Patent EA-003087-B1 (EA)
Title: Adenosine derivatives
Inventor: ELDRED COLIN DAVID
IPC: A61P9/00
Filed: 1998-11-06
Abstract: 1. A compound of formula (I)   wherein R<2> represents C1-4 alkyl, halogen or hydrogen; R3 represents straight or branched alkyl group of 1-6 carbon atoms; R<1> represents a group selected from: (1) -( C1-3 alk)n-( C3-7) cycloalkyl, including bridged (C4-7) cycloalkyl, said cycloalkyl group optionally substituted by one or more substituents selected from OH, halogen, -(C1-3) alkoxy, wherein n represents 0 or 1. (2) 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 -(C1-4) alkyl, -CO2-(C1-4) alkyl or =O (3) Straight or branched C1-6 alkyl, optionally including one or more O, S(=O)2 or N substituted within the alkyl chain, said alkyl optionally substituted by one or more of the following groups: phenyl, halogen, hydroxy or NH2; (4) 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(C1-4 alkyl); (5) a phenyl group optionally substituted by one or more substituents selected from: -halogen, -(C1-6 alk)n-OH, -( C2-6 alk)n-OH, -(O)m-(C1-6 alk)N-CO2R<c>, -(O)m-(C2-6 alkn)n-CO2R<c>, tetrazolyl, optionally substituted by C1-4 alkyl, wherein m and n are 0 or 1 and R<c> represents hydrogen or a -(C1-4) alkyl; with the proviso that, when R<3> represents C1-6 alkyl, R<2> represents C1-4 alkyl, R<1> cannot represent phenyl optionally substituted by one or more substituents selected from halogen, CO2R<c> and -OR<c>; and salts and solvates thereof, in particular, physiologically acceptable solvates and salts thereof. 2. A compound according to claim 1 wherein R<3> represents C1-3 alkyl. 3. A compound according to claim 2 wherein R<3> represents methyl or ethyl. 4. A compound according to claim 3 wherein R<3> represents methyl. 5. A compound according to any preceding claim wherein R<2> represents hydrogen, methyl or halogen. 6. A compound according to claim 5 wherein R<2> represents hydrogen or methyl. 7. A compound according to any of claims 1-6 wherein R<1> represents -(C1-3 alk)n-C5-7-cycloalkyl wherein n is 0 or 1, optionally substituted by at least one substituent selected from halogen, C1-3 alkoxy, and OH or is unsubstituted. 8. A compound according to claim 7 wherein the cycloalkyl group is unsubstituted or monosubstituted with fluorine. 9. A compound according to claim 7 or 8 wherein n is zero. 10 A compound according to any of claims 1-6 wherein R<1> represents a substituted or unsubstitued aliphatic heterocyclic group, which when substituted, the substituent being selected from the group consisting of C1-4 alkyl, CO2-(C1-4 alkyl) or = O. 11. A compound according to claim 10 wherein the substituent is CO2-(C1-4 alkyl) or methyl. 12. A compound according to claim 11 wherein the aliphatic heterocyclic group is unsubstituted or the substitutent is CO2-(C1-4 alkyl) and when the heteroatom is N, the substituent is directly attached to the ring N atom. 13. A compound according to any of claims 10-12 wherein the heterocyclic ring is 6 membered. 14. A compound according to claim 13 wherein the ring contains only one N, O or S heteroatom. 15. A compound according to any of claims 1-6 wherein R<1> represents a straight or branched alkyl of 1-6 carbon atoms optionally including at least one S(=O)2, O or N substituted in the chain, the alkyl optionally further substituted by at least one group selected from OH, phenyl and fluorine. 16. A compound according to any of claims 1-6 wherein R<1> represents a phenyl group substituted by one or more substituents selected from halogen, Om-(C1-6 alkylene)n-CO2R<c>, Om-(C2-6 alkenyl)n-CO2R<c>, -(C1-6 alkylene)n-OH and -(C2-6 alkenyl)n-CO2R<c>-OH. 17. A compound according to claim 16 wherein the phenyl group is disubstituted in the 2, 4 positions. 18. A compound according to claim 17 wherein both substitutents is halogen. 19. A compound according to claim 18 wherein the 2 substituent is fluoro and the 4 substituent is fluoro. 20. A compound according to claim 1-6 wherein R<1> represents a phenyl group substituted by a 5-tetrazolyl group this group itself optionally substituted by C1-4 alkyl. 21. A compound according to any of claims 1-6 wherein R<1> represents a fused group   wherein B represents a furan ring optionally substituted by CO2(C1-4 alkyl). 22. A compound according to claim 21 wherein the furan ring is substituted in the 2 position. 23. A compound according to claim 1 selected from: 5'-O-Methyl-N-(tetrahydro-furan-3R-yl)-adenosine, N-(2R-Hydroxy-(R)-cyclopentyl)-5'-O-methyl-adenosine, 5'-O-Methyl-N-(tetrahydro-fyran-4-yl)-adenosine, N-(2S-Methoxy-(S)-cyclopentyl)-5'-O-methyl-adenosine, 5'-O-Methyl-N-(2S-methyl-tetrahydro-furan-3R-yl)-adenosine, N-(3-Chloro-4-hydroxy-phenyl)-5'-O-methyl-adenosine, 5'-O-Methyl-N-(1R-methyl-2-phenyl-ethyl)-adenosine, N-tert-Butyl-5'-O-methyl-adenosine, N-(2S-Fluoro-(S)-cyclopentyl)-5'-O-methyl-adenosine, N-(2,3-Dihydroxy-propylamino)-5'-O-methyl-adenosine, N-rel-[(1S,4R)-Bicyclo[2.2.1 ]hept-2R-yl]-S'-O-methyl-adenosine, 4-[9-(3R,4S-Dihydroxy-5R-methoxymethyl-tetrahydro-furan-2R-yl)-9H purin-6-ylamino]-piperidine-1-carboxylic acid ethyl ester, 5'-O-Methyl-N-[4-(2-methyl-2H-tetrazol-5-yl)-phenyl]-adenosine, 3-{4-[9-(3R,4S-Dihydroxy-5R-methoxymethyl-tetrahydro-furan-2R-yl)-9H-purin-6-ylamino}-phenyl)-(E)-acrylic acid, N-(4-Hydroxymethyl-phenyl)-5'-O-methyl-adenosine, {4-[9-(3R,4S-Dihydroxy-SR-methoxymethyl-tetrahydro-furan-2R-yl)-9H-purin-6-ylamino]-phenoxy}-acetic acid, 5-[9-(3R,4S-Dihydroxy-5R-methoxymethyl-tetrahydro-furan-2R-yl)-9H-purin-6-ylamino]-benzofuran-2-carboxylic acid methyl ester, 5'-O-Methyl-N-(tetrahydro-thopyran-4-yl )-adenosine, N-rel-[(1R,5R)-Bicyclo[3.2.0]hept-6S-yl]-5'-O-methyl-adenosine, 4-[9-(3R,4S-Dihydroxy-5R-methoxymethyl-tetrahydro-furan-2R-yl)-2-methyl-9H-purin-6-ylamino]-piperidin-2-one, 5'-O-Methyl-N-(1S-methoxymethyl-2-methyl-propyl)-adenosine, N-(2-Hydroxy-1R-methyl-ethyl)-5'-O-methyl-adenosine, N-(2-Fluoro-1R-methyl-ethyl)-5'-O-methyl-adenosine, N-(1S-Fluoromethyl-2-methoxy-ethyl)-5'-O-methyl-adenosine, N-(3-Amino-propyl)-5'-O-methyl-adenosine, 2-[9-(3R,4S-Dihydroxy-5R-methoxymethyl-tetrahydro-furan-2R-yl)-2-methyl-9H-purin-6-ylamino]-ethanesulfonic acid methylamide, N-Cyclopentyl-2-methyl-5'-O-methyl-adenosine, N-Cyclopropylmethyl-2-methyl-5'-O-methyl-adenosine. 24. A compound according to any preceding claim with little or no activity at the A3 receptor. 25. A compound according to any of claims 1-24 for use in therapy. 26. A pharmaceutical composition comprising a compound according to claims 1-24 together with a pharmaceutical carrier and/or excipient. 27. Use of a compound according to any of claim 1-24 for the manufacture of a medicament for the treatment of a patient suffering from a condition where there is an advantage in decreasing plasma free fatty acid concentration, or reducing heart rate or which subject is suffering from or susceptible to ischaemic heart disease, peripheral vascular disease or stroke or which subject is suffering pain, a CNS disorder or sleep apnoea. 28. A method of treating a patient suffering from a condition where there is an advantage in decreasing plasma free fatty acid concentration, or reducing heart rate or which subject is suffering from or susceptible to ischaemic heart disease, peripheral vascular disease or stroke or which subject is suffering pain, a CNS disorder or sleep apnoea comprising administering a therapeutically effective amount of a compound according to any of claims 1-24. 29. A method of preparing a compound according to any of claims 1-24 which comprises reacting a compound of formula (II)   wherein L represents a leaving group and P<1> and P<2> represent protecting groups or H with a compound R<1>NH2 or a salt thereof under basic conditions, R<1>, R<2> and R3 being defined in claim 1.