Patent EA-004985-B1 (EA)
Title: Purine derivatives
Inventor: MONAGHAN SANDRA MARINA
IPC: A61P43/00
Filed: 2000-10-06
Abstract: 1. A compound of the formula or a pharmaceutically acceptable salt or solvate thereof, wherein R<1> is hydrogen or C1-C6 alkyl optionally substituted by 1 or 2 substituents each independently selected from 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-C3 alkylene; R<2> is (i) hydrogen, C1-C6 alkyl, C3-C7 cycloalkyl, phenyl or naphthyl, said C3-C7 cycloalkyl, phenyl or naphthyl being optionally substituted by C1-C6 alkyl, phenyl, C1-C6 alkoxy-(C1-C6)-alkyl, R<3>R<3>N-(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-C3 alkylene, -NR<8>R<9>, -OR<3>, -COOR<3>, -OCOR<4>, -SO2R<4>, -CN, -SO2NR<3>R<3>, -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, R<3>R<3>N-(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-C6 alkoxy-(C1-C6)-alkyl, R<3>R<3>N-(C2-C6)-alkyl, fluoro-(C1-C6)-alkyl, fluoro (C2-C5)-alkanoyl, R<6>, -COR<5>, -COOR<5>, -S(O)mR<6>, -SO2NR<5>R<5> or -CONR<5>R<5>; R<3> is H, C1-C6 alkyl, C3-C7 cycloalkyl or phenyl; R<4> is C1-C6 alkyl, C3-C7 cycloalkyl or phenyl; R<5> is H, C1-C6 alkyl, C3-C7 cycloalkyl, phenyl, naphthyl or het; R<6> is C1-C6alkyl, C3-C7 cycloalkyl, phenyl, naphthyl or het; m is 0,1 or 2; "het", used in the definitions of R<5> andR<6>, 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 optionally substituted by C1-C6 alkyl, C1-C6 alkoxy, cyano or halo; R<7> is methyl, ethyl or cyclopropylmethyl; and either, R<8> and R<9>, taken together with the nitrogen atom to which they are attached represent azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, homopiperidinyl, homopiperazinyl or tetrahydroisoquinolinyl, each being optionally substituted on a ring carbon atom by C1-C6 alkyl, C3-C8 cycloalkyl, phenyl, C1-C6 alkoxy-(C1-C6)-alkyl, R<3>R<3>N-(C1-C6)-alkyl, fluoro-(C1-C6)-alkyl, CONR<3>R<3>, -COOR<3> or C2-C5 alkanoyl, and optionally substituted on a ring carbon atom not adjacent to a ring nitrogen atom by fluoro-(C1-C6)-alkoxy, halo, -OR<3>, cyano, -S(O)mR<4>, -NR<3>R<3>, -SO2NR<3>R<3>, -NR<3>COR<4> or -NR<3>SO2R<4>, and said piperazin-1-yl and homopiperazin-1-yl being optionally substituted on the ring nitrogen atom not attached to A by C1-C6 alkyl, phenyl, C1-C6 alkoxy-(C2-C6)-alkyl, R<3>R<3>N-(C2-C6)-alkyl, fluoro-(C1-C6)-alkyl, C2-C5alkanoyl, -COOR<4>, C3-C8cycloalkyl, -SO2R<4>, -SO2NR<3>R<3> or -CONR<3>R<3>, R<8> is H, C1-C6 alkyl, C3-C8 cycloalkyl, phenyl or benzyl and R<9> is H, C1-C6 alkyl, C3-C8 cycloalkyl, phenyl, benzyl, fluoro-(C1-C6)-alkyl, -CONR<3>R<3>, -COOR<4>, C2-C5alkanoyl or -SO2NR<3>R<3>. 2. A compound as claimed in claim 1 wherein R<1> is hydrogen or C1-C6 alkyl optionally substituted by 1 or 2 substituents each independently selected from 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-C3 alkylene; R<2> is (i) hydrogen, C1-C6 alkyl, C3-C7 cycloalkyl, phenyl or naphthyl, said C3-C7 cycloalkyl, phenyl or 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-C7cycloalkyl, -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-C3alkylene, -NR<3>R<3>, -OR<3>, -COOR<3>, -OCOR<4>, -SO2R<4>, -CN, -SO2NR<3>R<3>, -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-C6 alkoxy-(C1-C6)-alkyl, amino-(C2-C6)-alkyl, fluoro-(C1-C6)-alkyl, fluoro-(C2-C5)-alkanoyl, R<6>, -COR<5>, -COOR<5>, -S(O)mR<6>, -SO2NR<5>R<5> or -CONR<5>R<5>, or (iv) when A is C2-C3 alkylene, N-linked azetidinyl, pyrrolidinyl, 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 optionally N- substituted by C1-C6 alkyl, phenyl, C1-C6 alkoxy-(C1-C6)-alkyl, amino-(C2-C6)alkyl, fluoro-(C1-C6)-alkyl, C2-C5 alkanoyl, -COOR<3>, C3-C7 cycloalkyl, -S(O)mR<4>, -SO2NR<3>R<3> or -CONR<3>R<3>; R<3> is H, C1-C6 alkyl or phenyl; R<4> is C1-C6 alkyl or phenyl; R<5> is H, C1-C6alkyl, C3-C7 cycloalkyl, phenyl, naphthyl or het; R<6> is C1-C6 alkyl, C3-C7 cycloalkyl, phenyl, naphthyl or het; m is 0,1 or 2; "het", used in the definitions of R<5> and R<6>, 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 optionally substituted by C1-C6 alkyl, C1-C6 alkoxy, cyano or halo; and R<7> is methyl, ethyl or cyclopropylmethyl. 3. A compound as claimed in claim 1 or claim 2 wherein A is a bond. 4. A compound as claimed in claim 1 or claim 2 wherein A is C1-C3 alkylene. 5. A compound as claimed in claim 1 wherein A is C2-C3 alkylene. 6. A compound as claimed in claim 5 wherein A is -CH2CH2-. 7. A compound as claimed in any one of the preceding claims wherein R<2> is C1-C6 alkyl, phenyl or naphthyl, said phenyl being optionally substituted by phenyl. 8. A compound as claimed in claim 7 wherein R<2> is methyl, n-propyl, isopropyl, 2-methylprop-1-yl, phenyl, 4-phenylphenyl, 1-naphthyl or 2-naphthyl. 9. A compound as claimed in claim 5 or 6 wherein R<2> is -NR<8>R<9>, R<8> and R<9> being as defined in claim 1. 10. A compound as claimed in claim 9 wherein R<3> and R<9> taken together with the nitrogen to which they are attached represent piperidinyl. 11. A compound as claimed in claim 1wherein -A-R<2> is methyl, n-propyl, isopropyl, 2-methylprop-1-yl, phenyl, 4-phenylphenyl, phenylmethyl, 1-naphthyl, 2-naphthyl or 2-(piperidin-1-yl) ethyl. 12. A compound as claimed in any preceding claim wherein R<1> is C1-C6 alkyl substituted by 1 or 2-phenyl group (s), said phenyl group (s) being optionally substituted by C1-C6 alkoxy. 13. A compound as claimed in claim 12 wherein R<1> is 2,2-diphenylethyl or (4-methoxyphenyl)methyl. 14. A compound as claimed in claim 1 which is selected from the group consisting of: (2S,3S,4R,5R)-5-{2-{[(benzylsulfonyl)amino]methyl}-6-[(2,2-diphenylethyl)amino]-9H-purin-9-yl}-N-ethyl-3,4-dihydroxytetrahydro-2-furancarboxamide; (2S,3S,4R,5R)-5-(6-[(2,2-diphenylethyl) amino]-2-{[(propylsulfonyl) amino]methyl}-9H-purin-9-yl)-N-ethyl-3,4-dihydroxytetrahydro2-furancarboxamide; (2S,3S,4R,5R)-5-(6-[(2,2-diphenylethyl) amino]-2-{[(isopropylsulfonyl) amino]methyl}-9H-purin-9-yl)-N-ethyl-3,4-dihydroxytetrahydro-2-furancarboxamide; (2S,3S,4R,5R)-5-(6-[(2,2-diphenylethyl) amino]-2-{[(phenylsulfonyl) amino]methyl}-9H-purin-9-yl)-N-ethyl-3,4-dihydroxytetrahydro-2-furancarboxamide; (2S,3S,4R,5R)-5-{2-{[([1,1'-biphenyl]-4-ylsulfonyl) amino]methyl}-6-[(2,2diphenylethyl)amino]-9H-purin-9-yl}-N-ethyl-3,4-dihydroxytetrahydro-2-furancarboxamide; (2S,3S,4R,5R)-5-(6-[(2, 2-diphenylethyl) amino]-2-{[(1-naphthylsulfonyl) amino] methyl}-9H-purin-9-yl)-N-ethyl-3,4-dihydroxytetrahydro-2-furancarboxamide; (2S,3S,4R,5R)-5-(6-[2,2-diphenylethyl)amino]-2-{[(2naphthylsulfonyl) amino]methyl}-9H-purin-9-yl)-N-ethyl-3,4-dihydroxytetrahydro-2-furancarboxamide; (2S,3S,4R,5R)-5-(6-[(2,2-diphenylethyl) amino]-2{[(methylsulfonyl) amino]methyl}-9H-purin-9-yl)-N-ethyl-3,4-dihydroxytetrahydro-2-furancarboxamide; (2S,3S,4R,5R)-5-(6-[(2, 2-diphenylethyl) amino]-2{[(isobutylsulfonyl) amino]methyl}-9H-purin-9-yl)-N-ethyl-3,4-dihydroxytetrahydro-2-furancarboxamide; (2S,3S,4R,5R)-N-ethyl-3,4-dihydroxy-5-{2-{[(isobutylsulfonyl) amino]methyl}-6-[(4-methoxybenzyl) amino]-9H-purin-9-yl} tetrahydro-2-furancarboxamide; and (2S,3S,4R,5R-5-{6-[(2,2-diphenylethyl) amino]-2-[({[2-(1-piperidinyl) ethyl] sulfonyl} amino)methyl]-9H purin-9-yl}-N ethyl-3,4-dihydroxytetrahydro-2-furancarboxamide; and the pharmaceutically acceptable salts and solvates thereof. 15. A pharmaceutical composition including a compound of the formula (I) or a pharmaceutically acceptable salt or solvate thereof, as claimed in any one of the preceding claims, together with a pharmaceutically acceptable excipient, diluent or carrier. 16. The use of a compound of the formula (I) or a pharmaceutically acceptable salt, solvate or composition thereof, as claimed in any one of claims 1 to 14, respectively, for the manufacture of a medicament to treat a disease for which an A2a receptor agonist is indicated. 17. The use of a compound of the formula (I) or a pharmaceutically acceptab