Patent EA-001450-B1 (EA)
Title: Halo-substituted protein kinase c inhibitors
Inventor: JOROUSEK MICHAEL R
IPC: A61P9/00
Filed: 1997-04-30
Abstract: 1. A compound of the formula:   wherein; R' is independently hydrogen, halo, hydroxy, C1-C4 alkyl, C1-C4 alkoxy, NR3R4 or -NHCO(C1-C4 alkyl); V is -NH- or -NC1-C4alkyl-; T is C1-C4 alkylene optionally substituted with halo or C1-C4 alkyl; W is C1-C2 alkylene optionally substituted with halo or C1-C4 alkyl; J is   or when T and W are both methylene, J is selected from the group consisting of   wherein n and m are independently 1 or 2; X is oxygen, sulfur or a bond between the carbon atoms bridged by X; Y is halo, C1-C4 alkyl or hydrogen; S is -CHO or the group   wherein M is hydrogen, -CH2OR5 , -CH2NR3R4 or -NR3R4; R2 is hydrogen or halo; and Z is hydrogen or -OR6; wherein R3 and R4 are independently hydrogen, C1-C4 alkyl, halo(C1-C4 alkyl), C1-C4 alkanoyl, halo(C1-C4 alkanoyl) or R3 and R4 taken together with the N atom to which they are bound form a 5 or 6-membered ring; and R5 and R6 are independently hydrogen, C1-C4 alkyl, halo(C1-C4 alkyl), C1-C4 alkanoyl, halo(C1-C4 alkanoyl) or together form a divalent group of the formula -CR7R8- wherein R7 and R8 are independently hydrogen, C1-C4 alkyl or halo(C1-C4 alkyl) or R7 and R8 taken together with the C atom to which they are bound form a 5 or 6-membered ring provided that at least one of Y, S, T or W is halo or a halo substituted group, or T and W are both methylene. 2. The compound of claim 1 wherein at least one of Y, S, T or W is fluoro or a fluoro substituted group. 3. A compound of the formula:   wherein: R1 is C1-C4 alkyl or hydrogen; T is C2-C4 alkylene optionally substituted with halo or C1-C4 alkyl; W is ethylene optionally substituted with halo or C1-C4 alkyl; X is oxygen, sulfur or a bond between the carbon atoms bridged by X; Y is halo, C1-C4 alkyl or hydrogen; S is -CHO or the group   wherein M is hydrogen, -CH2OR5 , -CH2NR3R4 or -NR3R4; R2 is hydrogen or halo; and Z is hydrogen or -OR6; wherein R3 and R4 are independently hydrogen, C1-C4 alkyl, halo(C1-C4 alkyl), C1-C4 alkanoyl, halo(C1-C4 alkanoyl) or R3 and R4 taken together with the N atom to which they are bound form a 5 or 6-membered ring; and R5 and R6 are independently hydrogen, C1-C4 alkyl, halo(C1-C4 alkyl), C1-C4 alkanoyl, halo(C1-C4 alkanoyl) or together form a divalent group of the formula -CR7R8- wherein R7 and R8 are independently hydrogen, C1-C4 alkyl, or halo(C1-C4 alkyl) or R7 and R8 taken together with the C atom to which they are bound form a 5 or 6-membered ring provided that at least one of Y, S, T or W is halo or a halo substituted group. 4. The compound of claim 3 wherein at least one of Y, S, T or W is fluoro or a fluoro substituted group. 5. The compound of claim 3 wherein W is fluoro substituted ethylene. 6. The compound of claim 3 wherein T is fluoro substituted ethylene. 7. The compound of claim 3 wherein T is fluoro substituted trimethylene. 8. The compound of claim 3 wherein R1 and Y are hydrogen and X is oxygen. 9. The compound of claim 5 wherein R1 and Y are hydrogen, X is oxygen and S is     10. The compound of claim 9 wherein T is ethylene. 11. A compound of the formula:   wherein J is selected from the group consisting of   wherein R1 is C1-C4 alkyl or hydrogen; n and m are independently 1 or 2; and R3 and R4 are independently hydrogen, C1-C4 alkyl, halo(C1-C4 alkyl), C1-C4 alkanoyl, halo(C1-C4 alkanoyl) or R3 and R4 taken together with the N atom to which they are bound form a 5 or 6-membered ring. 12. The compound of claim 9 wherein R1 is hydrogen. 13. The compound of claim 9 wherein the halo substituent of J is fluoro. 14. A compound of the formula:   wherein; R' is independently hydrogen, halo, hydroxy, C1-C4 alkyl, C1-C4 alkoxy, NR3R4 or -NHCO(C1-C4 alkyl); V is -O-; T is C1-C4 alkylene optionally substituted with halo or C1-C4 alkyl; W is C1-C2 alkylene optionally substituted with halo or C1-C4 alkyl; J is   or when T and W are both methylene, J is selected from the group consisting of   wherein n and m are independently 1 or 2; X is oxygen, sulfur or a bond between the carbon atoms bridged by X; Y is halo, C1-C4 alkyl or hydrogen; S is -CHO or the group   wherein M is hydrogen, -CH2OR5 , -CH2NR3R4 or -NR3R4; R2 is hydrogen or halo; and Z is hydrogen or -OR6; wherein R3 and R4 are independently hydrogen, C1-C4 alkyl, halo(C1-C4 alkyl), C1-C4 alkanoyl, halo(C1-C4 alkanoyl) or R3 and R4 taken together with the N atom to which they are bound form a 5 or 6-membered ring; and R5 and R6 are independently hydrogen, C1-C4 alkyl, halo(C1-C4 alkyl), C1-C4 alkanoyl, halo(C1-C4 alkanoyl) or together form a divalent group of the formula -CR7R8- wherein R7 and R8 are independently hydrogen, C1-C4 alkyl or halo(C1-C4 alkyl) or R7 and R8 taken together with the C atom to which they are bound form a 5 or 6-membered ring provided that at least one of Y, S, T or W is halo or a halo substituted group, or T and W are both methylene. 15. The pharmaceutical composition comprising a comound of formlula:   wherein; R' is independently hydrogen, halo, hydroxy, C1-C4 alkyl, C1-C4 alkoxy, NR3R4 or -NHCO(C1-C4 alkyl); R1 is C1-C4 alkyl or hydrogen; T is C1-C4 alkylene optionally substituted with halo or C1-C4 alkyl; W is C1-C2 alkylene optionally substituted with halo or C1-C4 alkyl; J is   or when T and W are both methylene, J is selected from the group consisting of   wherein n and m are independently 1 or 2; X is oxygen, sulfur or a bond between the carbon atoms bridged by X; Y is halo, C1-C4 alkyl or hydrogen; S is -CHO or the group   wherein M is hydrogen, -CH2OR5 , -CH2NR3R4 or -NR3R4; R2 is hydrogen or halo; and Z is hydrogen or -OR6; wherein R3 and R4 are independently hydrogen, C1-C4 alkyl, halo(C1-C4 alkyl), C1-C4 alkanoyl, halo(C1-C4 alkanoyl) or R3 and R4 taken together with the N atom to which they are bound form a 5 or 6-membered ring; and R5 and R6 are independently hydrogen, C1-C4 alkyl, halo(C1-C4 alkyl), C1-C4 alkanoyl, halo(C1-C4 alkanoyl) or together form a divalent group of the formula -CR7R8- wherein R7 and R8 are independently hydrogen, C1-C4 alkyl or halo(C1-C4 alkyl) or R7 and R8 taken together with the C atom to which they are bound form a 5 or 6-membered ring provided that at least one of Y, S, T or W is halo or a halo substituted group, or T and W are both methylene; and pharmaceutically acceptable excipient, carrier or diluent. 16. The pharmaceutical composition of claim 15 wherein J is   17. The pharmaceutical composition of claim 16 wherein S is    X is oxygen; and R1 is hydrogen. 18. The pharmaceutical composition of claim 17 wherein at least one of Y, S, T or W is fluoro or a fluoro substituted group. 19. The pharmaceutical composition of claim 15 wherein T and W are methylene and the halo substituent is fluoro. 20. A method of treating a mammal having a disease or condition associated with anomalous protein kinase C activity, said method comprising administering to said mammal a pharmaceutically effective amount of compound of the formula:   wherein; R' is independently hydrogen, halo, hydroxy, C1-C4 alkyl, C1-C4 alkoxy, NR3R4 or -NHCO(C1-C4 alkyl); R1 is C1-C4 alkyl or hydrogen; T is C1-C4 alkylene optionally substituted with halo or C1-C4 alkyl; W is C1-C2 alkylene optionally substituted with halo or C1-C4 alkyl; J is   or when T and W are both methylene, J is selected from the group consisting of   wherein n and m are independently 1 or 2; X is oxygen, sulfur or a bond between the carbon atoms bridged by X; Y is halo, C1-C4 alkyl or hydrogen; S is -CHO or the group   wherein M is hydrogen, -CH2OR5 , -CH2NR3R4 or -NR3R4; R2 is hydrogen or halo; and Z is hydrogen or -OR6; wherein R3 and R4 are independently hydrogen, C1-C4 alkyl, halo(C1-C4 alkyl), C1-C4 alkanoyl, halo(C1-C4 alkanoyl) or R3 and R4 taken together with the N atom to which they are bound form a 5 or 6-membered ring; and R5 and R6 are independently hydrogen, C1-C4 alkyl, halo(C1-C4 alkyl), C1-C4 alkanoyl, halo(C1-C4 alkanoyl) or together form a divalent group of the formula -CR7R8- wherein R7 and R8 are independently hydrogen, C1-C4 alkyl or halo(C1-C4 alkyl) or R7 and R8 taken together with the C atom to which they are bound form a 5 or 6-membered ring provided that at least one of Y, S, T or W is halo or a halo substituted group, or T and W are both methylene; and a pharmaceutically acceptable excipient, carrier, or diluent. 21. The method of claim 20 wherein J is   22. The method of claim 21 wherein S is   X is oxygen; and R1 is hydrogen. 23. The method of claim 21 wherein at least one of Y, S, T or W is fluoro or a fluoro substituted group. 24. The method of claim 20 wherein T and W are methylene and the halo substituent is fluoro. 25. The method of claim 20 wherein W is fluoro substituted ethylene. 26. The method of claim 20 wherein T is fluoro substituted ethylene. 27. The method of claim 20 wherein T is fluoro substituted trimethylene.