Substituted 2-aminopyridines as inhibitors of nitric oxide synthase

• US 5,972,975 A
• Filed: 05/22/1997
• Issued: 10/26/1999
• Est. Priority Date: 12/08/1995
• Status: Expired due to Fees

• Current Assignee: Merck Sharp & Dohme Corporation (Merck & Co., Inc.)
• Original Assignee: Merck & Co., Inc.
• Inventors: Caldwell, Charles, Hoffman, William, Wong, Kenny, Esser, Craig, Chabin, Renee, Maccoss, Malcolm, Shah, Shrenik, Guthikonda, Ravindra, Hagmann, William, Durette, Philippe
• Primary Examiner(s): Shah, Mukund J.
• Assistant Examiner(s): COLEMAN, BRENDA LIBBY
• Application Number:
  US08/836,953
• Time in Patent Office: 887 Days
• Field of Search: 514/230.5, 514/248, 514/255, 514/266, 514/269, 514/299, 514/300, 514/301, 514/307, 514/310, 514/311, 514/313, 514/314, 514/334, 514/344, 514/346, 514/349, 514/352 , 514/211, 514/212, 514/218, 514/224.2, 514/226.5, 514/226.8, 514/228.2, 514/228.5, 514/233.8, 514/234.2, 514/234.5, 514/249, 514/254, 514/256 , 514/258, 514/302, 514/303, 544/105, 544/277, 544/333, 544/350, 544/405, 544/48, 544/55, 544/61, 544/91, 544/96, 544/119, 544/127, 544/236, 544/238, 544/279, 546/112, 546/113, 546/114, 546/122, 546/143, 546/159, 546/257, 546/289, 546/292, 546/297, 546/304, 546/307, 546/308, 546/311, 546/115, 546/118, 546/119, 540/544, 540/553, 540/575, 540/597
• US Class Current: 514/352
• CPC Class Codes: A61K 31/44 Non condensed pyridines; Hydrogenated derivatives thereof

Abstract

Substituted 2-aminopyridine compounds of Formula (I) and pharmaceutically acceptable salts which have been found useful in the treatment of nitric oxide synthase mediated diseases and disorders. ##STR1##

Claims

1. A method for inhibiting the activity of nitric oxide synthases comprising administering to a subject suffering from a nitric oxide synthase mediated disease, a non-toxic therapeutically effective amount of a compound of Formula (I) ##STR83## or a pharmaceutically acceptable salt thereof wherein:

R₁, R₂, R₃ and R₄ are each independently selected from the group consisting of;

(a) hydrogen,

(b) hydroxy,

(c) amino,

(d) carboxyl,

(e) aminocarbonyl,

(f) cyano,

(g) nitro,

(h) halo, where halo is selected from fluoro, chloro, bromo, and iodo,

(i) trifluoromethyl,

(j) C_1-12 alkyl,

(k) C_2-12 alkenyl,

(l) C_2-12 alkynyl,

(m) C_1-12 alkoxy,

(n) C_1-12 alkylcarbonyl,

(o) C_1-12 alkoxycarbonyl,

(p) C_1-12 alkylaminocarbonyl,

(q) mono- and di-C_1-12 alkylamino,

(r) C_1-12 alkylthio,

(s) aryl, where aryl is selected from phenyl and naphthyl,

(t) aryloxy, where aryl is selected from phenyl and naphthyl,

(u) arylthio, where aryl is selected from phenyl and naphthyl,

(v) arylC_1-6 alkyl, where aryl is selected from phenyl and naphthyl,

(w) cycloalkyl, wherein the cycloalkyl is a 5- to 10-membered monocyclic ring which optionally contains 1 or 2 heteroatoms selected from S, O, and N,

(x) heteroaryl, wherein heteroaryl is selected from the group consisting of;

(1) pyridyl,

(2) pyrrolyl,

(3) furanyl,

(4) thienyl,

(5) isothiazolyl,

(6) imidazolyl,

(7) benzimidazolyl,

(8) tetrazolyl,

(9) pyrazinyl,

(10) pyrimidyl,

(11) quinolyl,

(12) isoquinolyl,

(13) benzofuranyl,

(14) isobenzofuryl,

(15) benzothienyl,

(16) pyrazolyl,

(17) pyrazinyl

(18) indolyl,

(19) isoindolyl,

(20) purinyl,

(21) carbazolyl,

(22) isoxazolyl,

(23) thiazolyl,

(24) triazolyl

(25) oxazolyl,

(26) oxadiazolyl,

(27) thiadiazolyl,

(28) benzthiazolyl and

(29) benzoxazolyl, and

(y) heteroarylC_1-6 alkyl, where heteroaryl is defined above in item (x),

each of (j) to (y) being optionally mono- or di- substituted, the substituents being independently selected from the group consisting of;

(1) hydroxy,

(2) C_1-6 alkyl,

(3) C_1-6 alkoxy,

(4) amino,

(5) mono- and di-C_1-6 alkylamino,

(6) carboxyl

(7) C_1-6 alkylthio,

(8) --S(O)_k -C_1-3 alkyl, where k is 1 or 2,

(9) C_1-6 alkoxycarbonyl,

(10) halo selected from fluoro, chloro, bromo, and iodo,

(11) oxo,

(12) amidino and

(13) guanidino; and

R₅ is selected from the group consisting of;

(a) hydrogen,

(b) C_1-12 alkyl,

(c) C_2-12 alkenyl,

(d) C_2-12 alkynyl,

(e) aryl, wherein the aryl group is as defined above,

(f) arylC_1-6 alkyl, wherein the aryl group is as defined above,

(g) heteroaryl, wherein heteroaryl is as defined above,

(h) heteroarylC_1-6 alkyl, wherein heteroaryl is as defined above, and

(i) cycloalkyl,wherein the cycloalkyl is a 5- to 10-membered monocyclic ring which optionally contains 1 or 2 heteroatoms selected from the group consisting of S, O and N,

each of (b) to (i) being optionally mono- or di- substituted, the substituents being independently selected from the group consisting of;

(1) hydroxy,

(2) C_1-6 alkyl,

(3) C_1-6 alkoxy,

(4) amino,

(5) mono- and di-C_1-6 alkylamino,

(6) carboxyl

(7) C_1-6 alkylthio,

(8) --S(O)_k --C_1-3 alkyl, where k is 1 or 2,

(9) C_1-6 alkoxycarbonyl,

(10) halo selected from fluoro, chloro, bromo, and iodo,

(11) oxo,

(12) amidino and

(13) guanidino,

with the proviso that R₂ is other than aryl, heteroaryl, arylC_1-4 alkyl, or heteroarylC_1-4 alkyl.

2. A method for inhibiting the activity of nitric oxide synthases comprising administering to a subject suffering from a nitric oxide synthase mediated disease, a non-toxic therapeutically effective amount of a compound of Formula (I) ##STR84## or a pharmaceutically acceptable salt thereof wherein:

R₁, R₂, R₃ and R₄ are each independently selected from the group consisting of;

(a) hydrogen,

(b) hydroxy,

(c) amino,

(d) cyano,

(e) fluoro, chloro, bromo, and iodo,

(f) trifluoromethyl,

(g) C_1-6 alkyl,

(h) C_1-6 alkoxy,

(i) C_1-6 alkylthio,

(j) C_1-6 alkylcarbonyl,

(k) mono- and di-C_1-6 alkylamino,

(l) aryl, where aryl is phenyl and naphthyl,

(m) aryloxy, where aryl is phenyl and naphthyl,

(n) cycloalkyl,wherein the cycloalkyl is a 5-, 6-, or 7-membered monocyclic ring which optionally contains 1 or 2 heteroatoms selected from S, O, and N, and

(o) heteroaryl, wherein heteroaryl is selected from the group consisting of;

(1) pyridyl,

(2) furanyl,

(3) thienyl,

(4) pyrazinyl,

(5) pyrimidyl,

(6) thiazolyl and

(7) triazolyl,

each of (g) to (o) being optionally mono- or di- substituted, the substituents being independently selected from the group consisting of;

(1) hydroxy,

(2) C_1-4 alkyl,

(3) C_1-3 alkoxy,

(4) C_1-3 alkylthio,

(5) mono- and di-C_1-3 alkylamino,

(7) --S(O)_k --C_1-3 alkyl, where k is 1 or 2,

(8) --C(O)--O--C_1-3 alkyl,

(9) halo selected from fluoro, chloro and bromo,

(10) amino and

(11) carboxyl,

and one of R₁ and R₂, R₂ and R₃ and R₃ and R₄ is taken together to form a 5-, 6- or 7-membered saturated monocyclic ring which together with the atoms to which R₁ and R₂, or R₂ and R₃ or R₃ and R₄ are attached there is formed a bicyclic ring according to Formulae (IIa-IIc), ##STR85## and R₅ is selected from the group consisting of;

(a) hydrogen,

(b) C_1-6 alkyl,

(c) aryl, wherein the aryl group is phenyl and naphthyl,

(d) arylC_1-6 alkyl, wherein the aryl group is phenyl and naphthyl,

(e) heteroaryl, wherein heteroaryl is as defined above,

(f) heteroarylC_1-6 alkyl, wherein heteroaryl is as defined above, and

(g) cycloalkyl,wherein the cycloalkyl is a 5-, 6-, or 7-membered monocyclic ring which optionally contains 1 or 2 heteroatoms selected from S, O, and N,

each of (b) to (g) being optionally mono- or di- substituted, the substituents being independently selected from the group consisting of;

(1) hydroxy,

(2) C_1-4 alkyl,

(3) C_1-3 alkoxy,

(4) C_1-3 alkylthio,

(5) mono- and di-C_1-3 alkylamino,

(7) --S(O)_k --C_1-3 alkyl, where k is 1 or 2,

(8) --C(O)--O--C_1-3 alkyl and

(9) halo selected from fluoro, chloro and bromo.

3. A method for inhibiting the activity of nitric oxide synthases comprising administering to a subject suffering from a nitric oxide synthase mediated disease, a non-toxic therapeutically effective amount of a compound of Formula (I) ##STR86## or a pharmaceutically acceptable salt thereof wherein:

R₁, R₂, R₃ and R₄ are each independently selected from the group consisting of;

(a) hydrogen,

(b) hydroxy,

(c) amino,

(d) cyano,

(e) fluoro, chloro, bromo, and iodo,

(f) trifluoromethyl,

(g) C_1-6 alkyl,

(h) C_1-6 alkoxy,

(i) C_1-6 alkylthio,

(j) C_1-6 alkylcarbonyl,

(k) mono- and di-C_1-6 alkylamino,

(l) aryl, where aryl is phenyl and naphthyl,

(m) aryloxy, where aryl is phenyl and naphthyl,

(n) cycloalkyl, wherein the cycloalkyl is a 5-, 6-, or 7-membered monocyclic ring which optionally contains 1 or 2 heteroatoms selected from S, O, and N, and

(o) heteroaryl, wherein heteroaryl is selected from the group consisting of;

(1) pyridyl,

(2) furanyl,

(3) thienyl,

(4) pyrazinyl,

(5) pyrimidyl,

(6) thiazolyl and

(7) triazolyl,

each of (g) to (o) being optionally mono- or di- substituted, the substituents being independently selected from the group consisting of;

(1) hydroxy,

(2) C_1-4 alkyl,

(3) C_1-3 alkoxy,

(4) C_1-3 alkylthio,

(5) mono- and di-C_1-3 alkylamino,

(7) --S(O)_k --C_1-3 alkyl, where k is 1 or 2,

(8) --C(O)--O--C_1-3 alkyl,

(9) halo selected from fluoro, chloro and bromo,

(10) amino and

(11) carboxyl,

and one of R₁ and R₂, R₂ and R₃ and R₃ and R₄ is taken together to form a 5-, 6- or 7-membered saturated monocyclic ring containing 1 or 2 heteroatoms which together with the atoms to which R₁ and R₂, or R₂ and R₃ or R₃ and R₄ are attached there is formed a bicyclic ring according to Formulae (IIa-IIc), the heteroatoms being selected from the group consisting of O, S and N, ##STR87## R₅ is selected from the group consisting of;

(a) hydrogen,

(b) C_1-6 alkyl,

(c) aryl, wherein the aryl group is phenyl and naphthyl,

(d) arylC_1-6 alkyl, wherein the aryl group is phenyl and naphthyl,

(e) heteroaryl, wherein heteroaryl is as defined above,

(f) heteroarylC_1-6 alkyl, wherein heteroaryl is as defined above, and

(g) cycloalkyl, wherein the cycloalkyl is a 5-, 6-, or 7-membered monocyclic ring which optionally contains 1 or 2 heteroatoms selected from S, O, and N,

each of (b) to (g) being optionally mono- or di- substituted, the substituents being independently selected from

(1) hydroxy,

(2) C_1-4 alkyl,

(3) C_1-3 alkoxy,

(4) C_1-3 alkylthio,

(5) mono- and di-C_1-3 alkylamino,

(7) --S(O)_k --C_1-3 alkyl, where k is 1 or 2,

(8) --C(O)--O--C_1-3 alkyl and

(9) halo selected from fluoro, chloro and bromo.

4. A method for inhibiting the activity of nitric oxide synthases comprising administering to a subject suffering from a nitric oxide synthase mediated disease, a non-toxic therapeutically effective amount of a compound selected from the group consisting of:

(a) 2-amino-3-benzylurea-4-picoline,

(b) 2-amino-3-methoxypyridine,

(c) 2-amino-3-methylthio-4-picoline,

(d) 2-amino-4-methylthiomethylpyridine,

(e) 2-amino-3-hydroxymethyl-4-picoline,

(f) 2-amino-3-ethyl-4-picoline dihydrochloride,

(g) 2-amino-3-methoxymethyl-4-picoline dihydrochloride,

(h) 2-amino-3-n-propyl-4-picoline dihydrochloride,

(i) 2-amino-3-dimethylamino-4-picoline trihydrochloride,

(j) 2-amino-3-chloro-4-picoline,

(k) 2-amino-5-chloro-4-picoline,

(l) 2,5-diamino-4-picoline,

(m) 5-acetylamino-2-amino-4-picoline,

(n) 2-amino-5-ethynyl-4-methyl-pyridine,

(o) 2-amino-4-methyl-5-pentyl-pyridine,

(p) 4-methylthio-2-aminopyridine,

(q) 4-chloro-6-methoxycarbonyl-2-aminopyridine,

(r) 4,6-dimethyl-5-ethenyl-2-aminopyridine,

(s) 2.4-diaminopyridine dihydrochloride,

(t) 2-amino-5-phenylpyridine,

(u) 2-amino-4-methyl-5-phenylpyridine,

(v) 2-amino-5-bromo-4-methylpyridine,

(w) 2-amino-5-cyano-4-methylpyridine,

(x) 2-amino-5-carboxy-4-methylpyridine,

(y) 2-amino-5-methoxycarbonyl-4-methylpyridine,

(z) 2-amino-5-aminomethyl-4-methylpyridine dihydrochloride,

(aa) 2-amino-5-acetamidomethyl-4-methylpyridine,

(ab) 2-amino-5-hydroxymethyl-4-methylpyridine,

(ac) 2-(2-amino-3-pyridinoxy)-ethyl-(S)-glycine dihydrochloride,

(ad) 2-amino-4,5-dimethylpyridine hydrochloride,

(ae) 2-amino-6-(3-buten-1-yl)-4-methylpyridine,

(af) 2-amino-6-ethyl-4-methylpyridine,

(ag) 2-amino-4-methyl-6-(1-methylethyl)pyridine,

(ah) 2-amino-6-(4-aminobutyl)-4-methylpyridine,

(ai) 6-(4-acetamidobutyl)-2-amino-4-methylpyridine,

(aj) 2-amino-6-(2-hydroxyethyl)-4-methylpyridine,

(ak) α

-(2-(6-amino-4-methylpyrid-2-yl) ethyl)glycine dihydrochloride,

(al) 2-amino-5-ethylpyridine,

(am) 2-amino-6-benzylpyridine,

(an) 2-amino-6,7-dihydro-(5H)-pyrindine,

(ao) 2-amino-6-(3-aminopropyl)-4-methylpyridine,

(ap) 2-amino-6-(2-aminoethyl)-4-methylpyridine,

(aq) 2-amino-4-methyl-6-propylpyridine,

(ar) 2-amino-4-methyl-6-(3-phenylpropyl)pyridine,

(as) 2-amino-4-methyl-6-(4-phenylbutyl)pyridine,

(at) 2-amino-4-methyl-6-(3-methylbutyl)pyridine,

(au) 2-amino-4-methyl-6-(2-methylpropyl)pyridine,

(av) 2-amino-4-methyl-6-(2-phenylethyl)pyridine,

(aw) 5-(6-amino-4-methyl-2-pyridinyl)pentanoic acid hydrochloride,

(ax) 4-(6-amino-4-methyl-2-pyridinyl)butanoic acid hydrochloride,

(ay) (S)-2-amino-6-(3-aminobutyl)-4-methylpyridine, and

(az) (R)-2-Amino-6-(3-aminobutyl)-4-methylpyridine,

or a pharmaceutically acceptable salt thereof.