Patent EA-003194-B1 (EA)
Title: 2-(purin-9-ul)-tetrahydrofuran-3,4-doil derivatives
Inventor: CHAN CHUEN
IPC: C07H17/00
Filed: 1999-01-29
Abstract: 1. A derivative of 1. 2-(purin-9-yl)-tetrahydrofuran-3, 4-diol of formula (I): wherein R<1> and R<2> independently represent a group selected from: (1) C3-8 cycloalkyl-; (2) hydrogen; (3) aryl2CHCH2-; (4) C3-8 cycloalkylC1-6 alkyl-; (5) C1-8 alkyl-; (6) arylC1-6 alkyl-; (7) R<4>R<5>N-C1-6 alkyl-; (8) C1-6 alkyl-CH (CH2OH)-; (9) aryl C1-5 alkyl-CH (CH2OH)-; (10) C3-8 cycloalkyl independently substituted by one or more -(CH2)p R<6> groups; (11) H2NC(=NH)NHC1-6alkyl-; (12) a group of formula or such a group in which one methylene carbon atom adjacent to X, or both if such exist, is substituted by methyl; (13) -C1-6alkyl-OH; (14) aryl; and (15) -(CH2)f SO2NHg(C1-4alkyl-)2-g or -(CH2)f SO2NH g(arylC1-4alkyl-)2-g; R3 represents methyl, ethyl, n-propyl, -CH(OH)CH3, -(CH2)q halogen, -(CH2)h Y(CH2)jH, -(CH2)k Z, or -(CH2)kC((CH2)u H)=NO(CH2)v H; Y represents O, S or N(CH2)jH; Z represents -COO(CH2)j H; a and b independently represent an integer 0 to 4 provided that a + b is in the range 3 to 5; f represents 2 or 3 and g represents an integer 0 to 2; p represents 0 or 1; q represents an integer 0 to 3; h represents an integer 0 to 2; i represents an integer 0 to 2 such that h+i is in the range 0 to 3; j represents an integer 0 to 2 such that h+i+j is in the range 0 to 3; k represents 0 or 1; l represents 1 or 2, such that k+ l is in the range 1 to 2; u and v independently represent 0 or 1 such that k+u+v is in the range 0 to 1; R<4> and R<5> independently represent hydrogen, C1-6alkyl, aryl, arylC1-6alkyl- or NR<4>R<5> together may represent pyridinyl, pyrrolidinyl, piperidinyl, morpholinyl, or 2-(1-methyl-1H-imidazol-4-yl)-; R<6> represents -OH, -NH2, -NHCOCH3; R<7> represents hydrogen, -C1-6alkyl, -C1-6alkylaryl or -COC1-6 alkyl; X represents NR<7>, O, S, SO or SO2; and salts and solvates thereof. 2. A compound of formula (I) according to claim 1 wherein R<3> represents methyl, ethyl or n-propyl and R<7> represents hydrogen, -C1-6alkyl, -C1- 6alkylaryl or -COCH3. 3. A compound of formula (I) according to claim 1 or claim 2 wherein R<1> and R<2> do not both represent hydrogen. 4. A compound of formula (I) according to any one of claims 1 to 3 wherein R<1> represents C3-8cycloalkyl, aryl2CHCH2-, arylC1-6alkyl-, C1-8alkyl-, aryl, -(CH2)f SO2NHg(C1-4alkyl)2-g, tetrahydropyran-n-yl or tetrahydrothiopyran-n-yl where n is 3 or 4, C3-8cycloalkylC1-6alkyl-, hydrogen, or R<4>R<5>N-C1-6alkyl-where NR<4>R<5> together represents piperidinyl or morpholinyl. 5. A compound of formula (I) according to any one of claims 1 to 3 wherein R<1> represents C1-6alkyl-CH(CH2OH)-, 1,1-dioxo-hexahydro-1.lambda.6-thiopyran-4-yl, N-acetyl-piperidin-4-yl, 1S-hydroxymethyl-2-phenylethyl, piperidin-4-yl and 1-oxo-hexahydro-1.lambda.4-thiopyran-4-yl. 6. A compound of formula (I) according to any one of claims 1 to 3 wherein R<1> represents -CH2CHPh2, -CH(Et)2 or phenylethyl. 7. A compound of formula (I) according to any one of claims 1 to 6 wherein R<2> represents -C1-6alkyl-OH, H2NC(=NH)NHC1-6alkyl-, R<4>R<5>NC1-6alkyl-where NR<4>R<5> together represents pyridinyl, piperidinyl, morpholinyl or 2-(1-methyl-1H-imidazol-4-yl), arylC1-5alkylCH(CH2OH)-, aryl, C3-8cycloalkylC1- 6alkyl-, tetrahydro-1,1-dioxide thiophen-3-yl, C3-8cycloalkyl, C1-6alkyl-CH(CH2OH)-, arylC1-6alkyl-, pyrrolidin-3-yl, 2-oxopyrrolidin-4-yl, 2-oxopyrrolidin-5y1, piperidin-3-yl, aryl C1-6alkyl, C3-8cycloalkyl independently substituted by one or more -(CH2)p R<6> groups, or piperidin-4-yl in which the ring nitrogen is optionally substituted by C1-6alkyl. 8. A compound of formula (I) according to any one of claims 1 to 6 wherein R<2> represents C1-8alkyl or R<4>R<5>NC1-6alkyl- wherein R<4> and R<5> independently represent hydrogen or aryl or R<4>R<5>N together represents pyrrolidinyl. 9. A compound of formula (I) according to any one of claims 1 to 6 wherein R<2> represents piperidin-1-ylethyl or 2-(1-methyl-1H-imidazol-4-yl)ethyl. 10. A compound of formula (I) according to any one of claims 1 and 3 to 9 wherein R<3> represents -CH=NOH, cyclopropyl, -COOCH3, -COOCH2CH3, -CH2OH, -CH(OH)CH3 or halogen. 11. A compound of formula (I) according to any one of claims 1 to 9 wherein R<3> represents methyl, ethyl or n-propyl. 12. A compound of formula (I) according to any one of claims 1 and 3 to 9 wherein R<3> represents ethyl or -CH2OH. 13. A compound of formula (I) according to any one of claims 1 to 9 wherein R<3> represents ethyl. 14. A compound of formula (I) according to any one of claims 1 to 13 wherein R<4> and R<5> independently represent hydrogen, C1-6alkyl, aryl, arylC1-6alkyl- or NR<4>R<5> together may represent pyrrolidinyl, piperidinyl, morpholinyl. 15. A compound of formula (I) according to any one of claims 1 to 13 wherein R<4> and R<5> independently represent hydrogen, C1-6alkyl or aryl or NR4R5 together represent pyrrolidinyl, piperidinyl, morpholinyl. 16. A compound of formula (I) which is (2R,3R,4S,5S)-2-[6-(2,2-Diphenyl-ethylamino)-2-(2-piperidin-1-yl-ethylamino)-purin-9-yl]-5-(3-ethyl-isoxazol-5-yl)-tetrahydro-furan-3,4-diol or a salt or solvate thereof. 17. A compound of formula (I) which is (2R,3R,4S,5S)-2-(3-Ethyl-isoxazol-5-yl)-5-[6-phenethylamino-2-(2-piperidin-1-yl-ethylamino)-purin-9-yl]-tetrahydro-furan-3,4-diol or a salt or solvate thereof. 18. A compound of formula (I) which is (2S,3S,4R,5R)-2-(3-Ethyl-isoxazol-5-yl)-5-[6-(1-ethyl-propylamino)-2-(2-piperidin-1-yl-ethylamino)-purin-9-yl]-tetrahydro-furan-3,4-diol or a salt or solvate thereof. 19. A compound of formula (I) which is (2R,3R,4S,5S)-2-{6-(1-Ethyl-propylamino)-2-[2-(1-methyl-1H-imidazol-4-yl)-ethylamino]-purin-9-yl}-5-(3-hydroxymethyl-isoxazol-5-yl)-tetrahydro-furan-3,4-diol or a salt or solvate thereof. 20. A compound of formula (I) which is (2R,3R,4S,5S)-2-[6-(2,2-Diphenyl-ethylamino)-2-(2-morpholin-4-yl-ethylamino)-purin-9-yl]-5-(3-ethyl-isoxazol-5-yl)-tetrahydro-furan-3,4-diol; (2R,3R,4S,5S)-2-[6-(2,2-Diphenyl-ethylamino)-2-(2-hydroxy-ethylamino)-purin-9-yl]-5-(3-ethyl-isoxazol-5-yl)-tetrahydro-furan-3,4-diol; (2S,3S,4R,5R)-2-(3-Ethyl-isoxazol-5-yl)-5-{6-(1-ethyl-propylamino)-2-[2-(1-methyl-1H-imidazol-4-yl)-ethylamino]-purin-9-yl}-tetrahydro-furan-3,4-diol; (2R,3R,4S,5S)-2-{6-(3,3-Dimethyl-butylamino)-2-[2-(1-methyl-1H-imidazol-4-yl)-ethylamino]-purin-9-yl}-5-(3-ethyl-isoxazol-5-yl)-tetrahydro-furan-3,4-diol; (2S,3S,4R,5R)-2-(3-Ethyl-isoxazol-5-yl)-5-[6-(cyclopentylamino)-2-(2-piperidin- 1-yl-ethylamino)-purin-9-yl]-tetrahydro-furan-3,4-diol; N-{2-[9-[5S-(3-Ethyl-isoxazol-5-yl)-3R,4S-dihydroxy-tetrahydro-furan-2R-yl]-6-(tetrahydro-thiopyran-4-ylamino)-9H-purin-2-ylamino]-ethyl}-guanidine; (2S,3S,4R,5R)-2-(3-Ethyl-isoxazol-5-yl)-5-[6-(3-fluoro-4-hydroxy-phenylamino)- 2-(2-piperidin-1-yl-ethylamino)-purin-9-yl]-tetrahydro-furan-3,4-diol; 2-[9-[5S-(3-Ethyl-isoxazol-5-yl)-3R,4S-dihydroxy-tetrahydro-furan-2R-yl]-2-(2-piperidin-1-yl-ethylamino)-9H-purin-6-ylamino]-ethanesulfonic acid methylamide; (2S,3S,4R,5R)-2-(3-Ethyl-isoxazol-5-yl)-5-[2-(2-piperidin-1-yl-ethylamino)-6-(tetrahydro-thiopyran-4-ylamino)-purin-9-yl]-tetrahydro-furan-3,4-diol; (2S,3S,4R,5R)-2-(3-Ethyl-isoxazol-5-yl)-5-[2-(2-pyridin-2-yl-ethylamino)-6- (tetrahydro-pyran-4-ylamino)-purin-9-yl]-tetrahydro-furan-3,4-diol; (2S,3S,4R,5R)-2-(3-Ethyl-isoxazol-5-yl)-5-[2-(2-piperidin-1-yl-ethylamino)-6-(tetrahydro-pyran-4-ylamino)-purin-9-yl]-tetrahydro-furan-3,4-diol; (2S,3S,4R,5R)-2-(3-Ethyl-isoxazol-5-yl)-5-[2-(1S-hydroxymethyl-2-phenyl-ethylamino)-6-(tetrahydro-pyran-4-ylamino)-purin-9-yl]-tetrahydro-furan-3,4-diol; (2R,3R,4S,5S)-2-{6-(2,2-Diphenyl-ethylamino)-2-[2-(pyridin-2-ylamino)-ethylamino]-purin-9-yl}-5-(3-ethyl-isoxazol-5-yl)-tetrahydro-furan-3,4-diol; (2R,3R,4S,5S)-2-[6-(2,2-Diphenyl-ethylamino)-2-(1S-hydroxymethyl-2-phenyl-ethylamino)-purin-9-yl]-5-(3-ethyl-isoxazol-5-yl)-tetrahydro-furan-3,4-diol; 4-(2-{6-Amino-9-[5S-(3-ethyl-isoxazol-5-yl)-3R,4S-dihydroxy-tetrahydro-furan- 2R-yl]-9H-purin-2-ylamino}-ethyl)-benzenesulfonamide; (2R,3R,4S,5S)-2-[2-(trans-4-Amino-cyclohexylamino)-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-5-(3-ethyl-isoxazol-5-yl)-tetrahydro-furan-3,4-diol; (2S, 3S,4R, 5R)-2-(3-Ethyl-isoxazol-5-yl)-5-(6-(3-iodo-benzylamino)-2-[2-(1-methyl-1H-imidazol-4-yl)-ethylamino]-purin-9-yl}-tetrahydro-furan-3,4-diol; (2R,3R,4S,5S)-2-(6-(2-Cyclohexyl-ethylamino)-2-[2-(1-methyl-1H-imidazol-4-yl)-ethylamino]-purin-9-yl}-5-(3-ethyl-isoxazol-5-yl)-tetrahydro-furan-3,4-diol; (2R,3R,4S,5S)-2-[6-(2-Cyclohexyl-ethylamino)-2-(1S-hydroxymethyl-2-phenyl-ethylamino)-purin-9-yl]-5-(3-ethyl-isoxazol-5-yl)-tetrahydro-furan-3,4-diol; N-(2-{6-(2,2-Diphenyl-ethylamino)-9-[5S-(3-ethyl-isoxazol-5-yl)-3R,4S-dihydroxy-tetrahydro-furan-2R-yl]-9H-purin-2-ylamino}-ethyl)-guanidine; N-(4-{6-(2,2-Diphenyl-ethylamino)-9-[5S-(3-ethyl-isoxazol-5-yl)-3R,4S-dihydroxy-tetrahydro-furan-2R-yl]-9H-purin-2-ylamino}-cyclohexyl)-acetamide; 2-[9-[5S-(3-Ethyl-isoxazol-5-yl)-3R,4S-dihydroxy-tetrahydro-furan-2R-yl]-2-(2-guanidino-ethylamino)-9H-purin-6-ylamino]-ethanesulfonic acid methylamide; N-(2-{6-(1,1-Dioxo-hexahydro-1.lambda.6-thiopyran-4-ylamino)-9-[5S-(3-ethyl-isoxazol-5-yl)-3R,4S-dihydroxy-tetrahydro furan-2R-yl]-9H-purin-2-ylamino}-ethyl)-guanidine; 2-[9-[5S-(3-Ethyl-isoxazol-5-yl)-3R,4S-dihydroxy-tetrahydro-furan-2R-yl]-2-(1S-hydroxymethyl-2-phenyl-ethylamino)-9H-purin-6-ylamino]-ethanesulfonic acid methylamide; 1-{4-[9-[5S-(3-Ethyl-isoxazol-5-yl)-3R,4S-dihydroxy-tetrahydro-furan-2R-yl]-2-(1S-hydroxymethyl-2-phenyl-ethylamino)-9H-purin-6-ylamino]-piperidin-1-yl}-ethanone; 1-(4-{2-(trans-4-Amino-cyclohexylamino)-9-[5S-(3-ethyl-isoxazol-5-yl)-3R,4S-dihydroxy-tetrahydro-furan-2R-yl]-9H-purin-6-ylamino}-piperidin-1-yl)-ethanone; (2R,3R,4S,5S)-2-(3-Ethyl-isoxazol-5-yl)-5-[2-(2-pyridin-2-yl-ethylamino)-6- (tetrahydro-thiopyran-4-ylamino)-purin-9-yl]-tetrahydro-furan-3,4-diol; (2R,3R,4S,5S)-2-[6-(1,1-Dioxo-hexahydro-1.lambda.6-thiopyran-4-ylamino)-2-(2-piperidin-1-yl-ethylamino)-purin-9-yl]-5-(3-ethyl-isoxazol-5-yl)-tetrahydro-furan-3,4-diol; (2R,3R,4S,5S)-2-[2-(trans-4-