Patent EA-003856-B1 (EA)
Title: Antipicornaviral compounds, their preparation and use
Inventor: DRAGOVICH PETER SCOTT
IPC: C07D261/18
Filed: 1999-01-05
Abstract: 1. A compound of the formula I: wherein: Y is-N(RY)-, -C(RY)2-, or -O-, where each RY is independently H or C1-4alkyl; R1 is H, F, C1-6alkyl group with linear or branched, saturated or unsaturated chain, optionally substituted by halogen; OH, SH, or an O-alkyl group: R2 and R3 are each independently H; or , where n is an integer from 0 to 5, A1 is CH or N, A2 and each A3 are independently selected from C(R41)(R41), N(R41), S, S(O), S(O)2, and O, and A4 is NH or NR41, where each R41 is independently H or C1-4alkyl with linear or branched chain, provided that no more than 2 heteroatoms occur consecutively in the ring formed by A1, A2, (A3)n, A4 and C=O; and provided that at least one of R2 and R3 is R5 and R6 are each independently H, F, C1-6arylalkyl group, an aryl part of which is optionally substituted by halogen or C1-4alkyl; R7 and R8 are each independently H, C1-6alkyl group optionally substituted by naphthyl or imidazole; R9 is a five-membered heterocycle having from one to three heteroatoms selected from O, N, and S; and Z and Z1 are each independently H or CO2R21 group, where R21 is H, C1-6alkyl group optionally substituted by pyridine; provided that Z and Z1 are both not H; or Z and Z1 together with the atoms to which they are bonded, form furanone. or a prodrug, pharmaceutically active metabolite, pharmaceutically acceptable salt, or solvate thereof. 2. A compound, prodrug, pharmaceutically active metabolite, pharmaceutically acceptable salt, or solvate according to claim 1, wherein R2 and R3 are each independently H; where n is an integer from 0 to 5, each R41, is independently H or C1-4alkyl with linear or branched chain, and, and the stereochemistry at the carbon denoted with an asterisk (*) may be R or S; provided that at least one of R2 and R3 is or 3. A compound, prodrug, pharmaceutically active metabolite, pharmaceutically acceptable salt, or solvate according to claim 1, wherein Y is-N (Ry)-, where Ry is H or linear or branched C1-4alkyl. 4. A compound, prodrug, pharmaceutically active metabolite, pharmaceutically acceptable salt, or solvate according to claim 3, wherein Z and Z1 are each independently selected from H, -CO2R21 group, where R21 is H, C1-6alkyl group optionally substituted by pyridine; provided that Z and Z1 are both not H; or Z and Z1 together with the atoms to which they are bonded, form furanone. 5. A compound, prodrug, pharmaceutically active metabolite, pharmaceutically acceptable salt, or solvate according to claim 3, wherein R1 is H, F, or methyl. 6. A compound, prodrug, pharmaceutically active metabolite, pharmaceutically acceptable salt, or solvate according to claim 3, wherein at least one of R2 or R3 is 7. A compound, prodrug, pharmaceutically active metabolite, pharmaceutically acceptable salt, or solvate according to claim 6, wherein one of R5 and R6 is H and the other is arylalkyl group optionally substituted by halogen or C1-4alkyl. 8. A compound, prodrug, pharmaceutically active metabolite, pharmaceutically acceptable salt, or solvate according to claim 3, wherein one of R5 and R6 is H and the other is arylalkyl group optionally substituted by halogen or C1-4alkyl. 9. A compound, prodrug, pharmaceutically active metabolite, pharmaceutically acceptable salt, or solvate according to claim 3, wherein one of R5 and R6 is H and the other is unsubstituted or substituted phenylmethyl. 10. A compound, prodrug, pharmaceutically active metabolite, pharmaceutically acceptable salt, or solvate according to claim 3, wherein R7 and R8 are each independently H, C1-6alkyl group, optionally substituted by naphthyl or imidazole. 11. A compound, prodrug, pharmaceutically active metabolite, pharmaceutically acceptable salt, or solvate according to claim 3, wherein one of R7 and R8 is H and the other is 2-propyl, 2-methyl-2-propyl, 2-methyl-1-propyl, naphthylmethyl. 12. A compound, prodrug, pharmaceutically active metabolite, pharmaceutically acceptable salt, or solvate according to claim 3, wherein R9 is a five-membered heterocycle having at least one nitrogen heteroatom and one oxygen heteroatom. 13. A compound, prodrug, pharmaceutically active metabolite, pharmaceutically acceptable salt, or solvate according to claim 3, wherein R9 is selected from substituted and unsubstituted 1,2-oxazolyl, 1,3-oxazolyl, and 1,2,4-oxadiazolyl. 14. A compound, prodrug, pharmaceutically active metabolite, pharmaceutically acceptable salt, or solvate according to claim 3, wherein R9 is 3-isoxazolyl or 5-isoxazolyl unsubstituted or substituted with one or two substituents selected from methyl and halogens. 15. A compound according to claim 3 of the formula I-A" : wherein R1, R2, R6, R7, R9, Ry, Z, and Z1 are as defined in claim 3, or a prodrug, pharmaceutically active metabolite, pharmaceutically acceptable salt, or solvate thereof. 16. A compound, prodrug, pharmaceutically active metabolite, pharmaceutically acceptable salt, or solvate according to claim 15, wherein R2 is 17. A compound, prodrug, pharmaceutically active metabolite, pharmaceutically acceptable salt, or solvate according to claim 16, wherein: Ry is H or methyl; R1 is H, F, or methyl; Z and Z1 are each independently selected from H, F,-CO2R21,-wherein R21is H, C1-6alkyl group, optionally substituted by pyridine; provided that Z and Z1 are both not H; or Z and Z1 together with the atoms to which they are bonded, form furanon; R2 is R6 is unsubstituted or substituted phenylmethyl; R7 is C1-6alkyl group, optionally substituted by naphthyl or imidazole; and R9 is 3-isoxazolyl or 5-isoxazolyl unsubstituted or substituted with one or two substituents selected from methyl and halogens. 18. A compound, prodrug, pharmaceutically active metabolite, pharmaceutically acceptable salt, or solvate according to claim 17, wherein R7 is selected from 2-propyl, 2methyl-2-propyl, 2-methyl-1-propyl and naphthylmethyl. 19. A compound, prodrug, pharmaceutically active metabolite, pharmaceutically acceptable salt, or solvate according to claim 15, wherein Ry, R1, and Z are each H, and: R2 is CH2CH2C(O)NH2, R6 is CH2Ph, R7 is CH2CH(CH3)2, Z1 is CO2CH2CH3, and R9 is R2 is CH2CH2C(O)NH2, R<6> is CH2Ph, R7 is CH2CH(CH3)2, Z1 is CO2CH2CH3, and R9 is R2 is CH2CH2C(O)NH2, R6 is R7 is C(CH3)3, Z1 is CO2CH2CH3, and R9 is R2 is CH2CH2C(O)NH2, R6 is R7 is C(CH3)3, Z1 is CO2CH2CH3, and R<9> R2 is , R6 is , R7 is CH(CH3)2, Z1 is CO2CH2CH3, and R9 is R2 is CH2CH2C(O)NH2, R6 is , R7 is CH(CH3)2, Z1 is CO2CH2CH3, and R<9> is R2 is , R6 is , R<7> is C(CH3)3, Z1 is CO2CH2CH3, and R<9> is or R2 is , R6 is , R7 is CH(CH3)2, Z1 is CO2CH2CH3, and R<9> is R2 is R6 is R7 is C(CH3)3, Z1 is CO2CH2CH3, and R<9> is 20. A compound, prodrug, pharmaceutically active metabolite, pharmaceutically acceptable salt, or solvate according to claim 15, wherein Ry is CH3, R1 and Z are each H, and R2 is CH2CH2C(O)NH2, R<6> is R7 is Z1 is CO2CH2CH3, and R9 is R2 is CH2CH2C(O)NH2, R6 is CH2Ph, R7 is CH2CH(CH3)2, and R9 is R2 is CH2CH2C(O)NH2, R6 is R7 is and R9 is R2 is CH2CH2C(O)NH2, R6 is R7 is CH2CH(CH3)2, and R9 is or R2 is CH2CH2C(O)NH2, R6 is R7 is and R9 is 21. A compound, prodrug, pharmaceutically active metabolite, pharmaceutically acceptable salt, or solvate according to claim 15 selected from the group consisting of : 22. A compound, prodrug, pharmaceutically active metabolite, pharmaceutically acceptable salt, or solvate according to claim 1, wherein Y is -CH2-. 23. A compound, prodrug, pharmaceutically active metabolite, pharmaceutically acceptable salt, or solvate according to claim 22, wherein Z and Z1 are each independently selected from H, -CO2R21, where R21 is H, C1-6alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group, an acyl group, optionally substituted by pyridine; provided that Z and Z1 are not both H; or Z and Z1, together with the atoms to which they are bonded, form furanone. 24. A compound, prodrug, pharmaceutically active metabolite, pharmaceutically acceptable salt, or solvate according to claim 22, wherein R1 is H, F, or methyl. 25. A compound, prodrug, pharmaceutically active metabolite, pharmaceutically acceptable salt, or solvate according to claim 22, wherein at least one of R2 and R3 is 26. A compound, prodrug, pharmaceutically active metabolite, pharmaceutically acceptable salt, or solvate according to claim 25, wherein one of R5 and R6 is H and the other is arylalkyl group, optionally substituted by halogen or C1-4alkyl. 27. A compound, prodrug, pharmaceutically active metabolite, pharmaceutically acceptable salt, or solvate according to claim 22, wherein one of R5 and R6 is H and the other is arylalkyl group, optionally substituted by halogen or C1-4alkyl. 28. A compound, prodrug, pharmaceutically active metabolite, pharmaceutically acceptable salt, or solvate according to claim 22, wherein one of R5 and R6 is H and the other is unsubstituted or substituted phenylmethyl. 29. A compound, prodrug, pharmaceutically active metabolite, pharmaceutically acceptable salt, or solvate according to claim 22, wherein R7 and R8 are each independently H or C1-6alkyl group, optionally substituted by naphthyl or imidazole. 30. A compound, prodrug, pharmaceutically active metabolite, pharmaceutically acceptable salt, or solvate according to claim 22, wherein one of R7 and R8 is H and the other is C1-6alkyl group, optionally substituted by naphthyl or imidazole. 31. A compound, prodrug, pharmaceutically active metabolite, pharmaceutically acceptable salt, or solvate according to claim 22, wherein one of R7 and R8 is H and the other is 2-propyl, 2-methyl-2-propyl, 2-methyl-1-propyl and naphthylmethyl. 32. A compound, prodrug, pharmaceutically active metabolite, pharmaceutically acceptable salt, or solvate according to claim 22, wherein R9 is a five-membered heterocycle having at least one nitrogen heteroatom and one oxygen heteroatom. 33. A compound, prodrug, pharmaceutically active metabolite, pharmaceutically acceptable salt, or solvate ac