Patent EA-004983-B1 (EA)
Title: 2-aminocarbonyl-9h-purine derivatives
Inventor: MANTELL SIMON JOHN
IPC: A61P3/10
Filed: 2001-06-05
Abstract: 1. A compound of the formula: or a pharmaceutical acceptable salt or solvate thereof, wherein R<1> is H, C1-C6 alkyl or fluorenyl, said C1-C6 alkyl being optionally substituted by1 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) R<2> is H or C1-C6 alkyl, R<15> is H or C1-C6 alkyl, and X is either (i) unbranched C2-C3 alkylene optionally substituted by C1-C6alkyl or C3-C8cycloalkyl, or (ii) a group of the formula: -(CH2)n-W-(CH2)p- where W is C5-C7cycloalkylene optionally substituted by C1-C6alkyl, n is 0 or 1 and p is 0 or 1, or (B) R<15> is H or C1-C6alkyl, and R<2> and X, taken together with the nitrogen atom to which they are attached, represent azetidin-3-yl, pyrrolidin-3-yl, piperidin-3-yl, piperidin-4-yl, homopiperidin-3-yl or homopiperidin-4-yl, each being optionally substituted by C1-C6 alkyl, or (C) R<2> is H or C1-C6alkyl, and R<15> and X, taken together with the nitrogen atom to which they are attached, representazetidin-3-yl, pyrrolidin-3-yl, piperidin-3-yl, piperidin-4-yl, homopiperidin-3-yl or homopiperidin-4-yl, each being optionally substituted by C1-C6 alkyl; either, R<3> and R<4>, taken together with the nitrogen atom to which they are attached, represent azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, homopiperidinyl or homopiperazinyl, each being optionally substituted on a ring nitrogen or carbon atom by C1-C6 alkyl or C3-C8 cycloalkyl and optionally substituted on a ring carbon atom not adjacent to a ring nitrogen atom by NR<6>R, or, R<3> is H, C1-C6 alkyl, C3 C8 cycloalkyl or benzyl and R<4> is (a) azetidin-3-yl, pyrrolidin-3-yl, piperidin-3-yl, piperidin-4-yl, homopiperidin-3-yl or homopiperidin-4-yl, each being optionally substituted by C1-C6 alkyl, C3-C8 cycloalkyl, phenyl, benzyl or het, or (b) -(C2-C6alkylene)-R<8>, (c) -(C1-C6alkylene)-R<18>, or (d) C1-C6alkyl or C3-C8cycloalkyl; R<5> is CH2OH or CONR<14>R<14>; R<6> and R<7> are either each independently H or C1-C6 alkyl or, taken together with the nitrogen atom to which they are attached, represent azetidinyl, pyrrolidinyl or piperidinyl, said azetidinyl, pyrrolidinyl and piperidinyl being optionally substituted by C1-C6 alkyl; R<8> is (i)azetidin-1-yl, pyrrolidin-1-yl, piperidin-1-yl, morpholin-4-yl, piperazin-1-yl, homopiperidin-1-yl, homopiperazin-1-yl or tetrahydroisoquinolin-1-yl, each being optionally substituted on a ring carbon atom by C1-C6alkyl, C3-C8cycloalkyl, phenyl, C1-C6alkoxy-(C1-C6)-alkyl, R<9>R<9>N-(C1-C8)-alkyl, fluoro-(C1C6)-alkyl,-CONR<9>R<9>, -COOR<9> 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<9>, cyano, -S(O)mR<10>, -R<9>R<9>, -SO2NR<9>R<9>, -NR<9>COR<10> or -NR<9>SO2R<10>, and said piperazin-1-yl and homopiperazin-1-yl being optionally substituted on the ring nitrogen atom not attached to the C2-C6alkylene group by C1-C6alkyl, phenyl, C1-C6alkoxy-(C2-C6)-alkyl, R<9>R<9>N-(C2-C6)-alkyl, fluoro-(C1-C6)-alkyl, C2-C5alkanoyl, -COOR<10>, C3-C8 cycloalkyl, -SO2R<10>, -SO2NR<9>R<9> or -CONR<9>R<9>, or (ii) NR<11>R<12>; R<9> is H, alkyl, C3-C8 cycloalkyl or phenyl; R<10> is C1-C6alkyl, C3-C8 cycloalkyl or phenyl; R<11> is H, C1-C6alkyl, C3-C8 cycloalkyl or benzyl; R<12> is H, C1-C6alkyl, C3-C8 cycloalkyl, phenyl, benzyl, fluoro-(C1-C6)-alkyl, -CONR<9>R<9>, -COOR<10>, C2-C5alkanoyl or -SO2NR<9>R<9>; R<13> is (a) phenyl, pyridin-2-yl, pyridin-3-yl or pyridin-4-yl, each being optionally substituted by C1-C6alkyl, C1-C6 alkoxy, -(C1-C3 alkylene)-(C1-C6 alkoxy), halo, cyano, -(C1-C3 alkylene)-CN, -CO2H, -(C1-C3 alkylene)-CO2H, -CO2(C1-C6 alkyl), -(C1-C3 alkylene)-CO2(C1-C6 alkyl), -(C1-C3 alkylene)-NR<14>R<14>, -CONR<14>R<14> or (C1-C3alkylene)-CONR<14>R<14>, or (b) azetidin-2-yl, azetidin-3-yl, pyrrolidin-2-yl, pyrrolidin-3-yl, piperidin-2-yl, piperidin-3-yl, piperidin-4-yl, homopiperidin-2-yl, homopiperidin-3-yl or homopiperidin-4-yl, each being optionally substituted by C1-C6 alkyl, C3-C8 cycloalkyl, phenyl, benzyl or het; R<14> is H or C1-C6 alkyl optionally substituted by cyclopropyl; m is 0, 1 or 2; Y is CO, CS, SO2 or C=N (CN); and "het", used in the definition of R<4> and R<13>, is a C-linked, 4-to 6-membered ring, heterocycle having either from 1 to 4 ring nitrogen heteroatoms or 1 or 2 nitrogen ring heteroatoms and 1 oxygen or 1 sulphur ring heteroatom, optionally substituted by C1-C6alkyl, C3-C8 cycloalkyl, C1-C6 alkoxy, C3-C8 cycloalkoxy, hydroxy, oxo 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, said phenyl being optionally substituted by C1-C6 alkyl or halo. 3. A compound as claimed in claim 2 wherein R' is diphenylethyl, bis (3-methylphenyl) ethyl or bis (3-chlorophenyl) ethyl. 4. A compound as claimed in claim 3 wherein R<1> is 2,2-diphenylethyl, 2,2-bis (3-methylphenyl) ethyl or 2,2-bis (3-chlorophenyl) ethyl. 5. A compound as claimed in claim 4 wherein R<1> is 2,2-diphenylethyl. 6. A compound as claimed in any one of the preceding claims wherein R<2> is H. 7. A compound as claimed in any one of the preceding claims wherein R<15> is H. 8. A compound as claimed in any one of the preceding claims wherein X is 1,2-ethylene or 1,3-propylene. 9. A compound as claimed in claim 8 wherein X is 1,2-ethylene. 10. A compound as claimed in any one of claims1 to 5 wherein R<2> is H, R<15> is H and X is 1,2-ethylene, 1,3-propylene or a group of the formula: - (CH2)n - W - (CH2)p- where W is C5-C7 cycloalkylene, n is 0 or 1 and p is 0 or 1. 11. A compound as claimed in claim 10 wherein R<2> is H, R<15> is H and X is 1,2-ethylene, 1,3-propylene or a group of the formula : -(CH2)n-W-(CH2)p- where W is C5-C7cycloalkylene, n is 0 and p is 0. 12. A compound as claimed in claim 11 wherein R<2> is H, R<15> is H and X is 1,2-ethylene, 1,3-propylene or 1,4-cyclohexylene. 13. A compound as claimed in claim 12 wherein R<2> is H, R<15> is H and X is 1,2-ethylene. 14. A compound as claimed in any one of claims 1 to 5 wherein R<15>is H and R<2> and X, taken together with the nitrogen atom to which they are attached, represent 3-pyrrolidinyl or 3- or 4-piperidinyl, each being optionally substituted by C1-C6 alkyl. 15. A compound as claimed in claim 14 wherein R<15>is H and R<2> and X, taken together with the nitrogen atom to which they are attached, represent 3-pyrrolidinyl or 4-piperidinyl. 16. A compound as claimed in any one of claims 1 to 5 wherein R<2> is H and R<15> and X, taken together with the nitrogen atom to which they are attached, represent 3-pyrrolidinyl or 3- or 4-piperidinyl, each being optionally substituted by C1-C6 alkyl. 17. A compound as claimed in claim 16 wherein R<2> is H and R<15> and X, taken together with the nitrogen atom to which they are attached, represent pyrrolidinyl or 4-piperidinyl. 18. A compound as claimed in any one of the preceding claims wherein R<3> is H. 19. A compound as claimed in any one of the preceding claims wherein R<4> ispiperidin-3-yl or piperidin-4-yl, each optionally substituted by benzyl, pyridin-2yl, pyridin-3-yl or pyridin-4-yl, said pyridin-2-yl, pyridin-3-yl and pyridin-4-yl each optionally substituted by C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 alkoxy, C3-C8 cycloalkoxy, hydroxy, oxo or halo. 20. A compound as claimed in claim 19 wherein R<4> is piperidin-3-yl or piperidin-4-yl, each substituted by benzyl, pyridin-2-yl, pyridin-3-yl or pyridin-4-yl. 21. A compound as claimed in claim 20 wherein R<4> is piperidin-4-yl substituted by pyridin-2-yl. 22. A compound as claimed in claim 21 wherein R<4> is 1-(pyridin-2-yl) piperidin-4-yl. 23. A compound as claimed in any one of claims 1 to 18 wherein R<4> (C2-C6alkylene)-R<8>. 24. A compound as claimed in claim 23 wherein R<4> is -CH2CH2R<8>. 25. A compound as claimed in any one of claims 1 to 18 wherein R<4> is- (C1-C6 alkylene)-R<13>. 26. A compound as claimed in claim 25 wherein R<4> is -CH2R<13> or -CH2CH2R<13>. 27. A compound as claimed in any one of claims 1 to 18 wherein R<4> is C3-C8 cycloalkyl. 28. A compound as claimed in claim 27 wherein R<4> is cyclohexyl. 29. A compound as claimed in any one of the preceding claims wherein R<5> is CH2OH or-CONH(C1-C6 alkyl). 30. A compound as claimed in claim 29 wherein R<5> is -CONHCH2CH3. 31. A compound as claimed in claim 23 or 24 wherein R<8> is (i) azetidin-1-yl, pyrrolidin-1-yl, piperidin-1-yl, morpholin-4-yl, piperazin-1-yl, homopiperidin-1-yl, homopiperazin-1-yl or tetrahydroisoquinolin-1-yl, each being optionally substituted on a ring carbon atom by C1-C6 alkyl and said piperazin-1-yl and homopiperazin-1-yl being optionally substituted on the ring nitrogen atom not attached to the C2-C6 alkylene group by C1-C6alkyl, or (ii) isNR<11>R<12>. 32. A compound as claimed in claim 31 wherein R<8> is piperidin-1-yl or tetrahydroisoquinolin-1-yl each optionally substituted on a ring carbon atom by C1-C6 alkyl. 33. A compound as claimed in claim 32 wherein R<8> is piperidin-1-yl, isopropylpiperidin-1-yl or tetrahydroisoquinolin-1-yl. 34. A compound as claimed in claim 31 wherein R<8> is NR<11>R<12> where NR<11>R<12> is N(C1-C6alkyl)2, N(C1-C6alkyl)(C3-C8cycloalkyl) or N(C1-C6alkyl) (benzyl). 35. A compound as claimed in claim 34 wherein NR<11> R<12> is N, N-diisopropylamino, N,N-di-n-butylamino, N-cyclopentyl-N-isopropylamino, N-cyclohexyl-N-isopropylamino or N-benzyl-N-isopropylamino. 36. A compound as claimed in claim 31 wherein R<11> is H or C1-C6alkyl and R<12> is H, C1-C6 alkyl, C3-C8 cycloalkyl or benzyl. 37. A compound as claimed in claim 36 wherein R<11> is C1-C6 alkyl and R<12> is C1-C6 alkyl, C3-C8 cycloalkyl or benzyl. 38. A compound as claimed in claim 37 wherein R<11> is isopropyl or n-butyl and R<12> is isopropyl, n-butyl, cyclopentyl, cyclohexyl or benzyl. 39. A compound as claimed in claim 25 or 26 wherein R<13> is either phenyl optionally substituted by -(C1-C3alkylene)-