) -5-methyl-l- (N- Boc) -hydantoin is then dissolved in trifluoroacetic acid and allowed to stand at room temperature until the t- butoxycarbonyl group is removed. The reaction mixture is then concentrated in vacuo to give 3-N- (5-tetrazolyl) -5- (3- (N- (1- (O-propionyloximino) ethyl) amino) prop-1-ynyl) -5- methyl-hydantoin trifluoroacetate .
Figure imgf000155_0001
Example 21 Ex-21a) a- (N-Boc) -0- (N-Z-2-aminoethyl) -2-methyl-L-serine (4.21 g, 11 mmol) is reacted with 2-aminoimidazole (0.95 g, 11.5 mmol) using the process described in Ex-2a to yield N- (2-imidazolyl) -a- (N-boc) -0- (N-Z-2-aminoethyl) -2-methyl-L- serinamide.
Ex-21b) N- (2-Imidazolyl) -a- (N-Boc) -O- (N-Z-2-aminoethyl) -2- methyl-L-serinamide is then subjected to conditions to remove the Z protecting group as described in Ex-2b to give N- (2-imidazolyl) -a- (N-Boc) -O- (2-aminoethyl) -2-methyl-L- serinamide.
Ex-21c) The resulting N- (2-imidazolyl) -a- (N-Boc) -O- (2- aminoethyl) -2-methyl-L-serinamide (3.36 g, 10 mmol) is reacted with methyl acetimidate hydrochloride (1.13 g) using the process in Ex-2c to yield N- (2-imidazolyl) -a- (N- boc) -O- (2- (N- (1-iminoethyl) amino) ethyl) -2-methyl-L- serinamide .
Ex-21d) N- (2-imidazolyl) -a- (N-boc) -O- (2- (N- (1- iminoethyl) amino) ethyl) -2-methyl-L-serinamide (3.68 g, 10 mmol) is dissolved in THF and cooled to -78°C. To the cooled mixture is added one equivalent of 2.0M lithium diisopropylamide solution (5 mL) over 30 minutes. One equivalent of 2-bromo-l , l-dimethoxy-4-thiomethylbutane (2.43 g, 10 mmol) dissolved in THF is added to the cooled mixture over 20 minutes. The mixture is allowed to warm to room temperature and 1 mL of water is added. The solvents are removed in vacuo and the product purified by chromatography to give N- (l-dimethoxy-4-thiomethyl-2- butyl) -N- (2-imidazolyl) -a- (N-boc) -O- (2- (N- (1- iminoethyl) amino) ethyl) -2-methyl-L-serinamide.
N- (l-dimethoxy-4-thiomethyl-2-butyl) -N- (2-imidazolyl) -a- (N- boc) -0- (2- (N- (1-iminoethyl) amino) ethyl) -2-methyl-L- serinamide (5 mmol) is then placed in 50 ml of aqueous 2N HCl. After standing at room temperature until the t- butoxycarbonyl and methoxy groups are removed, the reaction mixture is then concentrated in vacuo to give 1-N- (2-imidazolyl) -3- (2- (N- ( 1-iminoethyl) amino) ethoxy) methyl] 3-methyl-6- (2-methiothioethyl) -2-oxo-3 , 6-dihydropyrazine trihydrochloride .
Figure imgf000157_0001
Example 22
Ex-22a) a- (N-Boc) -S- (N-Z-aminoethyl ) -2-methyl-L-cysteine (4.38 g, 11 mmol) is reacted with 5-methylaminotetrazole hydrochloride (1.53 g, 11.5 mmol) using the process described in Ex-2a to yield N-methyl-N- (5-tetrazolyl) -a- (N- Boc) -S- (N-Z-aminoethyl) -2-methyl-L-cysteinamide.
Ex-22b) N-Methyl-N- (5-tetrazolyl) -a- (N-Boc) -S- (N-Z- aminoethyl ) -2-methyl-L-cysteinamide is then subject to conditions to remove the Z protecting group as described in Ex-2b to give N-methyl-N- (5-tetrazolyl ) -a- (N-Boc ) -S- (aminoethyl) -2-methyl-L-cysteinamide .
Ex-22c) The resulting N-methyl-N- ( 5-tetrazolyl) -a- (N-Boc) - S- (aminoethyl) -2-methyl-L-cystinamide (2.44 g, 10 mmol) is added to 50 mL of water in a 200 mL reaction flask and the pH adjusted to 6-7 with hydrochloric acid. After forming an equilibrium concentration of the imine, N-methyl-N- (5- tetrazolyl) -a- (N-Boc) -S- (2- (N- phosphonomethyleneamino) ethyl) -2-methyl-L-cysteinamide, by addition of 10 mmol of disodium formylphosphonate while maintaining a pH of 6-7, 50 ml of methanol is added. The reaction mixture is treated with 1.0M sodium cyanoborohydride in THF (40 L) . The excess borohydride is destroyed, the reaction mixture concentrated to remove organic solvents, and the residue purified by passing it through a reverse phase chromatographic column to give the product N-methyl-N- (5-tetrazolyl) -a- (N-Boc) -S- (2- (N- phosphonomethylamino) ethyl) -2-methyl-L-cysteinamide.
Ex-22d) N-methyl-N- (5-tetrazolyl) -a- (N-Boc) -S- (2- (N- phosphonomethy1amino) ethyl) -2-methyl-L-cysteinamide (8 mmol) is reacted with methyl acetimidate hydrochloride (1.75 g) using the process described in Ex-2c to yield N- methyl-N- (5-tetrazolyl) -a- (N-Boc) -S- (2- (N-phosphonomethyl- N- (1-iminoethyl) amino) ethyl) -2-methyl-L-cysteinamide .
N-methyl-N- (5-tetrazolyl) -a- (N-Boc) -S- (2- (N- phosphonomethyl-N- (1-iminoethyl) amino) ethyl) -2-methyl-L- cysteinamide is then placed in 50 ml of aqueous 2N HCl. After standing at room temperature until the t- butoxycarbonyl group is removed, the reaction mixture is then concentrated in vacuo to give N-methyl-N- (5- tetrazolyl) -S- (2- (N-phosphonomethyl-N- (1- iminoethyl) amino) ethyl) -2-methyl-L-cysteinamide hydrochloride .
N-methyl-N- (5-tetrazolyl) -S- (2- (N-phosphonomethyl-N- (1- iminoethyl) amino) ethyl) -2-methyl-L-cysteinamide hydrochloride (5 mmol) is placed in 50 ml water and stirred vigorously with a mixture of 5mmol of N,N- dimethyloctadecylamine in 75 ml of toluene. The aqueous layer is separated and two equivalents of NaOH (10 mmol) is added to generate the disodium salt of N-methyl-N- (5- tetrazolyl) -S- (2- (N-phosphonomethyl-N- (1- i inoethyl) amino) ethyl) -2-methyl-L-cysteinamide .
Figure imgf000159_0001
Example 23
Ex-23a) e- (N-Z-Amino) -a- (N-Boc-amino) -2-methylhexanoic acid (4.56 g, 12 mmol) is reacted with 5-(N- methylamino) tetrazole (1.06 g, 12.5 mmol) using the conditions to prepare on Page 94 in Example 1 to yield N- methyl-N- (5-tetrazolyl) -e- (N-Z-amino) -a- (N-Boc-amino) -2- methylhexanamide .
Ex-23b) N-Methyl-N- (5-tetrazolyl) -e- (N-Z-amino) -a- (N-Boc- amino) -2-methylhexanamide is then subject to conditions to remove the Z protecting group as described in Ex-lb to yield N-methyl-N- (5-tetrazolyl) -e- (amino) -a- (N-Boc-amino) - 2-methylhexanamide .
Ex-23c) The resulting N-methyl-N- (5-tetrazolyl) -e- (amino) - a- (N-Boc-amino) -2-methylhexanamide (3.89 g, 11 mmol) is reacted with methyl acetimidate hydrochloride (2.49 g) using the process in Ex-2c to yield N-methyl-N- ( 5- tetrazolyl) -e- (N- (1-iminoethyl) amino) -a- (N-Boc-amino) -2- methylhexanamide .
Ex-23d) N-methyl-N- (5-tetrazolyl) -e- (N- (1- iminoethyl) amino) -a- (N-Boc-amino) -2-methylhexanamide is then subject to conditions to remove the Boc protecting group as described in Ex-2d to give N-methyl-N- (5- tetrazolyl ) -e- (N- (1-iminoethyl ) amino) -2-amino-2- methylhexanamide . Ex-23e) N-methyl-N- (5-tetrazolyl) -e- (N- (1- iminoethyl) amino) -2 -amino-2-methylhexanamide (3.05 g, 11 mmol) is treated with one equivalent trichloroethyl chloroformate (2.29 g) and sodium carbonate in aqueous tetrahydrofuran under the conditions described by D. Gravel in Canadian Journal of Chemistry 50, 3846, 1972 to give N- methyl-N- (5-tetrazolyl) -e- (N- (1-iminoethyl) amino) -2- (N- (2,2, 2-trichloroethoxyformyl) ) amino-2-methylhexanamide .
Ex-23g) N-methyl-N- (5-tetrazolyl) -e- (N- (1- iminoethyl) amino) -2- (N- (2,2, 2-trichloroethoxyformyl) ) amino- 2-methylhexanamide (4.65 g) is treated with Lawesson's Reagent under the conditions described in Chem. Reviews, 84, 17-30, 1984 and references cited therein to yield N- methyl-N- (5-tetrazolyl) -e- (N- (1-iminoethyl) amino) -2- (N- (2 , 2 , 2-trichloroethoxythionoformyl) ) amino-2 -methyl- thionohexanamide .
Ex-23g) N-methyl-N- (5-tetrazolyl) -e- (N- (1- iminoethyl ) amino ) -2- (N- (2,2,2- trichloroethoxythionoformyl) ) amino-2-methyl- thionohexanamide (4.84 g, 10 mmol) is dissolved in acetic acid and treated with zinc dust (0.65g, 10 mmol) . After stirring two hours, saturated aqueous sodium carbonate is added. The solids are removed by filtration. 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 N-methyl-N- (5-tetrazolyl) - e- (N- (1-iminoethyl) amino) -2 -amino-2 -methyl-thionohexanamide is then eluted with 10% aqueous pyridine.
N-methyl-N- (5-tetrazolyl) -e- (N- (1-iminoethyl) amino) -2- amino-2-methyl-thionohexanamide (2.65 g, 9 mmol) is place in 20 ml of anhydrous THF containing 1.01 grams of triethylamine. After cooling to -78 °C, ethyl chloroformate (0.98 g, 9 mmol) in 10 ml anhydrous THF is added over 20 minutes. After warming to room temperature, the solvent is removed in vacuo, 50 ml methylene chloride added along with 20 ml of water. The methylene chloride layer is separated, back washed with water, and concentrated to afford N- methyl-N- (5-tetrazolyl) -e- (N- ( 1-iminoethyl) amino) -2- ( (N- ethoxycarbonyl) amino) -2 -methyl-thionohexanamide .
Figure imgf000161_0001
Example 24
Ex-24a) e- (N-Z-Amino) -a- (N-Boc-amino) -2-methylhexanoic acid (4.56 g, 12 mmol) is reacted with 5-(N- methylamino) tetrazole (1.06 g, 12.5 mmol) using the process in Ex-2a to yield N-methyl-N- (5-tetrazolyl) -e- (N-Z-amino) - a- (N-Boc-amino) -2-methylhexanamide.
Ex-24b) N-Methyl-N- (5-tetrazolyl) -e- (N-Z-amino) -a- (N-Boc- amino) -2-methylhexanamide is then subject to conditions to remove the Z protecting group as described in Ex-2b to give N-methyl-N- (5-tetrazolyl) -e- (amino) -a- (N-Boc-amino) -2- methylhexanamide .
Ex-24c) The resulting N-methyl-N- (5-tetrazolyl) -e- (amino) - a- (N-Boc-amino) -2-methylhexanamide (3.88 g, 11 mmol) is reacted with methyl 2-fluoroacetimidate hydrochloride (2.07) using the process in Ex-2c to yield N-methyl-N- (5- tetrazolyl) -e- (N- (1-imino-2-fluoroethyl) amino) -a- (N-Boc- amino) -2-methylhexanamide . Ex-24d) N-methyl-N- (5-tetrazolyl) -e- (N- (l-imino-2- fluoroethyl) amino) -a- (N-Boc-amino) -2-methylhexanamide is then subject to conditions to remove the Boc protecting group as described in Ex-2d to N-methyl-N- (5-tetrazolyl) -e- (N- (l-imino-2-fluoroethyl) amino) -2-amino-2 - methylhexanamide .
Ex-24e) N-methyl-N- (5-tetrazolyl) -e- (N- (l-imino-2- fluoroethyl) amino) -2-amino-2-methylhexanamide (3.09 g, 10 mmol) is placed in 20 mL of anhydrous THF containing 1.01 grams of triethylamine. After cooling to -78°C, trifluoroacetic anhydride (2.17 g, 10.3 mmol) in 10 mL anhydrous THF is added over 20 minutes. After warming to room temperature, the solvent is removed in vacuo to afford N-methyl-N- (5-tetrazolyl) -e- (N- (l-imino-2- fluoroethyl) amino) -2 -trifluoroacetamido-2 -methylhexanamide trifluoroacetate .
N-methyl-N- (5-tetrazolyl) -e- (N- (l-imino-2- fluoroethyl ) amino ) -2-trifluoroacetamido-2 -methylhexanamide trifluoroacetate (9 mmol) is dissolved in ethanol and treated with two equivalents of sodium borohydride (0.74 g, 20 mmol). After stirring several hours, the ethanol is removed in vacuo. Upon completion, 50 mL methylene chloride is added along with 20 mL of water. The methylene chloride layer is separated, back washed with water, dried over MgS04, and concentrated to afford N-methyl-N- (5-tetrazolyl) - e- (N- (1-imino-2-fluoroethyl) amino) -2- (N- (2 , 2 , 2-trifluoro-1- ethoxyethyl ) ) amino-2 -methylhexanamide .
Figure imgf000163_0001
Example 25
Ex-25a) a- (N-Z) -S- (N-hydroxy-2-aminoethyl) -2-methyl-L- cysteine methyl ester (3.28 g, 10 mmol) is treated with methyl (N- (benzoyloxymethyl) acetimidate hydrochloride (4.14 g) as described in Ex-2c to give a- (N-Z) -S- (2- (1- (N- (benzoyloxymethyl) imino) ethyl) -N-hydroxy) aminoethyl) -2- methyl-L-cysteine methyl ester.
Ex-25b) a- (N-Z) -S- (2- (1- (N- (benzoyloxymethyl) imino) ethyl) - N-hydroxy) aminoethyl) -2-methyl-L-cysteine methyl ester (4.63 g, 9 mmol) is dissolved in DMF and treated with N- methyl-5-amino-tetrazole (0.93 g, 9.5 mmol). The mixture is heated until replacement of the methoxy is observed. Upon completion, the reaction mixture is concentrated. The resulting material is dissolved in aqueous acetonitrile and passed through a reverse phase chromatographic column, giving N-methyl-N- (5-tetrazolyl) -a- (N-Z) -S- (2- (1- (N- (benzoyloxymethyl) imino) ethyl) -N-hydroxy) aminoethyl) -2- methyl-L-cysteinamide .
N-methyl-N- (5-tetrazolyl) -a- (N-Z) -S- (2- (1- (N- (benzoyloxymethyl) imino) ethyl) -N-hydroxy) aminoethyl) -2- methyl-L-cysteinamide is then subject to conditions to remove the Z protecting group as described in Ex-2b to give N-methyl-N- (5-tetrazolyl) -S- (2- (1- (N-
(benzoyloxymethyl) imino) ethyl) -N-hydroxy) aminoethyl) -2- methyl-L-cysteinamide .
Figure imgf000164_0001
Example 26
Ex-26a) a- (N-Z) -e- (N-Boc) -2-methyl-L-Lysine (3.80 g, 10 mmol) is treated with N-methyl-5-amino-tetrazole (0.89 g, 10.5 mmol) using the conditions to prepare Ex-3a to yield N-methyl-N- (5-tetrazolyl) -a- (N-Z) -e- (N-Boc) -2-methyl-L- Lysine .
Ex-26b) N-methyl-N- (5-tetrazolyl) -a- (N-Z) -e- (N-Boc) -2- methyl-L-Lysine is then subject to conditions to remove the Boc protecting group as described in Ex-3b to give N- methyl-N- (5-tetrazolyl ) -a- (N-Z) -2-methyl-L-Lysine .
Ex-26c) N-Methyl-N- (5-tetrazolyl) -a- (N-Z) -2-methyl-L- Lysine (3.51 g, 10 mmol) is added to 50 mL of toluene in 100 mL reaction flask. After adding 1.89 g of p- toluenesulfonic acid and 0.93 g (16 mmol) propionaldehyde 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 the iminium salt, N-methyl-N- (5-tetrazolyl) -a- (N- Z) -e-N- (1-propylene) - 2-methyl-L-Lysine p-toluenesulfonate.
Ex-26d) N-methyl-N- (5-tetrazolyl) -a- (N-Z) -e-N- (1- propylene) -2-methyl-L-Lysine p-toluenesulfonate (9 mmol) is dissolved in methanol and treated with 1.0M sodium cyanoborohydride in THF (19 mL) and potassium hydroxide using the conditions and work-up described by R. F. Borch in Organic Synthesis, 52, 124, 1972 to give the product, N- methyl-N- (5-tetrazolyl) -a- (N-Z) -e-N- (1-propyl) -2-methyl-L- Lysine .
Ex-26e) N-methyl-N- (5-tetrazolyl) -a- (N-Z) -e-N- (1-propyl) - 2-methyl-L-Lysine (3.38 g, 8 mmol) is treated with methyl (N- (benzoyloxymethyl) acetimidate hydrochloride (3.70 g) as described in Ex-2c to give N-methyl-N- (5-tetrazolyl) -a- (N- Z) -e-N- (2- (1- (N- (benzoyloxymethyl) imino) ethyl) ) - e-N- (1- propyl) -2-methyl-L-Lysine .
Ex-26f ) N-methyl-N- (5-tetrazolyl) -a- (N-Z) -e-N- (2- (1- (N- (benzoyloxymethyl) imino) ethyl) ) - e-N- (1-propyl) -2-methyl-L- Lysine is then subject to conditions to remove the Z protecting group as in Ex-2b to give N-methyl-N- ( 5- tetrazolyl) -e-N- (2- (1- (N- (benzoyloxymethyl) imino) ethyl) ) - e-N- (1-propyl) -2-methyl-L-Lysine.
N-methyl-N- (5-tetrazolyl) -e-N- (2- (1- (N-
(benzoyloxymethyl) imino) ethyl) ) - e-N- (1-propyl) -2-methyl-L- Lysine (3.30 g, 7 mmol) is placed in 20 mL of anhydrous THF containing 1.01 grams of triethylamine. After cooling to -78°C, benzoyl chloride (1.01 g, 7.2 mmol) in 10 mL anhydrous THF is added over 20 minutes. After warming to room temperature, the solvent is removed in vacuo, 50 mL methylene chloride is added along with 20 mL of water. The methylene chloride layer is separated, back washed with water, dried over MgSθ4 , and concentrated to afford N- methyl-N- (5-tetrazolyl) - a-N-benzoyl- e-N- (2- ( 1- (N- ( benzoyloxymethyl ) imino ) ethyl ) ) - e-N- ( 1 -propyl ) -2 -methyl -L- Lys ine .
Figure imgf000166_0001
EXAMPLE 27
Ex-27a) To a stirring DMF solution of ε-pnZ-α-Boc-2-methyl- L-Lysine (4.64 g, 10.0 mmol), 1- (4-nitrobenzyloxymethyl) -5- methylaminotetrazole (2.77 g, 10.5 mmol), 2.53 g triethylamine (0.025 mol) and 1-hydroxybenzotriazole hydrate (1.45 g, 10.5 mmol) in 75 mL of dimethylformamide (DMF) cooled in an ice bath is added [(N,N- dimethylamino) propyl] ethylcarbodiimide hydrochloride (1.93 g, 10.5 mmol) . After stirring 55 h at ambient temperature, the reaction mixture is concentrated in vacuum. The resulting material is dissolved in aqueous acetonitrile and passed through a reverse phase chromatographic column, giving N-methyl-N- (5- (4-nitrobenzyloxymethyl) tetrazolyl) -ε- pnZ-α-Boc-2-methyl-L-Lysinamide .
Ex-27b) N-methyl-N- (5- (4-nitrobenzyloxymethyl) tetrazolyl) - ε-pnZ-α-Boc-2-methyl-L-Lysinamide is then dissolved in 25 mL. anhydrous trifluoroacetic acid and allowed to stand at room temperature until the t-butoxycarbonyl group is removed. The reaction mixture is concentrated to dryness in vacuo, aqueous sodium carbonate added to neutralize residual acid, and the aqueous solution extracted with methylene chloride to yield N-methyl-N- (5- (4- nitrobenzyloxymethyl) tetrazolyl) -ε-pnZ-2-methyl-L- Lysinamide.
Ex-27c) N-methyl-N- (5- (4-nitrobenzyloxymethyl) tetrazolyl) - ε-pnZ-2-methyl-L-Lysinamide (4.68 g, 8.0 mmol) is placed in admixture with tetrahydrofuran (50 mL) and phthalic anhydride (1.19 g, 8.0 mmol) and heated at reflux until the reaction is complete. Removal of the tetrahydrofuran afforded the phthalimide of N-methyl-N- (5- (4- nitrobenzyloxymethyl) tetrazolyl) -ε-pnZ-2-methyl-L- Lysinamide .
Ex-27d) Phthalimide 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 on n-butyl lithium in hexane. Subsequently, 1.1 equivalents of N-chloromethyl-N,N'N' -trimethylurea was added. After warming to room temperature, the reaction mixture is filtered to remove the precipitant and concentrated in vacuo to give N-methyl-N- (5- (4- nitrobenzyloxymethyl) tetrazolyl) -α-N-phthaloyl-ε-pnZ-ε-N- (N,N'N' -trimethylureido-N-methylene) -2-methyl-L-Lysinamide.
Ex-27e) N-methyl-N- (5- (4-nitrobenzyloxymethyl) tetrazolyl) - α-N-phthaloyl-ε-pnZ-ε-N- (N,N'N' -trimethylureido-N- methylene) -2-methyl-L-Lysinamide 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 pnZ-functions generating the amino product N-methyl-N- (5- (tetrazolyl) -α- N-phthaloyl-ε-N- (N,N'N' -trimethylureido-N-methylene) -2- methyl-L-Lysinamide .
Ex-27g) To a 125 mL flask is added 2.36 g (0.005 mol) of N-methyl-N- (5- (tetrazolyl) -α-N-phthaloyl-ε-N- (N,N'N' - trimethylureido-N-methylene) -2-methyl-L-Lysinamide is converted to N-methyl-N- (5- (tetrazolyl) -α-N-phthaloyl-ε-N- (2-fluoro-1-iminoethyl) -ε-N- (N,N'N' -trimethylureido-N- methylene) -2-methyl-L-Lysinamide as described in Ex-17c.
N-methyl-N- (5- (tetrazolyl) -α-N-phthaloyl-ε-N- (2-fluoro-1- iminoethyl ) -ε-N- (N, N'N' -trimethylureido-N-methylene) -2- methyl-L-Lysinamide (1.64 g, 0.003 mol) is dissolved in 25 mL methanol and hydrazine (0.96 g, 0.003 mol) added. After refluxing for 6 hours, the methanol is removed, aqueous 10 % hydrochloric acid added to the residue in an ice bath until the pH was 3 to 4, and the precipitated hydrazide removed by filtration. The aqueous solution is concentrated in vacuo to give the dihydrochloride of N- methyl-N- (5- (tetrazolyl) -ε-N- (2-fluoro-1-iminoethyl) -ε-N- (N,N'N' -trimethylureido-N-methylene) -2-methyl-L-Lysinamide.
Figure imgf000168_0001
EXAMPLE 28
Ex-28a) To a stirring DMF solution of ε-Boc-α-pnZ-2-methyl- L-Lysine (4.64 g, 10.0 mmol), 1- (4-nitrobenzyloxymethyl) -5- methylaminotetrazole (2.77 g, 10.5 mmol), 2.53 g triethylamine (0.025 mol) and 1-hydroxybenzotriazole hydrate (1.45 g, 10.5 mmol) in 75 mL of dimethylformamide (DMF) cooled in an ice bath is added [(N,N- dimethylamino) propyl] ethylcarbodiimide hydrochloride (1.93 g, 10.5 mmol). After stirring 55 h at ambient temperature, the reaction mixture is concentrated in vacuum. The resulting material is dissolved in aqueous acetonitrile and passed through a reverse phase chromatographic column, giving N-methyl-N- (5- (4-nitrobenzyloxymethyl) tetrazolyl) -ε- Boc-α-pnZ-2-methyl-L-Lysinamide .
Ex-28b) N-methyl-N- (5- (4-nitrobenzyloxymethyl) tetrazolyl) - ε-Boc-α-pnZ-2-methyl-L-Lysinamide is then dissolved in 25 mL. anhydrous trifluoroacetic acid and allowed to stand at room temperature until the t-butoxycarbonyl group is removed. The reaction mixture is concentrated to dryness in vacuo, aqueous sodium carbonate added to neutralize residual acid, and the aqueous solution extracted with methylene chloride to yield N-methyl-N- (5- (4- nitrobenzyloxymethyl) tetrazolyl) -α-pnZ-2-methyl-L- Lysinamide .
Ex-28c) N-methyl-N- (5- (4-nitrobenzyloxymethyl) tetrazolyl) - α-pnZ-2-methyl-L-Lysinamide (4.68 g, 8.0 mmol) is placed in admixture with tetrahydrofuran (50 mL) and phthalic anhydride (1.19 g, 8.0 mmol) and heated at reflux until the reaction is complete. Removal of the tetrahydrofuran affords the phthalimide of N-methyl-N- (5- ( 4- nitrobenzyloxymethyl) tetrazolyl) -α-pnZ-2-methyl-L- Lysinamide.
Ex-28d) Phthalimide 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 on n-butyl lithium in hexane. Subsequently, 1.1 equivalents of N-chloromethyl-N,N'N' -trimethylurea is added. After warming to room temperature, the reaction mixture is filtered to remove the precipitant and concentrated in vacuo to give N-methyl-N- (5- (4- nitrobenzyloxymethyl) tetrazolyl) -ε-N-phthaloyl-α-pnZ-α-N- (N,N'N' -trimethylureido-N-methylene) -2-methyl-L-Lysinamide . Ex-28e) N-methyl-N- (5- (4-nitrobenzyloxymethyl) tetrazolyl) - ε-N-phthaloyl-α-pnZ-α-N- (N,N'N' -trimethylureido-N- methylene) -2-methyl-L-Lysinamide is dissolved in 25 mL methanol and one equivalent of hydrazine added. After refluxing for 6 hours, the methanol is removed, aqueous 10 % hydrochloric acid added to the residue in an ice bath until the pH is 7, and the precipitated hydrazide removed by filtration. The aqueous solution is concentrated in vacuo to give N-methyl-N- (5- (4- nitrobenzyloxymethyl) tetrazolyl) -α-pnZ-α-N- (N, N'N' - trimethylureido-N-methylene) -2-methyl-L-Lysinamide hydrochloride .
Ex-28f) The N-methyl-N- (5- ( 4- nitrobenzyloxymethyl) tetrazolyl) -α-pnZ-α-N- (N, N'N' - trimethylureido-N-methylene) -2-methyl-L-Lysinamide is converted to N-methyl-N- (5- (4-nitrobenzyloxymethyl) tetrazolyl) -α-pnZ-ε-N- (2-fluoro-1-iminoethyl) -α-N- (N,N'N' - trimethylureido-N-methylene) -2-methyl-L-Lysinamide as described in Ex-17c.
N-methyl-N- (5- (4-nitrobenzyloxymethyl) tetrazolyl) -α-pnZ-ε-N- (2-fluoro-1-iminoethyl) -α-N- (N,N'N' -trimethylureido-N- methylene) -2-methyl-L-Lysinamide 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 pnZ-functions generating the amino product N-methyl-N- (5-tetrazolyl) -ε-N- (2-fluoro-1-iminoethyl) -α-N- (N,N'N' -trimethylureido-N- methylene) -2-methyl-L-Lysinamide .
Figure imgf000171_0001
Example 29
Ex-29a) e- (N-Z-Amino) -a- (N-Boc-amino) -2-methylhexanoic acid (3.80 g, 10 mmol) is reacted with 5-(N- methylamino) tetrazole (0.89 g, 10.5 mmol) using the process described in Ex-2a to yield N-methyl-N- (5-tetrazolyl) -e- (N- Z-amino) -a- (N-Boc-amino) -2-methylhexanamide.
Ex-29b) N-Methyl-N- (5-tetrazolyl) -e- (N-Z-amino) -a- (N-Boc- amino) -2-methylhexanamide is then subject to conditions to remove the Z protecting group as described in Ex-2b to N- methyl-N- (5-tetrazolyl) -e- (amino) -a- (N-Boc-amino) -2- methylhexanamide .
Ex-29c) The resulting N-methyl-N- (5-tetrazolyl) -e- (amino) - a- (N-Boc-amino) -2-methylhexanamide (3.14 g, 9 mmol) is reacted with methyl 2-fluoroacetimidate hydrochloride (1.67 g) using the process described in Ex-2c in Example 2 to yield N-methyl-N- (5-tetrazolyl) -e- (N- (l-imino-2- fluoroethyl) amino) -a- (N-Boc-amino) -2-methylhexanamide.
Ex-29d) N-methyl-N- (5-tetrazolyl) -e- (N- (l-imino-2- fluoroethyl) amino) -a- (N-Boc-amino) -2-methylhexanamide is then subject to conditions to remove the Boc protecting group as described in Ex-2d to give N-methyl-N- (5- tetrazolyl) -e- (N- ( l-imino-2-fluoroethyl) amino) -2-amino-2- methylhexanamide .
Ex-29e) To a stirring DMF solution of N-Boc-phenylalanine (2.25 g, 8.5 mmol), N-methyl-N- (5-tetrazolyl) -e- (N- (1- imino-2-fluoroethyl) amino) -2 -amino-2 -methylhexanamide (2.28 g, 8 mmol), and 1-hydroxybenzotriazole hydrate (1.45 g, 10.5 mmol) in 75 mL of dimethylformamide (DMF) cooled in an ice bath is added [ (N,N-dimethylamino) propyl] ethylcarbodiimide hydrochloride (1.93 g, 10.5 mmol). After stirring 55 h at ambient temperature, the reaction mixture is concentrated in vacuum. The resulting material is dissolved in aqueous acetonitrile and passed through a reverse phase chromatographic column, giving N-methyl-N- ( 5- tetrazolyl) -e- (N- (l-imino-2-fluoroethyl) amino) -2- (N- (N-Boc- phenylalaninyl ) amino) -2-methylhexanamide .
N-methyl-N- (5-tetrazolyl) -e- (N- (l-imino-2- fluoroethyl) amino) -2- (N- (N-Boc-phenylalaninyl) amino) -2- methylhexanamide is then subject to conditions to remove the Boc protecting group as described in Ex-2d to give in Example 2 to give N-methyl-N- (5-tetrazolyl) -e- (N- (1-imino- 2 -fluoroethyl) amino) -2- (N- (phenylalaninyl) amino) -2- methylhexanamide .
Figure imgf000172_0001
EXAMPLE 30 Ex-30a) ε-Boc-α-pnZ-2-methyl-L-Lysine (4.64 g, 10.0 mmol) and 1- (4-nitrobenzyloxymethyl) aminotetrazole (2.62 g, 10.5 mmol) is converted to N-(5-(4- nitrobenzyloxymethyl) tetrazolyl) -ε-Boc-α-pnZ-2-methyl-L- Lysinamide analogous to that described in Example 28.
Ex-30b) N- (5- (4-nitrobenzyloxymethyl) tetrazolyl) -ε-Boc-α- pnZ-2-methyl-L-Lysinamide is then converted to N-(5-(4- nitrobenzyloxy methyl) tetrazolyl) -α-pnZ-2-methyl-L- Lysinamide analogous to that described in Example 28.
Ex-30c) N- (5- (4-nitrobenzyloxymethyl) tetrazolyl) -α-pnZ-2- methyl-L-Lysinamide (4.68 g, 8.0 mmol) is then converted to the phthalimide of N-(5-(4- nitrobenzyloxymethyl) tetrazolyl) -α-pnZ-2-methyl-L- Lysinamide analogous to that described in Example 28. Ex-30d) Phthalimide 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 on n-butyl lithium in hexane. Subsequently, 1.1 equivalents of chloromethyl acetate is added. After warming to room temperature, the reaction mixture is filtered to remove the precipitant and concentrated in vacuo to give N-acetoxymethyl-N- (5- (4- nitrobenzyloxymethyl) tetrazolyl) -ε-N-phthaloyl-α-pnZ-2- methyl-L-Lysinamide
Ex-30e) N-acetoxymethyl-N- (5- (4- nitrobenzyloxymethyl) tetrazolyl) -ε-N-phthaloyl-α-pnZ-2- methyl-L-Lysinamide is converted to N-acetoxymethyl-N- ( 5- (4-nitrobenzyloxymethyl) tetrazolyl) -α-pnZ-2-methyl-L- Lysinamide analogous to that described in Example 28.
Ex-30f) N-acetoxymethyl-N- (5- (4- nitrobenzyloxymethyl) tetrazolyl) -α-pnZ-2-methyl-L- Lysinamide is converted to N-acetoxymethyl-N- (5- (4- nitrobenzyloxymethyl) tetrazolyl) -α-pnZ-ε-N- (iminoethyl) -2- methyl-L-Lysinamide as described in Ex-2c.
N-acetoxymethyl-N- (5- (4-nitrobenzyloxymethyl) tetrazolyl) -α- pnZ-ε-N- (iminoethyl) -2-methyl-L-Lysinamide 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 pnZ- functions generating the amino product N-acetoxymethyl-N- ( 5-tetrazolyl) -ε-N- (iminoethyl) -2-methyl-L-Lysinamide .
Figure imgf000174_0001
(31)
Example 31
Ex-31a) To a 125 mL flask is added 3.14 g (0.011 mol) of e- amino-a- (N-Boc-amino) -2- (cyanomethyl) hexanoic acid and 70 mL of DMF. To this solution is added 2.41 g of methyl acetimidate hydrochloride. Triethylamine (TEA) (3.04 g, 0.03 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 e- (N- (1-Iminoethyl) amino) - a- (N-Boc-amino) -2- (cyanomethyl) hexanoic acid is then eluted with 10% aqueous pyridine and thoroughly dried.
Ex-31b) e- (N- ( 1-Iminoethyl ) amino) -a- (N-Boc-amino) -2- (cyanomethyl) hexanoic acid (3.33 g, 10 mmol) is dissolved in THF and cooled to -78°C. One equivalent of lithium diisopropylamine (LDA) 2.0M solution (5.0 mL) is added dropwise over a period of 20 minutes. Ethyl 2- bromopropionate (1.85 g, 10.3 mmol) is added over 30 minutes. The mixture is allowed to warm to room temperature. The solvents are removed in vacuo, and the product purified by chromatography to give (1- ethoxycarbonyl) ethyl e- (N- (1-iminoethyl) amino) -a- (N-Boc- amino) -2- (cyanomethyl ) hexanoate .
(1-Ethoxycarbonyl) ethyl e- (N- (1-iminoethyl) amino) -a- (N- Boc-amino) -2- (cyanomethyl) hexanoate is then dissolved in anhydrous trifluoroacetic acid and allowed to stand at room temperature until the t-butoxycarbonyl group is removed. The reaction mixture is then concentrated in vacuo to give (1-ethoxycarbonyl) ethyl e- (N- (1-iminoethyl) amino) -a-amino- 2- (cyanomethyl) hexanoate trifluoroacetate . This product is refluxed in toluene and sodium carbonate (3 equivalents) to give the cyclized product 3-(4-(N-(l- iminoethyl) amino) butyl) -3-cyanomethyl-6-methylmorpholine- 2 , 5-dione .
Figure imgf000175_0001
(32) Example 32
Ex-32a) To a 125 mL flask is added 3.21 g (0.01 mol) of e- amino-a- (N-Z-amino) -2- (N,N-dimethylaminomethyl) hexanoic acid and 70 mL of DMF. To this solution is added 2.54 g of methyl 2-fluoroacetimidate hydrochloride. Triethylamine (TEA) (3.04 g, 0.03 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 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 Z- protected product is then eluted with 10% aqueous pyridine.
Ex-32b) e- (N- (2-Fluoroiminoethyl ) amino) -a- (N-Z-amino) -2- (N,N-dimethylaminomethyl) hexanoic acid (3.5 g, 9 mmol) is dissolved in THF and cooled to -78°C. Two equivalents of lithium diisopropylamine (LDA) 2.0M solution (9.2 mL) is added dropwise over a period of 20 minutes. Phosgene (0.9 g, 9.3 mmol) is added through a gas inlet tube over 30 minutes. The mixture is allowed to warm to room temperature. The solvents are removed in vacuo, and the product purified by chromatography to give 3-(4-(N-(2- fluoroiminoethyl) amino)butyl) -4- (N-Z) -3- (N,N- di ethy1aminomethyl) oxazolidine-2 , 5-dione .
3- (4- (N- (2 -fluoroiminoethyl) amino) butyl) -4- (N-Z) -3- (N,N- dimethylaminomethyl) oxazolidine-2 , 5-dione is dissolved in ethyl acetate 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 3-(4-(N-(2- fluoroiminoethyl) amino) butyl) -3- (N,N- dimethylaminomethyl) oxazolidine-2 , 5-dione .
Figure imgf000177_0001
(33)
Example 33
Ex-33a) To a 125 mL flask is added 3.20 g (0.010 mol) of e- amino-a- (N-Boc-amino) -2- (2-methylthioethyl) hexanoic acid and 70 mL of DMF. To this solution is added 2.19 g of methyl acetimidate hydrochloride. Triethylamine (TEA) (3.04 g, 0.03 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 e- (N- (1-Iminoethyl) amino) - a- (N-Boc-amino) -2- (2-methylthioethyl) hexanoic acid is then eluted with 10% aqueous pyridine.
e- (N- (1-Iminoethyl) amino) -a- (N-Boc-amino) -2- (2- methylthioethyl) hexanoic acid (3.29 g, 9 mmol), 2- hydroxycyclohexanone dimer (1.03 g, 9 mmol) and 30 mmol of 2 , 2-dimethoxypropane are dissolved in 50 mL of 2.0M HCl in dioxane. After standing at room temperature for 12 hours, the solvent is removed in vacuo to afford 3-(4-(N-(l- iminoethyl) amino) butyl) -3- (2 -methylthioethyl) -
3H, 5H, 6H, 7H, 8H- 1 , 4-benzoxazin-2-one dihydrochloride.
Figure imgf000178_0001
(34)
Example 34
Ex-34a) e- (N- (2-Fluoroiminoethyl ) amino) -a- (N-Z-amino) -2-
(N,N-dimethylaminomethyl) hexanoic acid prepared in example 32 (3.82 g, 10 mmol) is dissolved in 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 removed in vacuo to afford the amino product e-(N-(2- fluoroiminoethyl) amino) -a-amino) -2- (N, - dimethylaminomethyl) hexanoic acid.
e- (N- (2-fluoroiminoethyl ) amino) -a-amino) -2- (N, N- dimethylaminomethyl) hexanoic acid (10 mmol), 2- hydroxypropanol (0.74 g, 10 mmol) and 30 mmol of 2,2- dimethoxypropane are dissolved in 50 mL of 2.0M HCl in dioxane. After standing at room temperature for 12 hours, the solvent is removed in vacuo to afford 3-(4-(N-(2- fluoroiminoethyl) amino) butyl) -3- (N,N-dimethylaminomethyl) - 6-methyl-3H, 6H-1 , 4-oxazin-2-one dihydrochloride .
Figure imgf000179_0001
(36)
Example 36
Ex-36a) Dibenzyl 2- (2- (N-Boc-amino) ethoxymethyl) -2- phthalimidomalonate (6.02 g, 10 mmol) is dissolved in ethanol/acetic acid and is combined with a hydrogenation catalyst 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 esters to give 2- (2- (N-Boc-amino) ethoxymethyl) -2- phthalimidomalonic acid.
Ex-36b) 2- (2- (N-Boc-amino) ethoxymethyl) -2- phthalimidomalonic acid is heated to 150°C until decarboxylation is complete to give 3- (2- (N-Boc- amino) ethoxy) -2 -phthalimidopropionic acid .
Ex-36c) 3- (2- (N-Boc-amino) ethoxy) -2-phthalimidopropionic acid (3.36 g, 9 mmol) is cooled in an ice bath and 1.0M borane-tetrahydrofuran complex (18 mL) added dropwise. When addition is complete, the reaction is allowed to warm to room temperature. When the reduction is complete, excess reagent is destroyed by addition of acetic acid. The reaction is concentrated at reduced pressure. The crude product is purified by column chromatography on silica gel to yield 3- (2- (N-Boc-amino) ethoxy) -2- phthalimidopropanol .
Ex-36d) 3- (2- (N-Boc-amino) ethoxy) -2-phthalimidopropanol
(2.8 g, 8 mmol) is dissolved in DMSO and treated with 1,3- dicyclohexylcarbodimide (DCC) (1.6 g, 8 mmol) and phosphoric acid. The reaction is stirred at room temperature . Upon completion, 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 MgS0 , filtered and solvents removed in vacuo. The product is passed through a reverse phase chromatographic column, giving 3- (2- (N-Boc-amino) ethoxy) -2- phthalimidopropanal .
Ex-36e) 3- (2- (N-Boc-amino) ethoxy) -2-phthalimidopropanal (1.81 g, 7 mmol) is added to 50 mL of hexane in 100 mL reaction flask. After adding 0.1 g of p-toluenesulfonic acid and 1.6 g (14 mmol) 2- (thienyl) methanol, the reaction mixture is refluxed with azeotropic distillation for removal of water using a Dean-Stark trap. After cooling, dilute aqueous sodium carbonate (20 mL) is added, the hexane separated, and then concentrated in vacuo to afford 1 , 1-bis- (2-thienylmethoxy) -3- (2- (N-Boc-amino) ethoxy) -2- phthalimidopropane .
Ex-36f) 1, 1-Bis- (2-thienylmethoxy) -3- (2- (N-Boc- amino) ethoxy) -2-phthalimidopropane is dissolved in 2.0M HCl in acetic acid. The reaction is allowed to stand at 25°C until the Boc group is removed to give, after concentrating in vacuo, 2- (3 , 3-Bis- (2-thienylmethoxy) -2- phthalimidopropoxy) ethanamine hydrochloride.
Ex-36g) To a 125 L flask is added 2.83 g (6 mmol) of 2-
(3 , 3-Bis- (2-thienylmethoxy) -2-phthalimidopropoxy) ethanamine hydrochloride and 70 mL of water. This solution is adjusted to pH = 9.5 by addition of 2.5 N NaOH. To this solution is added portion wise, 1.15 g of methyl 2- flouroacetimidate . During methyl 2-flouroacetimidate 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 N- (2-fluoro-1-iminoethyl) -2- (3 , 3-Bis- (2-thienylmethoxy) -2-phthalimidopropoxy) ethanamine is then eluted with a solvent of 10% pyridine, 50% methanol and 40% water.
The N- (2-fluoro-l-iminoethyl) -2- (3, 3-Bis- (2- thienylmethoxy) -2-phthalimidopropoxy) ethanamine (2.55 g, 5 mmol) is dissolved in methanol and 0.5 g hydrazine monohydrate and is heated to reflux. After complete removal of the phthaloyl protecting group and filtering to remove the phthaloylhydrazide, the methanolic solution is then adjusted to pH = 7.5 with aqueous hydrochloric acid and poured onto a Dowex 50 Cation exchange column. The column is washed with water, and the product N- (2-fluoro-1- iminoethyl) -2- (3 , 3-Bis- (2-thienylmethoxy) -2- aminopropoxy) ethanamine is then eluted with a solvent of 10% pyridine, 50% methanol and 40% water.
Figure imgf000181_0001
Ex-37a) Diethyl 2 - (4- (N-Boc-amino) but-2-enyl) -2- phthalimidomalonate (10 mmol) is dissolved in ethanol and sodium hydroxide (0.78g, 20 mmol) is added. When the ethyl esters have hydrolyzed, two equivalents of HCl are added through a gas inlet tube. The solvent is removed in vacuo. The sodium chloride is removed by washing with water, and the residue is dried at reduced pressure to give 2-(4-(N- Boc-amino)but-2-enyl) -2-phthalimidomalonic acid.
Ex-37b) 2- (4- (N-Boc-amino )but-2-enyl) -2-phthalimidomalonic acid is heated to 150°C until decarboxylation is complete to give 6- (N-Boc-amino) -2-phthalimido-hex-4-enoic acid.
Ex-37c) 6- (N-Boc-amino) -2-phthalimido-hex-4-enoic acid (3.34 g, 9 mmol) is cooled in an ice bath and 1.0M borane- tetrahydrofuran complex (18 mL) added dropwise. When addition is complete, the reaction is allowed to warm to room temperature. When the reduction is complete, excess reagent is destroyed by addition of acetic acid. The reaction is concentrated at reduced pressure. The crude product is purified by column chromatography on silica gel to yield 6- (N-Boc-amino) -2-phthalimido-hex-4-enol .
Ex-37d) 6- (N-Boc-amino) -2-phthalimido-hex-4-enol (2.7 g, 8 mmol) is dissolved in DMSO and treated with 1,3- dicyclohexylcarbodimide (DCC) (1.6 g, 8 mmol) and phosphoric acid. The reaction is stirred at room temperature . Upon completion, 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 MgS0 , filtered and solvents removed in vacuo. The product is passed through a reverse phase chromatographic column, giving 6- (N-Boc-amino) -2- phthalimido-hex-4-enal .
Ex-37e) 6- (N-Boc-amino) -2-phthalimido-hex-4-enal (2.50 g, 7 mmol) is added to 50 mL of cyclohexane in 100 mL reaction flask. After adding 0.1 g of p-toluenesulfonic acid and 1.0 g (7 mmol) 1, 2-benzenedithiol , the reaction mixture is refluxed with azeotropic distillation for removal of water using a Dean-Stark trap. After cooling, dilute aqueous sodium carbonate (20 mL) is added, the hexane separated, and then concentrated in vacuo to afford 2- (6- (N-Boc- amino) -2-phthalimido-hex-4-enyl) -3-thia-2H, 3H- benzothiophene .
Ex-37f) 2- (6- (N-Boc-amino) -2-phthalimido-hex-4-enyl) -3- thia-2H, 3H-benzothiophene is dissolved in trifluoroacetic acid. The reaction is allowed to stand at 25 °C until the Boc group is removed to give, after concentrating in vacuo, to give 2- (6-amino-2-phthalimido-hex-4-enyl) -3-thia-2H, 3H- benzothiophene trifluoroacetate .
Ex-37g) To a 125 mL flask is added 6 mmol of the 2- (6- amino-2-phthalimido-hex-4-enyl) -3-thia-2H, 3H-benzothiophene trifluoroacetate and 70 mL 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 2- ( 6- (N- (1-iminoethyl) amino) -2- phthalimido-hex-4-enyl) -3-thia-2H, 3H-benzothiophene is then eluted with a solvent of 10% pyridine, 50% methanol and 40% water .
2- (6- (N- ( 1-iminoethyl) amino) -2-phthalimido-hex-4-enyl) -3- thia-2H, 3H-benzothiophene (1.90 g, 5 mmol) is dissolved in methanol and 0.5 g hydrazine monohydrate and is heated to reflux. After complete removal of the phthaloyl protecting group and filtering to remove the phthaloylhydrazide, the methanolic solution is then adjusted to pH = 7.5 with aqueous hydrochloric acid and poured onto a Dowex 50 Cation exchange column. The column is washed with water, and the product 2- (6- (N- (1-iminoethyl) amino) -2-amino-hex-4-enyl) -3- thia-2H, 3H-benzothiophene is then eluted with a solvent of 10% pyridine, 50% methanol and 40% water.
Figure imgf000184_0001
(39)
Example 39
Ex-39a) Diethyl 2- (4- (N-Boc-amino) but-2-enyl) -2- phthalimidomalonate (10 mmol) is dissolved in ethanol and sodium hydroxide (0.78g, 10 mmol) is added. When one ethyl ester is hydrolyzed, the reaction mixture is then concentrated in vacuo, 50 ml anhydrous cyclohexane is added, and then is added (1.25 g, 10.5 mmol) of thionyl chloride. After the formation of the acid chloride is complete, sodium chloride is removed by filtration, and the mixture is concentrated in vacuo to give ethyl 2- (4- (N-Boc- amino) but-2-enyl) -2-phthalimido-3-chloro-3-oxopropionate .
Ex-39b) Ethyl 2- ( 4- (N-Boc-amino) but-2-enyl) -2-phthalimido- 3-chloro-3-oxopropionate (9 mmol) is dissolved in tetrahydrofuran, cooled to -78°C and treated with one equivalent (9 mL) of 1.0 M diisobutylaluminum hydride in THF. Acetic acid is added and the reaction is warmed to room temperature to generate the aldehyde. After the mixture is concentrated in vacuo, methylene chloride is added. The methylene chloride layer is washed with 10% aqueous sodium bicarbonate, water and brine. The methylene chloride layer is dried over MgS0 , filtered and solvents removed in vacuo. The product is passed through a reverse phase chromatographic column giving ethyl 2- (4- (N-Boc- amino) but-2-enyl ) -2-phthalimido-3 -oxopropionate .
Ex-39c) Ethyl 2- (4- (N-Boc-amino) but-2-enyl) -2-phthalimido- 3 -oxopropionate (8 mmol) is added to 50 mL of hexane in 100 mL reaction flask. After adding 0.1 g of p-toluenesulfonic acid and 1.30 g (17 mmol) 1 , 3-propandiol , the reaction mixture is refluxed with azeotropic distillation for removal of water using a Dean-Stark trap. After cooling, dilute aqueous sodium carbonate (20 mL) is added, the hexane separated, and then concentrated in vacuo to afford ethyl 2- (4- (N-Boc-amino) but-2-enyl) -2-phthalimido-3- (2- (1,3 -dioxanyl) ) acetate .
Ex-39d) Ethyl 2- (4- (N-Boc-amino) but-2-enyl) -2-phthalimido- 3- (2- (1, 3 -dioxanyl)) acetate (7 mmol) is dissolved in ethanol and treated with one equivalent of sodium hydroxide (0.26 g, 7 mmol) . When the ester group is removed, the mixture is concentrated in vacuum. The residue is dissolved in 10 mL of thionyl chloride and warmed. The excess thionyl chloride is removed in vacuo, anhydrous toluene added and removed in vacuo, and 20 mL of toluene containing phenol (0.71 g, 7.5 mmol) and triethylamine (1.01 g, 10 mmol) is added. After stirring 5 h at ambient temperature, the reaction mixture is concentrated in vacuum. The resulting material is dissolved in aqueous acetonitrile and passed through a reverse phase chromatographic column giving phenyl 2- (4- (N-Boc-amino) but- 2-enyl) -2-phthalimido-3 - (2- (1, 3 -dioxanyl) ) acetate . Ex-39e) Phenyl 2- (4- (N-Boc-amino) but-2-enyl) -2-phthalimido- 3- (2- (1, 3-dioxanyl) ) acetate is dissolved in anhydrous trifluoroacetic acid to remove the Boc-function generating the amino product, phenyl 2- (4-aminobut-2-enyl) -2- phthalimido-3- (2- (1 , 3-dioxanyl) ) acetate trifluoroacetate, after removal of solvent.
Ex-39f) To a 125 mL flask is added ( 6 mmol) phenyl 2- (4- aminobut-2-enyl) -2-phthalimido-3- (2- (1, 3-dioxanyl) ) acetate trifluoroacetate and 70 mL of DMF. To this solution is added 2.19 g of methyl acetimidate hydrochloride. Triethylamine (TEA) (3.04 g, 0.03 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 and poured onto a Dowex 50 Cation exchange column. The column is washed with water. The product Phenyl 2- (4-aminobut-2-enyl) -2-phthalimido-3-
(2- (1, 3-dioxanyl) ) acetate is then eluted with a solvent of 10% pyridine, 50% methanol and 40% water and taken to dryness in vacuo.
Phenyl 2- (4-aminobut-2-enyl) -2 -phthalimido-3- (2- (1, 3- dioxanyl) ) acetate (2.38 g, 5 mmol) is dissolved in methanol and 0.5 g hydrazine monohydrate. After complete removal of the phthaloyl protecting group and filtering to remove the phthaloylhydrazide, the methanolic solution is then concentrated to dryness to give the product.
Figure imgf000187_0001
(40)
Example 40
Ex-40a) Ethyl 6-phthalimido-2-cyano-2- (N-Boc- amino) hexanoate (4.29 g, 10 mmol) is dissolved in ethanol and treated with sodium hydroxide (0.38 g, 10 mmol) . When the ethyl ester group is hydrolyzed, one equivalent of HCl (0.36 g, 10 mmol) is added through a gas inlet tube. The solvent is removed in vacuo and the residue is heated to 150°C until decarboxylation is complete. The crude product is passed through a reverse phase chromatographic column giving 6-phthalimido- 2- (N-Boc-amino) hexanenitrile .
Ex-40b) 6-Phthalimido-2- (N-Boc-amino) hexanenitrile (3.21 g, 9 mmol) is dissolved in methanol and 0.9 g hydrazine monohydrate. The mixture is heated to reflux. After complete removal of the phthaloyl protecting group and filtering to remove the phthaloylhydrazide, the methanolic solution is then concentrated to dryness to give the product 6-amino-2- (N-Boc-amino) hexanenitrile .
Ex-40c) To a 125 mL flask is added 1.82 g (8 mmol) of 6- amino-2- (N-Boc-amino) hexanenitrile and 70 mL of water. This solution is adjusted to pH = 9.5 by addition of 2.5 N NaOH. To this solution is added portion wise, 2.11 g of methyl 2-fluoroacetimidate . During methyl 2- fluoroacetimidate 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 6- (N- (2-Fluoro-l-iminoethyl) amino) -2- (N-Boc-amino) -hexanenitrile is then eluted with 10% aqueous pyridine.
6- (N- (2-Fluoro-l-iminoethyl) amino) -2- (N-Boc-amino) - hexanenitrile (2.12 g, 7 mmol) is dissolved in methylene chloride and (0.98 g, 8 mmol) 2-piperazinylmethanethiol is added at with cooling to -10°C. HCl (1.9 g) gas is added by gas inlet tube. The reaction is allowed to warm to room temperature. When the reaction is completed, the solvent is removed in vacuo to yield 6- (N- (2-fluoro-1- iminoethyl) amino) -1-imino-l- (2-piperazinylmethylthio) -2- hexanamine pentahydrochloride .
Figure imgf000188_0001
(41)
Example 41
Ex-41a) Ethyl 6-phthalimido-2-cyano-2- (N-Boc- amino) hexanoate (4.29 g, 10 mmol) is dissolved in methanol and 1.0 g hydrazine monohydrate. The mixture is heated to reflux. After complete removal of the phthaloyl protecting group and filtering to remove the phthaloylhydrazide, the methanolic solution is then concentrated to dryness in an ice bath to give the product ethyl 6-amino-2-cyano-2- (N- Boc-amino) hexanoate .
Ex-41b) To a 125 mL flask is added 2.69 g (9 mmol) of ethyl 6-amino-2-cyano-2- (N-Boc-amino) hexanoate and 70 mL of water. This solution is adjusted to pH = 9.5 by addition of 2.5 N NaOH. To this solution is added portion wise, 2.05 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 Ethyl 6-(N-(l- iminoethyl) amino) -2-cyano-2- (N-Boc-amino) hexanoate is then eluted with 10% aqueous pyridine.
Ethyl 6- (N- (1-iminoethyl) amino) -2 -cyano-2- (N-Boc- amino) hexanoate (2.73 g, 8 mmol) is dissolved in methylene chloride and 10 mL anhydrous ethanol is added. The mixture is cooled to -10°C and (1.2 g) HCl gas is added by gas inlet tube. The reaction is allowed to warm to room temperature. When the reaction is completed, the solvent is removed in vacuo to yield ethyl 6-(N-(l- iminoethyl) amino) -2- (ethoxyiminomethyl) -2-aminohexanoate trihydrochloride .
Figure imgf000190_0001
(42)
Example 42
Ex-42a) Ethyl 6- (N- ( 1-iminoethyl) amino) -2-cyano-2- (N-Boc- amino) hexanoate (Ex-41c) (3.41 g, 10 mmol) is dissolved in ethanol and treated with one equivalent of sodium hydroxide (0.37 g, 10 mmol) . When the ester group is removed, p- toluenesulfonic acid (10 mmol) is added. The mixture is concentrated in vacuum. The residue is dissolved in 60 mL of DMF. 5-methylaminotetrazole hydrochloride (1.40 g, 10.5 mmol) and 1-hydroxybenzotriazole hydrate (1.46 g, 10.5 mmol) are added. The mixture is cooled in an ice bath then is added [ (N,N-dimethylamino) propyl] ethylcarbodiimide hydrochloride (1.93 g, 10.5 mmol) . After stirring 55 h at ambient temperature, the reaction mixture is concentrated in vacuum. The resulting material is dissolved in aqueous acetonitrile and passed through a reverse phase chromatographic column, giving N-methyl-N- (5-tetrazolyl) -6- (N- (1-iminoethyl ) amino) -2-cyano-2- (N-Boc-amino) hexanamide .
N-Methyl-N- (5-tetrazolyl) -6- (N- (1-iminoethyl) amino) -2- cyano-2- (N-Boc-amino) hexanamide (3.15 g, 8 mmol) is dissolved in methylene chloride and (0.26 g, 8 mmol) methanol is added. The mixture is cooled to -10°C and (1.9 g) HCl gas is added by gas inlet tube. The reaction is allowed to warm to room temperature. When the reaction is completed, the solvent is removed in vacuo to yield N- methyl-N- (5-tetrazolyl) -6- (N- (1-iminoethyl) amino) -2- (methoxyiminomethyl) -2-aminohexanamide .
Figure imgf000191_0001
(43)
Example 43
Ex-43a) tert-Butyl 6- (N-Z-amino) -2-cyano-2- phthalimidohexanoate 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 tert-butyl 6-amino-2-cyano-2- phthalimidohexanoate acetate.
Ex-43b) To a 125 mL flask is added 3.57 g (0.01 mol) of tert-butyl 6-amino-2-cyano-2-phthalimidohexanoate acetate and 70 mL of DMF. To this solution is added 2.19 g of methyl acetimidate hydrochloride. Triethylamine (TEA) (3.04 g, 0.03 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 and poured onto a Dowex 50 Cation exchange column. The column is washed with water. The product tert-Butyl 6- (N- (1-iminoethyl) amino) -2-cyano-2- phthalimidohexanoate is then eluted with a solvent of 10% pyridine, 50% methanol and 40% water and taken to dryness in vacuo .
Ex-43c) tert-Butyl 6- (N- (1-iminoethyl) amino) -2-cyano-2- phthalimidohexanoate is dissolved in acetic acid and is combined with a hydrogenation catalyst such as platinum on carbon and hydrogen. This reaction is shaken under pressure for an extended period of time in a standard Parr hydrogenation apparatus to reduce the nitrile. When the reaction is complete, 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 product tert-Butyl 6- (N- (1-iminoethyl) amino) -2-aminomethyl- 2-phthalimidohexanoate is then eluted with a solvent of 10% pyridine, 50% methanol and 40% water and taken to dryness in vacuo .
Ex-43d) tert-Butyl 6- (N- (1-iminoethyl) amino) -2 -aminomethyl- 2-phthalimidohexanoate (3.22 g, 8 mmol) is cooled in an ice bath and treated with N-Boc-glycyl chloride (1.39 g, 8.5 mmol) and triethyl amine (TEA) (0.8 g, 8 mmol) . 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 tert-butyl 6-(N-(l- iminoethyl ) amino) -2- (N- (N-Boc-glycyl ) ) aminomethyl-2- phthalimidohexanoate .
tert-Butyl 6- (N- (1-iminoethyl) amino) -2- (N- (N-Boc- glycyl) ) aminomethyl-2-phthalimidohexanoate (7 mmol) is dissolved in methanol and 0.5 g hydrazine monohydrate. The mixture is heated to reflux. After complete removal of the phthaloyl protecting group, cooling and filtering to remove the phthaloylhydrazide, the methanolic solution is then concentrated to dryness . The product is taken up and allowed to stand in 2N HCl and dioxane at 25 °C for two hours. Concentrating in vacuo affords the unprotected product 6- (N- ( 1-iminoethyl) amino) -2- (N-glycylaminomethyi; 2-phthalimidohexanoic acid trihydrochloride .
Figure imgf000193_0001
(45)
Example 45
Ex-45a) tert-Butyl 2-phthalimidoacetate (2.61 g, 10 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 (1.11 g, 11 mmol) of diisopropylamine followed by 1 equivalent on n-butyl lithium in hexane. Subsequently, 1.1 equivalents (2.15 g, 11 mmol) of 2- (3- bromopropyl) -1 , 3-dioxolane is added. After warming to room temperature, the reaction mixture is concentrated in vacuo, 50 mL methylene chloride is added, the solvent is washed with water, and the methylene chloride is dried over anhydrous K2CO3 and is taken to dryness to give, after chromatographic purification, the tert-butyl 2-phthalimido- 5- (1, 3-dioxolanyl)pentanoate .
Ex-45b) tert-Butyl 2-phthalimido-5- ( 1 , 3- dioxolanyDpentanoate (3.38 g, 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 (1.01 g, 10 mmol) of diisopropylamine followed by 1 equivalent on n- butyl lithium in hexane. Subsequently, 1.1 equivalents (2.15 g, 10 mmol) of 2-benzyloxy-l-bromoethane is added. After warming to room temperature, the reaction mixture is concentrated in vacuo, 50 mL methylene chloride is added, the solvent is washed with water, and the methylene chloride is dried over anhydrous K2CO3 and is taken to dryness . The crude product is purified by reverse phase chromatography to give tert-butyl 2-phthalimido-2- (2- benzyloxyethyl) -5- (1, 3-dioxolanyl)pentanoate.
Ex-45c) The tert-butyl 2 -phthalimido-2- (2-benzyloxyethyl) - 5- (1, 3-dioxolanyl) pentanoate is treated with 0.5 g of p- toluenesulfonic acid in 20 mL of ice water. The mixture is stirred and is allowed to warm to room temperature until the aldehyde is regenerated. The water mixture is extracted with methylene chloride. The methylene chloride is dried and concentrated to give tert-butyl 2-phthalimido- 2- (2-benzyloxyethyl) -6-oxohexanoate .
Ex-45d) tert-Butyl 2-phthalimido-2- (2-benzyloxyethyl) -6- oxohexanoate (3.72 g, 8 mmol) and ammonia are dissolved in methanol and treated with 1.0M sodium cyanoborohydride in THF and potassium hydroxide using the conditions and work- up described by R. F. Borch in Organic Synthesis, 52, 124, 1972 to give the product tert-butyl 2 -phthalimido-2- (2- benzyloxyethyl) -6-aminohexanoate .
Ex-45e) To a 125 mL flask is added 3.24 g (7 mmol) of tert- butyl 2-phthalimido-2- (2-benzyloxyethyl) -6-aminohexanoate and 70 mL of water. This solution is adjusted to pH = 9.5 by addition of 2.5 N NaOH. To this solution is added portion wise, 1.57 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 tert-Butyl 2- phthalimido-2- (2-benzyloxyethyl) -6- (N- (1- iminoethyl) amino) hexanoate is then eluted with a solvent of 10% pyridine, 50% methanol and 40% water and taken to dryness in vacuo.
Ex-45f) tert-Butyl 2-phthalimido-2- (2-benzyloxyethyl) -6- (N- ( 1-iminoethyl) mino) hexanoate is then dissolved in 2.0M HCl in acetic acid and allowed to stand at room temperature until the t-butyl group is removed. The reaction mixture is then concentrated in vacuo to give 2-phthalimido-2- (2- benzyloxyethyl) -6- (N- (1-iminoethyl) amino) hexanoic acid hydrochloride .
Ex-45g) To a stirring DMF solution of 2-phthalimido-2- (2- benzyloxyethyl) -6- (N- (1-iminoethyl) amino) hexanoic acid hydrochloride (2.71 g, 6 mmol), 5-(2'-N- methyl) hydrazinotetrazole (0.76 g, 6.5 mmol), and 1- hydroxybenzotriazole hydrate (0.90 g, 6.5 mmol) in 75 mL of dimethylformamide (DMF) cooled in an ice bath is added
[ (N, N-dimethylamino) propyl] ethylcarbodiimide hydrochloride (1.20 g, 6.5 mmol) . After stirring 55 h at ambient temperature, the reaction mixture is concentrated in vacuum. The resulting material is dissolved in aqueous acetonitrile and passed through a reverse phase chromatographic column, giving N-methyl-N- (N- (5- tetrazoyl ) amino) - 2-phthalimido-2- (2-benzyloxyethyl ) -6- (N- ( 1-iminoethyl) amino) hexanamide .
Ex-45h) N-methyl-N- (N- (5-tetrazoyl) amino) - 2-phthalimido-2- (2-benzyloxyethyl) -6- (N- (1-iminoethyl) 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 the benzyl group generating, after filtering to remove catalyst and concentration in vacuo, N- methyl-N- (N- (5-tetrazoyl) amino) - 2-phthalimido-2- (2- hydroxyethyl) -6- (N- ( 1-iminoethyl) amino) hexanamide .
N-Methyl-N- (N- ( 5-τetrazoyl) amino) - 2-phthalimido-2- (2- hydroxyethyl) -6- (N- (1-iminoethyl) amino) hexanamide (2.29 g, 5 mmol) is dissolved in methanol and 0.5 g hydrazine monohydrate. The mixture is heated to reflux. After complete removal of the phthaloyl protecting group, cooling and filtering to remove the phthaloylhydrazide, the methanolic solution is then concentrated to dryness to give N-Methyl-N- (N- (5-tetrazoyl) amino) - 2-amino-2- (2- hydroxyethyl) -6- (N- (1-iminoethyl) amino) hexanamide .
Figure imgf000196_0001
(46)
Example 46
Ex-46a) To a stirring DMF solution of 2-phthalimido-2- (2- benzyloxyethyl) -6- (N- (1-iminoethyl) amino) hexanoic acid hydrochloride (Ex-45f; prepared in example 45) (4.51 g, 10 mmol), glycine tert-butyl ester hydrochloride (1.76 g, 10.5 mmol) and 1-hydroxybenzotriazole hydrate (1.45 g, 10.5 mmol) in 75 mL of dimethylformamide (DMF) cooled in an ice bath is added [ (N,N-dimethylamino) propyl] ethylcarbodiimide hydrochloride (1.93 g, 10.5 mmol). After stirring 55 h at ambient temperature, the reaction mixture is concentrated in vacuum. The resulting material is dissolved in aqueous acetonitrile and passed through a reverse phase chromatographic column giving tert-butyl N- (2-phthalimido- 2- (2-benzyloxyethyl) -6- (N- (1-iminoethyl) amino) hexanoyl) aminoacetate .
Ex-46b) tert-Butyl" N- (2-phthalimido-2- (2-benzyloxyethyl) -6- (N- (1-iminoethyl) amino) hexanoyl) aminoacetate 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 tert-Butyl N- (2-phthalimido- 2- (2-hydroxyethyl) -6- (N- (1-iminoethyl) amino) hexanoyl) aminoacetate .
Ex-46c) tert-Butyl N- (2-phthalimido-2- (2-hydroxyethyl) -6- (N- (1-iminoethyl) amino) hexanoyl) aminoacetate (3.79 g, 8 mmol) in 50 mL THF is cooled in an ice bath and is treated with tosyl chloride (1.62 g, 8.5 mmol) and triethyl amine (TEA) (1.6 g, 16 mmol) . The mixture is allowed to warm to room temperature. Upon completion the mixture is concentrated in vacuum to give tert-Butyl N- (2-phthalimido- 2- (2-tosyloxyethyl) -6- (N- (1-iminoethyl) amino) hexanoyl) aminoacetate .
Ex-46d) tert-Butyl N- (2-phthalimido-2- (2-tosyloxyethyl) -6- (N- (1-iminoethyl) amino) hexanoyl) aminoacetate (2.96 g, 7 mmol) is treated with sodium cyanide (0.5 g, 7.5 mmol) in 20 mL of dimethylformamide and heated. When the substitution is complete, the reaction is concentrated. The resulting material is dissolved in aqueous acetonitrile and passed through a reverse phase chromatographic column giving tert-Butyl N- (2-phthalimido-2- (2-cyanoethyl) -6- (N- ( 1-iminoethyl) amino) hexanoyl) aminoacetate .
Ex-46e) tert-Butyl N- (2 -phthalimido-2- (2-cyanoethyl) -6- (N- ( 1-iminoethyl) amino) hexanoyl) aminoacetate is dissolved in methanol and 0.5 g hydrazine monohydrate. The mixture is heated to reflux. After complete removal of the phthaloyl protecting group, cooling and filtering to remove the phthaloylhydrazide, the methanolic solution is then concentrated to dryness to give tert-Butyl N- (2-amino-2- (2- cyanoethyl) -6- (N- (1-iminoethyl) amino) hexanoyl) aminoacetate ,
tert-Butyl N- (2-amino-2- (2-cyanoethyl) -6- (N- (1- iminoethyl) amino) hexanoyl) aminoacetate is allowed to stand in 2N HCl and dioxane at 25°C for two hours. The solution is then concentrated to dryness to give N- (2-amino-2- (2- cyanoethyl) -6- (N- (1-iminoethyl) amino) hexanoyl) aminoacetic acid hydrochloride.
Figure imgf000198_0001
(48)
Example 48
Ex-48a) tert-Butyl 2-phthalimido-5- (1, 3- dioxolanyl)pentanoate (Ex-45b; prepared in scheme 45) (3.76 g, 10 mmol) is dissolved in dry 2.0M HCl in dioxane. The reaction is stirred until the t-butyl group is removed, and then the reaction is concentrated. DMF (70 mL) , 2,2,2- trichloroethanol (1.56 g, 10.5 mmol), and 1- hydroxybenzotriazole hydrate (1.45 g, 10.5 mmol) are added and the mixture is cooled in an ice bath. When cold [(N,N- dimethylamino) propyl] ethylcarbodiimide hydrochloride (1.93 g, 10.5 mmol) is added. After stirring 55 h at ambient temperature, the reaction mixture is concentrated in vacuum. The resulting material is then purified by column chromatography giving 2 , 2 , 2 -trichloroethyl 2-phthalimido-5- (1,3-dioxolanyl ) pentanoate .
Ex-48b) 2, 2, 2-Trichloroethyl 2-phthalimido-5- (1, 3- dioxolanyl) pentanoate (4.06 g, 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 on n-butyl lithium in hexane. Subsequently, 1.1 equivalents (0.75 g) of chloroacetonitrile is added. After warming to room temperature, the reaction mixture is filtered to remove the precipitant and concentrated in vacuo. The resulting material is then purified by column chromatography giving 2,2, 2-trichloroethyl 2-cyanomethyl-2-phthalimido-6- (1,3- dioxolanyl ) pentanoate .
Ex-48c) 2 , 2 , 2-Trichloroethyl 2-cyanomethyl-2-phthalimido-6- (1, 3 -dioxolanyl) pentanoate (3.92 g, 8 mmol) is added to ice water with 0.1 g of p-toluenesulfonic acid, is stirred and is allowed to warm to room temperature to generate the aldehyde. The resulting solution is extracted with methylene chloride, the extracting is dried over MgSθ4 , and is concentrated in vacuo to give 2 , 2 , 2-trichloroethyl 2- cyanomethyl-2-phthalimido-6-oxopentanoate .
Ex-48d) 2 , 2, 2-Trichloroethyl 2-cyanomethyl-2-phthalimido-6- oxopentanoate (3.02 g, 7 mmol) is dissolved in methanol and is treated with ammonia (0.13 g, 7.5 mmol), and 1.0M sodium cyanoborohydride in THF (8 mL) and potassium hydroxide using the conditions and work-up described by R. F. Borch in Organic Synthesis, 52, 124, 1972 to give the product 2,2, 2-trichloroethyl 2-cyanomethyl-2 -phthalimido-6- aminohexanoate .
Ex-48e) To a 125 L flask is added 4.32 g (10 mmol) of 2 , 2 , 2-trichloroethyl 2-cyanomethyl-2-phthalimido-6- aminohexanoate and 70 mL of water. This solution is adjusted to pH = 9.5 by addition of 2.5 N NaOH. To this solution is added portion wise, 2.19 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 2 , 2 , 2-trichloroethyl 2-cyanomethyl-2- phthalimido-6- (N- ( 1-iminoethyl) amino) hexanoate is then eluted with a solvent of 10% pyridine, 50% methanol and 40% water and taken to dryness in vacuo.
Ex-48f) 2, 2, 2-trichloroethyl 2-cyanomethyl-2-phthalimido-6- (N- (1-iminoethyl) amino) hexanoate (4.26 g, 9 mmol) is dissolved in tetrahydrofuran. Zinc dust (1.17 g) is added, and the mixture is allowed to stir. When the trichloroethyl protecting group is completely removed, the reaction mixture is acidified with 2 N HCl. The solids are filtered for removal, and the solvent is removed in vacuo. The resulting material is purified by reverse phase chromatography to give 2-cyanomethyl-2 -phthalimido-6- (N- (1- iminoethyl) amino) hexanoic acid.
Ex-48g) To a stirring solution of 2-cyanomethyl-2- phthalimido-6- (N( 1-iminoethyl) amino) hexanoic acid (2.74 g, 8 mmol), 5- (N-methylsulfonylmethylamino) tetrazole (1.50 g, 8.5 mmol), and 1-hydroxybenzotriazole hydrate (1.17 g, 8.5 mmol) in 75 mL of dimethylformamide (DMF) cooled in an ice bath is added [ (N,N-dimethylamino) propyl] ethylcarbodiimide hydrochloride (1.56 g, 8.5 mmol). After stirring 55 h at ambient temperature, the reaction mixture is concentrated in vacuum. The resulting material is dissolved in aqueous acetonitrile and is passed through a reverse phase chromatographic column, giving N-methylsulfonylmethyl-N- (5- tetrazolyl) -2 -cyanomethyl-2-phthalimido-6- (N- (1- iminoethyl ) amino) hexanamide .
N-methylsulfonylmethyl-N- (5-tetrazolyl) -2-cyanomethyl-2- phthalimido-6- (N- (1-iminoethyl) amino) hexanamide (3.61 g, 7 mmol) is dissolved in methanol and 0.5 g hydrazine monohydrate. The mixture is heated to reflux. After complete removal of the phthaloyl protecting group, cooling and filtering to remove the phthaloylhydrazide, the methanolic solution is then concentrated to dryness to give N-methylsulfonylmethyl-N- (5-tetrazolyl) -2 -cyanomethyl-2- amino-6- (N- (1-iminoethyl) amino) hexanamide .
Figure imgf000201_0001
(49)
Example 49
Ex-49a) tert-Butyl 2-phthalimido-5- ( 1 , 3- dioxolanyl) pentanoate (Ex-45b; prepared in scheme 45) (3.76 g, 10 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 on n-butyl lithium in hexane. Subsequently, 1.1 equivalents of chloroacetonitrile is added. After warming to room temperature, the reaction mixture is filtered to remove the precipitant and is concentrated in vacuo. The resulting material is then purified by column chromatography giving tert-Butyl 2 -cyanomethyl-2- phthalimido-5- (1, 3-dioxolanyl) pentanoate .
Ex-49b) tert-Butyl 2-cyanomethyl-2-phthalimido-5- (1, 3- dioxolanyl) pentanoate (3.74 g, 9 mmol) is added to ice water with 0.1 g of p-toluenesulfonic acid, is stirred and is allowed to warm to room temperature to generate the aldehyde. The resulting solution is extracted with methylene chloride, the extractant is dried over MgSθ4 , and is concentrated in vacuo to give tert-Butyl 2-cyanomethyl- 2 -phthalimido-6-oxohexanoate .
Ex-49c) tert-Butyl 2-cyanomethyl-2-phthalimido-6- oxohexanoate (2.98 g, 8 mmol) is dissolved in methanol and is treated with ammonia (0.15 g, 8.5 mmol) and 1.0M sodium cyanoborohydride in THF (8 mL) and potassium hydroxide using the conditions and work-up described by R. F. Borch in Organic Synthesis, 52, 124, 1972 to give the product tert-Butyl 2-cyanomethyl-2-phthalimido-6-aminohexanoate .
To a 125 mL flask is added 2.60 g (7 mmol) of tert-Butyl 2- cyanomethyl-2-phthalimido-6-aminohexanoate and 70 mL of water. This solution is adjusted to pH = 9.5 by addition of 2.5 N NaOH. To this solution is added portion wise, 1.53 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 is poured onto a Dowex 50 Cation exchange column. The column is washed with water. The protected product tert-Butyl 2-cyanomethyl- 2-phthalimido-6- (N- (1-iminoethyl) amino) hexanoate is then eluted with a solvent of 10% pyridine, 50% methanol and 40% water and taken to dryness in vacuo.
Figure imgf000203_0001
(50)
Example 50
Ex-50a) tert-Butyl 2 -cyanomethyl-2 -phthalimido-6- (N- (1- iminoethyl) amino) hexanoate (Ex-49) is deprotected by allowing it to stand in 2N HCl and dioxane at 25°C for two hours. Concentrating in vacuo affords 2 -cyanomethyl-2 - phthalimido-6- (N- (1-iminoethyl) amino) hexanoic acid hydrochloride.
Ex-50b) 2-Cyanomethyl-2-phthalimido-6- (N- (1- iminoethyl) amino) hexanoic acid hydrochloride (6 mmol) is dissolved in tetrahydrofuran, is cooled in an ice bath and is treated with ethylchloroformate (0.70 g, 6.5 mmol) and triethylamine (TEA) (1.3 g, 13 mmol). The mixture is allowed to warm to room temperature. The resulting material is treated with O-methoxymethyl-N- methanesulfonylmethylhydroxylamine (1.10 g, 6.5 mmol). The mixture is stirred vigorously until the substitution is complete. The solvent is removed in vacuo, the residue is dissolved in water, is adjusted to pH = 7.5 with IN HCl, and is poured onto a Dowex 50 Cation exchange column. The column is washed with water. The protected product N- Methanesulfonylmethyl-N- (O-methoxymethoxy) -2-cyanomethyl-2- phthalimido-6- (N- (1-iminoethyl) amino) hexanamide is then eluted with a solvent of 10% pyridine, 50% methanol and 40% water and taken to dryness in vacuo.
N-Methanesulfonylmethyl-N- (O-methoxymethoxy) -2 -cyanomethyl- 2-phthalimido-6- (N- (1-iminoethyl) amino) hexanamide (2.54 g, 5 mmol) is dissolved in methanol and 0.5 g hydrazine monohydrate. The mixture is heated to reflux. After complete removal of the phthaloyl protecting group, cooling and filtering to remove the phthaloylhydrazide, the methanolic solution is then concentrated to dryness to give N-methanesulfonylmethyl-N- (methoxymethoxy) -2-cyanomethyl-2- amino-6- (N- (1-iminoethyl) amino) hexanamide .
Figure imgf000204_0001
(51)
Example 51
Ex-51a) To a stirring DMF solution of 2-cyanomethyl-2- phthalimido-6- (N- (1-iminoethyl) amino) hexanoic acid hydrochloride (Ex-50a; prepared in example 50) (2.14 g, 6 mmol), t-butyl alanine hydrochloride (1.19 g, 6.5 mmol), and 1-hydroxybenzotriazole hydrate (0.90 g, 10.5 mmol) in 75 mL of dimethylformamide (DMF) cooled in an ice bath is added [ (N, N-dimethylamino ) propyl ] ethylcarbodiimide hydrochloride (1.19 g, 10.5 mmol). After stirring 55 h at ambient temperature, the reaction mixture is concentrated in vacuum. The resulting material is dissolved in aqueous acetonitrile and passed through a reverse phase chromatographic column giving t-butyl N- (2 -cyanomethyl-2- phthalimido-6- (N- (1-iminoethyl ) amino) hexanoyl ) alaninate . Ex-51b) t-Butyl N- (2-cyanomethyl-2-phthalimido-6- (N- ( 1- iminoethyl) amino) hexanoyl) alaninate (2.42 g, 5 mmol) is dissolved in methanol and 0.5 g hydrazine monohydrate. The mixture is heated to reflux. After complete removal of the phthaloyl protecting group, cooling and filtering to remove the phthaloylhydrazide, the methanolic solution is then concentrated to dryness to give t-Butyl N- (2-cyanomethyl-2- amino-6- (N- (1-iminoethyl) amino) hexanoyl) alaninate .
t-Butyl N- (2-cyanomethyl-2-amino-6- (N- (1- iminoethyl) amino) hexanoyl) alaninate is dissolved and allowed to stand in 2.0M HCl in dioxane at 25°C for two hours. Concentrating in vacuo affords N- (2-cyanomethyl-2- amino-6- (N- (1-iminoethyl) amino) hexanoyl) alanine dihydrochloride .
Figure imgf000205_0001
(52)
Example 52
Ex-52a) N-Boc-5-nitropentanamine (2.31 g, 10 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 on n-butyl lithium in hexane. Subsequently, 1.1 equivalents of 2-butanoyl chloride is added. After warming to room temperature, the reaction mixture is filtered to remove the precipitant and concentrated in vacuo to give 1- (N-Boc- amino) -4-nitrononan-5-one which is purified by chromatography .
Ex-52b) 1- (N-Boc-amino) -4-nitrononan-5-one (2.67 g, 9 mol) 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 on n-butyl lithium in hexane. Subsequently, 1.1 equivalents of bromoacetonitrile is added. After warming to room temperature, the reaction mixture is filtered to remove the precipitant and concentrated in vacuo to give 1- (N-Boc- amino) -4-nitro-4-cyanomethyl-nonan-5-one .
Ex-52c) 1- (N-Boc-amino) -4-nitro-4-cyanomethylnonan-5-one is dissolved in 50 mL anhydrous cyclohexane, is treated with 2 mL BF3 etherate and 1, 2-propanediol (9 mmol), and is allowed to stir until the ketal forms. The reaction mixture is washed with aqueous sodium carbonate, and the cyclohexane is dried over anhydrous potassium carbonate.
Evaporation of the solvent and chromatography gave 2-(5-(N- Boc-amino) -1-nitro-l-cyanomethylpentyl) -2-propyl-4-methyl- 1 , 3-dioxolane .
Ex-52d) 2- (5- (N-Boc-amino) -1-nitro-l-cyanomethylpentyl) -2- propyl-4-methyl-1 , 3-dioxolane is deprotected by allowing it to stand in anhydrous trifluoroacetic acid at 25°C for two hours. Concentrating in vacuo affords 2- (5-amino-l-nitro- 1-cyanomethylpentyl) -2-propyl-4-methyl-l, 3-dioxolane trifluoroacetate.
Ex-52e) To a 125 mL flask is added 8 mmol of 2- (5-amino-l- nitro-1-cyanomethylpentyl) -2-propyl-4-methyl-l, 3-dioxolane trifluoroacetate and 70 mL of water. This solution is adjusted to pH = 9.5 by addition of 2.5 N NaOH. To this solution is added portion wise, 1.75 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 product is then eluted with 10% aqueous pyridine.
The 2- (5- (N- (1-iminoethyl) amino) -1-nitro-l- cyanomethylpentyl) -2-propyl-4-methyl-l, 3-dioxolane is dissolved in ethanol with 30 mmol ammonium formate 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. The solvent is removed and 50 mL of water added. The solution is then adjusted to pH = 7.5 with IN HCl and is poured onto a Dowex 50 Cation exchange column. The column is washed with water. The product is then eluted with 10% aqueous pyridine and is taken to dryness to give 2- (5- (N- (1-iminoethyl) amino) -1-amino-l- cyanomethylpentyl) -2-propyl-4-methyl-l , 3-dioxolane .
Figure imgf000207_0001
(53)
Example 53
Ex-53a) 6- (N-Boc-amino) -2-phthalimido-hex-4-enal (Ex-37d) (10 mmol) is added to 50 mL of cyclohexane in 100 mL reaction flask. After adding 0.1 g of p-toluenesulfonic acid and 0.70 g (10 mmol) ethylene glycol, the reaction mixture is refluxed with azeotropic distillation for removal of water using a Dean-Stark trap. After cooling, the solvent is removed in vacuo to give 2- (5- (N-Boc-amino) - l-phthalimido-pent-3-enyl) -1, 3-dioxolane .
Ex-53b) 2- (5- (N-Boc-amino) -l-phthalimido-pent-3-enyl) -1,3- dioxolane is dissolved in ethanol and is combined with a hydrogenation catalyst palladium on carbon and hydrogen. This reaction is shaken under pressure for an extended period of time in a standard Parr hydrogenation apparatus to reduce the alkenyl group. Evaporation of the solvent gives 2- (5- (N-Boc-amino) -1-phthalimido-pentyl) -1, 3- dioxolane .
Ex-53c) 2- (5- (N-Boc-amino) -1-phthalimido-pentyl ) -1,3- dioxolane (7 mmol) is dissolved in anhydrous acetic acid with 2.5 g of dry HCl added through a gas inlet tube. The reaction is allowed to stand at 25°C until the Boc group is removed to give 2- (5-amino-l-phthalimido-pentyl) -1, 3- dioxolane hydrochloride .
Ex-53d) To a 125 mL flask is added 2.04 g (6 mmol) of 2- (5- amino-1-phthalimido-pentyl) -1 , 3-dioxolane hydrochloride and 70 mL 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 2-(5-(N-(l- Iminoethyl) amino) -1-phthalimidopentyl) -1, 3-dioxolane is then eluted with 10% aqueous pyridine.
Ex-53e) 2- (5- (N- ( 1-Iminoethyl) amino) -1-phthalimidopentyl) - 1, 3-dioxolane (1.73 g, 5 mmol) is dissolved in methanol and 0.5 g hydrazine monohydrate. The mixture is heated to reflux. After complete removal of the phthaloyl protecting group, cooling and filtering to remove the phthaloylhydrazide, the methanolic solution is then concentrated to dryness to give 2-(5-(N-(l- Iminoethyl) amino) -1-aminopentyl) -1 , 3-dioxolane .
Ex-53f) 2- (5- (N- (1-Iminoethyl) amino) -1-aminopentyl) -1,3- dioxolane (0.86 g, 4 mmol) is allowed to stir with t- butoxycarbonylazide (0.64 g, 4.5 mmol) and MgO (0.20 g, 4.E mmol) in dioxane/water solution. Upon completion, the magnesium salts are removed by filtration. The resulting material is passed through a reverse phase chromatographic column giving 2- (5- (N- (1-Iminoethyl) amino) -1- (N-Boc- amino) pentyl) -1 , 3-dioxolane .
Ex-53g) 2- (5- (N- (1-Iminoethyl) amino) -1- (N-Boc- amino) pentyl ) -1, 3-dioxolane is treated with 30 mL of water with 5 mL of phosphoric acid added and allowed to stir until the acetal is cleaved. The solution is then adjusted to pH = 7.5 and poured onto a Dowex 50 Cation exchange column. The column is washed with water. The product is then eluted with 10% aqueous pyridine and taken to dryness to give to give 6- (N- (1-Iminoethyl) amino) -2- (N-Boc- aminohexanal .
Ex-53h) 6- (N- (1-Iminoethyl) amino) -2- (N-Boc-aminohexanal
(0.95 g, 3.5 mmol) is added to 50 mL of cyclohexane in 100 mL reaction flask. After adding 1.33 g (7 mmol) of p- toluenesulfonic acid and 0.26 g (3.5 mmol) butylamine, the reaction mixture is refluxed with azeotropic distillation complete removal of water using a Dean-Stark trap. After cooling, the solvent is removed in vacuo to give an essentially quantitative yield of 6- (N-butylimino) -N- (1- iminoethyl) -2- (N-Boc-aminohexanamine di-para- toluenesulfonate .
Ex-53i) 6- (N-Butylimino) -N- (1-iminoethyl) -2- (N-Boc- aminohexanamine di-para-toluenesulfonate (1.14 g, 3.5 mmol) is dissolved in 10 mL dimethylformamide and treated with (0.54 g, 4 mmol) of N-chlorosuccinimide . The reaction is stirred until complete. 40 mL of tolune was added to precipitate the succinimide which is removed. The toluene solvent is removed in vacuo, and the DMF solution is used in the next step without isolation of resulting 6-(N- butylimino) -6-chloro-N- (1-iminoethyl) -2- (N-Boc- aminohexanamine di-para-toluenesulfonate .
Ex-53j) 6- (N-butylimino) -6-chloro-N- (1-iminoethyl) -2- (N- Boc-aminohexanamine di-para-toluenesulfonate (3.5 mmol) solution is added to 50 mL of anhydrous methanol in 100 mL reaction flask. After the reaction mixture is stirred, the solvent and methanol are removed in vacuo to give 6- (N- butylimino) -6-methoxy-N- (1-iminoethyl) -2- (N-Boc- aminohexanamine di-para-toluenesulfonate .
6- (N-butylimino) -6-methoxy-N- (1-iminoethyl) -2- (N-Boc- aminohexanamine di-para-toluenesulfonate is deprotected by allowing it to stand in 2N HCl in methyl acetate at 25°C for two hours. Concentrating in vacuo affords 6-(N- butylimino) -6-methoxy-N- (1-iminoethyl) -1 , 2-hexanediamine di-para-toluenesulfonate hydrochloride .
Biological Data
The subject compounds of formula I and II 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 is measured by monitoring the conversion of L- [2, 3-^H] -arginine to L- [2 , 3-3H] -citrulline . Mouse inducible NOS (miNOS) is prepared from an extract of LPS- treated mouse RAW 264.7 cells and rat brain constitutive NOS (rnNOS) is prepared from an extract of rat cerebellum. Both preparations are partially purified by DEAE-Sepharose chromatography. Enzyme (10 m L) is added to 40 m L of 50 mM Tris (pH 7.6) and the reaction initiated by the addition of 50 m L 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 m
M FAD, 100 &M tetrahydrobiopterin, 2.0 mM NADPH and 60 m M
L-arginine containing 0.9 m Ci of L- [2 , 3- H] -arginine. For constitutive NOS, calmodulin was included at a final concentration of 40 nM. Following incubation at 37°C for 15 minutes, the reaction is terminated by addition of 300 m L cold buffer containing 10 mM EGTA, 100 mM HEPES (pH
5.5) and 1.0 mM L-citrulline . The [^H] -citrulline is 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 are plated to confluency on a 96-well tissue culture plate grown overnight (17h) in the presence of LPS to induce NOS. A row of 3-6 wells are left untreated and served as controls for subtraction of nonspecific background. The media is removed from each well and the cells are 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 Ih. The assay is initiated by warming the plate to 37%C in a water bath for lh. Production of nitrite by intracellular iNOS is linear with time. To terminate the cellular assay, the plate of cells is 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) . All values are the average of triplicate wells and are compared to a background-subtracted induced set of cells (100% value) .
In Vivo Assay
Rats are treated with an intraperitoneal injection of lOmg/kg of endotoxin (LPS) with or without oral administration of the nitric oxide synthase inhibitors . Plasma nitrites are measured 5 hours post-treatment. The results 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 be 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 or II
Figure imgf000213_0001
II
and pharmaceutically acceptable salts thereof, wherein;
22
J is selected from the group consisting of O, NR and S;
29 29
J can be R , wherein R is a group selected from
28 28 28 28 24 28 24 OR O, OR S, SR S, OR NR and SR NR provided that A
26 is R
J1 and J2 are independently selected from the group
23 23 24 24 25 consisting of OR , SR NHR and N(R )R provided
26 that A is R
G is selected from the group consisting of 0, S, CH2 ,
15 15 15
CHR , C ( R ) 2 , NH and NR ; A is selected from the group consisting of O, N(R ), S and heterocyclyl with the proviso that J is selected from other than O, and A is selected from other than 0, S and
8 heterocyclyl unless R is other than hydrogen,
7 hydroxyalkyl, alkoxyalkyl, alkyl and haloalkyl, or R is selected from other than aryl, heteroaryl, aralkyl, heteroaralkyl, H, alkyl, alkenyl, CH2OC (=0) GR15 , hydroxyalkyl, polyhydroxyalkyl , amino, hydroxy, (poly) acyloxyalkyl and carboxyalkyl wherein G is independently selected from the group consisting from O, S,
CH2, CHR15, C(R15)2, NH, and NR15 and R15 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl and heteroaryl,
7 with the proviso that when A is H, R is not present.
A can be selected from the group consisting of 0,
N(R ) and S connected to the point of attachment of R by a spacer selected from a group consisting of a covalent bond and a linear moiety having a chain length of 1 to 3 atoms to form C7 to CIO heterocyclyl with the proviso that when J
1 . is selected from O and A is selected from O and S, R is selected from other than H, S(0)R13, SO2R13 , CH2θC(0)R15 and C(0)R15 wherein C(0)R15 can represent natural and synthetic amino acids and wherein R15 is selected from substituted dihydropyridyl, alkyl, alkylthio, alkoxy, amino
2 and cycloalkoxy, R is selected from other than H, alkanoyl
8 and aroyl, or R is selected from other than hydrogen, hydroxyalkyl, alkoxyalkyl, alkyl and haloalkyl;
A can be selected from the group selected from 0,
5 . 4
N(R ) and S connected to the point of attachment of R by a spacer group selected from a group consisting of a covalent bond and a linear moiety having a chain length of 1 to 4 atoms to form C6 to CIO heterocyclyl provided that the linear moiety is selected from other than 0 and S;
A can be selected from the group selected from 0,
N(R ) and S connected to the point of attachment of any one
1 2 of R and R by a spacer group selected from a linear moiety having a chain length of 1 to 6 atoms to form C5 to
5 1 CIO heterocyclyl provided that, when A is N(R ), R is selected from other than H, S(0)R13, SO2R13 , CH2θC(0)R15 and C(0)R15 wherein C(0)R15 may represent natural and synthetic amino acids and wherein R^5 is selected from substituted dihydropyridyl, alkyl, alkylthio, alkoxy, amino
2 and cycloalkoxy, or R is selected from other than H,
8 alkanoyl and aroyl or R is selected from other than hydrogen, hydroxyalkyl, alkoxyalkyl, alkyl and haloalkyl;
A can be selected from the group consisting of 0,
5 1
N(R ) and S connected to the points of attachment of R and
2 R by a spacer group selected from a linear moiety having a chain length of 1 to 6 to form C5 to CIO heterocyclyl;
A can be selected from the group consisting of 0,
5 N(R ) and S connected to X through substituent selected from hydroxyl, sulfhydryl, amino, carboxyl, and carbonyl substituents of group X by a spacer selected from a covalent bond and a linear moiety having a chain length of 1 to 4 atoms to form C5 to CIO heterocyclyl;
26 . 26 8
A can be R with the proviso that when R is H, R is
1 selected from other than hydrogen, or R is selected from other than H, S(0)R13, SO2R13 , CH2θC(0)R15 and C(0)R15 wherein C(0)R15 can represent natural and synthetic amino acids and wherein R15 is selected from substituted
2 dihydropyridyl, alkyl, alkylthio and alkoxy, or R is selected from other than H, alkanoyl and aroyl, or J is selected from other than 0;
27 . 27 .
A can be R , wherein R is selected from the group
5 7 5 7 25 5 13 consisting of N(R ) OR , N(R )N(R )R , N(R ) SO2R ,
5 15 5 15 19 20 5 19 20 N(R )C(0)R , N(R )C(S)R , R (R )C=N-N(R ), R (R ) C=N-
5 13 6 0, natural and synthetic ammo acids, N(R )P(0) (OR ) ]_R and
N(R )P(0) (OR )2;
1 2 R and R are independently selected from the group
6 6 consisting of hydrogen, hydroxyl, sulfhydryl, OR , SR , cyanoalkyl, dicyanoalkyl, carboxamidoalkyl, dicarboxamidoalkyl , cyanocarboalkoxyalkyl , carboalkoxyalkyl, dicarboalkoxyalkyl, cyanocycloalkyl, dicyanocycloalkyl , carboxamidocycloalkyl , dicarboxamidocycloalkyl, carboalkoxycyanocycloalkyl, carboalkoxycycloalkyl , dicarboalkoxycycloalkyl ,
- + - -2 formylalkyl, acylalkyl, CH2SO3 M , CH2CH2SO3 M+ , CH2PO3
2M+, CH2CH2PO3" 2M+, CH(OR ) CF3 , S(0)R , S02R ,
, 30 31 , 30v 31 15 15 15
P(0)R R , P(O) (R )2R , C(0)R , C(S)R , CH20C(0)R ,
19 , 15 19 , 15 15 15 CH2NR C(0)R , CH2NR C(S)R , CH2SC(0)R , CH2SC(S)R ,
15 19 , v 15 19 , 15 CH2OC(0)GR , CH2NR C(0)GR , CH2NR C(S)GR , , , 15 15 13 13 15
CH2OC(S)GR , CH2SC(S)GR , OS02R , OS(0)R , OC(S)R ,
15 15 15 15 15
SC(S)R , OC(S)GR , SC(S)GR , OC(0)R , SC(0)R ,
15 15 19 20 1
OC(0)GR , SC(0)GR and R (R ) CH provided that R is selected from other than H, S(0)R13, SO2R13 , CH2θC(0)-R15 and C(0)R15 wherein C(0)R15 can represent natural and synthetic amino acids and wherein R15 is selected from substituted dihydropyridyl, alkyl, alkylthio, alkoxy, amino
22 29 and cycloalkoxy, unless J is selected from NR , R and S,
2 (s
R is selected from other than H, alkanoyl and aroyl, R is
27 8 . present, A is R , or R is selected from other than hydrogen, hydroxyalkyl, alkoxyalkyl, alkyl and haloalkyl or
2 provided that R is selected from other than H, alkanoyl
1 and aroyl, unless R is selected from other than H,
S(0)R13, SO2R13, CH20C(0)R15 and C(0)R15 wherein C(0)R15 can represent natural and synthetic amino acids wherein R15 is selected from substituted dihydropyridyl, alkyl, alkylthio, alkoxy, amino and cycloalkoxy, J is selected
22 29 26 . . 27 8 . from NR , R and S, R is present, A is R , or R is selected from other than hydrogen, hydroxyalkyl, alkoxyalkyl, alkyl or haloalkyl ,-
1 2 R and R can be taken together forming a group
19 "? 0 selected from a group consisting of R (R )C=,
30 31 . .
D(C(R ) (R ) ) ZD wherein z is 2 to 5 and D is selected from
the group consisting of oxygen, C=0, C=S, S(0)m wherein m
31 30 30 30 19 20 is 0 to 2, OP(OR )R , P(0)R , P(S)R and Si (R )R
19 20 19 20 , D((R )R C)eW(C(R )R )kD wherein e is 1 to 2, k is 1 to 2, with the proviso that only one D can be oxygen or sulfur at any time, and W is selected from the group consisting of oxygen, C=0, C=S, S(0)m, Se(0)m wherein m is 0 to 2,
30 30 19 19 20
P(0)R , P(S)R , N(R ), and Sι(R )R , cycloalkyl radicals, cycloalkenyl radicals wherein said cycloalkyl radicals and cycloalkenyl radicals may be optionally
30 31 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- substitutents are independently selected from the group
19 32 consisting of C=0, C=S, C(R )R , S(O), S(0)2,
31 30 , ( 30 30 19 20
OP(OR )R , P(0)R , P(S)R , and Si (R )R , cιs-1,2- disubstituted alkanes and cis-1,2- disubstituted alkenes wherein said 1, 2-substitutents are independently selected
19 32 31 30 from C=0, C=S, C(R )R , S(O), S(0)2, OP(OR )R ,
30 30 19 20
P(0)R , P(S)R , and Sι(R )R and said alkyl and alkenyl
30 31 may be optionally substituted with one or more R or R substituents ;
3 4 R and R are independently selected from the group
6 6 consisting of hydrogen, hydroxyl, sulfhydryl, OR , SR ,
+ - _2 + _2 +
CH2S03 M , CH2CH2S03 M+ , CH2Pθ3 2M , CH2CH2P03 2M ,
6 13 13 30 31 30 31
CH(OR )CF3, S(0)R , S02R , P(0)R R , P(0)(R ) 2R ,
15 15 15 19 15
C(0)R , C(S)R , CH2OC(0)R , CH NR C(0)R ,
19 , 15 15 15 15 CH2NR C(S)R , CH2SC(0)R , CH2SC(S)R , CH2OC(0)GR ,
19 15 19 15 15
CH2NR C(0)GR , CH2NR C(S)GR , CH2OC(S)GR ,
-i [- 1 *2 1 *3 1 CT 1 r
CH2SC(S)GR , OS02R , OS(0)R , OC(S)R , SC(S)R , OC ( S ) GR , SC ( S ) GR , 0C ( 0 ) R , SC ( 0 ) R1 5 , OC ( 0 ) GR 5 and
15 3 4
SC(0)GR with the proviso that R and R are selected from other than H, OH, SH, OR6, SR6 , OC(=0)R15, SC(=0)R15, CH20C(=0)GR15, OC(=0)GR15, SC(=0)GR15, OS02R13 and OS(0)R13 wherein R6, R13 and R15 are independently selected from the group selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl and heteroaryl unless J is
22 29 1 2 selected from NR , R and S, R and R are taken together,
26 . . 27 8 .
R is present, A is R , or R is selected from other than hydrogen, hydroxyalkyl, alkoxyalkyl, alkyl and haloalkyl;
5 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 , formylalkyl, acylalkyl, heteroaryl polyhydroxyalkyl,
13 13 30 31 polyacycloalkyl, carboalkoxy, S(0)R , SO2R , P(0)R R *2 "1 •] c 1 1 t
P(O) (R )2R , C(0)R , C(S)R , CH2OC(0)R ,
19 , , 15 19 , 15 15 15
CH2NR C(0)R , CH2NR C(S)R , CH2SC(0)R , CH2SC(S)R ,
, , 15 19 , , 15 19 15 CH2OC(0)GR , CH2NR C(0)GR , CH2NR C(S)GR ,
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;
with the proviso that R is selected from other than the group consisting of hydrogen, alkyl, alkenyl, aryl, heteroaryl, aralkyl, heteroaralkyl, hydroxyalkyl, polyhydroxyalkyl , amino, hydroxy, polyacyloxyalkyl,
15 carboalkoxy and CH2OC(0)GR wherein G is independently selected from O, S, CH2 , CHR15, C(R15)2, NH, and NR15 and wherein R 5 is selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl and heteroaryl
22 29 1 2 unless J is selected from NR , R and S, R and R are
26 27 8 taken together, R is present, A is R , or R is selected from other than hydrogen, hydroxyalkyl, alkoxyalkyl, alkyl and haloalkyl;
5 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 C5 to C8 heterocyclyl;
R can be 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 the group consisting of 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, loweralkylamino, 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 with the proviso that that Q 5 1
R is selected from other than H when A is N(R ) unless R
2 and R are taken together;
6 R is selected from the group selected from hydrogen, heterocyclic, heteroaryl, hydroxyalkyl, minoalkyl, 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, natural and synthetic amino acids and polyhydroxy compounds of carbon with the proviso that R6 is selected from other than hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl and heteroaryl unless J is
22 29 26 selected from the group consisting of NR , R and S, R
27 1 2 8 is present, A is R , R and R are taken together, or R is selected from other than hydrogen, hydroxyalkyl, alkoxyalkyl, alkyl and haloalkyl;
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 formylalkyl, acylalkyl, S(0)R , S02R , P(0)R R ,
30 31 , 15 , % 15 15
P(O) (R )2R , C(0)R , C(S)R , CH2OC(0)R ,
19 15 19 15 15 15
CH2NR C(0)R , CH2NR C(S)R , CH2SC(0)R , CH2SC(S)R ,
15 19 , , 15 19 15 CH2OC(0)GR , CH2NR C(0)GR , CH2NR C(S)GR ,
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
7 sulfonylalkylamino with the proviso that R is selected from other than the group consisting of hydrogen, alkyl, alkenyl, aryl, heteroaryl, aralkyl, heteroaralkyl, hydroxyalkyl, polyhydroxyalkyl, amino, hydroxy,
15 polyacyloxyalkyl, carboalkoxy and CH20C(0)GR wherein G is selected from the group consisting of O, S, CH2 , CHR15, C(R15)2/ NH, and NR15 and wherein R15 is selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl and heteroaryl unless J is selected
22 29 26 . 27 1 . 2 from NR , R and S, R is present, A is R , R and R
8 are taken together, or R is selected from other than hydrogen, hydroxyalkyl, alkoxyalkyl, alkyl and haloalkyl; or
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 C5 to C8 heterocyclyl;
7 R can be a heterocyclyl radical m 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 with the proviso that A is selected from other than 0 and S unless J is selected from
22 29 NR , R and S or J1 and J2 are selected from two groups
23 23 24 independently selected from OR , SR NHR and
, 24, 25 1 . 2 η . . 26
N(R )R , R and R are taken together when A is R , or
8 . provided that R is selected from other than H when A is
N(R ) ;
8 R is selected from hydrogen, hydroxyalkyl, haloalkyl, alkyl, alkoxyalkyl, aminoalkyl, alkylaminoalkyl , alkylthioalkyl, cyanoalkyl, sulfhydrylalkyl, formyl, C(0)A- 7 7 7 19 7 19
R , C(S)A-R , CH2OC(0)A-R , CH2NR C(O) A-R , CH2NR C(S)A-
R , CH SC(0)A-R , CH2SC(S)A-R , CH2OC(0)GR1 ,
19 , , 15 19 15 15 15
CH2NR C(0)GR , CH2NR C(S)GR , CH2OC(S)GR , CH2SC(S)GR g and acyl with the proviso that R is selected from other than hydrogen, hydroxyalkyl, haloalkyl, alkyl, alkoxyalkyl unless Jι and. J2 are selected-, f ,rom NR22 , R29 and S, R26 i.s
1 2 27 present, R and R are taken together, or A is R
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, natural and synthetic amino acids and polyhydroxy compounds 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 , icarboalkoxycycloalkyl, formylalkyl, acylalkyl, dialkoxyphosphonoalkyl , diaralkoxyphosphonoalkyl , phosphonoalkyl , dialkoxyphosphonoalkoxy, diaralkoxyphosphonoalkoxy, phosphonoalkoxy, dialkoxyphosphonoalkylamino , diaralkoxyphosphonoalkylamino, phosphonoalkylamino, dialkoxyphosphonoalkyl, diaralkoxyphosphonoalkyl , sulfonylalkyl , alkoxysulfonylalkyl , aralkoxysulfonylalkyl , alkoxysulfonylalkoxy, aralkoxysulfonylalkoxy, sulfonylalkoxy, alkoxysulfonylalkylamino, aralkoxysulfonylalkylamino, sulfonylalkylamino, natural and synthetic amino acids and polyhydroxy compounds of carbon;
+ M is a pharmaceutically acceptable cation; X is selected from the group consisting of alkylene, alkenylene, and alkynylene groups which may be optionally substituted from the group consisting of alkyl, alkoxy, hydroxy, sulfhydryl, halogen, trifluoromethyl , nitro, cyano and amino; or
X can be - (CH2 )pQ (CH2 ) r~ wherein p is 1 to 3 , r is 1 to
3 and Q is selected from oxygen, C=0, S(0)t- Se(0)t wherein
21 21 t is 0 to 2 , P(0)R wherein R is hydroxyl or alkyl which may be optionally substituted with one of the group consisting of alkyl, alkoxy, hydroxy, halogen,
12 trifluoromethyl, nitro, cyano, amino, carboxy, and N(R )n
12 wherein n is 1 to 2 and R is selected from the group consisting of hydrogen, oxy, hydroxyl and alkyl which may be optionally substituted from the group consisting of alkyl, alkoxy, hydroxy, halogen, trifluoromethyl , nitro, cyano and amino ;
X can be - (CH2 ) ST (CH2 ) v _ wherein s is 0 to 2 , v is 0 to
2 and T is selected from a 3 to 6 membered carbocyclic radical, aryl radical and a heterocyclyl radical wherein all said radicals may be optionally substituted with alkyl, alkoxy, hydroxy, halogen, trifluoromethyl , nitro, cyano and amino ,-
Y is selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxyalkyl, cycloalkyl, cycloalkenyl, cycloalkenyloxy, alkenyloxyalkyl, alkylthioalkyl,
9 10 9 10 alkylam oalkyl 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 C3 to C8 heterocyclyl;
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 with
19 20 the proviso that only one of R and R is hydrogen;
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 to form a group consisting of C3 to C8 cycloalkyl, C3 to C8 cycloalkenyl and C3 to C8 heterocyclyl;
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 together to form a spacer group independently selected from a linear moiety having a chain length of 4 to 7 atoms to form C5 to C8 heterocyclyl;
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 with the proviso that J is selected from other
8 . than 0 unless R is other than hydrogen;
28 R is independently selected from a group consisting
23 23 23 of CH(R )CH2, CH(R )CH2CH2/ CH2CH(R ) CH2 , cycloalkylene and heterocyclylene;
30 31 R and R are independently selected from the group consisting of 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, natural and synthetic amino acids, and polyhydroxy compounds of carbon;
30 31 R and R can be taken together to form a linear moiety spacer group having a chain length of 2 to 7 atoms selected from the group consisting of C3 to C8 cycloalkyl, C3 to C8 cycloalkenyl, and C3 to C8 heterocyclyl substituted independently and optionally with one or more alkyl, haloalkyl, aryl, heteroaryl, alkoxyalkyl, alkoxy, haloalkoxy, cyano, carboalkoxy, hydroxy, hydroxyalkyl, and halo groups .
2. A compound having the Formula:
Figure imgf000233_0001
and pharmaceutically acceptable salts thereof, wherein;
1 2 R and R are independently selected from the group
consisting of hydroxyl, sulfhydryl, OR , SR , cyanoalkyl, dicyanoalkyl, carboxamidoalkyl, dicarboxamidoalkyl, cyanocarboalkoxyalkyl , carboalkoxyalkyl , dicarboalkoxyalkyl, cyanocycloalkyl, dicyanocycloalkyl, carboxamidocycloalkyl , dicarboxamidocycloalkyl , carboalkoxycyanocycloalkyl, carboalkoxycycloalkyl, dicarboalkoxycycloalkyl, formylalkyl, acylalkyl, CH2SO3 M ,
-2 + _2 + 6
CH2CH2SO3 M+, CH2P03 2M , CH2CH2P03 2M , CH(OR ) CF3 ,
30 31 , , 30v 31 , , 15 15
P(0)R R , P(O) (R )2R , C(S)R , CH2SC(0)R ,
15 15 15 15
CH2SC(S)R , CH2OC(0)GR , CH2OC(S)GR , CH2SC(S)GR ,
13 13 15 15 15 15 OS02R , OS(0)R , 0C(S)R , SC(S)R , OC(S)GR , SC(S)GR ,
15 15 15 15 19 20
OC(0)R , SC(0)R , OC(0)GR , SC(0)GR and R (R ) CH
6 wherein R is selected from the group consisting of hydroxyalkyl, aminoalkyl, heteroaryloxyalkyl, aralkyl, aryloxyalkyl, aralkoxyalkyl, alkylsulfinylalkyl , alkylsulfonylalkyl, aralkylthioalkyl , heteroaralkoxythioalkyl, alkoxyalkyl, heteroaryloxyalkyl, alkenyloxyalkyl, alkylthioalkyl, arylthioalkyl, 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, natural and synthetic amino acids and
13 polyhydroxy compounds of carbon, R is selected from the group consisting of 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, natural and synthetic amino acids and polyhydroxy compounds of carbon,
15 R is selected from the group consisting of 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 , icarboalkoxycycloalkyl, formylalkyl, acylalkyl, dialkoxyphosphonoalkyl, diaralkoxyphosphonoalkyl, phosphonoalkyl , dialkoxyphosphonoalkoxy, diaralkoxyphosphonoalkoxy, phosphonoalkoxy, dialkoxyphosphonoalkylamino , diaralkoxyphosphonoalkylamino, phosphonoalkylamino , dialkoxyphosphonoalkyl , diaralkoxyphosphonoalkyl, sulfonylalkyl, alkoxysulfonylalkyl , aralkoxysulfonylalkyl , alkoxysulfonylalkoxy, aralkoxysulfonylalkoxy, sulfonylalkoxy, alkoxysulfonylalkylamino, aralkoxysulfonylalkylamino, sulfonylalkylamino, natural and synthetic amino acids and polyhydroxy compounds of carbon, 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 with r- 19 20 . 30 the proviso that only one of R and R is hydrogen, R
31 and R are independently selected from the group consisting of 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, natural and synthetic amino acids, and polyhydroxy compounds of carbon,
30 31 wherein R and R can be taken together to form a linear moiety spacer group having a chain length of 2 to 7 atoms selected from the group consisting of C3 to C8 cycloalkyl, C3 to C8 cycloalkenyl, and C3 to C8 heterocyclyl substituted independently and optionally with one or more alkyl, haloalkyl, aryl, heteroaryl, alkoxyalkyl, alkoxy, haloalkoxy, cyano, carboalkoxy, hydroxy, hydroxyalkyl, and halo groups, M is a pharmaceutically acceptable cation; and G is selected from the group
15 15 15 , . consisting of 0, S, CH , CHR , C(R ) 2 , NH and NR wherein
R15 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl and heteroaryl 3 4 R and R are independently selected from the group
- + - -2 + consisting of CH2Sθ3 M , CH2CH2S03 M+ , CH2PO3 2M ,
-2 „ + , 6( , 4 13 13 30 31 CH2CH2Pθ3 2M , CH(OR ) CF3 , S(0)R , SO2R , P(0)R R ,
30 31 15 15 15
P(O) (R )2R , C(0)R , C(S)R , CH2OC(0)R ,
19 15 19 , v 15 15 15 CH2NR C(0)R , CH2NR C(S)R , CH2SC(0)R , CH2SC(S)R ,
19 15 19 , , 15 , , 15 CH2NR C(0)GR , CH2NR C(S)GR , CH20C(S)GR ,
15 15 , 15 15 15
CH2SC(S)GR , OC(S)R , SC(S)R , OC(S)GR , SC(S)GR ;
7 R is selected from the group consisting of alkynyl, cyanoalkyl, dicyanoalkyl, carboxamidoalkyl, dicarboxamidoalkyl, cyanocarboalkoxyalkyl, carboalkoxyalkyl, dicarboalkoxyalkyl, cyanocycloalkyl, dicyanocycloalkyl , carboxamidocycloalkyl , dicarboxamidocycloalkyl , carboalkoxycyanocycloalkyl , carboalkoxycycloalkyl , dicarboalkoxycycloalkyl ,
13 13 30 31 formylalkyl, acylalkyl, S(0)R , S02R , P(0)R R ,
30 31 15 15 15
P(O) (R )2R , C(0)R , C(S)R , CH2OC(0)R ,
19 15 19 15 15 15
CH2NR C(0)R , CH2NR C(S)R , CH2SC(0)R , CH2SC(S)R ,
19 15 19 , 15 15
CH2NR C(0)GR , CH2NR C(S)GR , CH2OC(S)GR ,
15 CH2SC(S)GR , heteroaryloxyalkyl, 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 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 with the proviso that A is selected from other than O and S or provided that R is
5 selected from other than H when A is N(R );
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 C5 to C8 heterocyclyl;
8 R is selected from the group consisting of aminoalkyl, alkylaminoalkyl, alkylthioalkyl, cyanoalkyl,
7 7 7 sulfhydrylalkyl, formyl, C(0)A-R , C(S)A-R , CH2OC(0)A-R ,
19 7 19 7 7 CH2NR C(0)A-R , CH2NR C(S)A-R , CH2SC(0)A-R , CH2SC(S)A-
7 15 19 15 19 15
R , CH2OC(0)GR , CH2NR C(0)GR , CH NR C(S)GR ,
15 15
CH2OC(S)GR , CH2SC(S)GR and acyl;
X is selected from the group consisting of alkylene, alkenylene, and alkynylene groups which may be optionally substituted from the group consisting of alkyl, alkoxy, hydroxy, sulfhydryl, halogen, trifluoromethyl , nitro, cyano and amino ; X can be - (CH ) pQ (CH2 ) r- wherein p is 1 to 3 , r is 1 to
3 and Q is selected from oxygen, C=0, S(0)t/ Se(0)t wherein
21 , 21 . t is 0 to 2 , P(0)R wherein R is hydroxyl or alkyl which may be optionally substituted with one of the group consisting of alkyl, alkoxy, hydroxy, halogen,
12 trifluoromethyl, nitro, cyano, amino, carboxy, and N(R )n
12 . wherein n is 1 to 2 and R is selected from the group consisting of hydrogen, oxy, hydroxyl and alkyl which may be optionally substituted from the group consisting of alkyl, alkoxy, hydroxy, halogen, trifluoromethyl, nitro, cyano and amino ;
X can be - (CH2 ) ST (CH2 ) v _ wherein s is O to 2 , v is 0 to
2 and T is selected from a 3 to 6 membered carbocyclic radical, aryl radical and a heterocyclyl radical where all said radicals may be optionally substituted with alkyl, alkoxy, hydroxy, halogen, trifluoromethyl, nitro, cyano and amino ;
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 C3 to C8 heterocyclyl; 5 A is selected from the group consisting of O, N(R ), S and heterocyclyl with the proviso that J is selected from
5 other than 0, wherein R is selected from the group consisting of alkynyl, cyanoalkyl, dicyanoalkyl, carboxamidoalkyl , dicarboxamidoalkyl , cyanocarboalkoxyalkyl , carboalkoxyalkyl , dicarboalkoxyalkyl, cyanocycloalkyl, dicyanocycloalkyl, carboxamidocycloalkyl , dicarboxamidocycloalkyl , carboalkoxycyanocycloalkyl , carboalkoxycycloalkyl ,
13 dicarboalkoxycycloalkyl, formylalkyl, acylalkyl, S(0)R
13 30 31 30 31 15 15 S02R , P(0)R R , P(O) (R ) 2R , C(0)R , C(S)R ,
15 19 , , 15 19 15 15
CH2OC(0)R , CH2NR C(0)R , CH2NR C(S)R , CH2SC(0)R ,
15 19 15 19 15 15
CH2SC(S)R , CH2NR C(0)GR , CH2NR C(S)GR , CH2OC(S)GR ,
15 CH2SC(S)GR , heteroaryloxyalkyl, 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;
A can be selected from the group consisting of 0,
5 N(R ) and S connected to X through substituent selected from hydroxyl, sulfhydryl and substituents of group X by a spacer selected from a covalent bond and a linear moiety having a chain length of 1 to 4 atoms to form C5 to CIO heterocyclyl ;
27 27 A can be R , wherein R is selected from the group
, 5^ 7 5 7 25 5 13 consisting of N(R ) OR , N(R )N(R )R , N(R ) SO2R ,
5 15 , 5, , 15 19 20 5 19 20 N(R )C(0)R , N(R )C(S)R , R (R )C=N-N(R ), R (R ) C=N-
0, natural and synthetic amino acids, N(R )P(0) (OR ) ]_R and
5 13 25
N(R )P(0) (OR )2 wherein R is 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 ;
1 2 R and R can be taken together to form a group independently selected from a group consisting of
19 20 30 31
R (R ) C=, D(C (R ) (R ) ) ZD where z is 2 to 5 and D is selected from the group consisting of oxygen, C=0, C=S,
31 30 30 30 S(0)m where m is 0 to 2, OP(OR )R , P(0)R , P(S)R and
19 20 19 20 19 20 Si(R )R , D((R . )R C)eW(C(R )R ) j^D where e is 1 to 2, k is 1 to 2, with the proviso that only one D can be oxygen or sulfur at any time, and W is selected from the group consisting of oxygen, C=0, C=S, S(0)m, Se(0)m where m
30 30 19 19 20 is 0 to 2, P(0)R , P(S)R , N(R ), and Si (R )R ;
5 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 C5 to C8 heterocyclyl;
22
J is selected from the group consisting of 0, NR
22 and S wherein 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 arylsulfinylalkyl , arylsulfonylalkyl, cycloalkylsulfinylalkyl , cycloalkylsufonylalkyl , heteroarylsulfonylalkyl , heteroarylsulfinylalkyl , aralkylsulfinylalkyl and aralkylsulfonylalkyl ; , heteroarylthioalkyl , heteroaralkylthioalkyl ,
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 to form a group consisting of C3 to C8 cycloalkyl, C3 to C8 cycloalkenyl and C3 to C8 heterocyclyl.
3. The compound and pharmaceutically acceptable salts as recited in Claim 2 wherein:
1 2 R and R are independently selected from the group
consisting of hydroxyl, sulfhydryl, OR , SR , CH2Sθ3~ M+,
-2 n + _2 + 30 31
CH CH2S03 M+, CH2Pθ3 2M , CH2CH2Pθ3 2M , P(0)R R ,
30 31 % 15 15 15
P{0) (R )2R / C(S)R , CH2SC(0)R , CH2SC(S)R ,
15 15 15 13 13 CH2OC(0)GR , CH20C(S)GR , CH2SC(S)GR , OS0 R , OS(0)R ,
15 15 15 15 15
OC(S)R , SC(S)R , OC(S)GR , SC(S)GR , OC(0)R ,
15 15 15 6
SC(0)R , OC(0)GR ,and SC(0)GR , wherein R is selected from the group consisting of hydroxyalkyl, aminoalkyl, heteroaryloxyalkyl, aralkyl, aryloxyalkyl, aralkoxyalkyl, alkylsulfinylalkyl , alkylsulfonylalkyl, aralkylthioalkyl , heteroaralkoxythioalkyl, alkoxyalkyl, heteroaryloxyalkyl, alkenyloxyalkyl, alkylthioalkyl, arylthioalkyl, 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, natural and synthetic amino acids and
13 polyhydroxy compounds of carbon, R is selected from the group consisting of 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, natural and synthetic amino acids and polyhydroxy compounds of carbon,
15 . R is selected from the group consisting of 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 , icarboalkoxycycloalkyl, formylalkyl, acylalkyl, dialkoxyphosphonoalkyl , diaralkoxyphosphonoalkyl , phosphonoalkyl , dialkoxyphosphonoalkoxy, diaralkoxyphosphonoalkoxy, phosphonoalkoxy, dialkoxyphosphonoalkylamino , diaralkoxyphosphonoalkylamino , phosphonoalkylamino, dialkoxyphosphonoalkyl, diaralkoxyphosphonoalkyl , sulfonylalkyl , alkoxysulfonylalkyl , aralkoxysulfonylalkyl , alkoxysulfonylalkoxy, aralkoxysulfonylalkoxy, sulfonylalkoxy, alkoxysulfonylalkylamino, aralkoxysulfonylalkylamino, sulfonylalkylamino, natural and synthetic amino acids and polyhydroxy compounds of carbon ;
30 31 R and R are independently selected from the group consisting of 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, natural and synthetic amino acids, and polyhydroxy compounds of carbon,
30 31 wherein R and R can be taken together to form a linear moiety spacer group having a chain length of 2 to 7 atoms selected from the group consisting of C3 to C8 cycloalkyl, C3 to C8 cycloalkenyl, and C3 to C8 heterocyclyl substituted independently and optionally with one or more alkyl, haloalkyl, aryl, heteroaryl, alkoxyalkyl, alkoxy, haloalkoxy, cyano, carboalkoxy, hydroxy, hydroxyalkyl, and
+ halo groups, M is a pharmaceutically acceptable cation; and G is selected from the group consisting of 0, S, CH2 ,
15 15 15 CHR , C(R )2/ NH and NR wherein R15 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl and heteroaryl; 3 4 R and R are independently selected from the group
- + - -2 + consisting of CH2Sθ3 M , CH2CH2S03 M+ , CH2P03 2M ,
-2 „ + , 6, , , 13 13 30 31 CH2CH2P03 2M , CH(OR ) CF , S(0)R , S02R , P(0)R R ,
30 31 , , 15 , 15 , , 15 P(O) (R )2R , C(0)R , C(S)R , CH OC(0)R ,
19 15 19 15 15 15 CH2NR C(0)R , CH2NR C(S)R , CH2SC(0)R , CH2SC(S)R ,
19 15 19 , 15 15
CH2NR C(0)GR , CH2NR C(S)GR , CH20C(S)GR ,
CH2SC(S)GR , 0C(S)R , SC(S)R , OC(S)GR , SC(S)GR15;
7 R is selected from the group consisting of alkynyl, cyanoalkyl, dicyanoalkyl, carboxamidoalkyl, dicarboxamidoalkyl, cyanocarboalkoxyalkyl, carboalkoxyalkyl, dicarboalkoxyalkyl, cyanocycloalkyl, dicyanocycloalkyl , carboxamidocycloalkyl , dicarboxamidocycloalkyl , carboalkoxycyanocycloalkyl , carboalkoxycycloalkyl , dicarboalkoxycycloalkyl ,
13 13 30 31 formylalkyl, acylalkyl, S(0)R , S02R , P(0)R R ,
30 31 15 , 15 , 15 P(O) (R )2R , C(0)R , C(S)R , CH2OC(0)R ,
19 , 15 19 15 , 15 , , 15
CH2NR C(0)R , CH2NR C(S)R , CH2SC(0)R , CH2SC(S)R ,
19 , , 15 19 , 15 , 15 CH2NR C(0)GR , CH2NR C(S)GR , CH2OC(S)GR ,
15 CH2SC(S)GR , heteroaryloxyalkyl, 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
19 sulfonylalkylamino wherein R is 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 ;
7 R can be 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 with the proviso that A is
Q selected from other than 0 and S or provided that R is
selected from other than H when A is N(R ) ;
o
R is selected from the group consisting of aminoalkyl, alkylaminoalkyl, alkylthioalkyl, cyanoalkyl,
7 7 7 sulfhydrylalkyl, formyl, C(0)A-R , C(S)A-R , CH2OC(0)A-R ,
19 7 19 , , 7 7
CH NR C(0)A-R , CH2NR C(S)A-R , CH2SC(0)A-R , CH2SC(S)A-
7 , 15 19 , , 15 19 15
R , CH2OC(0)GR , CH2NR C(0)GR , CH2NR C(S)GR ,
15 15
CH2OC(S)GR , CH SC(S)GR and acyl;
Q R can be selected from the group consisting of hydrogen, hydroxyalkyl, haloalkyl, alkyl and alkoxyalkyl
22 with the proviso that J is NR or S;
X is selected from the group consisting of alkylene, alkenylene, and alkynylene groups which may be optionally substituted from the group consisting of alkyl, alkoxy, hydroxy, sulfhydryl, halogen, trifluoromethyl , nitro, cyano and amino ;
X can be - (CH2 ) pQ (CH2 ) r- wherein p is 1 to 3, r is 1 to
3 and Q is selected from oxygen, C=0, S(0)t/ Se(0)t wherein
21 21 . t is 0 to 2, P(0)R wherein R is hydroxyl or alkyl which may be optionally substituted with one of the group consisting of alkyl, alkoxy, hydroxy, halogen,
12 trifluoromethyl , nitro, cyano, amino, carboxy, and N(R )n
12 , wherein n is 1 to 2 and R is selected from the group consisting of hydrogen, oxy, hydroxyl and alkyl which may be optionally substituted from the group consisting of alkyl, alkoxy, hydroxy, halogen, trifluoromethyl, nitro, cyano and amino;
X can be - (CH2 ) ST (CH2 ) v- wherein s is O to 2 , v is 0 to
2 and T is selected from a 3 to 6 membered carbocyclic radical, aryl radical and a heterocyclyl radical where all said radicals may be optionally substituted with alkyl, alkoxy, hydroxy, halogen, trifluoromethyl, nitro, cyano and amino ;
Y is selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxyalkyl, cycloalkyl, cycloalkenyl, cycloalkenyloxy, alkenyloxyalkyl, alkylthioalkyl,
9 10 9 10 alkylammoalkyl 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 C3 to C8 heterocyclyl;
A is selected from the group consisting of O, N(R ) , S and heterocyclyl with the proviso that J is selected from
5 . other than 0, wherein R is selected from the group consisting of alkynyl, cyanoalkyl, dicyanoalkyl, carboxamidoalkyl , dicarboxamidoalkyl , cyanocarboalkoxyalkyl , carboalkoxyalkyl , dicarboalkoxyalkyl, cyanocycloalkyl, dicyanocycloalkyl, carboxamidocycloalkyl , dicarboxamidocycloalkyl , carboalkoxycyanocycloalkyl , carboalkoxycycloalkyl ,
13 dicarboalkoxycycloalkyl, formylalkyl, acylalkyl, S(0)R
13 30 31 , 30 31 15 , 15 S02R , P(0)R R , P(O) (R ) 2R , C(0)R , C(S)R , 15 19 15 19 , 15 15
CH2OC(0)R , CH2NR C(0)R , CH2NR C(S)R , CH2SC(0)R ,
15 19 , 15 19 , , 15 15
CH2SC(S)R , CH2NR C(0)GR , CH2NR C(S)GR , CH20C(S)GR ,
15 CH2SC(S)GR , heteroaryloxyalkyl, 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;
A can be selected from the group consisting of 0, N(R ) and S connected to X through substituent selected from hydroxyl, sulfhydryl and substituents of group X by a spacer selected from a covalent bond and a linear moiety having a chain length of 1 to 4 atoms to form C5 to CIO heterocyclyl ;
27 27 A can be R , wherein R is selected from the group
consisting of N(R ) OR , N(R )N(R )R , N(R ) S02R ,
5 15 5 15 19 20 5 19 20 N(R )C(0)R , N(R )C(S)R , R (R )C=N-N(R ), R (R ) C=N-
5 13 6 0, natural and synthetic ammo acids, N(R )P(0) (OR ) ]_R and
5 13 25
N(R )P(0) (OR )2 wherein R is 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
20 aralkylsulfonylalkyl and R is 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;
1 2 R and R can be taken together to form a group independently selected from a group consisting of
19 20 30 31
R (R )C=, D(C(R ) (R ))ZD where z is 2 to 5 and D is
selected from the group consisting of oxygen, C=0, C=S,
31 30 30 30 S(0)m where m is 0 to 2, OP(OR )R , P(0)R , P(S)R and
19 20 , 19, 20 , , 19 20 Sι(R )R , D((R )R C)eW(C(R )R ) ^D where e is 1 to 2, k is 1 to 2 , with the proviso that only one D can be oxygen or sulfur at any time, and W is selected from the group consisting of oxygen, C=0, C=S, S(0)m, Se(0)m where m
30 30 19 19 20 is 0 to 2, P(0)R , P(S)R , N(R ), and Si(R )R ;
22 J is selected from the group consisting of O, NR ,
22 and S wherein 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 arylsulfinylalkyl, arylsulfonylalkyl , cycloalkylsulfinylalkyl , cycloalkylsufonylalkyl , heteroarylsulfonylalkyl , heteroarylsulfinylalkyl , aralkylsulfinylalkyl and aralkylsulfonylalkyl,-, heteroarylthioalkyl , heteroaralkylthioalkyl ,
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 to form a group consisting of C3 to C8 cycloalkyl, C3 to C8 cycloalkenyl and C3 to C8 heterocyclyl.
4. The compound and pharmaceutically acceptable salts as recited in Claim 2 wherein:
1 2 R and R are independently selected from the group
6 6 30 31 consisting of hydroxyl, sulfhydryl, OR , SR , P(0)R R
30 31 , 15 13 13 15 P(O) (R )2R . C(S)R , 0S02R , OS(0)R , OC(S)R ,
SC(S)R , 0C(S)GR , SC(S)GR , 0C(0)R , SC(0)R ,
15 15 6 OC(0)GR , and SC(0)GR , wherein R is selected from the group consisting of hydroxyalkyl, aminoalkyl, heteroaryloxyalkyl, aralkyl, aryloxyalkyl, aralkoxyalkyl, alkylsulfinylalkyl , alkylsulfonylalkyl, aralkylthioalkyl , heteroaralkoxythioalkyl, alkoxyalkyl, heteroaryloxyalkyl, alkenyloxyalkyl, alkylthioalkyl, arylthioalkyl, 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, natural and synthetic amino acids and
13 polyhydroxy compounds of carbon, R is selected from the group consisting of 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, natural and synthetic amino acids and polyhydroxy compounds of carbon, 15 R is selected from the group consisting of 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 , icarboalkoxycycloalkyl , formylalkyl, acylalkyl, dialkoxyphosphonoalkyl , diaralkoxyphosphonoalkyl , phosphonoalkyl , dialkoxyphosphonoalkoxy, diaralkoxyphosphonoalkoxy, phosphonoalkoxy, dialkoxyphosphonoalkylamino , diaralkoxyphosphonoalkylamino , phosphonoalkylamino , dialkoxyphosphonoalkyl , diaralkoxyphosphonoalkyl , sulfonylalkyl , alkoxysulfonylalkyl , aralkoxysulfonylalkyl , alkoxysulfonylalkoxy, aralkoxysulfonylalkoxy, sulfonylalkoxy, alkoxysulfonylalkylamino, aralkoxysulfonylalkylamino, sulfonylalkylamino, natural and synthetic amino acids and polyhydroxy compounds of carbon,
30 31 R and R are independently selected from the group consisting of 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, natural and synthetic amino acids, and polyhydroxy compounds of carbon,
30 31 wherein R and R can be taken together to form a linear moiety spacer group having a chain length of 2 to 7 atoms selected from the group consisting of C3 to C8 cycloalkyl, C3 to C8 cycloalkenyl, and C3 to C8 heterocyclyl substituted independently and optionally with one or more alkyl, haloalkyl, aryl, heteroaryl, alkoxyalkyl, alkoxy, haloalkoxy, cyano, carboalkoxy, hydroxy, hydroxyalkyl, and
+ halo groups, M is a pharmaceutically acceptable cation; and G is selected from the group consisting of 0, S, CH2 ,
15 15 15 1C
CHR , C(R )2 NH and NR wherein R1^ is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl and heteroaryl
3 4 R and R are independently selected from the group
13 13 30 31 30 31 consisting of S(0)R , SO2R , P(0)R R , P(0)(R ) 2R ,
C(0)R , C(S)R , OC(S)R , SC(S)R 5, OC(S)GR15, SC(S)GR15;
7 R is selected from the group consisting of alkynyl, cyanoalkyl, dicyanoalkyl, carboxamidoalkyl, dicarboxamidoalkyl , cyanocarboalkoxyalkyl , carboalkoxyalkyl, dicarboalkoxyalkyl, cyanocycloalkyl, dicyanocycloalkyl, carboxamidocycloalkyl, dicarboxamidocycloalkyl , carboalkoxycyanocycloalkyl , carboalkoxycycloalkyl , dicarboalkoxycycloalkyl ,
13 13 30 31 formylalkyl, acylalkyl, S(0)R , S02R , P(0)R R ,
, , 30, 31 , 15 15 15 15
P(O) (R )2R , C(0)R , C(S)R , CH2OC(0)R , CH2SC(0)R ,
15 15 15 CH2SC(S)R , CH2OC(S)GR , CH2SC(S)GR , heteroaryloxyalkyl, 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 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 with the proviso that A is
Q selected from other than 0 and S or provided that R is
selected from other than H when A is N(R ) ;
8 R is selected from the group consisting of hydrogen, hydroxyalkyl, haloalkyl, alkyl and alkoxyalkyl with the
22 proviso that J is NR or S;
X is selected from the group consisting of alkylene, alkenylene, and alkynylene groups which may be optionally substituted from the group consisting of alkyl, alkoxy, hydroxy, sulfhydryl, halogen, trifluoromethyl, nitro, cyano and amino ;
X can be - (CH2 )pQ (CH2 ) r ~ wherein p is 1 to 3, r is 1 to
3 and Q is selected from oxygen, C=0, S(0)f Se(0)t wherein
21 21 t is 0 to 2 , P(0)R wherein R is hydroxyl or alkyl which may be optionally substituted with one of the group consisting of alkyl, alkoxy, hydroxy, halogen,
12 trifluoromethyl, nitro, cyano, amino, carboxy, and N(R )n
12 . wherein n is 1 to 2 and R is selected from the group consisting of hydrogen, oxy, hydroxyl and alkyl which may be optionally substituted from the group consisting of alkyl, alkoxy, hydroxy, halogen, trifluoromethyl , nitro, cyano and amino;
X can be - (CH2 ) s τ (CH2 ) v~ wherein s is O to 2 , v is 0 to
2 and T is selected from a 3 to 6 membered carbocyclic radical, aryl radical and a heterocyclyl radical where all said radicals may be optionally substituted with alkyl, alkoxy, hydroxy, halogen, trifluoromethyl, nitro, cyano and amino ;
Y is selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxyalkyl, cycloalkyl, cycloalkenyl, cycloalkenyloxy, alkenyloxyalkyl, alkylthioalkyl,
9 10 " 9 10 alkylammoalkyl 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 C3 to C8 heterocyclyl;
A is selected from the group consisting of 0, N(R ), S and heterocyclyl with the proviso that J is selected from
5 other than O, wherein R is selected from the group consisting of alkynyl, cyanoalkyl, dicyanoalkyl, carboxamidoalkyl , dicarboxamidoalkyl , cyanocarboalkoxyalkyl , carboalkoxyalkyl , dicarboalkoxyalkyl, cyanocycloalkyl, dicyanocycloalkyl, carboxamidocycloalkyl , dicarboxamidocycloalkyl , carboalkoxycyanocycloalkyl , carboalkoxycycloalkyl ,
13 dicarboalkoxycycloalkyl, formylalkyl, acylalkyl, S(0)R ,
13 30 31 30 31 15 15 S02R , P(0)R R , P(O) (R ) 2R , C(0)R , C(S)R ,
15 15 15 15 CH2OC(0)R , CH2SC(0)R , CH2SC(S)R , CH20C(S)GR ,
15 CH2SC(S)GR , heteroaryloxyalkyl, 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;
27 27
A can be R , wherein R is selected from the group
5 7 5 7 25 5 13 consisting of N(R ) OR , N(R )N(R )R , N(R ) SO2R ,
5 15 5 15 N(R )C(0)R , N(R )C(S)R , natural and synthetic ammo r~ 1 "3 £T tZ "I 'D [IT acids, N(R )P(0) (OR ) iR and N(R )P(0) (OR )2 wherein R is 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; 1 2 R and R can be taken together to form a group independently selected from a group consisting of
30 31 D(C(R ) (R ) ) ZD where z is 2 to 5 and D is
selected from the group consisting of oxygen, C=0, C=S,
31 30 30 30 S(0)m where m is 0 to 2, OP(OR )R , P(0)R , P(S)R ;
22 J is selected from the group consisting of 0, NR
22 and S wherein 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 arylsulfinylalkyl , arylsulfonylalkyl, cycloalkylsulfinylalkyl , cycloalkylsufonylalkyl , heteroarylsulfonylalkyl , heteroarylsulfinylalkyl , aralkylsulfinylalkyl and aralkylsulfonylalkyl;, heteroarylthioalkyl , heteroaralkylthioalkyl .
5. The compound and pharmaceutically acceptable salts as recited in Claim 2 wherein:
1 2 R and R are independently selected from the group
6 6 13 consisting of hydroxyl, sulfhydryl, OR , SR , 0S02R
13 15 15 15 15
OS(0)R , 0C(S)R , SC(S)R , OC(S)GR , SC(S)GR ,
0C(0)R , SC(0)R , OC(0)GR , and SC(0)GR , wherein R is selected from the group consisting of hydroxyalkyl, aminoalkyl, heteroaryloxyalkyl, aralkyl, aryloxyalkyl, aralkoxyalkyl, alkylsulfinylalkyl , alkylsulfonylalkyl, aralkylthioalkyl, heteroaralkoxythioalkyl, alkoxyalkyl, heteroaryloxyalkyl, alkenyloxyalkyl, alkylthioalkyl, arylthioalkyl, 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, natural and synthetic amino acids and
13 polyhydroxy compounds of carbon, R is selected from the group consisting of 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, natural and synthetic amino acids and polyhydroxy compounds of carbon,
15 R is selected from the group consisting of 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, icarboalkoxycycloalkyl, formylalkyl, acylalkyl, dialkoxyphosphonoalkyl , diaralkoxyphosphonoalkyl , phosphonoalkyl , dialkoxyphosphonoalkoxy, diaralkoxyphosphonoalkoxy, phosphonoalkoxy, dialkoxyphosphonoalkylamino, diaralkoxyphosphonoalkylamino, phosphonoalkylamino , dialkoxyphosphonoalkyl , diaralkoxyphosphonoalkyl , sulfonylalkyl , alkoxysulfonylalkyl , aralkoxysulfonylalkyl, alkoxysulfonylalkoxy, aralkoxysulfonylalkoxy, sulfonylalkoxy, alkoxysulfonylalkylamino, aralkoxysulfonylalkylamino, sulfonylalkylamino, natural and synthetic amino acids and polyhydroxy compounds of carbon,
+ . M is a pharmaceutically acceptable cation; and G is
15 selected from the group consisting of 0, S, CH2 , CHR
15 15 C(R ) 2 NH and NR wherein R15 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl and heteroaryl
3 4 R and R are independently selected from the group
13 13 15 15 consisting of S(0)R , SO2R , OC(S)R , SC(S)R ,
15 15 0C(S)GR , SC(S)GR ;
7 R is selected from the group consisting of alkynyl, cyanoalkyl, dicyanoalkyl, carboxamidoalkyl, dicarboxamidoalkyl , cyanocarboalkoxyalkyl , carboalkoxyalkyl, dicarboalkoxyalkyl, cyanocycloalkyl, dicyanocycloalkyl, carboxamidocycloalkyl, dicarboxamidocycloalkyl , carboalkoxycyanocycloalkyl , carboalkoxycycloalkyl , dicarboalkoxycycloalkyl ,
13 13 30 31 formylalkyl, acylalkyl, S(0)R , SO2R , P(0)R R ,
30 31 15 15 15 15
P(0)(R )2R , C(0)R , C(S)R , CH2OC(0)R , CH2SC(0)R ,
CH2SC(S)R , CH2OC(S)GR , CH2SC(S)GR , heteroaryloxyalkyl, 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 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 with the proviso that A is
Q selected from other than 0 and S or provided that R is selected from other than H when A is N(R ) ;
8 R is selected from the group consisting of hydrogen, hydroxyalkyl, haloalkyl, alkyl and alkoxyalkyl with the
22 proviso that J is NR or S;
X is selected from the group consisting of alkylene, alkenylene, and alkynylene groups which may be optionally substituted from the group consisting of alkyl, alkoxy, hydroxy, sulfhydryl, halogen, trifluoromethyl , nitro, cyano and amino;
X can be - (CH2 )pQ (CH2 ) r~ wherein p is 1 to 3 , r is 1 to
3 and Q is selected from oxygen, C=0, S(0)t, Se(0)t wherein
21 . 21 t is 0 to 2, P(0)R wherein R is hydroxyl or alkyl which may be optionally substituted with one of the group consisting of alkyl, alkoxy, hydroxy, halogen,
12 trifluoromethyl, nitro, cyano, amino, carboxy, and N(R )n
12 wherein n is 1 to 2 and R is selected from the group consisting of hydrogen, oxy, hydroxyl and alkyl which may be optionally substituted from the group consisting of alkyl, alkoxy, hydroxy, halogen, trifluoromethyl , nitro, cyano and amino;
X can be - (CH2 ) ST (CH2 ) v- wherein s is O to 2 , v is 0 to 2 and T is selected from a 3 to 6 membered carbocyclic radical, aryl radical and a heterocyclyl radical where all said radicals may be optionally substituted with alkyl, alkoxy, hydroxy, halogen, trifluoromethyl, nitro, cyano and amino ;
Y is selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxyalkyl, cycloalkyl, cycloalkenyl, cycloalkenyloxy, alkenyloxyalkyl, alkylthioalkyl,
9 10 9 10 alkylammoalkyl 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 C3 to C8 heterocyclyl;
5 A is selected from the group consisting of O, N(R ), S and heterocyclyl with the proviso that J is selected from
5 other than 0, wherein R is selected from the group consisting of alkynyl, cyanoalkyl, dicyanoalkyl, carboxamidoalkyl , dicarboxamidoalkyl , cyanocarboalkoxyalkyl , carboalkoxyalkyl , dicarboalkoxyalkyl, cyanocycloalkyl, dicyanocycloalkyl, carboxamidocycloalkyl , dicarboxamidocycloalkyl , carboalkoxycyanocycloalkyl , carboalkoxycycloalkyl ,
13 dicarboalkoxycycloalkyl, formylalkyl, acylalkyl, S(0)R ,
13 , , 15 , , 15 15 15
S02R , C(0)R , C(S)R , CH2OC(0)R , CH2SC(0)R ,
15 15 15
CH2SC(S)R , CH OC(S)GR , CH2SC(S)GR , heteroaryloxyalkyl, 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;
27 27
A can be R , wherein R is selected from the group
^ , 5 7 5 7 25 5 13 consisting of N(R ) OR , N(R )N(R )R , N(R ) S02R ,
5 15 5 15 N(R )C(0)R , N(R )C(S)R , natural and synthetic ammo
5 13 6 5 13 . 25 acids, N(R )P(0) (OR ) iR and N(R )P(0) (0R )2 wherein R is 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;
22 J is selected from the group consisting of O, NR ,
22 and S wherein 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 arylsulfinylalkyl, arylsulfonylalkyl , cycloalkylsulfinylalkyl , cycloalkylsufonylalkyl, heteroarylsulfonylalkyl , heteroarylsulfinylalkyl , aralkylsulfinylalkyl and aralkylsulfonylalkyl;, heteroarylthioalkyl , heteroaralkylthioalkyl .
6. The compound and pharmaceutically acceptable salts as recited in Claim 2 wherein: 1 2 R and R are independently selected from the group consisting of hydroxyl, sulfhydryl, OR , SR , OS02R
"1 "-? "1 C "1 C "1 C i r~
OS(0)R , OC(S)R , SC(S)R , OC(S)GR , SC(S)GR ,
15 15 15 15 6
OC(0)R , SC(0)R , OC(0)GR , and SC(0)GR , wherein R is selected from the group consisting of hydroxyalkyl, aminoalkyl, heteroaryloxyalkyl, aralkyl, aryloxyalkyl, aralkoxyalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl, aralkylthioalkyl, heteroaralkoxythioalkyl, alkoxyalkyl, heteroaryloxyalkyl, alkenyloxyalkyl, alkylthioalkyl, arylthioalkyl, 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, natural and synthetic amino acids and
13 polyhydroxy compounds of carbon, R is selected from the group consisting of 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, natural and synthetic amino acids and polyhydroxy compounds of carbon,
15 R is selected from the group consisting of 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 , icarboalkoxycycloalkyl , formylalkyl, acylalkyl, dialkoxyphosphonoalkyl , diaralkoxyphosphonoalkyl , phosphonoalkyl, dialkoxyphosphonoalkoxy, diaralkoxyphosphonoalkoxy, phosphonoalkoxy, dialkoxyphosphonoalkylamino , diaralkoxyphosphonoalkylamino , phosphonoalkylamino , dialkoxyphosphonoalkyl , diaralkoxyphosphonoalkyl , sulfonylalkyl , alkoxysulfonylalkyl , aralkoxysulfonylalkyl, alkoxysulfonylalkoxy, aralkoxysulfonylalkoxy, sulfonylalkoxy, alkoxysulfonylalkylamino, aralkoxysulfonylalkylamino, sulfonylalkylamino, natural and synthetic amino acids and polyhydroxy compounds of carbon,
+ M is a pharmaceutically acceptable cation, and G is
15 selected from the group consisting of O, S, CH2 , CHR
15 15
C(R )2, NH and NR wherein R15 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl and heteroaryl;
3 4 R and R are independently selected from the group
15 15 15 15 consisting of OC(S)R , SC(S)R , OC(S)GR , SC(S)GR ;
7 R is selected from the group consisting of alkynyl, cyanoalkyl, dicyanoalkyl, carboxamidoalkyl, dicarboxamidoalkyl , cyanocarboalkoxyalkyl , carboalkoxyalkyl, dicarboalkoxyalkyl, cyanocycloalkyl, dicyanocycloalkyl , carboxamidocycloalkyl , dicarboxamidocycloalkyl , carboalkoxycyanocycloalkyl , carboalkoxycycloalkyl , dicarboalkoxycycloalkyl ,
13 13 30 31 formylalkyl, acylalkyl, S(0)R , S02R , P(0)R R ,
30, 31 15 , 15 15 15 P(O) (R )2R , C(0)R , C(S)R , CH2OC(0)R , CH2SC(0)R , 15 15 15
CH2SC(S)R , CH2OC(S)GR , CH2SC(S)GR , heteroaryloxyalkyl, 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 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 with the proviso that A is
8 . selected from other than O and S or provided that R is
5 selected from other than H when A is N(R );
8 R is selected from the group consisting of hydrogen, hydroxyalkyl, haloalkyl, alkyl and alkoxyalkyl with the
22 proviso that J is NR or S;
X is selected from the group consisting of alkylene, alkenylene, and alkynylene groups which may be optionally substituted from the group consisting of alkyl, alkoxy, hydroxy, sulfhydryl, halogen, trifluoromethyl , nitro, cyano and amino; X can be - (CH2 ) pQ (CH2 ) r- wherein p is 1 to 3 , r is 1 to
3 and Q is selected from oxygen, C=0, S(0)t» Se(0)t wherein
21 21 t is 0 to 2 , P(0)R wherein R is hydroxyl or alkyl which may be optionally substituted with one of the group consisting of alkyl, alkoxy, hydroxy, halogen,
12 trifluoromethyl, nitro, cyano, amino, carboxy, and N(R )n
12 wherein n is 1 to 2 and R is selected from the group consisting of hydrogen, oxy, hydroxyl and alkyl which may be optionally substituted from the group consisting of alkyl, alkoxy, hydroxy, halogen, trifluoromethyl, nitro, cyano and amino ;
X can be - (CH2 ) ST (CH2 ) v- wherein s is O to 2 , v is 0 to
2 and T is selected from a 3 to 6 membered carbocyclic radical, aryl radical and a heterocyclyl radical where all said radicals may be optionally substituted with alkyl, alkoxy, hydroxy, halogen, trifluoromethyl, nitro, cyano and amino ;
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 C3 to C8 heterocyclyl; 5 A is selected from the group consisting of O, N(R ), S and heterocyclyl with the proviso that J is selected from other than 0, wherein R is selected from the group consisting of alkynyl, cyanoalkyl, dicyanoalkyl, carboxamidoalkyl, dicarboxamidoalkyl, cyanocarboalkoxyalkyl , carboalkoxyalkyl , dicarboalkoxyalkyl, cyanocycloalkyl, dicyanocycloalkyl, carboxamidocycloalkyl , dicarboxamidocycloalkyl , carboalkoxycyanocycloalkyl , carboalkoxycycloalkyl ,
13 dicarboalkoxycycloalkyl, formylalkyl, acylalkyl, S(0)R
S02R , C(0)R , C(S)R , CH2OC(0)R , CH2SC(0)R15,
CH2SC(S)R , CH2OC(S)GR , CH2SC(S)GR , heteroaryloxyalkyl, 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;
27 . 27 . A can be R , wherein R is selected from the group
5 7 5 13 5 15 consisting of N(R ) OR , N(R ) S02R , N(R )C(0)R , 5 15 N(R )C(S)R , natural and synthetic ammo acids,
5 13 6 5 13 N(R )P(0)(OR )ιR and N(R )P(0)(OR )2;
22 J is selected from the group consisting of 0, NR ,
22 and S wherein 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 arylsulfinylalkyl, arylsulfonylalkyl, cycloalkylsulfinylalkyl , cycloalkylsufonylalkyl, heteroarylsulfonylalkyl , heteroarylsulfinylalkyl , aralkylsulfinylalkyl and aralkylsulfonylalkyl;, heteroarylthioalkyl , heteroaralkylthioalkyl .
7. A compound as recited in claim 2 wherein said compound is selected from the group consisting of:
L-N- (2-cyanoethyl ) -N- ( 2-thiazolyl ) - e-N- (methoxyiminoethyl) -2-methyllysinamide dihydrochloride;
L-N- (2-dimethylamino) -N- (2-pyridyl ) - e-N- ( iminoethyl) -2- methyl-L-lysinamide tetrahydrochloride;
N- (2-acetoxyethyl) -N- (2-thiazolyl) -S- (2- (N- (2- acetoxyiminoethyl) amino) ethyl) -2-methyl-L-Cysteinamide;
N-acetyl-N- (4-pyridyl) -S- (2- (N- ( iminoethyl ) amino) ethyl) -2- methyl-L-Cysteinamide; N- (phenyl) -N- (2-imidazolyl) -a-N- (2 , 2-dicyanoethyl) -e- (N- Boc-1-iminoethyl) -2-methyl-L-Lysinamide;
N- (phenyl) -N- (2-imidazolyl) -a-N- (2 , 2-dicyanoethyl) -e- (1- iminoethyl) -2-methyl-L-lysinamide trihydrochloride;
N-methoxy-N- (5-tetrazoyl) -e-amino- a- (N-hydroxy-N- acetamido) hexanamide hydrochloride;
N- (2-thiazolyl) -e- (amino) -a- (N-methoxyacetamido)hexanamide hydrochloride;
N- (2-imidazolyl) -S- (2-aminoethyl) - a-N- (4- morpholmomethylbenzoyl) -2-methyl-D, L-homocysteinamide;
N- (3-quiniclidinyl) -a- (N-methoxyformyl) -D, L-2 , 5- dimethylornithinamide ;
N- ( 2-g-butyrolactone) -a- (N-methansulfonyl) -ortho- (aminomethyl ) -2-methylphenylalanmamide ;
N- (2-pyrimidinyl) - 3- (5- (aminomethyl) thiophenyl) -2- acetamido-2-methylpropionamide;
N-methyl-N- (2-pyridyl) -α- (N-cyclopentyl) -α-N- (3,3,3- trifluoropropanoyl) -O- (2- (N- (1-iminoethyl) amino) ethyl) -2- methy1-L-serinamide;
N-methyl-N- (4-imidazolyl) -α- (N- (1-pyrrolylethylenyl) ) -O- (2- (N- (1- (0- (methoxycarbonyl) oximino) ethyl) amino) ethyl) -2- methyl-L-serinamide;
N-methyl-N- (4-thiazolyl) -0- (2- (N- (2-fluoro-1- iminoethyl) amino) ethyl) -2-methyl-L-serinamide;
N-methyl-N- (3-oxacycloheptyl) -a-N- (2-furanylacetyl) -e-N- (1- imino-3 -butenyl) -2 -methyl-L-thionolysmamide; N-Ethyl-N- (4- (1,2, 3-triazolyl) )-e-N-(l-(2- fluorocyclopropyl) oximinomethyl) amino-2-N- (1- (1- cyclopentyl-2-methylthioethyl) ) -2-cyanopropanamido-2- ethy1-thionohex-4-enamide;
3-N- (5-tetrazolyl) -5- (3- (N- (1- (O- propionyloximino) ethyl) amino) prop-1-ynyl) -5-methyl- hydantoin trifluoroacetate ;
1-N- (2-imidazolyl) -3-(2-(N-(l- iminoethyl) amino) ethoxy) methyl) - 3-methyl-6- (2- methiothioethyl) -2-oxo-3 , 6-dihydropyrazine trihydrochloride;
N-methyl-N- (5-tetrazolyl) -S- (2- (N-phosphonomethyl-N- (1- iminoethyl) amino) ethyl) -2-methyl-L-cysteinamide hydrochloride;
N-methyl-N- (5-tetrazolyl) -e- (N- (1-iminoethyl) amino) -2- ( (N- ethoxycarbonyl) amino) -2-methyl-thionohexanamide;
N-methyl-N- (5-tetrazolyl) -e- (N- (l-imino-2- fluoroethyl) amino) -2- (N- (2,2, 2-trifluoro-1- ethoxyethyl) ) amino-2-methylhexanamide;
N-methyl-N- (5-tetrazolyl) -S- (2- (1- (N-
(benzoyloxymethyl) imino) ethyl) -N-hydroxy) aminoethyl) -2- methyl-L-cysteinamide;
N-methyl-N- (5-tetrazolyl) - a-N-benzoyl- e-N- (2- (1- (N- (benzoyloxymethyl) imino) ethyl) ) - e-N- (1-propyl) -2-methyl-L- Lysine;
N-methyl-N- (5- (tetrazolyl) -ε-N- (2-fluoro-1-iminoethyl) -ε-N- (N,N'N' -trimethylureido-N-methylene) -2-methyl-L-Lysinamide; N-methyl-N- (5-tetrazolyl) -e- (N- (l-imino-2- fluoroethyl) amino) -2- (N- (phenylalaninyl) amino) -2- methylhexanamide;
N-acetoxymethyl-N- (5-tetrazolyl) -ε-N- (iminoethyl) -2-methyl- L-Lysinamide, 3- (4- (N- (1-iminoethyl) amino) butyl) -3- cyanomethyl-6-methylmorpholine-2, 5-dione;
3- (4- (N- (2-fluoroiminoethyl) amino) butyl) -3- (N,N- dimethylaminomethyl) oxazolidine-2 , 5-dione;
3- (4- (N-( 1-iminoethyl) amino) butyl) -3- (2-methylthioethyl) - 3H,5H,6H,7H,8H- 1 , 4-benzoxazin-2-one dihydrochloride;
6- (N- (2-fluoro-1-iminoethyl) amino) -1-imino-l- (2- piperazinylmethylthio) -2-hexanamine pentahydrochloride;
ethyl 6- (N- (1-iminoethyl) amino) -2- (ethoxyiminomethyl) -2- aminohexanoate trihydrochloride;
N-methyl-N- (5-tetrazolyl) -6- (N- (1-iminoethyl) amino) -2- (methoxyiminomethyl ) -2-aminohexanamide ;
6- (N- (1-iminoethyl) amino) -2- (N-glycylaminomethyl) -2- phthalimidohexanoic acid trihydrochloride;
N-Methyl-N- (N- ( 5-tetrazoyl) amino) - 2-amino-2- (2- hydroxyethyl) -6- (N- (1-iminoethyl) amino) hexanamide;
N- (2-amino-2- (2-cyanoethyl) -6- (N- (1- iminoethyl) amino) hexanoyl) aminoacetic acid hydrochloride;
N-methylsulfonylmethyl-N- (5-tetrazolyl) -2-cyanomethyl-2- amino-6- (N- (1-iminoethyl) amino) hexanamide;
tert-Butyl 2-cyanomethyl-2-phthalimido-6- (N- ( 1- iminoethyl ) amino) hexanoate ;
N-methanesulfonylmethyl-N- (methoxymethoxy) -2 -cyanomethyl-2- amino-6- (N- ( 1-iminoethyl) amino) hexanamide; N- (2-cyanomethyl-2-amino-6- (N- ( 1- iminoethyl) amino) hexanoyl) alanine dihydrochloride; and
6- (N-butylimino) -6-methoxy-N- (1-iminoethyl) -1, 2- hexanediamine di-para-toluenesulfonate hydrochloride.
8. 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 Claims 1, 2, 3, 4, 5, 6 or 7.
9. 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 Claims 1, 2, 3, 4, 5, 6 or 7.
10. A method of lowering nitric oxide levels in a subject in need of such by administering a therapeutically effective amount of a compound of Claims 1, 2, 3, 4, 5, 6 or 7.
11. A pharmacuetical composition comprising a compound of Claims 1,2, 3, 4, 5, 6 or 7 together with one or more pharmaceutically acceptable carriers .
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