Patent EA-004987-B1 (EA)
Title: Purine derivatives
Inventor: MANTELL SIMON JOHN
IPC: A61P11/02
Filed: 2001-02-09
Abstract: 1. A compound of the formula or a pharmaceutically acceptable salt or solvate thereof, wherein R<1> is hydrogen, C1-C6alkyl or C3-C7 cycloalkyl, each optionally substituted by 1 or 2 substituents each independently selected from hydroxyl, fluorenyl, phenyl and naphthyl, said phenyl and naphthyl being optionally substituted by C1-C6 alkyl, C1-C6 alkoxy, halo or cyano; A is a bond or C1-C6 alkylene; R<2> is (i) hydrogen, C1-C6 alkyl, C3-C7 cycloalkyl, phenyl or naphthyl, said C3-C7 cycloalkyl, phenyl and naphthyl being optionally substituted by C1-C6 alkyl, phenyl, C1-C6 alkoxy-(C1-C6)-alkyl, amino-(C1-C6)-alkyl, fluoro-(C1-C6)-alkyl, fluoro-(C1-C6)-alkoxy, C2-C5 alkanoyl, halo, -OR<3>, cyano, -COOR<3>, C3-C7 cycloalkyl, -S(O)mR<4>, -NR<3>R<3>, -SO2NR<3>R<3>, -CONR<3>R<3>, -NR<3>COR<4> or -NR<3>SO2R<4>, with the proviso that R<2> is not hydrogen when A is a bond, or (ii) when A is C2-C6 alkylene, -NR<3>R<3>, -OR<3>, -COOR<3>, -OCOR<4>, -SO2R<4>, -CN, -SO2NR<3>R<4>, -NR<3>SO2R<4>, -NR<3>COR<4> or -CONR<3>R<3>, or (iii) a C-linked, 4 to 11 membered, mono or bicyclic heterocycle having either from 1 to 4 ring nitrogen atom (s) or 1 or 2 nitrogen and 1 oxygen or 1 sulphur ring atoms, optionally C-substituted by oxo, C1-C6 alkoxy-(C1-C6)-alkyl, amino-(C1-C6)-alkyl, fluoro-(C1-C6)-alkyl, fluoro-(C1-C6)-alkoxy, fluoro-(C2-C5)-alkanoyl, halo, cyano, -OR<5>, R<6>, -COR<5>, -NR<5>R<5>, -COOR<5>, -S(O)mR<6>, -SO2NR<5>R<5>, -CONR<5>R<5>, -NR<5>SO2R<6> or -NR<5>COR<6> and optionally N-substituted by C1-C6alkoxy-(C1-C6)-alkyl, amino-(C2-C6)-alkyl, fluoro-(C1-C6)-alkyl, fluoro-(C2-C5)-alkanoyl, R<6>, COR<5>, -COOR<6>, -SO2R<6>, -SO2NR<5>R<5> or -CONR<5>R<5>, or (iv) when A is C2-C6 alkylene, N-linked azetidinyl, pyrrolidinyl, morpholinyl, tetrahydroisoquinolinyl, piperidinyl or piperazinyl, each being optionally C-substituted by C1-C6 alkyl, phenyl, C1-C6 alkoxy-(C1-C6)-alkyl, amino-(C1-C6)-alkyl, fluoro-(C1-C6)-alkyl, fluoro-(C1-C6)-alkoxy, C2-C5 alkanoyl, halo, -OR<3>, cyano, -COOR<3>, C3-C7 cycloalkyl, -S(O)mR<4>, -NR<3>R<3>, -SO2NR<3>R<3>, -CONR<3>R<3>, -NR<3>COR<4> or -NR<3>SO2R<4> and said piperazinyl being optionally N-substituted by C1-C6alkyl, phenyl, C1-C6 alkoxy-(C1-C6)-alkyl, amino-(C2-C6)-alkyl, fluoro-(C1-C6)-alkyl, C2-C5alkanoyl, -COOR<4>, C3-C7 cycloalkyl, -SO2R<4>, -SO2NR<3>R<3> or -CONR<3>R<3>; each R<3> is independently selected from H, C1-C6 alkyl, phenyl or pyridinyl; R<4> is C1-C6 alkyl or phenyl; R<5> is H, C1-C6 alkyl, C3-C7 cycloalkyl, phenyl, naphthyl or het; R6 is C1-C6 alkyl, C3-C7 cycloalkyl, phenyl, naphthyl or het; m is 0, 1 or 2; R<7> is hydrogen, C1-C6 alkyl, C3-C7 cycloalkyl, phenyl, naphthyl, azetidin 3-yl, pyrrolidin-3-yl, piperidin-3-yl, piperidin-4-yl or het, said azetidin-3-yl, pyrrolidin-3-yl, piperidin-3-yl andpiperidin-4-yl being optionally substituted by C1-C6 alkyl; R<8> is H or C1-C6 alkyl; and "het", used in the definitions of R<5>, R<6> and R<7>, means C-linked pyrrolyl, imidazolyl, triazolyl, thienyl, furyl, thiazolyl, oxazolyl, thiadiazolyl, oxadiazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, quinolinyl, isoquinolinyl, benzimidazolyl, quinazolinyl, phthalazinyl, benzoxazolyl or quinoxalinyl, each being optionally substituted by C1-C6 alkyl, C1-C6 alkoxy, cyano or halo. 2. A compound as claimed in claim 1, wherein R<1> is cyclohexyl or optionally substituted C1-C6 alkyl. 3. A compound as claimed in claim 2, wherein R<1> is optionally substituted C1-C5 alkyl. 4. A compound as claimed in claim 3, wherein R<1> is optionally substituted C1-C2 alkyl. 5. A compound as claimed in any of claims 2, 3 or 4, wherein the C1-C6, C1-C5 or C1-C2 alkyl substituents are selected from benzyl, fluorenyl, phenyl and hydroxyl. 6. A compound as claimed in claim 5, wherein there are 1 or 2 phenyl group (s) when R<1> is substituted by phenyl. 7. A compound as claimed in any of claims 2 to 5, wherein R<1> is selected from 2,2-diphenylethyl, cyclohexyl, 1-ethylpropyl, 1-benzyl-2-hydroxyethyl, 9H-fluoren-9-ylmethyl, and 1-benzyl-2-phenylethyl. 8. A compound as claimed in claim 7, wherein R<1> is diphenylethyl. 9. A compound as claimed in claim 8, wherein R<1> is 2,2-diphenylethyl. 10. A compound as claimed in any proceeding claim, wherein A is C1-C6 alkylen. 11. A compound as claimed in claim 10, wherein A is C1-C4 alkylene. 12. A compound as claimed in claim 11, wherein A is selected from methylene, 1,2-ethylene, 1, 3-propylene, and 1,4-butylene. 13. A compound as claimed in claim 12, wherein A is 1,2-ethylene. 14. A compound as claimed in any proceeding claim, wherein R<2> is selected from phenyl, pyrrolidinyl, pyridinyl, optionally substituted piperidinyl, optionally substituted piperazinyl, optionally substituted imidazolyl, morpholinyl, tetrahydroisoquinolyl, C1-C6 alkylamino, di-C1-C6alkylamino, pyridinyiamino and -NR<3>SO2R<4>. 15. A compound as claimed in claim 14, wherein R<2> is selected from phenyl, 2-pyridinyl, 1-piperidinyl, 4-piperazinyl, 1-pyrrolidinyl, 4 morpholinyl, 3,4-tetrahydro-2(1H)-isoquinolinyl, C1-C3alkylamino, di C1-C3alkylamino, and substituted 1H-imidazol-4-yl. 16. A compound as claimed in claim 15, wherein R<2> is selected from 3 isopropylamino, methylamino, dimethylamino, diethylamino, 1-methyl-1H-imidazol-4-yl, 5-methyl-1H-imidazol4-yl, 4-methylpiperazin-1-yl, 1 (2-propyl) piperidin-4-yl and 2-pyridylamino. 17. A compound as claimed in claim 15, wherein R<2> is piperidinyl optionally substituted by C1-C6 alkyl or methoxy. 18. A compound as claimed in claim 17, wherein R<2> is piperidinyl optionally substituted in the 1-positionor 4-position by C1-C6 alkyl or methoxy. 19. A compound as claimed in claim 18, wherein R<2> is N-linked piperidinyl optionally C-substituted by C1-C6 alkyl or methoxy. 20. A compound as claimed in claim 19, wherein R is N-linked piperidinyl optionally C-substituted by C1-C3 alkyl or methoxy. 21. A compound as claimed in claim 20, wherein R<2> is N-linked piperidinyl optionally C-substituted by methyl, methoxy or propyl. 22. A compound as claimed in claim 21, wherein R<2> is N-linked piperidinyl optionally substituted in the 4-position by methyl, methoxy or propyl. 23. A compound as claimed in claim 22, wherein R<2> is piperidin-1-yl, 4 (methyl)piperidin-1-yl, 4-(methoxy) piperidin-1-yl or 4-(prop-2-yl) piperidin-1-yl. 24. A compound as claimed in any proceeding claim, wherein R<3> is methyl. 25. A compound as claimed in any proceeding claim, wherein R<4> is methyl or phenyl. 26. A compound as claimed in any proceeding claim, wherein R<7> is C1-C6 alkyl. 27. A compound as claimed in claim 26, wherein R<7> is C1-C4 alkyl. 28. A compound as claimed in claim 27, wherein R<7> is ethyl or n-propyl. 29. A compound as claimed in any proceeding claim, wherein R<8> is H. 30. A compound as claimed in claim 1 selected from the group comprising: 6-[(2,2-diphenylethyl) amino]-9-{(2R,3R,4S,5S)-[(ethylamino)carbonyl]-3,4-dihydroxytetrahydro-2-furanyl}-N-(2-pyridinylmethyl)-9H-purine-2-carboxamide; N-benzyl-6-[(2,2-diphenylethyl) amino]-9-{(2R,3R,4S,5S)-(ethylamino) carbonyl]-3,4-dihydroxytetrahydro-2-furanyl}-9H-purine-2-carboxamide; 6-[(2,2-diphenylethyl) amino]-9-{(2R,3R,4S,5S)-[(ethylamino) carbonyl]-3,4-dihydroxytetrahydro-2-furanyl}-N-(2-phenylethyl)-9H-purine-2-carboxamide; N-[2-(dimethylamino) ethyl]-6-[(2,2-diphenylethyl) amino]-9-{(2R,3R,4S,5S)-5-[(ethylamino) carbonyl]-3,4-dihydroxytetrahydro-2-furanyl}-9H-purine-2-carboxamide; 6-[(2,2-diphenylethyl)amino]-9-{(2R,3R,4S,5S)-[(ethylamino)carbonyl]-3,4-dihydroxytetrahydro-2-furanyl}-N-[3-(1-pyrrolidinyl)propyl]-9H-purine-2-carboxamide; 6-[(2,2-diphenylethyl)amino]-9-{(2R,3R,4S,5S)-[(ethylamino)carbonyl]-3,4-dihydroxytetrahydro-2-furanyl}-N-[2-(2-pyridinyl)ethyl]-9H-purine-2-carboxamide; 6-[(2,2-diphenylethyl)amino]-9-{(2R,3R,4S,5S)-[(ethylamino)carbonyl]-3,4-dihydroxytetrahydro-2-furanyl}-N-[2-(4-morpholinyl)ethyl]-9H-purine-2-carboxamide; 9-{(2R,3R,4S,5S)-5-[(ethylamino)carbonyl]-3,4-dihydroxytetrahydro-2-furanyl}-6-[(1-ethylpropyl)amino]-N-[2-(1-piperidinyl)ethyl]-9H-purine-2-carboxamide; 6-{[(1S)-1-benzyl-2-hydroxyethyl]amino}-9-{(2R,3R,4S,5S)-[(ethylamino)carbonyl]-3,4-dihydroxytetrahydro-2-furanyl}-N-[2-(1-piperidinyl)ethyl]-9H-purine-2-carboxamide; 6-[(2,2-diphenylethyl)amino]-9-{(2R,3R,4S,5S)-[(ethylamino)carbonyl]-3,4-dihydroxytetrahydro-2-furanyl}-N-[2-(4-isopropyl-1-piperidinyl)ethyl]-9H-purine-2-carboxamide; N-[2-(3,4-dihydro-2(1H)-isoquinolinyl)ethyl]-6-[(2,2-diphenylethyl)amino]-9-{(2R,3R,4S,5S)-5-[(ethylamino)carbonyl]-3,4-dihydroxytetrahydro-2-furanyl}-9H-purine-2-carboxamide; 6-[(2,2-diphenylethyl)amino]-9-{(2R,3R,4S,5S)-5[(ethylamino)carbonyl]-3,4-dihydroxytetrahydro-2-furanyl}-N-(4-piperidinylmethyl)-9H-purine-2-carboxamide; 6-[(2,2-diphenylethyl)amino]-9-{(2R,3R,4S,5S)-[(ethylamino)carbonyl]-3,4-dihydroxytetrahydro-2-furanyl}-N-[4-(1-piperidinyl)butyl]-9H-purine-2-carboxamide; 6-[(2,2-diphenylethyl)amino]-9-{(2R,3R,4S,5S)-[(ethylamino)carbonyl]-3,4-dihydroxytetrahydro-2-furanyl}-N-[3-(isopropylamino)propyl]-9H-purine-2-carboxamide; 6-[(2,2-diphenylethyl)amino]-9-{(2R,3R,4S,5S)-[(ethylamino)carbonyl]-3,4-dihydroxytetrahydro-2-furanyl}-N-[3-(2-pyridinylamino)propyl]-9H-purine-2-carboxamide; 6-[(2,2-diphenylethyl)amino]-9-{(2R,3R,4S,5S)-[(ethylamino)carbonyl]-3,4-dihydroxytetrahydro-2-furanyl}-N-{3-[methyl(phenylsulfonyl)amino]propyl}-9H-purine-2-carboxamide; 6-[(2,2-diphenylethyl)amino]-9-{(2R,3R,4S,5S)-[(ethylamino)carbonyl]-3,4-dihydroxytetrahydro-2-furanyl}-N-{3-[methyl(methylsulfonyl)amino]propyl}-9H-purine-2-carboxamide; 9-{(2R,3R,4S,5S)-5-[(ethylamino)carbonyl]-3,4-dihydroxytetrahydro-2-furanyl}-6-[(9H-fluoren-9-ylmethyl)amino]-N-[2-(1-piperidinyl)ethyl]-9H-purine-2-carboxamide; N-[3-(diethylamino)propyl]-6-[(2,2-diphenylethyl)amino]-9{(2R,3R,4S,5S)-5-[(ethylamino)carbonyl]-3,4-dihydroxytetrahydro-2-furanyl}-9H-purine-2-carboxamide; 6-[(2,2-diphenylethyl)amino]-9-{(2R,3R,4S,5S)-5[(ethylamino)carbonyl]-3,4-dihydroxytetrahydro-2-furanyl}-N-[3-(4-morpholinyl)propyl]-9H-purine-2-carb