Neuroprotective treatment methods using selective iNOS inhibitors

A method for treating or preventing a neurodegenerative condition in a subject in need of such treatment or prevention, said method comprising administering to the subject a neuroprotective effective amount of an inducible nitric oxide synthase selective inhibitor or pharmaceutically acceptable salt thereof or prodrug thereof, wherein the inducible nitric oxide synthase inhibitor is selected from the group consisting of:

• a compound having Formula I
• 229
• or a pharmaceutically acceptable salt thereof, wherein:
• R1 is selected from the group consisting of H, halo and alkyl which may be optionally substituted by one or more halo;
• R2 is selected from the group consisting of H, halo and alkyl which may be 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;
• J is selected from the group consisting of hydroxy, alkoxy, and NR3R4 wherein;
• R3 is selected from the group consisting of H, lower alkyl, lower alkylenyl and lower alkynyl;
• 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;
• a compound having a structure corresponding to Formula II
• 230
• or a pharmaceutically acceptable salt thereof, wherein X is selected from the group consisting of —S—, —S(O)—, and —S(O)2—. Preferably, X is —S—. R12 is selected from the group consisting of C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C5 alkoxy-C1 alkyl, and C1-C5 alkylthio-C1 alkyl wherein each of these groups is optionally substituted by one or more substituent selected from the group consisting of —OH, alkoxy, and halogen. Preferably, R12 is C1-C6 alkyl optionally substituted with a substituent selected from the group consisting of —OH, alkoxy, and halogen. With respect to R13 and R18, R18 is selected from the group consisting of —OR24 and —N(R25)(R26), and R13 is selected from the group consisting of —H, —OH, —C(O)—R27, —C(O)—O—R28, and —C(O)—S—R29;
• or R18 is —N(R30)—, and R13 is —C(O)—, wherein R18 and R13 together with the atoms to which they are attached form a ring;
• or R18 is —O—, and R13 is —C(R31)(R32)—, wherein R18 and R13 together with the atoms to which they are attached form a ring. If R13 is —C(R321)(R32)—, then R14 is —C(O)—O—R33;
• otherwise R14 is —H. R11, R15, R16, and R17 independently are selected from the group consisting of —H, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, and C1-C5 alkoxy-C1 alkyl. R19 and R20 independently are selected from the group consisting of —H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, and C1-C5 alkoxy-C1 alkyl. With respect to R21 and R22, R21 is selected from the group consisting of —H, —OH, —C(O)—O—R34, and —C(O)—S—R35, and R22 is selected from the group consisting of —H, —OH, —C(O)—O—R36, and —C(O)—S—R37;
• or R21 is —O—, and R22 is —C(O)—, wherein R21 and R22 together with the atoms to which they are attached form a ring;
• or R21 is —C(O)—, and R22 is —O—, wherein R21 and R22 together with the atoms to which they are attached form a ring. R23 is C1 alkyl. R24 is selected from the group consisting of —H and C1-C6 alkyl, wherein when R24 is C1-C6 alkyl, R24 is optionally substituted by one or more moieties selected from the group consisting of cycloalkyl, heterocyclyl, aryl, and heteroaryl. With respect to R25 and R26, R25 is selected from the group consisting of —H, alkyl, and alkoxy, and R26 is selected from the group consisting of —H, —OH, alkyl, alkoxy, —C(O)—R38, —C(O)—O—R39, and —C(O)—S—R40;
• wherein when R25 and R26 independently are alkyl or alkoxy, R25 and R26 independently are optionally substituted with one or more moieties selected from the group consisting of cycloalkyl, heterocyclyl, aryl, and heteroaryl;
• or R25 is —H;
• and R26 is selected from the group consisting of cycloalkyl, heterocyclyl, aryl, and heteroaryl. R27, R28, R29, R30, R31, R32, R33, R34, R35, R36, R37, R38, R39, and R40independently are selected from the group consisting of —H and alkyl, wherein alkyl is optionally substituted by one or more moieties selected from the group consisting of cycloalkyl, heterocyclyl, aryl, and heteroaryl. When any of R11, R12, R13, R14, R15, R16, R17, R18, R199, R20 , R21 , R22, R23 R24, R25, R26, R27, R28, R29, R30, R31, R32, R33, R34, R35, R36, R37, R38, R39 and R40 Indenpendently is a moiety selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylthio, cycloalkyl, heterocyclyl, aryl, and heteroaryl, then the moiety is optionally substituted by one or more substituent selected from the group consisting of —OH, alkoxy, and halogen;
• a compound is represented by Formula III
• 231
• or a pharmaceutically acceptable salt thereof, wherein:
• R41 is H or methyl;
• and
• R42 is H or methyl;
• a compound of formula IV
• 232
• or a pharmaceutically acceptable salt thereof;
• a compound of Formula V:
• 233
• or a pharmaceutically acceptable salt thereof, wherein:
• R43 is selected from the group consisting of hydrogen, halo, C1-C5 alkyl and C1-C5 alkyl substituted by alkoxy or one or more halo;
• R44 is selected from the group consisting of hydrogen, halo, C1-C5 alkyl and C1-C5 alkyl substituted by alkoxy or one or more halo;
• R45 is C1-C5 alkyl or C1-C5 alkyl be substituted by alkoxy or one or more halo;
• a compound of Formula VI:
• 234
• or a pharmaceutically acceptable salt thereof, wherein:
• R46 is C1-C5 alkyl said C1-C5 alkyl optionally substituted by halo or alkoxy, said alkoxy optionally substituted by one or more halo;
• A compound of Formula VII
• 235
• or a pharmaceutically acceptable salt thereof, wherein:
• R47 is selected from the group consisting of hydrogen, halo, C1-C5 alkyl and C1-C5 alkyl substituted by alkoxy or one or more halo;
• R48 is selected from the group consisting of hydrogen, halo, C1-C5 alkyl and C1-C5 alkyl substituted by alkoxy or one or more halo;
• R49 is C1-C5 alkyl or C1-C5 alkyl be substituted by alkoxy or one or more halo;
• a compound of Formula VIII
• 236
• or a pharmaceutically acceptable salt thereof, wherein:
• R50 is C1-C5 alkyl, said C1-C5 alkyl optionally substituted by halo or alkoxy, said alkoxy optionally substituted by one or more halo;
• a compound of formula IX
• 237
• or a pharmaceutically acceptable salt thereof, wherein:
• R50 is selected from the group consisting of hydrogen, halo, and C1-C5 alkyl, said C1-C5 alkyl optionally substituted by halo or alkoxy, said alkoxy optionally substituted by one or more halo;
• R51 is selected from the group consisting of hydrogen, halo, and C1-C5alkyl, said, C1-C5 alkyl optionally substituted by halo or alkoxy, said alkoxy optionally substituted by one or more halo;
• R52 is C1-C5 alkyl, said C1-C5 alkyl optionally substituted by halo or alkoxy, said alkoxy optionally substituted by one or more halo;
• R53 is selected from the group consisting of hydrogen, halo, and C1-C5 alkyl, said C1-C5 alkyl optionally substituted by halo or alkoxy, said alkoxy optionally substituted by one or more halo;
• and
• R54 is selected from the group consisting of halo and C1-C5 alkyl, said C1-C5 alkyl optionally substituted by halo or alkoxy, said alkoxy optionally substituted by one or more halo;
• and
• a compound of formula X
• 238
• or a pharmaceutically acceptable salt thereof, wherein:
• R55 is C1-C5 alkyl, said C1-C5 alkyl optionally substituted by halo or alkoxy, said alkoxy optionally substituted by one or more halo.