Halogenated 2-amino-3, 4 heptenoic acid derivatives useful as nitric oxide synthase inhibitors

A compound selected from the group consisting of:

• (2S,3Z)-2-amino-4-fluoro-7-[(1-iminoethyl)amino]-3-heptenoic acid, dihydrochloride;
• (2S,3E)-2-amino-4-fluoro-7-[(1-iminoethyl)amino]-3-heptenoic acid, dihydrochloride;
• (3Z)-2-amino-3-fluoro-7-[(1-iminoethyl)amino]-3-heptenoic acid, dihydrochloride;
• (3E)-2-amino-3-fluoro-7-[(1-iminoethyl)amino]-3-heptenoic acid, dihydrochloride;
• (3E)-2-amino-3,4-difluoro-7-[(1-iminoethyl)amino]-3-heptenoic acid, dihydrochloride;
• and
• (3Z)-2-amino-3,4-difluoro-7-[(1-iminoethyl)amino]-3-heptenoic acid, dihydrochloride.

A compound having the Formula IV:

• wherein
• R5 is selected from the group consisting of H, F, and methyl;
• R6 is selected from the group consisting of H, F, and methyl;
• with the proviso that either R5 or R6 must be F;
• J is selected from the group consisting of H, hydroxy, alkoxy;
• and NR3R4 where R3 is selected from the group consisting of H, lower alkyl, lower alkylenyl and lower alkynyl;
• and R4 is selected from the group consisting of H, and a heterocyclic ring in which at least one member of the ring is carbon and in which 1 to about 4 heteroatoms are independently selected from oxygen, nitrogen and sulfur and said heterocyclic ring 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;
• Q is H, or an appropriate nitrogen protecting moiety.

A method of treating an inflammation related condition in a human subject in need of such treatment or prevention comprising:

• administering a treatment effective amount of a compound of formula I
• or a pharmaceutically acceptable salt thereof, wherein:
• R1 is selected from the group consisting of H, halo and alkyl which is optionally substituted by one or more halo;
• R2 is selected from the group consisting of H, halo and alkyl which is optionally substituted by one or more halo;
• with the proviso that at least one of R1 or R2 is halo or alkyl substituted by one or more halo;
• R1 is selected from the group consisting of H, halo and alkyl which is optionally substituted by one or more halo;
• R2 is selected from the group consisting of H, halo and alkyl which is optionally substituted by one or more halo;
• with the proviso that at least one of R1 or R2 contains a halo;
• R7 is selected from the group consisting of H and hydroxy;
• and
• J is selected from the group consisting of hydroxy, carboxyl, carboalkoxy, and C(O)NR3R4 wherein;
• R3 is selected from the group consisting of H, lower alkyl, lower alkylenyl and lower alkynyl;
• and
• R4 is selected from the group consisting of H, and a heterocyclic ring in which at least one member of the ring is carbon and in which 1 to about 4 heteroatoms are independently selected from oxygen, nitrogen and sulfur;
• and said heterocyclic ring is optionally substituted with a moiety selected from the group consisting of heteroarylamino, N-aryl-N-alkylamino, N-heteroarylamino-N-alkylamino, haloalkylthio, alkanoyloxy, alkoxy, heteroaralkoxy, cycloalkoxy, cycloalkenyloxy, hydroxy, amino, thio, nitro, alkylamino, dialkyamino, alkylthio, alkylthioalkyl, arylamino, aralkylamino, arylthio, alkylsulfinyl, alkylsulfonyl, alkylsulfonamido, alkylaminosulfonyl, aminosulfonyl, monoalkyl aminosulfonyl, dialkyl aminosulfonyl, monoarylamidosulfonyl, arylsulfonamido, diarylamidosulfonyl, monoalkyl monoaryl amidosulfonyl, arylsulfinyl, arylsulfonyl, heteroarylthio, heteroarylsulfinyl, heteroarylsulfonyl, alkanoyl, alkenoyl, aroyl, heteroaroyl, aralkanoyl, heteroaralkanoyl, haloalkanoyl, alkyl, alkenyl, alkynyl, alkylenedioxy, haloalkylenedioxy, carboxyl, alkoxycarboxyl, 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, carboxyalkoxyalkyl, dicarboxyalkoxyalkyl, cyanocycloalkyl, dicyanocycloalkyl, carboxamidocycloalkyl, dicarboxamidocycloalkyl, carboalkoxycyanocycloalkyl, carboalkoxycycloalkyl, dicarboalkoxycycloalkyl, formylalkyl, acylalkyl, dialkoxyphosphonoalkyl, diaralkoxyphosphonoalkyl, phosphonoalkyl, dialkoxyphosphonoalkoxy, diaralkoxyphosphonoalkoxy, phosphonoalkoxy, dialkoxyphosphonoalkylamino, diaralkoxyphosphonoalkylamino, phosphonoalkylamino, dialkoxyphosphonoalkyl, diaralkoxyphosphonoalkyl, guanidino, amidino, and acylamino
• to a human subject in need of such treatment.

A method of treating a malignant neoplasia in a human subject in need of such treatment comprising:

• administering a treatment or prevention effective amount of a compound of formula I
• or a pharmaceutically acceptable salt thereof, wherein:
• R1 is selected from the group consisting of H, halo and alkyl which is optionally substituted by one or more halo;
• R2 is selected from the group consisting of H, halo and alkyl which is optionally substituted by one or more halo;
• with the proviso that at least one of R1 or R2 R2 is halo or alkyl substituted by one or more halo;
• R1 is selected from the group consisting of H, halo and alkyl which is optionally substituted by one or more halo;
• R2 is selected from the group consisting of H, halo and alkyl which is optionally substituted by one or more halo;
• with the proviso that at least one of R1 or R2 is halo or alkyl substituted by one or more halo;
• R7 is selected from the group consisting of H and hydroxy;
• and
• J is selected from the group consisting of hydroxy, carboxyl, carboalkoxy, and C(O)NR3R4 wherein;
• R3 is selected from the group consisting of H, lower alkyl, lower alkylenyl and lower alkynyl;
• and
• R4 is selected from the group consisting of H, and a heterocyclic ring in which at least one member of the ring is carbon and in which 1 to about 4 heteroatoms are independently selected from oxygen, nitrogen and sulfur;
• and said heterocyclic ring is optionally substituted with a moiety selected from the group consisting of heteroarylamino, N-aryl-N-alkylamino, N-heteroarylamino-N-alkylamino, haloalkylthio, alkanoyloxy, alkoxy, heteroaralkoxy, cycloalkoxy, cycloalkenyloxy, hydroxy, amino, thio, nitro, alkylamino, dialkyamino, alkylthio, alkylthioalkyl, arylamino, aralkylamino, arylthio, alkylsulfinyl, alkylsulfonyl, alkylsulfonamido, alkylaminosulfonyl, aminosulfonyl, monoalkyl aminosulfonyl, dialkyl aminosulfonyl, monoarylamidosulfonyl, arylsulfonamido, diarylamidosulfonyl, monoalkyl monoaryl amidosulfonyl, arylsulfinyl, arylsulfonyl, heteroarylthio, heteroarylsulfinyl, heteroarylsulfonyl, alkanoyl, alkenoyl, aroyl, heteroaroyl, aralkanoyl, heteroaralkanoyl, haloalkanoyl, alkyl, alkenyl, alkynyl, alkylenedioxy, haloalkylenedioxy, carboxyl, alkoxycarboxyl, 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, carboxyalkoxyalkyl, dicarboxyalkoxyalkyl, cyanocycloalkyl, dicyanocycloalkyl, carboxamidocycloalkyl, dicarboxamidocycloalkyl, carboalkoxycyanocycloalkyl, carboalkoxycycloalkyl, dicarboalkoxycycloalkyl, formylalkyl, acylalkyl, dialkoxyphosphonoalkyl, diaralkoxyphosphonoalkyl, phosphonoalkyl, dialkoxyphosphonoalkoxy, diaralkoxyphosphonoalkoxy, phosphonoalkoxy, dialkoxyphosphonoalkylamino, diaralkoxyphosphonoalkylamino, phosphonoalkylamino, dialkoxyphosphonoalkyl, diaralkoxyphosphonoalkyl, guanidino, amidino, and acylamino
• to a human subject in need of such treatment.

A method of treating addiction in a human subject in need of such treatment comprising:

• administering a treatment effective amount of a compound of formula I
• or a pharmaceutically acceptable salt thereof, wherein:
• R1 is selected from the group consisting of H, halo and alkyl which is optionally substituted by one or more halo;
• R2 is selected from the group consisting of H, halo and alkyl which is optionally substituted by one or more halo;
• with the proviso that at least one of R1 or R2 is halo or alkyl substituted by one or more halo;
• R1 is selected from the group consisting of H, halo and alkyl which is optionally substituted by one or more halo;
• R2 is selected from the group consisting of H, halo and alkyl which is optionally substituted by one or more halo;
• with the proviso that at least one of R1 or R2 contains a halo;
• R7 is selected from the group consisting of H and hydroxy;
• and
• J is selected from the group consisting of hydroxy, carboxyl, carboalkoxy, and C(O)NR3R4 wherein;
• R3 is selected from the group consisting of H, lower alkyl, lower alkylenyl and lower alkynyl;
• and
• R4 is selected from the group consisting of H, and a heterocyclic ring in which at least one member of the ring is carbon and in which 1 to about 4 heteroatoms are independently selected from oxygen, nitrogen and sulfur;
• and said heterocyclic ring is optionally substituted with a moiety selected from the group consisting of heteroarylamino, N-aryl-N-alkylamino, N-heteroarylamino-N-alkylamino, haloalkylthio, alkanoyloxy, alkoxy, heteroaralkoxy, cycloalkoxy, cycloalkenyloxy, hydroxy, amino, thio, nitro, alkylamino, dialkyamino, alkylthio, alkylthioalkyl, arylamino, aralkylamino, arylthio, alkylsulfinyl, alkylsulfonyl, alkylsulfonamido, alkylaminosulfonyl, aminosulfonyl, monoalkyl aminosulfonyl, dialkyl aminosulfonyl, monoarylamidosulfonyl, arylsulfonamido, diarylamidosulfonyl, monoalkyl monoaryl amidosulfonyl, arylsulfinyl, arylsulfonyl, heteroarylthio, heteroarylsulfinyl, heteroarylsulfonyl, alkanoyl, alkenoyl, aroyl, heteroaroyl, aralkanoyl, heteroaralkanoyl, haloalkanoyl, alkyl, alkenyl, alkynyl, alkylenedioxy, haloalkylenedioxy, carboxyl, alkoxycarboxyl, 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, carboxyalkoxyalkyl, dicarboxyalkoxyalkyl, cyanocycloalkyl, dicyanocycloalkyl, carboxamidocycloalkyl, dicarboxamidocycloalkyl, carboalkoxycyanocycloalkyl, carboalkoxycycloalkyl, dicarboalkoxycycloalkyl, formylalkyl, acylalkyl, dialkoxyphosphonoalkyl, diaralkoxyphosphonoalkyl, phosphonoalkyl, dialkoxyphosphonoalkoxy, diaralkoxyphosphonoalkoxy, phosphonoalkoxy, dialkoxyphosphonoalkylamino, diaralkoxyphosphonoalkylamino, phosphonoalkylamino, dialkoxyphosphonoalkyl, diaralkoxyphosphonoalkyl, guanidino, amidino, and acylamino,
• to a human subject in need of such treatment.