Patent EA-001714-B1 (EA)
Title: 2-(purin-9-yl)-tetrahydrofuran-3,4-diol derivatives
Inventor: COX BRIAN
IPC: A61P29/00
Filed: 1997-12-22
Abstract: 1. A compound of formula I:   wherein R<1> and R<2> independently represent a group selected from: (i) C3-8 cycloalkyl; (ii) hydrogen; (iii) aryl2CHCH2-; (iv) C3-8cycloalkylC1-6alkyl; (v) C1-8alkyl (vi) arylC1-6alkyl; (vii) R<4>R<5>N-C1-6alkyl; (viii) C1-6alkyl-CH(CH2OH)-; (ix) arylC1-5alkyl-CH(CH2OH)-; (x) arylC1-5alkyl-C(CH2OH)2-; (xi) C3-8cycloalkyl independently substituted by one or more -(CH2)pR<6> groups; (xii) a group of formula   or such a group in which one methylene carbon atom adjacent to X, or both if such exist, are substituted by methyl; (xiii) -C1-6alkyl-OH; (xiv) -C1-8haloalkyl; (xv) a group of formula   (xvii) aryl; R<3> represents methyl, ethyl or isopropyl; R<4> and R<5> independently represent hydrogen, C1-6alkyl, aryl, arylC1-6alkyl- or NR<4>R<5> together may represent pyrrolidinyl, piperidinyl, morpholinyl, azetidinyl, azepinyl, piperazinyl or N-C1-6alkylpiperazinyl; R<6> represents OH, NH2 or halogen; R<7> represents hydrogen, C1-6alkyl or C1-6alkylaryl; X represents NR<7>, O, S, SO or SO2; p represents 0 or 1; a and b independently represent an integer 0 to 4 provided that a+b is in the range 3 to 5; c, d and e independently represent an integer 0 to 3 provided that c+d+e is in the range 2 to 3; and salts and solvates thereof. 2. A compound of formula I according to Claim 1 wherein R<1> and R<2> independently represent a group selected from: (i) C3-8cycloalkyl; (ii) hydrogen; (iii) aryl2CHCH2-; (iv) C3-8cycloalkylC1-6alkyl; (v) C1-8alkyl (vi) arylC1-6alkyl; (vii) R<4>R<5>N-C1-6alkyl; (viii) C1-6alkyl-CH(CH2OH)-; (ix) arylC1-5alkyl-CH(CH2OH)-; (x) arylC1-5alkyl-C(CH2OH)2-; (xi) C3-8cycloalkyl independently substituted by one or more -(CH2)pR<6> groups; (xii) a group of formula   (xiii) a group of formula   (xiv) aryl; R<4> and R<5> independently represent hydrogen, C1-6alkyl, aryl or NR<4>R<5> together may represent pyrrolidinyl, piperidinyl, morpholinyl, azetidinyl, azepinyl, piperazinyl or N-methylpiperazinyl; R<6> represents OH or NH2; X represents NR<7> or SO2; and a and b independently represent an integer 0 to 4 provided that a+b is in the range 3 to 4. 3. A compound according to Claim 1 or Claim 2 wherein R<1> represents Ph2CHCH2-, arylC1-6alkyl-, C1-8alkyl-, arylC1-5alkylCH(CH2OH)-, C3-8cycloalkyl-, C3-8cycloalkylC1-6alkyl-, R<4>R<5>N-C1-6alkyl-, hydrogen, tetrahydropyran-4-yl, tetrahydrothiopyran-4-yl or 1,1-dioxo-hexahydro-1.lamda.6-thiopyran-4-yl. 4. A compound according to any of Claims 1-3 wherein R<2> represents R<4>R<5>N-C1-6alkyl-, aryl, C3-8cycloalkylC1-6alkyl-, -C1-6alkyl-OH, arylC1-5alkylCH(CH2OH)-, tetrahydro-1,1-dioxid thiophene-3-yl, C3-8cycloalkyl, C3-8cycloalkyl independently substituted by one or more -(CH2)pR<6> groups, C1-6alkyl-CH(CH2OH)-, arylC1-6alkyl- or pyrrolidin-3-yl, 2-oxopyrrolidin-4-yl, 2-oxopyrrolidin-5-yl, piperidin-3-yl or piperidin-4-yl in which the ring nitrogen is optionally substituted by C1-6alkyl or arylC1-6alkyl, or tetrahydropyran-4-yl, tetrahydrothiopyran-4-yl or 1,1-dioxo-hexahydro-1.lamda.6-thiopyran-4-yl. 5. A compound according to any one of Claims 1 to 4 wherein R<3> represents ethyl. 6. A compound of formula I which is (2R,3R,4S,5R)-2-[6-amino-2-(1S-hydroxymethyl-2-phenyl-ethylamino)-purin-9-yl]-5-(2-ethyl-2H-tetrazol-5-yl)-tetrahydro-furan-3,4-diol or a salt or solvate of any one thereof. 7. A compound of formula I which is (2R,3R,4S,5R)-2-[6-amino-2-(1S-hydroxymethyl-2-phenyl-ethylamino)-purin-9-yl]-5-(2-ethyl-2H-tetrazol-5-yl)-tetrahydro-furan-3,4-diol maleate. 8. A compound of formula I which is (2R,3R,4S,5R)-2-[6-(2,2-diphenyl-ethylamino)-2-(pyrrolidin-3R-yl-amino)-purin-9-yl]-5-(2-ethyl-2H-tetrazol-5-yl)-tetrahydro-furan-3,4-diol; (2R,3S,4R,5R)-2-(2-ethyl-2H-tetrazol-5-yl)-5-{2-[2-(1-methyl-1H-imidazol-4-yl)-ethylamino]-6-phenethylamino-purin-9-yl}-tetrahydro-furan-3,4-diol; (2R,3R,4S,5R)-2-[2-(trans-4-amino-cyclohexylamino)-6-(2,2-diphenylethylamino)-purin-9-yl]-5-(2-ethyl-2H-tetrazol-5-yl)-tetrahydro-furan-3,4-diol; (2R,3R,4S,5R)-2-[6-amino-2-(2R-hydroxy-cyclopent-lR-ylamino)-purin-9-yl]-5-(2-ethyl-2H-tetrazol-5-yl)-tetrahydro-furan-3,4-diol; (2R,3R,4S,5R)-2-[6-(2,2-diphenyl-ethylamino)-2-pyrrolidin-3-ylamino)-purin-9-yl]-5-(2-ethyl-2H-tetrazol-5-yl)-tetrahydro-furan-3,4-diol; (2R,3S,4R,5R)-2-(2-ethyl-2H-tetrazol-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,5R)-2-{6-benzylamino-2-[2-(1-methyl-1H-imidazol-4-yl)-ethylamino]-purin-9-yl}-5-(2-ethyl-2H-tetrazol-5-yl)-tetrahydro-furan-3,4-diol; (2R,3R,4S,5R)-2-{6-(1-ethyl-propylamino)-2-[2-(1-methyl-1H-imidazol-4-yl)-ethylamino]-purin-9-yl}-5-(2-methyl-2H-tetrazol-5-yl)tetrahydro-furan-3,4-diol; (2R,3R,4S,5R)-(2-{6-cyclopentylamino-2-[2-(l-methyl-lH-imidazol-4-yl)-ethylamino]-purin-9-yl}-5-(2-ethyl-2H-tetrazol-5-yl)-tetrahydro-furan-3,4-diol; (2R,3S,4R,5R)-2-(2-ethyl-2H-tetrazol-5-yl)-5-{6-(1S-hydroxymethyl-2-phenylethylamino)-2-[2-(1-methyl-1H-imidazol-4-yl)-ethylamino]-purin-9-yl}-tetrahydrofuran-3,4-diol; (2R,3R,4S,5R)-2-{6-(3,3-dimethyl-butylamino)-2-[2-(1-methyl-1H-imidazol-4-yl)-ethylamino]-purin-9-yl}-5-(2-ethyl-2H-tetrazol-5-yl)-tetrahydro-furan-3,4-diol; (2R,3R,4S,5R)-2-(6-amino-2-cyclopentylamino-purin-9-yl)-5-(2-ethyl-2H-tetrazol-5-yl)-tetrahydro-furan-3,4-diol; (2R,3R,4S,5R)-2-[6-amino-2-(4-fluoro-phenylamino)-purin-9-yl]-5-(2-ethyl-2H-tetrazol-5-yl)-tetrahydro-furan-3,4-diol; (2R,3R,4S,5R)-2-{6-amino-2-[2-(4-amino-phenyl)-ethylamino]-purin-9-yl}-5-(2-ethyl-2H-tetrazol-5-yl)-tetrahydro-furan-3,4-diol; (2R,3R,4S,5R)-2-(6-amino-2-[2-(3,4-dihydroxy-phenyl)-ethylamino]-purin-9-yl}-5-(2-ethyl-2H-tetrazol-5-yl)-tetrahydro-furan-3,4-diol; (2R,3R,4S,5R)-2-{6-amino-2-[2-(4-hydroxy-phenyl)-ethylamino]-purin-9-yl}-5-(2-ethyl-2H-tetrazol-5-yl)-tetrahydro-furan-3,4-diol; 4-(2-{6-amino-9-[5R-(2-ethyl-2H-tetrazol-5-yl)-3R,4S-dihydroxy-tetrahydro-furan-2R-yl]-9H-purin-2-ylamino}-ethyl)-benzenesulfonamide; (2R,3R,4S,5R)-2-{6-amino-2-[2-(4-methoxy-phenyl)-ethylamino]-purin-9-yl}-5-(2-ethyl-2H-tetrazol-5-yl)-tetrahydro-furan-3,4-diol; (2R,3R,4S,5R)-2-[6-amino-2-(bicyclo[2.2.1]hept-2-ylamino)-purin-9-yl]-5-(2-ethyl-2H-tetrazol-5-yl)-tetrahydro-furan-3,4-diol; (2R,3R,4S,5R)-2-{6-amino-2-[2-(3,4-dimethoxy-phenyl)-ethylamino]-purin-9-yl}-5-(2-ethyl-2H-tetrazol-5-yl)-tetrahydro-furan-3,4-diol; (2R,3R,4S,5R)-2-[2-[2-(6-amino-pyridin-2-yl)-ethylamino]-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-5-(2-ethyl-2H-tetrazol-5-yl)-tetrahydro-furan-3,4-diol; (2R,3S,4R,5R)-2-(2-ethyl-2H-tetrazol-5-yl)-5-[6-(3-iodo-benzylamino)-2-(pyrrolidin-3R-ylamino)-purin-9-yl]-tetrahydro-furan-3,4-diol; (2R,3R,4S,5R)-2-[6-(1-ethyl-propylamino)-2-(2-piperidin-1-yl-ethylamino)-purin-9-yl]-5-(2-methyl-2H-tetrazol-5-yl)-tetrahydro-furan-3,4-diol; (2R,3R,4S,5R)-2-[6-cyclopentylamino-2-(2-piperidin-1-yl-ethylamino)-purin-9-yl]-5-(2-methyl-2H-tetrazol-5-yl)-tetrahydro-furan-3,4-diol; (2R,3R,4S,5R)-2-[6-(2,2-diphenyl-ethylamino)-2-(2-piperidin-1-yl-ethylamino)purin-9-yl]-5-(2-methyl-2H-tetrazol-5-yl)-tetrahydro-furan-3,4-diol; (2R,3R,4S,5R)-2-{6-(2,2-diphenyl-ethylamino)-2-[2-(1-methyl-1H-imidazol-4-yl)-ethylamino]-purin-9-yl}-5-(2-methyl-2H-tetrazol-5-yl)-tetrahydro-furan-3,4-diol; (2R,3R,4S,5R)-2-{6-(3,3-dimethyl-butylamino)-2-[2-(1-methyl-1H-imidazol-4-yl)-ethylamino]-purin-9-yl}-5-(2-methyl-2H-tetrazol-5-yl)-tetrahydro-furan-3,4-diol; (2R,3R,4S,5R)-2-{6-(3-iodo-benzylamino)-2-[2-(1-methyl-1H-imidazol-4-yl)-ethylamino]-purin-9-yl}-5-(2-methyl-2H-tetrazol-5-yl)-tetrahydro-furan-3,4-diol; (2R,3R,4S,5R)-2-{6-benzylamino-2-[2-(l-methyl-lH-imidazol-4-yl)-ethylamino]-purin-9-yl}-5-(2-methyl-2H-tetrazol-5-yl)-tetrahydro-furan-3,4-diol; (2R,3R,4S,5R)-(6-{2-cyclohexyl-ethylamino)-2-[2-(1-methyl-1H-imidazol-4-yl)-ethylamino]-purin-9-yl}-5-(2-methyl-2H-tetrazol-5-yl)-tetrahydro-furan-3,4-diol; (2R,3R,4S,5R)-2-{6-(1S-hydroxymethyl-2-phenyl-ethylamino)-2-[2(1-methyl-1H-imidazol-4-yl)-ethylamino]-purin-9-yl}-5-(2-methyl-2H-tetrazol-5-yl)-tetrahydro-furan-3,4-diol; (2R,3R,4S,5R)-2-{6-(1-ethyl-propylamino)-2-[2-(1-methyl-lH-imidazol-4-yl)-ethylamino]-purin-9-yl}-5-(2-methyl-2H-tetrazol-5-yl)-tetrahydro-furan-3,4-diol; (2R,3R,4S,5R)-2-{2-[2-(1-methyl-1H-imidazol-4-yl)-ethylamino]-6-phenethylamino-purin-9-yl}-5-(2-methyl-2H-tetrazol-5-yl)-tetrahydro-furan-3,4-diol; (2R,3R,4S,5R)-2-[2-(trans-4-amino-cyclohexylamino)-6-(1S-hydroxymethyl-2-phenyl-ethylamino)-purin-9-yl]-5-(2-methyl-2H-tetrazol-5-yl)-tetrahydro-furan-3,4-diol; (2R,3R,4S,5R)-2-[6-cyclopentylamino-2-(1S-hydroxymethyl-2-phenyl-ethylamino)-purin-9-yl]-5-(2-methyl-2H-tetrazol-5-yl)-tetrahydro-furan-3,4-diol; (2R,3R,4S,5R)-2-[6-amino-2-(1S-hydroxymethyl-2-phenyl-ethyl-amino)-purin-9-yl]-5-(2-methyl-2H-tetrazol-5-yl)-tetrahydro-furan-3,4-diol; (2R,3R,4S,5R)-2-{6-amino-2-[2-(3,4-dimethoxy-phenyl)-ethylamino]-purin-9-yl}-5-(2-methyl-2H-tetrazol-5-yl)-tetrahydro-furan-3,4-diol; (2R,3R,4S,5R)-2-[6-amino-2-(bicyclo[2.2.1]hept-2-ylamino)-purin-9-yl]-5-(2-methyl-2H-tetrazol-5-yl)-tetrahydro-furan-3,4-diol; (2R,3R,4S,5R)-2-{6-(1S-hydroxymethyl-2-phenyl-ethylamino)-2-[2(1-methyl-lH-imidazol-4-yl)-ethylamino]-purin-9-yl}-5-(2-isopropyl-2H-tetrazol-5-yl)-tetrahydrofuran-3,4-diol; (2R,3R,4S,5R)-2-{6-cyclopentylamino-2-[2-(1-methyl-1H-imidazol-4-yl)-ethylamino]-purin-9-yl}-5-(2-isopropyl-2H-tetrazol-5-yl)-tetrahydro-furan-3,4-diol; (2R,3R,4S,5R)-2-{6-amino-2-[2-(3,4-dimethoxy-phenyl)-ethylamino]-purin-9-yl}5-(2-isopropyl-2H-tetrazol-5-yl)-tetrahydro-furan-3,4-diol; (2R,3R,4S,5R)-2-[6-(2,2-diphenyl-ethylamino)-2-(2-pyrrolidin-1-yl-ethylamino)-purin-9-yl]-5-(2-ethyl-2H-tetrazol-5-yl)-tetrahydro-furan-3,4-diol; (2R,3R,4S,5R)-2-[6-(2,2-diphenyl-ethylamino)-2-(2-morpholin-4-yl-ethylamino)-purin-9-yl]-5-(2-ethyl-2H-tetrazol-5-yl)-tetrahydro-furan-3,4-diol; (2R,3R,4S,5R)-2-[2-(1,1-dioxo-tetrahydro-1.lambda.6-thiophen-3-ylamino)-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-5-(2-ethyl-2H-tetrazol-5-yl)-tetrahydro-furan-3,4-diol; (2R,3R,4S,5R)-2-[6-(2,2-diphenyl-ethylamino)-2-(2-piperidin-1-yl-ethylamino)-purin-9-yl]-5-(2-ethyl-2H-tetr