Patent EA-001185-B1 (EA)
Title: Heterocyclic compounds for the treatment of pain and use thereof
Inventor: DIMAIO JOHN
IPC: A61P25/04
Filed: 1996-07-12
Abstract: 1. A compound of formula (I):   wherein R1 is H, C1-6 alkyl, or C6-12 aryl optionally substituted with groups -COOH, -NH2 or guanidine; R2 and R3 are independently H, OH, C1-6 alkyl, -C(NH)-NH2, a positively charged group, or C7-13 aralkyl optionally substituted with NH2, OH, C1-6 alkyl, or halogen; or  R2 and R3 together form a 5 to 6 member ring optionally incorporating a heteroatom; R4 is H, C1-6 alkyl, OR6, SR6 or N(R6)2, wherein each R6 is independently H, C1-3 alkyl;  X is S, SO, or SO2, N-R5, wherein each R5 is independently H, C1-6 alkyl or C7-13 aralkyl, which can be interrupted with one or more heteroatom(s):  n is an integer from 0 to 2;  m is an integer from 1 to 3. 2. A comund according to claim 1, wherein X is selected from S and SO2, m is 3 and n is 0. 3. A compound according to claim 2, wherein X is S. 4. A compound according to claim 3, wherein R2 is H and R3 is selected from H, OH and --C(NH)--NH2. 5. A compound according to claim 3, wherein R1 is methyl. 6. A compound according to claim 3, wherein R4 is selected from OH and methoxy. 7. A compound according to claim 6, wherein R4 is OH. 8. A compound according to claim 1, selected from:  #8b: 5,6,7,8,9,11,12-heptahydro-3-methoxy-5-methyl-10-thia-5,11-methanobenzocyclodecen-13-amine;  #9: 5,6,7,8,9,11,12-heptahydro-3-hydroxy-5-metyl-10-thia-5,11-methanobenzocyclodecen-13-amine (sulphazocine);  #10: 5, 6,7,8,9,11,12-heptahydro-3-hydroxy-5-methyl-10-thia-5,11-methanobenzocyclodecen-13-hydroxylamine;  #8a: 5,6,7,8,9,11,12-hetahydro-3-methoxy-5-methyl-10-thia-5,11-methanobenzocyclodecen-13-hydroxylamine; #9a: (-)-trans-5,6,7,8,9,11,12-heptahydro-10-thia-3-hydroxy-5-methyl-5,11-methanobezocyclodecen-13-amine; #9b: (+)-trans-5,6,7,8,9,11,12-heptahydro-10-thia-3-hydroxy-5-methyl-5,11-methanobenzocyclodecen-13amine; #11: trans-5,6,7,8,9,11,12-heptahydro-10-thia-3-hydroxy-5-methyl-5,11-methanobenzocyclodecen-13-guanidine; #12: trans-5,6,7,8,9,11,12-heptahydro-10-sulphono-3-hydroxy-5-methyl-5,11-methanobenzocyclo-decen-13-amine; 9. A compound according to claim 1, selected from:  #9: 5,6,7,8,9,11,12-heptahydro-3-hydroxy-5-methyl-10-thia-5,11-methanobenzocyclodecen-13-amine (sulphazocine); and  #9a: (-)-trans-5,6,7,8,9,11,12-heptahydro-10-thia-3-hydroxy-5-methyl-5,11-methanobenzocyclodecen-13-amine. 10. A method of inducing analgesia in a mammal comprising administering to said mammal a pharmaceutically effective amount of a compound of formula (I) according to claim 1. 11. The method according to claim 10, wherein X is selected from S and SO2, m is 3 and n is 0. 12. The method according to claim 11, wherein, wherein X is S. 13. The method according to claim 10, wherein R2 is H and R3 is selected from H, OH and --C(NH)--NH2. 14. The method according to claim 10, wherein R1 is methyl and R4 is OH. 15. The method according to claim 10, wherein said compound is selected from:  #8b: 5,6,7,8,9,11,12-heptahydro-3-methoxy-5-methyl-10-thia-5,11-methanobenzocyclodecen-13-amine;  #9: 5,6,7,8,9,11,12-heptahydro-3-hydroxy-5-methyl-10-thia-5,11-methanobenzocyclodecen-13-amine (sulphazocine);  #10: 5,6,7,8,9,11,12-heptahydro-3-hydroxy-5-methyl-10-thia-5,11-methanobenzocyclodecen-13-hydroxylamine;  #8a: 5,6,7,8,9,11,12-heptahydro-3-methoxy-5-methyl-10-thia-5,11-methanobenzocyclodecen-13-hydroxylamine; #9a:(-)-trans-5,6,7,8,9,11,12-heptahydro-10-thia-3-hydroxy-5-methyl-5,11-methanobenzocyclodecen-13-amine; #9b: (+)-trans-5,6,7,8,9,11,12-heptahydro-10-thia-3-hydroxy-5-methyl-5,11-methanobenzocyclodecen-13-amine; #11: trans-5,6,7,8,9,11,12-heptahydro-10-thia-3-hydroxy-5-methyl-5,11-methanobenzocyclodecen-13-guanidine;  #12: trans-5,6,7,8,9,11,12-heptahydro-10-sulphono-3-hydroxy-5-methyl-5,11-methanobenzocyclodecen-13-amine. 16. A method of activating opioid receptors in a mammal comprising administering to said mammal an opioid receptor activating amount of a compound of formula (I) according to claim 1. 17. The method according to claim 16, wherein X is selected from S and SO2, m is 3 and n is 0. 18. The method according to claim 16, wherein R2 is H and R3 is selected from H, OH and --C(NH)--NH2. 19. The method according to claim 16, wherein R1 is methyl and R4 is OH. 20. The method according to claim 16, wherein said compound is selected from: #8b: 5,6,7,8,9,11,12-heptahydro-3-methoxy-5-methyl-10-thia-5,11-methanobenzocyclodecen-13-amine;  #9: 5,6,7,8,9,11,12-heptahydro-3-hydroxy-5-methyl-10-thia-5,11-methanobenzocyclodecen-13-amine (sulphazocine);  #10: 5,6,7,8,9,11,12-heptahydro-3-hydroxy-5-methyl-10-thia-5,11-methanobenzocyclodecen-13-hydroxylamine;  #8a: 5,6,7,8,9,11,12-heptahydro-3-methoxy-5-methyl-10-thia-5,11-methanobenzocyclodecen-13-hydroxylamine; #9a:(-)-trans-5,6,7,8,9,11,12-heptahydro-10-thia-3-hydroxy-5-methyl-5,11-methanobenzocyclodecen-13-amine; #9b: (+)-trans-5,6,7,8,9,11,12-heptahydro-10-thia-3-hydroxy-5-methyl-5,11-methanobenzocyclodecen-13-amine; #11: trans-5,6,7,8,9,11,12-heptahydro-10-thia-3-hydroxy-5-methyl-5,11-methanobenzocyclodecen-13-guanidine;  #12: trans-5,6,7,8,9,11,12-heptahydro-10-sulphono-3-hydroxy-5-methyl-5,11-methanobenzocyclodecen-13-amine. 21. Use of inducing analgesia in a mammal comprising administering to said mammal a pharmaceutically effective amount of a compound of formula (I) according to claim 1. 22. Use of activating opioid receptors in a mammal comprising administering to said mammal an opioid receptor activating amount of a compound of formula (I) according to claim 1.