Patent EA-003828-B1 (EA)
Title: Adenosine derivatives
Inventor: BAYS DAVID EDMUND
IPC: C07H19/16
Filed: 1999-06-21
Abstract: 1. A compound of formula (Ib) wherein X represents O or CH2; R<2> represents C1-3alkyl, C1-3alkoxy, halogen or hydrogen; R3 represents H, phenyl (optionally substituted by halogen), a 5 or 6-membered heteroaryl group, C1-6 alkoxy, C1-6 alkylO(CH2)n, where n is 0-6, C3-7 cycloalkyl, C1-6 hydroxyalkyl, halogen or a C1-6 straight or branched alkyl, C1-6 alkenyl or C1-6 alkynyl group, optionally substituted by one or more halogens; Y and Z represent O, N, CH, N(C1-6 alkyl); W represents CH, O, N, S or N(C1-6 alkyl); and wherein at least one of W and Z represents a heteroatom (and when Y, Z and/or W is N, the presence or absence of an additional H would be apparent to a person skilled in the art); with the proviso that when W represents CH, Z represents N and Y represents O, R<3> cannot be H; R<4> and R<5> independently represent H or a C1-6 straight chain or branched alkyl group; R<1> represents hydrogen or a group selected from: (1) an aliphatic heterocyclic group of 4 to 6-membered rings containing at least one heteroatom selected from O, N or S, optionally substituted by one or more substituents selected from the group consisting of -(C1-3)alkyl, -CO2-(C1-4)alkyl, -CO(C1-3alkyl), -S(=O)n-(C1-3alkyl), -CONR<A>R<B> (wherein R<A> and R<B> independently represent H or C1-3alkyl) or =O; where there is a sulfur atom in the heterocyclic ring, said sulfur is optionally substituted by (=O)n, where n is 1 or 2; (2) a fused bicyclic aromatic ring wherein B represents a 5 or 6-membered heterocyclic aromatic group containing 1 or more O, N or S atoms, wherein the bicyclic ring is attached to the nitrogen atom of formula (I) via a ring atom of ring A and ring B is optionally substituted by -CO2-(C1-3alkyl); (3) a phenyl group optionally substituted by one or more substituents selected from: -halogen, -SO3H, -(alk)nOH, -(alk)n-cyano, -(O)n-(C1-6)alkyl (optionally substituted by one or more halogens), -(alk)n-nitro, -(O)m-(alk)n-CO2R<C>, -(alkn)-CONR<C>R<D>, -(alk)n-COR<C>, -(alk)n-SOR<C>, -(alk)n-SO2R<E>, -(alk)n-SO2NR<C>R<D>, -(alk)n OR<C>, -(alk)n-(CO)m-NHSO2R<E>, -(alk)n-NHCOR<C>, -(alk)n-NR<C>R<D> wherein m and n are 0 or 1 and alk represents a C1-6alkylene group or C2-6 alkenyl group. (4) a phenyl group substituted by a 5 or 6-membered heterocyclic aromatic group, said heterocyclic aromatic group optionally being substituted by C1-3alkyl or NR<C>R<D>; R<C> and R<D> may each independently represent hydrogen, or C1-3 alkyl or when part of a group NR<C> R<D>, R<C> and R<D> together with the nitrogen atom may form a 5 or 6-membered heterocyclic ring optionally containing other heteroatoms, which heterocyclic ring may optionally be substituted further by one or more C1-3 alkyl groups; R<E> represents C1-3alkyl; and salts and solvates thereof, in particular, physiologically acceptable solvates and salts thereof; with the proviso that when R<4> and R<5> both represent H and R<2> represents halogen, R<3> cannot represent methyl, ethyl, n-propyl, isopropyl, cyclopropyl, CH(OH)CH3 or C1-3alkoxy. 2. A compound of formula (Ic) wherein X represents O or CH2; R<2> represents C1-3alkyl, C1-3alkoxy, halogen or hydrogen; R<3> represents H, phenyl (optionally substituted by halogen), a 5 or 6-membered heteroaryl group, C1-6 alkoxy, C1-6 straight or branched alkyl optionally substituted by one or more halogens, C3-7 cycloalkyl, C1-6 hydroxyalkyl or halogen; Y and Z represent O, N, CH; W represents CH, O, N or S; and wherein at least one of W and Z represents a heteroatom (and when Y, Z and/or W is N, the presence or absence of an additional H would be apparent to a person skilled in the art); with the proviso that when W represents CH, Z represents N and Y represents O, R<3> cannot be H; R<4> and R<5> independently represent H or a C1-6 straight chain or branched alkyl group; R<1> represents a group selected from: (1) an aliphatic heterocyclic group of 4 to 6-membered rings containing at least one heteroatom selected from O, N or S, optionally substituted by one or more substituents selected from the group consisting of -(C1-3)alkyl, -CO2-(C1-4)alkyl, -CO(C1-3alkyl), -S(=O)n-(C1-3alkyl), -CONR<A>R<B> (wherein R<A> and R<B> independently represent H or C1-3alkyl) or =O; where there is a sulfur atom in the heterocyclic ring, said sulfur is optionally substituted by (=O)n, where n is 1 or 2; (2) a fused bicyclic aromatic ring wherein B represents a 5 or 6-membered heterocyclic aromatic group containing 1 or more O, N or S atoms, wherein the bicyclic ring is attached to the nitrogen atom of formula (I) via a ring atom of ring A and ring B is optionally substituted by -CO2-(C1-3alkyl); (3) a phenyl group optionally substituted by one or more substituents selected from: -halogen, -SO3H, -(alk)nOH, -(alk)n-cyano, -(O)n-(C1-6)alkyl (optionally substituted by one or more halogens), -(alk)n-nitro, -(O)m-(alk)n-CO2R<C>, -(alkn)-CONR<C>R<D>-(alk)n-COR<C>, -(alk)n-SOR<E>, -(alk)n-SO2R<E>, -(alk)n-SO2NR<C>R<D>, -(alk)nOR<C>, -(alk)n-(CO)m-NHSO2R<E>, -(alk)n-NHCOR<C> and -(alk)n-NR<C>R<D> wherein m and n are 0 or 1 and alk represents a C1-6alkylene group or C2-6alkenyl group; and (4) a phenyl group substituted by a 5 or 6-membered heterocyclic aromatic group, said heterocyclic aromatic group optionally being substituted by C1-3alkyl or NR<C>R<D>; R<C> and R<D> may each independently represent hydrogen, or C1-3alkyl or when part of a group NR<C>R<D>, R<C> and R<D> together with the nitrogen atom may form a 5 or 6-membered heterocyclic ring optionally containing other heteroatoms, which heterocyclic ring may optionally be substituted further by one or more C1-3alkyl group; R<E> represents C1-3alkyl; and salts and solvates thereof, in particular, physiologically acceptable solvates and salts thereof; with the proviso that when R<4> and R<5> both represent H, and R<2> represents halogen, R<3> cannot represent methyl, ethyl, n-propyl, isopropyl, cyclopropyl, CH(OH)CH3 or C1-3alkoxy. 3. A compound according to claims 1 or 2, which exhibits or no a little agonist activity at the A3 receptor. 4. A compound according to claims 1-3, wherein the W, Y and Z containing heterocyclic group is selected from isoxazoles, oxadiazoles, pyrazoles, oxazoles, triazoles, thiadiazoles. 5. A compound according to claims 1-4, wherein the W, Y and Z containing heterocyclic group is selected from isoxazoles, and 1,2,4- and 1,3,4- oxadiazoles. 6. A compound according to claims 1-5, wherein R<2> represents hydrogen, methyl, methoxy or halogen. 7. A compound according to claims 1-6, wherein R<1> may represent a substituted or unsubstituted aliphatic heterocyclic group, the substitutent being selected from the group consisting of -CO2-(C1-4)alkyl. 8. A compound according to claim 7, wherein the aliphatic heterocyclic group is unsubstituted or when the substituent is -CO2(C1-4)alkyl, the heteroatom is N and the substituent is directly attached to said ring nitrogen atom. 9. A compound according to claim 7 or 8, wherein the heterocyclic group is 6-membered. 10. A compound according to claim 7-9, wherein the heterocyclic ring contains only one O, N or S heteroatom. 11. A compound according to any of claims 1-6, wherein R<1> may represent a phenyl group, which is substituted by one or two substituents selected from OH, C1-4alkyl and halogen. 12. A compound according to claim 11, wherein the phenyl is disubstituted in the 2,4 positions. 13. A compound according to claims 11 or 12, wherein both substituents are halogen. 14. A compound according to any of claims 1-13, wherein R<4> and R<5> both represent hydrogen. 15. A compound selected from: (2S,3S,4R,5R)-2-(5-tert-butyl-[1,3,4]oxadiazol-2-yl)-5-[6-(tetrahydro-pyran-4-ylamino)-purin-9-yl]-tetrahydro-furan-3,4-diol; 4-{9-[5S-(5-tert-butyl-[1,3,4]oxadiazol-2-yl)-3R,4S-dihydroxy-tetrahydro-furan-2R-yl]-9H-purin-6-ylamino}-piperidine-1-carboxylic acid ethyl ester; (2S,3S,4R,5R)-2-(5-isopropyl-[1,3,4]oxadiazol-2-yl)-5-[6-(tetrahydro-pyran-4-ylamino)-purin-9-yl]-tetrahydro-furan-3,4-diol; 4-{9-[5S-(5-cyclopropyl-[1,3,4]oxadiazol-2-yl)-3R,4S-dihydroxy-tetrahydro-furan-2R-yl]-9H-purin-6-ylamino}-piperidine-1-carboxylic acid ethyl ester; (2S,3S,4R,5R)-2-(5-tert-butyl-[1,3,4]oxadiazol-2-yl)-5-[6-(4-chloro-2-fluoro-phenylamino)-purin-9-yl]-tetrahydro-furan-3,4-diol; (2S,3S,4R,5R)-2-(5-ethyl-oxazol-2-yl)-5-[6-(tetrahydro-pyran-4-ylamino)-purin-9-yl]-tetrahydro-furan-3,4-diol; (2S,3S,4R,5R)-2-(3-cyclopropyl-[1,2,4]oxadiazol-5-yl)-5-[6-(tetrahydro-pyran-4-ylamino)-purin-9-yl]-tetrahydro-furan-3,4-diol; (2S,3S,4R,5R)-2-(3-tert-butyl-isoxazol-5-yl)-5-[6-(tetrahydro-pyran-4-ylamino)-purin-9-yl]-tetrahydro-furan-3,4-diol; ethyl-4-({9-[(2R,3R,4S,5S)-3,4-dihydroxy-5-(3-methyl-1,2,4-oxadiazol-5-yl)tetrahydrofuran-2-yl]-9H-purin-6-yl}amino)piperidine-1-carboxylate; (2R,3R,4S,5S)-2-[6-3,4-difluoroanilino)-9H-purin-9-yl]-5-(3-isopropyl-1,2,4-oxadiazol-5-yl)tetrahydrofuran-3,4-diol; (2R,3R,4S,5S)-2-[6-(4-chloro-2-fluoroanilino)-9H-purin-9-yl]-5-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)tetrahydrofuran-3,4-diol; (2R,3S,4R,5R)-2-[5-(tert-butyl)-4H-1,2,4-triazol-3-yl]-5-[6-(4-chloro-2-fluoroanilino)-9H-purin-9-yl]tetrahydrofuran-3,4-diol; (2R,3R,4S,5R)-2-[6-(2-chloro-4-fluoroanilino)-9H-purin-9-yl]-5-(5-isopropyl-4H-1,2,4-triazol-3-yl)tetrahydrofuran-3,4-diol; (2S,3S,4R,5R)-2-(5-cyclopropyl-[1,3,4]oxadiazol-2-yl)-5-[6-(tetrahydro-2H-pyran-4-ylamino)-9H-purin-9-yl]-tetrahydrofuran-3,4-diol; (2S,3S,4R,5R)-2-[5-(tert-butyl)-1,3,4-oxadiazol-2-yl]-5-[6-(2-chloro-4-fluoroanilino)-9H-purin-9-yl]tetrahydrofuran-3,4-diol; (2S,3S,4R,5R)-2-[3-(tert-butyl)isoxazol-5-yl]-5-{6-[(1,1-dioxytetrahydro-2H-tiopyran-4-yl)amino]-9H-purin-9-yl}tetrahydrofuran-3,4-diol; (2S,3S,4R,5R)-2-(3-ethylisoxazol-5-yl)-5-[6-(tetrahydro-2H-pyran-4-ilamino)-9H-purin-9-yl]tetrahydrofuran-3,4-diol; ethyl-4-({9-[(2R,3R,4S,5S)-5-(3-ethylisoxazol-5-yl)-3,4-dihydroxytetrahydrofuran-2-yl]-9H-purin-6-yl}amino)piperidine-1-carboxylate; 2R,3S,4R,5R)-2-[5-(tert-butyl)-4H-1,2,4-triazol-3-yl]-5-[6-(tetrahydro-2H-pyran-4-y