Claims for Patent: 7,144,884

Summary for Patent: 7,144,884

Title:	Phenyl-piperazine derivatives as serotonin reuptake inhibitors
Abstract:	The invention provides compounds represented by the general formula I wherein the substituents are defined in the application. The compounds are useful in the treatment of an affective disorder, including depression, anxiety disorders including general anxiety disorder and panic disorder and obsessive compulsive disorder
Inventor(s):	Thomas Ruhland, Garrick Paul Smith, Benny Bang-Andersen, Ask Puschl, Ejner Knud Moltzen, Kim Andersen
Assignee:	H Lundbeck AS
Application Number:	US10/488,280
Patent Litigation and PTAB cases:	See patent lawsuits and PTAB cases for patent 7,144,884
Patent Claims:	1. A compound represented by the general formula I wherein p is 0, 1, 2, 3, or 4; q is 0, 1, or 2; s is 2; each R1 is independently C1-6-alkyl; each R2 is independently halogen, cyano, nitro, C1-6-alk(en/yn)yl, C1-6-alk(en/yn)yloxy, C1-6-alk(en/yn)ylsulfanyl, hydroxy, hydroxy-C1-6-alk(en/yn)yl, halo-C1-6-alk(en/yn)yl, halo-C1-6-alk(en/yn)yloxy, C3-8-cycloalk(en)yl, C3-8-cycloalk(en)yl-C1-6-alk(en/yn)yl, acyl, C1-6-alk(en/yn)yloxycarbonyl, C1-6-alk(en/yn)ylsulfonyl, or —NRxRy; each R3 is independently halogen, cyano, nitro, C1-6-alk(en/yn)yl, C1-6-alk(en/yn)yloxy, C1-6- alk(en/yn)ylsulfanyl, hydroxy, hydroxy-C1-6-alk(en/yn)yl, halo-C1-6-alk(en/yn)yl, halo-C1-6-alk(en/yn)yloxy, C3-8-cycloalk(en)yl, C3-8-cycloalk(en)yl-C1-6-alk(en/yn)yl, C1-6-alk(en/yn)ylsulfonyl, aryl, C1-6-alk(en/yn)yloxycarbonyl, acyl, —NHCO—C1-6-alk(en/yn)yl, —CONRxRy or NRxRy; wherein each Rx and Ry is independently hydrogen, C1-6-alk(en/yn)yl, C3-8-cycloalk(en)yl, C3-8-cycloalk(en)yl-C16-alk(en/yn)yl, or aryl; or a pharmaceutically acceptable acid addition salt thereof. 2. The compound according to claim 1, wherein p is 0, 1 or 2. 3. The compound according to claim 1, wherein R2 is trifluoromethyl, or C1-6-alkyl. 4. The compound according to claim 1, wherein each R3 is independently halogen, C1-6-alkoxy, C1-6-alkylsulfanyl, C1-6-alkyl, hydroxy or trifluoromethyl. 5. A compound selected from the group consisting of 1-[2-(2-Trifluoromethylphenylsulfanyl)phenyl]piperazine, 1-[2-(4-Bromophenylsulfanyl)phenyl]piperazine, 1-{2-[4-(Methylsulfanyl)phenylsulfanyl]phenyl}piperazine, 1-[2-(4-Hydroxyphenylsulfanyl]phenyl}piperazine, 1-[2-(2,4-Dimethylphenylsulfanyl)phenyl]piperazine, 1-[2-(3,5-Dimethylphenylsulfanyl)phenyl]piperazine, 1-[2-(2,6-Dimethylphenylsulfanyl)phenyl]piperazine, 1-[2-(2,5-Dimethylphenylsulfanyl)phenyl]piperazine, 2-(4-Methylphenylsulfanyl)phenyl-1-piperazine, 1-[2-(4-Chlorophenylsulfanyl)phenyl]-piperazine, 1-[2-(4-Methoxyphenylsulfanyl)-4-chlorophenyl]piperazine, 1-[2-(4-Methoxyphenylsulfanyl)-4-methylphenyl]piperazine, 1-[2-(4-Methoxyphenylsulfanyl)-5-methylphenyl]piperazine, 1-[2-(4-Fluorophenylsulfanyl)-5-methylphenyl]piperazine, 1-[2-(4-Methoxyphenylsulfanyl)-5-trifluoromethylphenyl]piperazine, 1-[2-(4-Chlorophenylsulfanyl)phenyl]-3-methylpiperazine and 1-[2-(4-Chlorophenylsulfanyl)phenyl]-3,5-dimethylpiperazine; or a pharmaceutically acceptable acid addition salt thereof. 6. A pharmaceutical composition comprising a compound according to claim 1 or a pharmaceutically acceptable acid addition salt thereof and at least one pharmaceutically acceptable carrier or diluent. 7. A method for the treatment of an affective disorder in a living animal body, comprising administering a therapeutically effective amount of a compound represented by the general formula I wherein X represents O or S; p is 0, 1, 2, 3, 4, 5, 6, 7 or 8; q is 0, 1, 2, 3 or 4; s is 0, 1, 2, 3, 4 or 5; each R1 is independently C1-6-alkyl; each R2 is halogen, cyano, nitro, C1-6-alk(en/yn)yl, C1-6-alk(en/yn)yloxy, C1-6-alk(en/yn)ylsulfanyl, hydroxy, hydroxy-C1-6-alk(en/yn)yl, halo-C1-6-alk(en/yn)yl, halo-C1-6-alk(en/yn)yloxy, C3-8-cycloalk(en)yl, C3-8-cycloalk(en)yl-C1-6-alk(en/yn)yl, acyl, C1-6-alk(en/yn)yloxycarbonyl, C1-6-alk(en/yn)ylsulfonyl, —NRxRy or —NRxCO—C1-6-alk(en/yn)yl; each R3 is independently halogen, cyano, nitro, C1-6-alk(en/yn)yl, C1-6-alk(en/yn)yloxy, C1-6-alk(en/yn)ylsulfanyl, hydroxy, hydroxy-C1-6-alk(en/yn)yl, halo-C1-6-alk(en/yn)yl, or halo-C1-6-alk(en/yn)yloxy, C3-8-cycloalk(en)yl, C3-8-cycloalk(en)yl-C1-6-alk(en/yn)yl, C1-6-alk(en/yn)ylsulfonyl, aryl, C1-6-alk(en/yn)yloxycarbonyl, acyl, —NRxCO—C1-6-alk(en/yn)yl, —CONRxRy or NRxRy; wherein each Rx and Ry is independently hydrogen, C1-6-alk(en/yn)yl, C3-8-cycloalk(en)yl, C3-8-cycloalk(en)yl-C1-6-alk(en/yn)yl, or aryl; or a pharmaceutically acceptable acid addition salt thereof. 8. The method of claim 7, wherein the living animal body is a human. 9. The method of claim 7, wherein the affective disorder is selected from the group consisting of depression, anxiety disorder, and obsessive compulsive disorder. 10. The method of claim 9, wherein the anxiety disorder is selected from the group consisting of general anxiety disorder and panic disorder. 11. The method of claim 7, comprising administering a compound represented by general formula I wherein p is 0, 1, 2, 3, or 4; q is 0, 1, or 2; s is 0, 1, 2, or 3; each R1 is independently C1-6-alkyl; each R2 is independently halogen, cyano, nitro, C1-6-alk(en/yn)yl, C1-6-alk(en/yn)yloxy, C1-6-alk(en/yn)ylsulfanyl, hydroxy, hydroxy-C1-6-alk(en/yn)yl, halo-C1-6-alk(en/yn)yl, halo-C1-6-alk(en/yn)yloxy, C3-8-cycloalk(en)yl, C3-8-cycloalk(en)yl-C1-6-alk(en/yn)yl, acyl, C1-6-alk(en/yn)yloxycarbonyl, C1-6-alk(en/yn)ylsulfonyl, or —NRxRy; each R3 is independently halogen, cyano, nitro, C1-6-alk(en/yn)yl, C1-6-alk(en/yn)yloxy, C1-6-alk(en/yn)ylsulfanyl, hydroxy, hydroxy-C1-6-alk(en/yn)yl, halo-C1-6-alk(en/yn)yl, halo-C1-6-alk(en/yn)yloxy, C3-8-cycloalk(en)yl, C3-8-cycloalk(en)yl-C1-6-alk(en/yn)yl, C1-6-alk(en/yn)ylsulfonyl, aryl, C1-6-alk(en/yn)yloxycarbonyl, acyl, —NHCO—C1-6-alk(en/yn)yl, —CONRxRy or NRxRy; wherein each Rx and Ry is independently hydrogen, C1-6-alk(en/yn)yl, C3-8-cycloalk(en)yl, C3-8-cycloalk(en)yl-C1-6-alk(en/yn)yl, or aryl; or a pharmaceutically acceptable acid addition salt thereof. 12. The method of claim 7, wherein the administered compound is selected from the group consisting of 1-[2-(2-Trifluoromethylphenylsulfanyl)phenyl]piperazine, 1-[2-(4-Bromophenylsulfanyl)phenyl]piperazine, 1-{2-[4-(Methylsulfanyl)phenylsulfanyl]phenyl}piperazine, 1-[2-(4-Hydroxyphenylsulfanyl]phenyl}piperazine, 1-[2-(2,4-Dimethylphenylsulfanyl)phenyl]piperazine, 1-[2-(3,5-Dimethylphenylsulfanyl)phenyl]piperazine, 1-[2-(2,6-Dimethylphenylsulfanyl)phenyl]piperazine, 1-[2-(2,5-Dimethylphenylsulfanyl)phenyl]piperazine, 2-(4-Methylphenylsulfanyl)phenyl-1-piperazine, 1-[2-(4-Chlorophenylsulfanyl)phenyl]-piperazine, 1-[2-(4-Methoxyphenylsulfanyl)-4-chlorophenyl]piperazine, 1-[2-(4-Methoxyphenylsulfanyl)-4-methylphenyl]piperazine, 1-[2-(4-Methoxyphenylsulfanyl)-5-methylphenyl]piperazine, 1-[2-(4-Fluorophenylsulfanyl)-5-methylphenyl]piperazine, 1-[2-(4-Methoxyphenylsulfanyl)-5-trifluoromethylphenyl]piperazine, 1-[2-(4-Chlorophenylsulfanyl)phenyl]-3-methylpiperazine and 1-[2-(4-Chlorophenylsulfanyl)phenyl]-3,5-dimethylpiperazine; or a pharmaceutically acceptable acid addition salt thereof. 13. The compound according to claim 5, wherein the compound is 1-[2-(2-Trifluoromethylphenylsulfanyl)phenyl]piperazine, or a pharmaceutically acceptable acid addition salt thereof. 14. The compound according to claim 5, wherein the compound is 1-[2-(4-Bromophenylsulfanyl)phenyl]piperazine, or a pharmaceutically acceptable acid addition salt thereof. 15. The compound according to claim 5, wherein the compound is 1-{2-[4-(Methylsulfanyl)phenylsulfanyl]phenyl}piperazine, or a pharmaceutically acceptable acid addition salt thereof. 16. The compound according to claim 5, wherein the compound is 1-[2-(4-Hydroxyphenylsulfanyl]phenyl}piperazine, or a pharmaceutically acceptable acid addition salt thereof. 17. The compound according to claim 5, wherein the compound is 1-[2-(2,4-Dimethylphenylsulfanyl)phenyl]piperazine, or a pharmaceutically acceptable acid addition salt thereof. 18. The compound according to claim 5, wherein the compound is 1-[2-(3,5-Dimethylphenylsulfanyl)phenyl]piperazine, or a pharmaceutically acceptable acid addition salt thereof. 19. The compound according to claim 5, wherein the compound is 1-[2-(2,6-Dimethylphenylsulfanyl)phenyl]piperazine, or a pharmaceutically acceptable acid addition salt thereof. 20. The compound according to claim 5, wherein the compound is 1-[2-(2,5-Dimethylphenylsulfanyl)phenyl]piperazine, or a pharmaceutically acceptable acid addition salt thereof. 21. The compound according to claim 5, wherein the compound is 2-(4-Methylphenylsulfanyl)phenyl-1-piperazine, or a pharmaceutically acceptable acid addition salt thereof. 22. The compound according to claim 5, wherein the compound is 1-[2-(4-Chlorophenylsulfanyl)phenyl]-piperazine, or a pharmaceutically acceptable acid addition salt thereof. 23. The compound according to claim 5, wherein the compound is 1-[2-(4-Methoxyphenylsulfanyl)-4-chlorophenyl]piperazine, or a pharmaceutically acceptable acid addition salt thereof. 24. The compound according to claim 5, wherein the compound is 1-[2-(4-Methoxyphenylsulfanyl)-4-methylphenyl]piperazine, or a pharmaceutically acceptable acid addition salt thereof. 25. The compound according to claim 5, wherein the compound is 1-[2-(4-Methoxyphenylsulfanyl)-5-methylphenyl]piperazine, or a pharmaceutically acceptable acid addition salt thereof. 26. The compound according to claim 5, wherein the compound is 1-[2-(4-Fluorophenylsulfanyl)-5-methylphenyl]piperazine, or a pharmaceutically acceptable acid addition salt thereof. 27. The compound according to claim 5, wherein the compound is 1-[2-(4-Methoxyphenylsulfanyl)-5-trifluoromethylphenyl]piperazine, or a pharmaceutically acceptable acid addition salt thereof. 28. The compound according to claim 5, wherein the compound is 1-[2-(4-Chlorophenylsulfanyl)phenyl]-3-methylpiperazine, or a pharmaceutically acceptable acid addition salt thereof. 29. The compound according to claim 5, wherein the compound is 1-[2-(4-Chlorophenylsulfanyl)phenyl]-3,5-dimethylpiperazine, or a pharmaceutically acceptable acid addition salt thereof.