ADENOSINE ANALOGUES HAVING ANTIHYPERTENSIVE, CARDIOPROTECTIVE, ANTI-ISCHEMIC AND ANTILIPOLYTIC PROPERTIES

摘要

1. A compound of the formula wherein: K - N, N - O, or CH; Q - CH2 or O; R6 is hydrogen, C1-10 alkyl, allyl, 2-methylallyl, 2-butenyl, or C3-10cycloalkyl; X is where the nitrogen of the ring of X is substituted by Y; E is O or S; Y is hydrogen, C1-20alkyl, C1-20alkyl, substituted with phenyl, C1-20alkyl, substituted with naphtyl, C1-20alkyl, substituted with substituted phenyl, C1-20alkyl, substituted with substituted naphtyl, 4-10 membered heterocyclic ring, comprising at least one atom N, O or S, substituted 4-10 membered heterocyclic ring, comprising at least one atom N, O, S, C1-20alkyl, substituted with 4-10 membered heterocyclic ring, comprising at least one atom N, O, S, or C1-20alkyl, substituted with substituted 4-10 membered heterocyclic ring, comprising at least one atom N, O, S; n and p are independently 0,1, 2, or 3, provided that n + p is at least 1; T is hydrogen, C1-20alkyl, C1-20acyl, C1-20thioacyl, halo, carboxyl, or R3O-CH2; R1, R2, and R3 are independently H, C1-20alkyl, C3-10cycloalkyl; A is hydrogen, C1-20alkyl, C1-20hydroxyalkyl, C1-20alkyl, substituted C1-20alkoxy, OR'; B is hydrogen, C1-20alkyl, C1-20hydroxyalkyl, C1-20alkyl, substituted C1-20alkoxy, or OR''; R' and R'' are independently hydrogen, C1-20alkyl, C1-20alkyl substituted with phenyl, C1-20alkyl substituted with naphtyl, carbamoyl, C1-20alkylcarbamoyl, di-(C1-20alkyl)-carbamoyl, acyl, C1-20alkoxycarbonyl, phenylC1-20aralkoxycarbonyl, naphtylC1-20aryloxycarbonyl, phenyloxycarbonyl, nathtyloxycarbonyl, or, when A and B are OR' and OR'', respectively, R' and R'' together may form H, ORc, wherein Rc - hydrogen, C1-20alkyl, wherein Rd and Re - are independently hydrogen, C1-20alkyl; together with the carbon atom to which they are attached may form a C3-101,1-cycloalkyl group; or a pharmaceutically acceptable salt thereof. 2. A compound according to Claim 1 wherein K is N; T is hydroxymethyl or methoxymethyl; A and B are hydroxy: X is and n + p is 3 or 4; or a pharmaceutically acceptable salt thereof. 3. A compound according to Claim 2 which is (2R,3R,4S,5R)-2-hydroxymethyl-5-[6-[1-(5-chloropyridin-2-yl)-pyrrolidin-3(S)-yl-amino]-purin-9-yl]-tetrahydrofuran-3,4-diol, (2R,3S,4R,5R)-2-hydroxymethyl-5-[6-[1-(5-trifluoromethylpyridin-2-yl)-pyrrolidin-3(R)-ylamino]-purin-9-yl]tetrahydrofuran-3,4-diol, (2R,3R,4S,5R)-2-hydroxymethyl-5-[6-[1-(5-trifluoromethylpyridin-2-yl)-pyrrolidin-3(S)-ylamino]-purin-9-yl]tetrahydrofuran-3,4-diol, (2R,3R,4S,5R)-2-hydroxymethyl-5-[6-[1-(4-trifluoromethylpyridin-2-yl)-pyrrolidin-3(S)-ylamino]-purin-9-yl]tetrahydrofuran-3,4-diol, (2R,3R,4S,5R)-2-hydroxymethyl-5-[6-[1-(5-bromopyridin-2-yl)-pyrrolidin-3(S)-ylamino]-purin-9-yl]tetrahydrofuran-3,4-diol, (2R,3R,4S,5R)-2-hydroxymethyl-5-[6-[1-(4-nitrophenyl)-pyrrolidin-3(S)-ylamino]-purin-9-yl]tetrahydrofuran-3,4-diol, (2R,3R,4S,5R)-2-hydroxymethyl-5-[6-(5'-trifluoromethyl-3,4,5,6-tetrahydro-2H-[l,2']-bipyridinyl-3-yl)-purin-9-yl]tetrahydrofuran-3,4-diol, (2R, 3R,4S,5R)-2-hydroxymethyl-5-[6-(phenylpyrrolidin-3(S)-ylamino)-purin-9-yl]tetrahydrofuran-3,4-diol, (2R,3R,4S,5R)-2-hydroxymethyl-5-[6-(1-pyridin-2-ylpyrrolidin-3(S)-ylamino]-purin-9-yl]tetrahydrofuran-3,4-diol, (2R,3R,4S,5R)-2-hydroxymethyl-5-[6-[1-(4-chlorophenyl)-pyrrolidin-3(S)-ylamino]-purin-9-yl]tetrahydrofuran-3,4-diol, (2R ,3R,4S,5R)-2-hydroxymethyl-5-[6-[1-(5-methylpyridin-2-yl)-pyrrolidin-3(S)-ylamino]-purin-9-yl]tetrahydrofuran-3,4-diol, (2R,3R,4S,5R)-2-hydroxymethyl-5[6-[1-(5-thiophen-2-ylpyridin-2-yl)-pyrrolidin-3(S)-ylamino]-purin-9-yl]tetrahydrofuran-3,4-diol, (2R,3R,4S,5R)-2-hydroxymethyl-5-[6-[l-(5-methylmercaptopyridin-2-yl)-pyrrolidin-3(S)-ylamino]-purin-9-yl]tetrahydrofuran-3,4-diol, (2R,3R,4S,5R)-2-hydroxymethyl-5-[6-[1-(6-methoxypyrimidin-4-yl)pyrrolidin-3(S)-ylamino]-purin-9-yl]tetrahydrofuran-3,4-diol, (2R,3R,4S,5R)-2-hydroxymethyl-5-[6-[1-(6-chloropyrimidin-4-yl)pyrrolidin-3(S)-ylamino]-purin-9-yl]tetrahydrofuran-3,4-diol, (2R,3R,4S,5R)-2-hydroxymethyl-5-[6-[1-(6-chloropyridazin-3-yl)pyrrolidin-3-ylamino]-purin-9-yl]-tetrahydrofuran-3,4-diol, (2R,3R,4S,5R)-2-methoxymethyl-5-[6-[1-(5-trifluoromethylpyridin-2-yl)pyrrolidin-3(S)-ylamino]-purin-9-yl]tetrahydrofuran-3,4-diol, (1S,2R,3R,5R)-3-hydroxymethyl-5-[6-[1-(4-nitrophenyl)piperidin-4-yl]-purin-9-yl]cyclopentane-1,2-diol, (1S,2R,3R,5R)-3-hydroxymethyl-5-[6-((3S)-pyrrolidin-3-ylamino)-purin-9-yl]cyclopentane-1,2-diol dihydrochloride, (1S,2R,3R,5R)-3-hydroxymethyl-5-[6-[1-(4-nitrophenyl)pyrrolidin-3-ylamino]-purin-9-yl]cyclopentane-1,2-diol, (1S,2R,3R,5R)-3-hydroxymethyl-5-[6-[1-(5-trifluoromethylpyridin-2-yl)pyrrolidin-3(R)-ylamino]-purin-9-yl]cyclopentane-1,2-diol, (1S,2R,3R,5R)-3-hydroxymethyl-5-[6-((3R)-pyrrolidin-3-ylamino)-purin-9-yl]cyclopentane-1,2-diol, (1R,2S,3R,5R)-3-hydroxymethyl-5-[6-[1-(5-trifluoromethylpyridin-2-yl)pyrrolidin-3(S)-ylamino]-purin-9-yl]cyclopentane-1,2-diol, (1R,2S,3R,5R)-5-[6-[1-(5-bromopyridin-2-yl)pyrrolidin-3(S)-ylamino]-purin-9-yl]-3-hydroxymethylcyclopentane-1,2-diol, (1R,2S,3R,5R)-5-[6-[1-(5-chloropyridin-2-yl)pyrrolidin-3(S)-ylamino]-purin-9-yl]-3-hydroxymethylcyclopentane-1,2-diol, (1R,2S,3R,5R)-3-hydroxymethyl-5-[6-[1-(4-trifluoromethylpyridin-2-yl)pyrrolidin-3(S)-ylamino]-purin-9-yl]cyclopentane-1,2-diol, (1R,2S,3R,5R)-3-hydroxymethyl-5-[6-[1-(pyridin-2-yl)pyrrolidin-3(S)-ylamino]-purin-9-yl]cyclopentane-1,2-diol, (1 R,2S,3R,5R)-3-hydroxymethyl-5-[6-[1-(quinolin-3-yl)pyrrolidin-3(S)-ylamino]-purin-9-yl]cyclopentane-1,2-diol, (1R,2S,3R,5R)-3-hydroxymethyl-5-[6-[1-S-(4-nitrophenyl)-pyrrolidin-3(S)-ylamino]-purin-9-yl]cyclopentane-1,2-diol, (1R,2S,3R,5R)-5-[6-[1-(4,5-bis-trifluorpyridin-2-yl)pyrrolidin-3(S)-ylamino]-purin-9-yl]-3-hydroxymethylcyclopentane-1,2-diol, (1R,2S,3R,5R)-3-methoxymethyl-5-[6-[1-(5-trifluoromethylpyridin-2-yl)pyrrolidin-3(S)-ylamino]-purin-9-yl]cyclopentane-1,2-diol, (1R,2S,3R,5R)-3-hydroxymethyl-5-[6-[1-(phenyl)-pyrrolidin-3(S)-ylamino]-purin-9-yl]cyclopentane-1,2-diol, 4-[3(S)-[9-(2,3-dihydroxy-4-hydroxymethylcyclopentyl)-9H-purin-6-ylamino]pyrrolidin-1-yl]benzonitrile, (1R,2S,3R,5R)-3-hydroxymethyl-5-[6-[1-(isoquinolin-1-yl)pyrrolidin-3(S)-ylamino]-purin-9-yl]cyclopentane-l,2-diol, (1R,2S,3R,5R)-5-[6-[1-(6-bromoquinolin-2-yl)pyrrolidin-3(S)-ylamino]-purin-9-yl]-3-hydroxymethylcyclopentane-1,2-diol, (1R,2S,3R,5R)-5-[6-[1-(4-chlorophenyl)pyrrolidin-3(S)-ylamino]-purin-9-yl]-3-hydroxymethylcyclopentane-1,2-diol, (1R,2S,3R,5R)-3-[6-[1-(3-chloro-5-trifluoromethylpyridin-2-yl)pyrrolidin-3(S)-ylamino]-purin-9-yl]-3-methoxymethylcyclopentane-1,2-diol, (1R,2S,3R,5R)-5-[6-[1-(6-chloropyrimidin-4-yl)pyrrolidin-3(S)-ylamino]-purin-9-yl]-3-hydroxymethylcyclopentane-1,2-diol, (1R,2S,3R,5R)-5-[6-[1-(6-chloropyrimidin-4-yl)pyrrolidin-3-(S)-ylamino]-purin-9-yl]-3-hydroxymethylcyclopentane-1,2-diol, (1R,2S,3R,5R)-5-[6-[1-(6-chloropyrimidin-4-yl)pyrrolidin-3(S)-ylamino]-purin-9-yl]-3-methoxymethylcyclopentane-1,2-diol, (1R, 2S,3R,5R)-5-[6-[1-(6-chloropyridazin-3-yl)pyrrolidin-3(S)-ylamino]-purin-9-yl]-3-hydroxymethylcyclopentane-1,2-diol, (1R,2S,3R,5R)-3-methoxymethyl-5-[6-[1-(6-methoxypyrimidin-4-yl)pyrrolidin-3(S)-ylamino]-purin-9-yl]cyclopentane-1,2diol, (1R,2S,3R,5R)-5-[6-[1-(6-chloropyridazin-3-yl)pyrrolidin-3(S)-ylamino]-purin-9-yl]-3-methoxymethylcyclopentane-1,2-diol, (1R,2S,3R,5R)-5-(-[6-[1-(4-trifluoromethylphenyl)-pyrrolidin-3(S)-ylamino]-purin-9-yl]-3-hydroxymethylcyclopentane-1,2-diol, (1R,2S,3R,5R)-5-[6-[1-(5-bromopyridin-2-yl)pyrrolidin-3(S)-ylamino]-purin-9-yl]-3-methoxymethylcyclopentane-1,2-diol, (1R,2S,3R,5R)-5-[6-[1-(5-chlorpyridin-2-yl)pyrrolidin-3(S)-ylamino]-purin-9-yl]-3-methoxymethylcyclopentane-1,2-diol, (1R,2S,3R,5R)-3-methoxymethyl-5-[6-[1-(4-trifluoromethylphenyl)pyrrolidin-3(S)-ylamino]-purin-9-yl]cyclopentane-1,2-diol, (1R,2S,3R,5R)-5-(-[6-[1-(4-chlorophenyl)-pyrrolidin-3(S)-ylamino]-purin-9-yl]-3-methoxymethylcyclopentane-1,2-diol, (1R,2S,3R,5R)-5-[6-[1-(3-chlorophenyl)pyrrolidin-3(S)-ylamno]-purin-9-yl]-3-methoxymethylcyclopentane-1,2-diol, (1R,2S,3R,5R)-5-[6-[1-(3-chlorophenyl)-pyrrolidin-3(S)-ylamino]-purin-9-yl]-3-hydroxymethylcyclopentane-1,2-diol, (1R,2S,3R,5R)-3-methoxymethyl-5-[6-[1-phenylpyrrolidin-3(S)-ylamino]-purin-9-yl]cyclopentan-1,2-diol, (1R,2S,3R,5R)-3-[6-(1-benzyl-pyrrolidin-3(S)-ylamino)purin-9-yl]-5-hydroxymethylcyclopentane-1,2-diol, or (1R,2S,3R,5R)-3-[6-(1-benzyl-pyrrolidin-3(S)-ylamino)purin-9-yl]-5-methoxymethylcyclopentane-l,2-diol; or a pharmaceutically acceptable salt thereof. 4. A compound according to Claim 1 wherein Q is CH2; K is N; T is wherein R1 is H and R2 is C1-6 alkyl; A and B are hydroxy; X is , and n + p is 3 or 4; or a pharmaceutically acceptable salt thereof. 5. A compound according to Claim 4 which comprises (1S,2R,3S,4R)-2,3-dihydroxy-4-[6-[1-(5-trifluormethylpyridin-2-yl)pyrrolidin-3-ylamino]-purin-9-yl]cyclopentanecarboxylic acid ethylamide, (S)-sec-butylamide (1S,2R,3S,4R)-2,3-dihydroxy-4-[6-[1-(5-trifluormethylpyridin-2-yl)pyrrolidin-3-ylamino]-purin-9-yl]cyclopentanecarboxylic acid, and (R)-sec-butylamide (1S,2R,3S,4R)-2,3-dihydroxy-4-[6-[1-(5-trifluormethylpyridin-2-yl)pyrrolidin-3-ylamino]-purin-9-yl]cyclopentanecarboxylic acid, and a pharmaceutically acceptable salt thereof. 6. A compound according to Claim 1 wherein Q is CH2; K is N; T is hydroxymethyl or methoxymethyl; A and B are hydroxy; X is , and n + p is 3 or 4; or a pharmaceutically acceptable salt thereof. 7. A compound according to Claim 6 which is (1S,2R,3R,5R)-3-hydroxymethyl-5-[6-[1-(4-nitrophenyl)piperidin-4-yl]-purin-9-yl]cyclopentane-1,2-diol, (1S,2R,3R,5R)-3-hydroxymethyl-5-[6-((3S)-pyrrolidin-3-ylamino)-purin-9-yl]cyclopentane-1,2-diol dihydrochloride, (1S,2R,3R,5R)-3-hydroxymethyl-5-[6-[1-(4-nitrophenyl)pyrrolidin-3-ylamino]-purin-9-yl]cyclopentane-1,2-diol, (1S,2R, 3R,5R)-3-hydroxymethyl-5-[6-[l-(5-trifluoromethylpyridin-2-yl)pyrrolidin-3(R)-ylamino]-purin-9-yl]cyclopentane-1,2-diol, (1S,2R,3R,5R)-3-hydroxymethyl-5-[6-((3R)-pyrrolidin-3-ylamino)-purin-9-yl]cyclopentane-1,2-diol, (1R,2S,3R,5R)-3-hydroxymethyl-5-[6