Claims for Patent: 7,067,539

Summary for Patent: 7,067,539

Title:	Cannabinoid receptor ligands
Abstract:	The invention relates to compounds of the formula ##STR00001## a prodrug thereof, or a pharmaceutically acceptable salt, solvate or stereoisomer of the compound or of said prodrug; which exhibit anti-inflammatory and immunodulatory activity. Also disclosed are pharmaceutical compositions containing said compounds and methods of using the compounds for the treatment of various diseases and conditions.
Inventor(s):	Kozlowski; Joseph A. (Princeton, NJ), Shih; Neng-Yang (North Caldwell, NJ), Lavey; Brian J. (Chatham, NJ), Rizvi; Razia K. (Bloomfield, NJ), Shankar; Bandarpalle B. (Branchburg, NJ), Spitler; James M. (Westfield, NJ), Tong; Ling (Warren, NJ), Wolin; Ronald L. (San Diego, CA), Wong; Michael K. (North Brunswick, NJ)
Assignee:	Schering Corporation (Kenilworth, NJ)
Application Number:	10/214,897
Patent Claims:	1. A compound of the formula ##STR00378## or a pharmaceutically acceptable salt or solvate thereof; wherein: R.sup.1 is selected from the group consisting of H, alkyl, haloC.sub.1 C.sub.6alkyl, cycloalkyl, cycloalkylNH--, arylalkyl, heterocycloalkyl, heteroaryl, --N(R.sup.2).sub.2, --N(R.sup.2)aryl, unsubstituted aryl and aryl substituted with one to three X, wherein each R.sup.2 can be the same or different and is independently selected when there are more than one R.sup.2 present; R.sup.2 is selected from the group consisting of H and C.sub.1 C.sub.6 alkyl; R.sup.3 is 1 3 substituents selected from the group consisting of H, C.sub.1 C.sub.6 alkyl, Cl, F, CF.sub.3, OCF.sub.2H, OCF.sub.3, OH and C.sub.1 C.sub.6 alkoxy, wherein R.sup.3 can be the same or different and is independently selected when there are more than one R.sup.3 present; R.sup.4 is pyridine-N-oxide or pyridyl optionally substituted with one to three X, wherein X can be the same or different and is independently selected when there are more than one X present; R.sup.5 is H or C.sub.1 C.sub.6 alkyl; R.sup.6 is H or C.sub.1 C.sub.6 alkyl; or R.sup.5 and R.sup.6 taken together with the carbon atom to which they are attached form a carbonyl group; L.sup.1 is --SO.sub.2--, --SO--, or --S--; L.sup.2 is --SO.sub.2--, --SO--, or --S--; X is selected from the group consisting of H, halogen, CF.sub.3, CN, OCF.sub.2H, OCF.sub.2CF.sub.3, OCF.sub.3, OR.sup.2, C.sub.1 C.sub.6 alkyl, cycloalkyl, cycloalkoxy, C.sub.1 C.sub.6 alkoxy, alkoxyC.sub.1 C.sub.6 alkoxy, O-cycloalkyl, cycloalkylamino, cycloalkylalkoxy, heteroalkyl, --OSO.sub.2R.sup.2, --COOR.sup.2, --CON(R.sup.2).sub.2, N(R.sup.2).sub.2, and NR.sup.2aryl, wherein X can be the same or different, and is independently selected when there are more than one X present; Y is a covalent bond, --CH.sub.2--, --SO.sub.2--, or --C(O)--; Z is a covalent bond, --CH.sub.2--, --SO.sub.2-- or --C(O)--; or Y, R.sup.1, Z and R.sup.2 can be taken together with the nitrogen atom to which they are attached to form a heterocycloalkyl; with the following provisos: L.sup.2 and R.sup.4, when taken together, cannot have two heteroatoms covalently bonded together; when R.sup.2 is H, Z cannot be --S(O)--, --SO.sub.2--, or --C(O)--; and when Y is a covalent bond, R.sup.1 cannot form a N--N bond with the nitrogen atom. 2. A compound according to claim 1 wherein L.sup.1 is --SO.sub.2--, --S-- or --S(O)--; L.sup.2 is --SO.sub.2--; R.sup.1 is H, --CH.sub.3NH.sub.2, --CH.sub.2CF.sub.3, --NHC.sub.3H.sub.7, --NHC.sub.2H.sub.6, --NHC.sub.4H.sub.9, C.sub.1 C.sub.6alkyl, --CF.sub.3, --CH(CH.sub.2).sub.2, thiophenyl, morpholinyl, cyclopropyl, benzyl, naphthyl, --C(CH.sub.3).sub.3, NHphenyl, 3,5-difluorophenyl, phenyl, N-cyclopentyl or N(CH.sub.3).sub.2; R.sup.2 is H or CH.sub.3; R.sup.3 is OH; R.sup.4 is pyridyl optionally substituted with one to three X, wherein X can be the same or different and are independently selected when the are more than one X present; R.sup.5 and R.sup.6 are independently H or CH.sub.3; Y is a covalent bond, --SO.sub.2-- or --C(O)--; Z is a covalent bond; or R.sup.1, Y, R.sup.2 and Z taken together with the nitrogen atom form a morpholinyl group. 3. The compound according to claim 2 wherein X is halogen, OH, or cyclopropyl; R.sup.3 is OH; R.sup.5 and R.sup.6 are independently H or CH.sub.3; X is H, halogen, CF.sub.3, OCH.sub.3, OH, OCF.sub.3, OCF.sub.2H, CH.sub.3 or C.sub.1 C.sub.6 cycloalkyl; Y is a covalent bond; Z is --SO.sub.2-- or --C(O)--; L.sup.1 is --SO.sub.2--; L.sup.2 is --SO.sub.2--; R.sup.1 is CH.sub.3 or CF.sub.3; and R.sup.4 is pyridyl, and said pyridyl group is optionally substituted with one to three substituents selected from the group consisting of C.sub.1 C.sub.6 alkyl, C.sub.1 C.sub.6 alkoxy, OH, CF.sub.3 and halogen, wherein said substituents can be the same or different and are independently selected when there is more than one substituent. 4. The compound according to claim 1 of the formula ##STR00379## or a pharmaceutically acceptable salt or solvate thereof, wherein X and R.sup.4 are as shown in the table below: TABLE-US-00004 Example X R.sup.4 T Cl ##STR00380## AO Cl ##STR00381## 5. The compound according to claim 1 of the formula ##STR00382## or a pharmaceutically acceptable salt or solvate thereof, wherein X and R.sup.4 are as shown in the table below: TABLE-US-00005 Example X R.sup.4 GG Cl ##STR00383## GH CF.sub.3 ##STR00384## 6. The compound according to claim 1 of the formula ##STR00385## or a pharmaceutically acceptable salt or solvate thereof; wherein X, R.sup.1 and R.sup.4 are as shown in the table below: TABLE-US-00006 Example X R.sup.1 R.sup.4 GG Cl CF.sub.3 ##STR00386## GH CF.sub.3 CF.sub.3 ##STR00387## XXIX ##STR00388## CF.sub.3 ##STR00389## XXXI ##STR00390## CF.sub.3 ##STR00391## XXXV Cl CF.sub.3 ##STR00392## XXXVI Cl CF.sub.3 ##STR00393## XXXVII ##STR00394## CF.sub.3 ##STR00395## XXXVIII CN CF.sub.3 ##STR00396## XXXXXV OCH.sub.3 CF.sub.3 ##STR00397## XXXXXVI ##STR00398## CH.sub.3 ##STR00399## 7. The compound according to claim 1 of the formula ##STR00400## or a pharmaceutically acceptable salt or solvate thereof, wherein X is cyclopropyl and R.sup.1 is CF.sub.3. 8. The compound according to claim 1 of the formula ##STR00401## or a pharmaceutically acceptable salt or solvate thereof, wherein X is Cl and R.sup.1 is CF.sub.3. 9. The compound according to claim 1 of the formula ##STR00402## or a pharmaceutically acceptable salt or solvate thereof, wherein X is CF.sub.3 and R.sup.1 is CF.sub.3. 10. The compound according to claim 1 of the formula ##STR00403## or a pharmaceutically acceptable salt or solvate thereof, wherein X is cyclopropyl and R.sup.1 is CF.sub.3. 11. The compound according to claim 1 of the formula ##STR00404## or a pharmaceutically acceptable salt or solvate thereof, wherein X is Cl and R.sup.1 is CF.sub.3. 12. The compound according to claim 1 of the formula ##STR00405## or a pharmaceutically acceptable salt or solvate thereof, wherein X is cyclopropyl and R.sup.1 is CH.sub.3. 13. A pharmaceutical composition comprising one or more compounds according to claim 1 and one or more pharmaceutically acceptable carriers. 14. A pharmaceutical composition comprising one or more compounds according to claim 5 and one or more pharmaceutically acceptable carriers. 15. A pharmaceutical composition made by combining one or more compounds of claim 1 and one or more pharmaceutically acceptable carriers. 16. A composition which comprises one or more compounds selected from the group consisting of a COX-2 inhibitor, a COX-1 inhibitor, an immunosuppressive, a steroid, and an anti-TNF-.alpha. compound, and one or more compounds of claim 1. 17. A composition which comprises one or more compounds selected from the group consisting of a COX-2 inhibitor, a COX-1 inhibitor, an immunosuppressive, a steroid, and an anti-TNF-.alpha. compound, and one or more compounds of claim 5. 18. The composition of claim 16 wherein the COX-2 inhibitor is celecoxib or rofecoxib, the COX-1 inhibitor is piroxicam, the immunosuppressive is methotrexate, leflunomide, sulfasalazine or cyclosporin, the steroid is .beta.-methasone and the anti-TNF-.alpha. compound is etanercept or infliximab. 19. The composition of claim 17 wherein the COX-2 inhibitor is celecoxib or rofecoxib, the COX-1 inhibitor is piroxicam, the immunosuppressive is methotrexate, leflunomide, sulfasalazine or cyclosporin, the steroid is .beta.-methasone and the anti-TNF-.alpha. compound is etanercept or infliximab. 20. A composition which comprises one or more compounds selected from the group consisting of interferon beta-1a, interferon beta-1b, and glatiramer acetate, and one or more compounds of claim 1. 21. A composition which comprises one or more compounds selected from the group consisting of interferon beta-1a, interferon beta-1b, and glatiramer acetate, and one or more compounds of claim 5. 22. A composition which comprises one or more compounds selected from the group consisting of an immunosuppressive, a steroid, and an anti-TNF-.alpha. compound, and one or more compounds of claim 1. 23. A composition which comprises one or more compounds selected from the group consisting of an immunosuppressive, a steroid, and an anti-TNF-.alpha. compound, and one or more compounds of claim 5. 24. The composition of claim 22 wherein the immunosuppressive is methotrexate, leflunomide, sulfasalazine or cyclosporin, the steroid is .beta.-methasone and the anti-TNF-.alpha. compound is etanercept or infliximab. 25. The composition of claim 23 wherein the immunosuppressive is methotrexate, leflunomide, sulfasalazine or cyclosporin, the steroid is .beta.-methasone and the anti-TNF-.alpha. compound is etanercept or infliximab. 26. The compound according to claim 1 of the formula ##STR00406## or a pharmaceutically acceptable salt or solvate thereof, wherein X is cyclopropyl and R.sup.1 is CF.sub.3. 27. The compound according to claim 1 of the formula ##STR00407## or a pharmaceutically acceptable salt or solvate thereof, wherein X is Cl and R.sup.1 is CF.sub.3. 28. The compound according to claim 1 of the formula ##STR00408## or a pharmaceutically acceptable salt or solvate thereof, wherein X is CF.sub.3 and R.sup.1 is CF.sub.3. 29. The compound according to claim 1 of the formula ##STR00409## or a pharmaceutically acceptable salt or solvate thereof, wherein X is cyclopropyl and R.sup.1 is CF.sub.3. 30. The compound according to claim 1 of the formula ##STR00410## or a pharmaceutically acceptable salt or solvate thereof, wherein X is Cl and R.sup.1 is CF.sub.3. 31. compound according to claim 1 of the formula ##STR00411## or a pharmaceutically acceptable salt or solvate thereof, wherein X is cyclopropyl and R.sup.1 is CH.sub.3.

Details for Patent 7,067,539

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Bayer Healthcare Pharmaceuticals Inc.	BETASERON	interferon beta-1b	For Injection	103471	07/23/1993		2021-02-08
Biogen Inc.	AVONEX	interferon beta-1a	For Injection	103628	05/17/1996		2021-02-08
Biogen Inc.	AVONEX	interferon beta-1a	Injection	103628	05/28/2003		2021-02-08
Biogen Inc.	AVONEX	interferon beta-1a	Injection	103628	02/27/2012		2021-02-08
Janssen Biotech, Inc.	REMICADE	infliximab	For Injection	103772	08/24/1998		2021-02-08
Emd Serono, Inc.	REBIF	interferon beta-1a	Injection	103780	03/07/2002		2021-02-08
Emd Serono, Inc.	REBIF	interferon beta-1a	Injection	103780	12/17/2004		2021-02-08