Substituted 2-acylamino-pyridines as inhibitors of nitric oxide synthase

• US 5,908,842 A
• Filed: 05/20/1997
• Issued: 06/01/1999
• Est. Priority Date: 12/08/1995
• Status: Expired due to Fees

• Current Assignee: Merck & Co., Inc.
• Original Assignee: Merck & Co., Inc.
• Inventors: Maccoss, Malcolm, Shah, Shrenik, Guthikonda, Ravindra, Hagmann, William, Durette, Philippe
• Primary Examiner(s): NORTHINGTON DAVIS, ZINNA
• Application Number:
  US08/836,863
• Time in Patent Office: 742 Days
• Field of Search: 546/306, 546/112, 546/113, 546/114, 546/143, 546/159, 514/353, 514/231.5, 514/252, 514/253, 514/299, 514/300, 514/301, 514/310, 514/313, 544/105, 544/350, 544/360
• US Class Current: 514/253.01
• CPC Class Codes: C07D 213/75 Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates

Abstract

Substituted 2-acylaminopyridine compounds and pharmaceutically acceptable salts which have been found useful in the treatment of nitric oxide synthase mediated diseases and disorders.

Claims

1. A compound of Formula (I) ##STR35## or a pharmaceutically acceptable salt thereof wherein:

one of R₁ and R₂, R₂ and R₃ or R₃ and R₄ including the optional substituents present thereon, is joined together to form a 5-, 6- or 7-membered saturated monocyclic ring containing 0, 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, ##STR36## and wherein the rings of Formulae IIa, IIb and IIc are selected from the group consisting of ##STR37## and the remaining R₁, R₂, R₃ and R₄ groups are each independently selected from the group consisting of;

(a) hydrogen,

(b) hydroxy,

(c) amino,

(d) cyano,

(e) halo selected from the group consisting of;

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,

(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;

(1) hydroxy,

(2) C_1-4 alkyl,

(3) C1-3alkoxy,

(4) amino,

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

(6) carboxyl,

(7) C_1-3 alkylthio,

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

(9) C_1-4 alkoxyearbonyl,

(10) halo selected from the group consisting of;

fluoro, chloro, bromo, and iodo,

(11) oxo and

(12) amidino, and

R₅ is selected from the group consisting of

(a) amino-C(═

S)--,

(b) C_1-6 alkylcarbonyl,

(c) aroyl, wherein the aroyl group is benzoyl,

(d) C_1-6 alkylamino-C(═

S)--,

(e) C_2-6 alkenylamino-C(═

S)--,

(f) arylamino-C(═

S)--, wherein the aryl group is phenyl and naphthyl

(g) arylC1-6alkylamino-C(═

S)--, wherein the aryl group is phenyl and naphthyl,

(h) cycloC_5-7 alkylamino-C(═

S)--,

(i) aroylaminocarbonyl, wherein the aroyl group is benzoyl and naphthoyl,

(j) R₆ R₇ N--SO₂ --NH--C(═

O)--, wherein R₆ and R₇ are independently selected from the group consisting of

(1) hydrogen,

(2) C_1-6 alkyl

(3) aryl, wherein the aryl group is selected from phenyl,

(4) R₆ and R₇ may be joined together to form a 5-, 6- or 7-membered ring containing 0, 1 or 2 heteroatoms, the heteroatoms being elected from the group of oxygen, sulfur and nitrogen,

each of (b) to (j) 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) amino,

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

(6) carboxyl,

(7) C_1-3 alkylthio,

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

(9) C_1-4 alkoxycarbonyl,

(10) halo selected from the group consisting of;

fluoro, chloro, bromo, and iodo,

(11) oxo, and

(12) amidino.

2. A compound according to claim 1 wherein

the remaining R₁, R₂, R₃ and R₄ groups are each independently selected from the group consisting of:

(a) hydrogen,

(b) hydroxy,

(c) amino,

(d) cyano,

(e) fluoro, chloro or bromo,

(f) trifluoromethyl,

(g) C_1-4 alkyl,

(h) C_1-4 alkoxy,

(i) C_1-4 alkylthio,

(j) mono- and di-C_1-4 alkylamino, and

R₅ is selected from the group consisting of

(a) amino-C(═

S)--,

(b) C_1-4 alkylamino-C(═

S)--,

(c) C_2-4 alkenylamino-C(═

S)--,

(d) arylamino-C(═

S)--, wherein the aryl group is phenyl and naphthyl,

(e) arylC1-4alkylamino-C(═

S)--, wherein the aryl group is phenyl,

(f) R₆ R₇ N--SO₂ --NH--C(═

O)--, wherein R₆ and R₇ are independently selected from the group consisting of

(1) hydrogen,

(2) C_1-4 alkyl

(3) phenyl,

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

(1) hydroxy,

(2) C1 4alkyl,

(3) C_1-3 alkoxy,

(4) amino,

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

(6) carboxyl,

(7) C_1-3 alkylthio, and

(8) halo selected from the group consisting of;

fluoro, chloro and bromo.

3. A compound according to claim 2 wherein

R₂ is hydrogen or methyl,

R₄ is hydrogen or methyl,

R₁ and R₃ are each independently selected from

(a) hydrogen,

(b) methyl, ethyl, propyl or butyl,

(c) chloro,

(d) --CN, and

(e) --CF₃,

R₅ is selected from the group consisting of

(a) amino-C(═

S)--,

(b) C_1-4 alkylamino-C(═

S)--,

(c) C_2-4 alkenylamino-C(═

S)--,

(d) arylamino-C(═

S)--, wherein the aryl group is phenyl and naphthyl,

(e) arylC1-4alkylamino-C(═

S)--, wherein the aryl group is phenyl,

(f) R₆ R₇ N--SO₂ --NH--C(═

O)--, wherein R₆ and R₇ are independently selected from the group consisting of

(1) hydrogen,

(2) C_1-2 alkyl,

(3) phenyl,

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

(1) hydroxy,

(2) C_1-2 alkyl,

(3) C_1-2 alkoxy,

(4) amino,

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

(6) C_1-3 alkylthio,

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

4. A pharmaceutical composition for treating a nitric oxice synthase mediated disease comprising a pharmaceutical carrier and a non-toxic effective amount of the compound of claim 1.

5. 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 the compound of claim 1.

6. A pharmaceutical composition for treating a nitric oxide synthase mediated disease comprising a pharmaceutical carrier and a non-toxic effective amount of the compound selected from

(a) N-(2-(4-Methylpyridyl))-N'"'"'-(4-methylphenyl)-urea;

(b) N-(2-(4-Methylpyridyl))-thiourea;

(c) N-(2-(4,6-dimethylpyridyl))-thiourea;

(d) N-(2-(5-trifluoromethylpyridyl))-N'"'"'-allyl-thiourea;

(e) N-(2-(4,6-dimethylpyridyl))-N'"'"'-allyl-thiourea;

(f) N-(2-(4-Methylpyridyl))-N'"'"'-isopropyl-thiourea;

(g) N-(2-(4-Methylpyridyl))-N'"'"'-ethyl-thiourea;

(h) N-(2-(4-Methylpyridyl))-N'"'"'-phenyl-thiourea;

(i) N-(2-Pyridyl)-N'"'"'-(4-bromophenyl)-thiourea;

(j) N-(2-(4-Methylpyridyl))-N'"'"'-(1-naphthyl)-thiourea;

(k) N-(2-(4-Methylpyridyl))-N'"'"'-(3-fluorophenyl)-thiourea;

(l) N-(2-(4-Methylpyridyl)-N'"'"'-benzyl-thiourea;

(m) N-(2-(4-Methylpyridyl))-N'"'"'-(3,3,5-trimethylcyclohexyl)-thiourea;

(n) N-(2-(4-Methylpyridyl))-N'"'"'-benzoyl-urea; and

(o) N-(2-(4-Methylpyridyl))-N'"'"'-(((S)-4-amino-4-carboxy)-n-butyl)-thiourea;

(p) N-(2-Pyridyl)-N'"'"'-(1-piperazinylsulfonyl)-urea;

(q) N-(2-(3-Methylpyridyl)-N'"'"'-(diethylaminosulfonyl)-urea;

(r) N-(2-(4-Methylpyridyl)-N'"'"'-(diethylaminosulfonyl)-urea;

(s) N-(2-(5-Methylpyridyl)-N'"'"'-(diethylarninosulfonyl)-urea;

(t) N-(2-(4-Methylpyridyl)-N'"'"'-(diethylaminosulfonyl)-N'"'"'-methyl-urea;

(u) Oxalamide, N-(4-methyl-2-pyridyl), methyl ester; and

(v) Malonamide, N-(4-methyl-2-pyridyl), methyl ester.