Patent EA-004861-B1 (EA)
Title: Purine derivatives
Inventor: MANTELL SIMON JOHN
IPC: A61P15/10
Filed: 2000-06-13
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; R<2> is H or C1-C6 alkyl; A is C1-C6alkylene; R<3> is (i) hydrogen, C1-C6alkyl, -COOR<4>, -CN, -CONR<4>R<4>, C3-C8cycloalkyl, phenyl or naphthyl, said C3-C8 cycloalkyl, phenyl and naphthyl being optionally substituted C1-C6 alkyl, phenyl, C1-C6alkoxy(C1-C6)alkyl, R<4>R<4>N(C1-C6)alkyl, halo (C1-C6)alkyl, fluoro (C1-C6) alkoxy, C2-C5 alkanoyl, halo, -OR<4>, cyano, COOR<4>, C3-C8cycloalkyl, S(O)mR<5>, -NR<4>R<4>, -SO2NR<4>R<4>, -CONR<4>R<4>, -NR<4>COR<5> or -NR<4>SO2R<5>, or (ii) when A is C2-C6alkylene, then -NR<4>R<4>, -OR<4>, -OCOR<5>, -SO2R<5>, -SO2NR<4>R<4> or -NR<4>COR<5>, or (iii) a C-linked, 4-to 11-membered ring, 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, being optionally C-substituted by oxo, C1-C6 alkoxy (C1 C6)alkyl, R<6>R<6>N(C1-C6)alkyl, halo(C1-C6)alkyl, fluoro(C1-C6)alkoxy, fluoro(C2-C5)alkanoyl, halo, cyano, -OR<6>, R<7>, -COR<6>, -NR<6>R<6>, -COOR<6>, -S(O)mR<7>, -SO2NR<6>R<6>, -CONR<6>R<6>, -NR<6>SO2R<7> or -NR<6>COR<7> and optionally N-substituted by C1-C6alkoxy(C1-C6)alkyl, R<6>R<6>N(C2-C6)alkyl, halo(C1-C6)alkyl, fluoro(C2-C5)alkanoyl, R<7>, COR<6>, -COOR<7>, -SO2R<7>, -SO2NR<6>R<6> or -CONR<6>R<6>, or (iv) when A is C2-C6alkylene, then N-linked azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, homopiperazinyl or morpholinyl, each being optionally C-substituted by C1-C6alkyl, phenyl, C1-C6 alkoxy(C1-C6)alkyl, R<4>R<4>N (C1-C6) alkyl, halo (C1-C6)alkyl, fluoro (C1-C6) alkoxy, C2-C5 alkanoyl, halo, -OR<4>, cyano, -COOR<4>, C3-C8 cycloalkyl, -S(O)mR<5>, -NR<4>R<4>, -SO2NR<4>R<4>, -CONR<4>R<4>, -NR<4>COR<5> or -NR<4>SO2R<5>, and said piperazinyl and homopiperazinyl being optionally N-substituted by C1-C6 alkyl, phenyl, C1-C6alkoxy(C2-C6)alkyl, R<4>R<4>N(C2-C6)alkyl, fluoro(C1-C6)alkyl, C2-C5alkanoyl, COOR<5>, C3-C8cycloalkyl, -SO2R<5>, -SO2NR<4>R<4> or -CONR<4>R<4>; R<4> is H, C1-C6 alkyl, C3-C8 cycloalkyl or phenyl; R<5> is C1-C6alkyl, C3-C8 cycloalkyl or phenyl; R<5> is H, C, -C6 alkyl, C3-C8 cycloalkyl, phenyl, naphthyl or het; R<6> is C1-C6 alkyl, C3-C8 cycloalkyl, phenyl, naphthyl or het; m is 0,1 or 2; and "het", used in the definitions of R<6> and R<7>, means C-linked pyrrolyl, imidazolyl, triazolyl, thienyl, furyl, thiazolyl, oxazolyl, thiadiazolyl, oxadiazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, indolyl, isoindolyl, 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 C1-C6 alkyl optionally substituted by 1 or 2 phenyl substituents. 3. A compound as claimed in claim 2 wherein R<1> is 2,2-diphenylethyl. 4. A compound as claimed in any one of the preceding claims wherein R<2> is H. 5. A compound as claimed in any one of the preceding claims wherein A is C1-C4 alkylene. 6. A compound as claimed in claim 5 wherein A is methylene, 1,2-ethylene or 1,3-propylene. 7. A compound as claimed in claim 6 wherein A is 1,2-ethylene. 8. A compound as claimed in any one of the preceding claims wherein R<3> is phenyl optionally substituted as defined for this definition in claim 1; or, when A is C2-C6 alkylene, R<3> is -NR<4>R<4> wherein R<4> is as defined in claim 1; or R<3> is a linked, 5- to 7-membered ring monocyclic 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 substituted as defined for this definition in claim 1; or, when A is C2-C6alkylene, R<3> is N-linked pyrrolidinyl, piperidinyl or morpholinyl, each being optionally C-substituted as defined for this definition in claim 1. 9. A compound as claimed in claim 8 wherein R<3> is phenyl; or, when A is C2-C6 alkylene, R<3> is -NR<4>R<4> wherein R<4> is C1-C6 alkyl; or, R<3> is a C-linked, 5- or 6membered ring monocyclic aromatic heterocycle having from 1 to 4 ring nitrogen atom (s), optionally substituted as defined for this definition in claim 1: or, when A is C2-C6 alkylene, R<3> is N-linked pyrrolidinyl, piperidinyl or morpholinyl, each being optionally C-substituted by C1-C6 alkyl or -OR<4> wherein R<4> is as previously defined in claim 1. 10. A compound as claimed in claim 9 wherein R<3> is phenyl; or, when A is C2-C6 alkylene, R<3> is -N(CH3)2; or R<3> is C-linked pyridinyl optionally substituted by OR<6>, R<7>, C1-C6 alkoxy (C1-C6) alkyl, R<6>R<6>N (C1-C6) alkyl or -NR<6>R<6> wherein R<6> and R<7> are as previously defined in claim 1; or when A is C2-C6 alkylene, R<3> is pyrrolidin-1-yl, piperidin-1-yl, 4-isopropylpiperidin-1-yl or morpholin-4-yl. 11. A compound as claimed in claim 10 wherein R<3> is phenyl; or, when A is C2-C6 alkylene, R<3> is -N(CH3)2; or R<3> is 2-pyridinyl; or when A is C2-C6 alkylene, R<3> is pyrrolidin-1-yl, piperidin-1-yl, 4-isopropylpiperidin-1-yl or morpholin-4-yl. 12. A compound as claimed in claim 11 wherein, when A is C2-C6 alkylene, R<3> is piperidin-1-yl. 13. A compound as claimed in any one of claims 1 to 4 wherein-A-R<3> is phenethyl, 2-(dimethylamino)ethyl, 2-pyridinylmethyl, 2-(2-pyridinyl) ethyl, 3-(1-pyrrolidinyl) propyl, 2-(1-piperidinyl) ethyl, 2-(4-isopropyl-1-piperidinyl) ethyl or 2 (4-morpholinyl) ethyl. 14. A compound as claimed in claim 13 wherein -A-R<3> is 2-(1-piperidinyl)ethyl. 15. A compound as claimed in claim 1 which is selected from the group consisting of: 9-[(2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydro-2-furanyl]-6-[(2,2-diphenylethyl)amino]-N-[2-(1-piperidinyl)ethyl]-9H-purine-2-carboxamide; 9-[(2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydro-2-furanyl]-6-[(2,2-diphenylethyl)amino]-N-phenethyl-9H-purine-2-carboxamide; 9-[(2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydro-2-furanyl]-6-[(2,2-diphenylethyl)amino]-N-[2-(4-isopropyl-1-piperidinyl)ethyl]-9H-purine-2-carboxamide; 9-[(2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydro-2-furanyl]-6-[(2,2diphenylethyl)amino]-N-[3-(1-pyrrolidinyl)propyl]-9H-purine-2-carboxamide; 9-[(2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydro-2-furanyl]-6-[(2,2-diphenylethyl)amino]-N-[2-(4-morpholinyl)ethyl]-9H-purine-2-carboxamide; 9-[(2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydro-2-furanyl]-6-[(2,2-diphenylethyl)amino]-N-(2-pyridinylmethyl)-9H-purine-2-carboxamide; 9-[(2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydro-2-furanyl]-6-[(2,2-diphenylethyl)amino]-N-[2-(2-pyridinyl)ethyl]-9H-purine-2-carboxamide; and 9-[(2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydro-2-furanyl]-N-[2-(dimethylamino)ethyl]-6-[(2,2-diphenylethyl)amino]-9H-purine-2-carboxamide and the pharmaceutically acceptable salts and solvates thereof. 16. A compound as claimed in claim 1 which is 9-[(2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydro-2-furanyl]-6-[(2,2-diphenylethyl) amino N-[2-(1-piperidinyl)ethyl]-9H-purine-2-carboxamide, or a pharmaceutically acceptable salt or solvate thereof. 17. A compound as claimed in claim 1 wherein R<1> is hydrogen or C1-C6 alkyl substituted by 1 or 2 substituents each independently selected from phenyl and naphthyl; R<2> is hydrogen or C1-C6 alkyl; A is C1-C6 alkylene; and R<3> is phenyl, naphthyl, C3-C8 cycloalkyl, azetidinyl, pyrrolidinyl, piperidinyl, amino, -NH(C1-C6 alkyl) or -N(C1-C6alkyl)2, said phenyl, naphthyl, C3-C8 cycloalkyl, azetidinyl, pyrrolidinyl and piperidinyl being optionally substituted by one or more substituents each independently selected from C1-C6 alkyl, C1-C6 alkoxy, halo(C1-C6) alkyl, halo and cyano; with the proviso that when R<3> is N-linked, optionally substituted-azetidinyl, -pyrrolidinyl or -piperidinyl, or is amino,-NH(C1-C6alkyl) or -N(C1-C6alkyl)2, A is C2-C6alkylene. 18. 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. 19. A compound of the formula (I) or a pharmaceutically acceptable salt, solvate or composition thereof, as claimed in any one claims 1 to 17 for use as a medicament. 20. The use of a compound of the formula (I) or of a pharmaceutically acceptable salt, solvate or composition thereof, as claimed in any one claims 1 to 17 for the manufacture of a medicament having A2a receptor agonist activity. 21. The use of a compound of the formula (I) or of a pharmaceutically acceptable salt, solvate or composition thereof, as claimed in any one claims 1 to 17 for the manufacture of an anti-inflammatory agent. 22. The use of a compound of the formula (I) or of a pharmaceutically acceptable salt, solvate or composition thereof, as claimed in any one claims 1 to 17 for the manufacture of a medicament for the treatment of a respiratory disease. 23. Use as claimed in claim 22 where the disease is selected from the group consisting of adult respiratory distress syndrome (ARDS), bronchitis, chronic bronchitis, chronic obstructive pulmonary disease, cystic fibrosis, asthma, emphysema, bronchiectasis, chronic sinusitis and rhinitis. 24. The use of a compound of the formula (I) or of a pharmaceutically acceptable salt, solvate or composition thereof, as claimed in any one claims 1 to 17 and 18, respectively, for the manufacture of a medicament for the treatment of septic shock, male erectile dysfunction, hypertension, stroke, epilepsy, cerebral ischaemia, peripheral vascular disease, post-ischaemic reperfusion injury, diabetes, rheumatoid arthritis, multiple sclerosis, psoriasis, dermatitis, allergic dermatitis, eczema, ulcerativecolitis, Crohns disease, inflammatory bowel disease, Hel