Patent EA-004655-B1 (EA)
Title: Purine derivatives
Inventor: MONAGHAN SANDRA MARINA
IPC: C07H19/167
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-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-C3 alkylene, -NR<7>R<8>, -OR<3>, -COOR<3>, -COOR<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, 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, 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-C6alkyl, C3-C7 cycloalkyl, phenyl, naphthyl or het; R<6> is C1-C6 alkyl, C3-C7 cycloalkyl, phenyl, naphthyl or het; either R<7> and R<8> 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-C6alkyl, C3-C8 cycloalkyl, phyenyl, C1-C6alkoxy-(C1-C6)-alkyl, R<3>R<3>N-(C1-C6)-alkyl, fluoro-(C1-C6)-alkyl, CONR<3>R<3>, -COOR<3> or C2-C5alkanoyl, 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>, or R<7> is H, C1-C6 alkyl, C3-C8 cycloalkyl, phenyl or benzyl and R<8> is H, C1-C6alkyl, C3-C8 cycloalkyl, phenyl, benzyl, fluoro-(C1-C6)-alkyl, -CONR<3>R<3>, -COOR<4>, C2-C5 alkanoyl or -SO2NR<3>R<3>; m is 0, 1 or 2; and "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. 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-C6alkoxy-(C1-C6)-alkyl, amino-(C1-C6)-alkyl, fluoro-(C1-C6)-alkyl, fluoro-(C1-C6)-alkoxy, C2-C5alkanoyl, 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-C6alkoxy-(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-C6alkyl, phenyl, C1-C6alkoxy-(C1-C6)-alkyl, amino-(C1-C6)-alkyl, fluoro-(C1-C6)-alkyl, fluoro-(C1-C6alkoxy, 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> and optionally N-substituted by C1-C6 alkyl, phenyl, C1-C6alkoxy-(C1-C6)-alkyl, amino-(C2-C6)-alkyl, fluoro-(C1-C6)-alkyl, C2-C5alkanoyl, -COOR<3>, C3-C7cycloalkyl, -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-C6 alkyl, C3-C7cycloalkyl, phenyl, naphthyl or het; R<6> is C1-C6alkyl, C3-C7cycloalkyl, phenyl, naphthyl or het; m is 0, 1 or 2; and "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-C6alkyl, C1-C6alkoxy, cyano or halo. 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-C3alkylene. 5. A compound as claimed in claim 1 wherein A is C2-C3alkylene. 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 or phenyl. 8. A compound as claimed in claim 7 wherein R<2> is 2-methylprop-1-yl or phenyl. 9. A compound as claimed in claim 5 or claim 6 wherein R<2> is -NR<7>R<8>. 10. A compound as claimed in claim 9 wherein R<7> is C1-C6 alkyl and R<8> is C3-C8cycloalkyl. 11. A compound as claimed in claim 10 wherein R<7> is prop-2-yl and R<8> is cyclopentyl. 12. A compound as claimed in any preceding claim wherein R<1> is C1-C6alkyl substituted by 1 or 2 substituents each independently selected from phenyl and naphthyl. 13. A compound as claimed in claim 12 wherein R is 2-phenylethyl, 2,2-diphenylethyl or 1-naphthylmethyl. 14. A compound as claimed in claim 1wherein-A-R<2> is 2-[(2-propyl)(cyclopentyl)amino]ethyl, 2-methylprop-1-yl or phenyl. 15. A compound as claimed in claim 1 which is selected from the group consisting of: N-({9-[(2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl) tetrahydro-2-furanyl]-6-[(2,2-diphenylethyl) amino]-9H-purin-2-yl}methyl)-2-methyl-1-propanesulfonamide; N-{[9-[(2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydro-2-furanyl]-6-(phenethylamino)-9H-purin-2-yl]methyl}benzenesulfonamide; N-({9-[(2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydro-2-furanyl]-6-[(1-naphthylmethyl)amino]-9H-purin-2-yl}methyl)benzenesulfonamide; and 2-[cyclopentyl(isopropyl)amino]-N-({9-[(2R,3R,4S,5R)-3,4-dihydroxy-(hydroxymethyl)tetrahydro-2-furanyl]-6-[(2,2-diphenylethyl)amino]-9H-purin-2-yl}methyl)ethanesulfonamide; and the pharmaceutically acceptable salts and solvates thereof. 16. 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. 17. A compound of the formula (I) or a pharmaceutically acceptable salt, solvate or composition thereof, as claimed in any one of claims 1 to 15 and 16, respectively, for use as a medicament. 18. 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 15 and 16, respectively, for the manufacture of a medicament to treat a disease for which an A2a receptor agonist is indicated. 19. 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 15 and 16, respectively, for the manufacture of an anti-inflammatory agent. 20. 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 15 and 16, respectively, for the manufacture of a medicament for the treatment of a respiratory disease. 21. Use as claimed in claim 20 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. 22. 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 15 and 16, 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, allergic dermatitis, eczema, ulcerative colit