Patent
TRP-M8 receptor ligands and their use in treatments
| العنوان: | TRP-M8 receptor ligands and their use in treatments |
|---|---|
| Patent Number: | 8,476,297 |
| تاريخ النشر: | July 02, 2013 |
| Appl. No: | 12/746292 |
| Application Filed: | December 04, 2008 |
| مستخلص: | Tetrahydroisoquinoline compounds of formula (I), and compositions containing them, for the treatment of acute, inflammatory and neurophatic pain, dental pain, general headache, migraine, cluster headache, mixed-vascular and non-vascular syndromes, tension headache, general inflammation, arthritis, rheumatic diseases, osteoarthritis, inflammatory bowel disorders, inflammatory eye disorders, inflammatory or unstable bladder disorders, psoriasis, skin complaints with inflammatory components, chronic inflammatory conditions, inflammatory pain and associated hyperalgesia and allodynia, neurophatic pain and associated hyperalgesia and allodynia, diabetic neuropathy pain, causalgia, sympathetically maintained pain, deafferentation syndromes, asthma, epithelial tissue damage or dysfunction, herpes simplex, disturbances of visceral motility at respiratory, genitourinary, gastrointestinal or vascular regions, wounds, burns, allergic skin reactions, pruritus, vitiligo, general gastrointestinal disorders, gastric ulceration, duodenal ulcers, diarrhea, gastric lesions induced by necrotising agents, hair growth, vasomotor or allergic rhinitis, bronchial disorders or bladder disorders. [chemical expression included] |
| Inventors: | Norman, Mark H. (Thousand Oaks, CA, US); Bo, Yunxin Y. (Thousand Oaks, CA, US); Gore, Vijay K. (Thousand Oaks, CA, US); Horne, Daniel (Thousand Oaks, CA, US); Kaller, Matthew (Ventura, CA, US); Ma, Vu Van (Simi Valley, CA, US); Monenschein, Holger (Camarillo, CA, US); Nguyen, Thomas (Thousand Oaks, CA, US); Nishimura, Nobuko (West Hills, CA, US); Tamayo, Nuria (Newbury Park, CA, US) |
| Assignees: | Amgen Inc. (Thousand Oaks, CA, US) |
| Claim: | 1. A compound having the structure: [chemical expression included] or any pharmaceutically-acceptable salt thereof, wherein: J is —N(R a)—; m is 0 or 1; n is independently in each instance 0, 1, 2 or 3; o is 1; X is O; R 1 is selected from H or F; R 2 is selected from H or F; R 3 is [chemical expression included] R 4 is selected from CH 3 , CF 3 , F, or Cl; R 5 is C 1-11 alkyl, C 6-11 cycloalkyl or a saturated, partially saturated or unsaturated 5-, 6- or 7-membered monocyclic or 8-, 9-, 10- or 11-membered bicyclic ring containing 0, 1, 2, 3 or 4 atoms selected from N, O and S, wherein the C 1-11 alkyl, C 6-11 cycloalkyl and ring are substituted by 0, 1, 2 or 3 substituents selected from C 1-8 alk, C 1-4 -haloalk, halo, cyano, nitro, —C(═O)R b , —C(═O)OR b , —C(═O)NR a R a , —C(═NR a)NR a R a , —OR a , —OC(═O)R b , —OC(═O)NR a R a , —OC 2-6 alkNR a R a , —OC 2-6 alkOR a , —SR a , —S(═O)R b , —S(═O) 2 R b , —S(═O) 2 NR a R a , —NR a R a , —N(R a)C(═O)R b , —N(R a)C(═O)OR b , —N(R a)C(═O)NR a R a , —N(R a)C(═NR a)NR a R a , —N(R a)S(═O) 2 R b , —N(R a)S(═O) 2 NR a R a , —NR a C 2-6 alkNR a R a and —NR a C 2-6 alkOR a ; or R 5 may also be C 3-5 cycloalkyl substituted by 0, 1, 2 or 3 substituents selected from C 1-8 alk, C 1-4 -haloalk, halo, cyano, nitro, —C(═O)R b , —C(═O)OR b , —C(═O)NR a R a , —C(═NR a)NR a R a , —OR a , —OC(═O)R b , —OC(═O)NR a R a , —OC 2-6 alkNR a R a , —OC 2-6 alkOR a , —SR a , —S(═O)R b , —S(═O) 2 R b , —S(═O) 2 NR a R a , —NR a R a , —N(R a)C(═O)R b , —N(R a)C(═O)OR b , —N(R a)C(═O)NR a R a , —N(R a)C(═NR a)NR a R a , —N(R a)S(═O) 2 R b , —N(R a)S(═O) 2 NR a R a , —NR a C 2-6 alkNR a R a and —NR a C 2-6 alkOR a ; R 6 is independently in each instance, selected from F, Cl, Br, I, C 2-6 alk, cyano, —OR a , —C(═O)R b , —C(═O)OR b , —C(═O)NR a R a , —C(═NR a)NR a R a , —S(═O)R b , —S(═O) 2 R b , —S(═O) 2 NR a R a , —NR a R a , —N(R a)C(═O)R b , —N(R a)C(═O)OR b , —N(R a)C(═O)NR a R a , —N(R a)C(═NR a)NR a R a , —N(R a)S(═O) 2 R b , —N(R a)S(═O) 2 NR a R a , —NR a C 2-6 alkNR a R a and —NR a C 2-6 alkOR a ; or R 6 is C 1-6 alk substituted by 1, 2 or 3 substituents selected from C 1-4 haloalk, halo, cyano, nitro, —C(═O)R b , —C(═O)OR b , —C(═O)NR a R a , —C(═NR a)NR a R a , —OR a , —OC(═O)R b , —OC(═O)NR a R a , —OC 2-6 alkNR a R a , —OC 2-6 alkOR a , —SR a , —S(═O)R b , —S(═O) 2 R b , —S(═O) 2 NR a R a , —NR a R a , —N(R a)C(═O)R b , —N(R a)C(═O)OR b , —N(R a)C(═O)NR a R a , —N(R a)C(═NR a)NR a R a , —N(R a)S(═O) 2 R b , —N(R a)S(═O) 2 NR a R a , —NR a C 2-6 alkNR a R a and —NR a C 2-6 alkOR a ; R 7 is selected from C 1-6 alk, cyano, —C(═O)R b , —C(═O)OR b , —C(═O)NR a R a , —C(═NR a)NR a R a , —S(═O)R b , —S(═O) 2 R b , —S(═O) 2 NR a R a , —NR a R a , —N(R a)C(═O)R b , —N(R a)C(═O)OR b , —N(R a)C(═O)NR a R a , —N(R a)C(═NR a)NR a R a , —N(R a)S(═O) 2 R b , —N(R a)S(═O) 2 NR a R a , —NR a C 2-6 alkNR a R a and —NR a C 2-6 alkOR a ; or R 7 is C 1-6 alk substituted by 1, 2 or 3 substituents selected from C 1-4 haloalk, halo, cyano, nitro, —C(═O)R b , —C(═O)OR b , —C(═O)NR a R a , —C(═NR a)NR a R a , —OR a , —OC(═O)R b , —OC(═O)NR a R a , —OC 2-6 alkNR a R a , —OC 2-6 alkOR a , —SR a , —S(═O)R b , —S(═O) 2 R b , —S(═O) 2 NR a R a , —NR a R a , —N(R a)C(═O)R b , —N(R a)C(═O)OR b , —N(R a)C(═O)NR a R a , —N(R a)C(═NR a)NR a R a , —N(R a)S(═O) 2 R b , —N(R a)S(═O) 2 NR a R a , —NR a C 2-6 alkNR a R a and —NR a C 2-6 alkOR a ; R a is H; R b is independently, at each instance, phenyl, benzyl or C 1-6 alk; and R f is independently in each instance H or F. |
| Claim: | 2. A compound according to claim 1 , wherein R 3 is [chemical expression included] and R 6 is C 1-6 alk substituted by 1, 2 or 3 substituents selected from C 1-4 haloalk, halo, cyano, nitro, —C(═O)R b , —C(═O)OR b , —C(═O)NR a R a , —C(═NR a)NR a R a , —OR a , —OC(═O)R b , —OC(═O)NR a R a , —OC 2-6 alkNR a R a , —OC 2-6 alkOR a , —SR a , —S(═O)R b , —S(═O) 2 R b , —S(═O) 2 NR a R a , —NR a R a , —N(R a)C(═O)R b , —N(R a)C(═O)OR b , —N(R a)C(═O)NR a R a , —N(R a)C(═NR a)NR a R a , —N(R a)S(═O) 2 R b , —N(R a)S(═O) 2 NR a R a , —NR a C 2-6 alkNR a R a and —NR a C 2-6 alkOR a . |
| Claim: | 3. A compound according to claim 1 , wherein R 5 is C 1-11 alkyl or C 6-11 cycloalkyl both of which are substituted by 0, 1, 2 or 3 substituents selected from C 1-8 alk, C 1-4 haloalk, halo, cyano, nitro, —C(═O)R b , —C(═O)OR b , —C(═O)NR a R a , —C(═NR a)NR a R a , —OR a , —OC(═O)R b , —OC(═O)NR a R a , —OC 2-6 alkNR a R a , —OC 2-6 alkOR a , —SR a , —S(═O)R b , —S(═O) 2 R b , —S(═O) 2 NR a R a , —NR a R a , —N(R a)C(═O)R b , —N(R a)C(═O)OR b , —N(R a)C(═O)NR a R a , —N(R a)C(═NR a)NR a R a , —N(R a)S(═O) 2 R b , —N(R a)S(═O) 2 NR a R a , —NR a C 2-6 alkNR a R a and —NR a C 2-6 alkOR a . |
| Claim: | 4. A compound according to claim 1 , wherein R 5 is a saturated, partially saturated or unsaturated 5-, 6- or 7-membered monocyclic or 8-, 9-, 10- or 11-membered bicyclic ring containing 0, 1, 2, 3 or 4 atoms selected from N, O and S, wherein the ring is substituted by 0, 1, 2 or 3 substituents selected from C 1-8 alk, C 1-4 haloalk, halo, cyano, nitro, —C(═O)R b , —C(═O)OR b , —C(═O)NR a R a , —C(═NR a)NR a R a , —OR a , —OC(═O)R b , —OC(═O)NR a R a , —OC 2-6 alkNR a R a , —OC 2-6 alkOR 1 , —SR a , —S(═O)R b , —S(═O) 2 R b , —S(═O) 2 NR a R a , —NR a R a , —N(R a)C(═O)R b , —N(R a)C(═O)OR b , —N(R a)C(═O)NR a R a , —N(R a)C(═NR a)NR a R a , —N(R a)S(═O) 2 R b , —N(R a)S(═O) 2 NR a R a , —NR a C 2-6 alkNR a R a , and —NR a C 2-6 alkOR a . |
| Claim: | 5. The compound of claim 1 , wherein the compound is [chemical expression included] or the pharmaceutically-acceptable salt thereof. |
| Claim: | 6. The compound of claim 1 , wherein the compound is [chemical expression included] or the pharmaceutically-acceptable salt thereof. |
| Claim: | 7. The compound of claim 1 , wherein the compound is [chemical expression included] or the pharmaceutically-acceptable salt thereof. |
| Claim: | 8. The compound of claim 1 , wherein the compound is [chemical expression included] or the pharmaceutically-acceptable salt thereof. |
| Claim: | 9. The compound of claim 1 , wherein the compound is [chemical expression included] or the pharmaceutically-acceptable salt thereof. |
| Claim: | 10. The compound of claim 1 , wherein the compound is [chemical expression included] or the pharmaceutically-acceptable salt thereof. |
| Claim: | 11. A pharmaceutical composition comprising a compound according to claim 1 and a pharmaceutically-acceptable diluent or carrier. |
| Current U.S. Class: | 514/307 |
| Patent References Cited: | 4001244 January 1977 Yonan 6177443 January 2001 Madsen et al. 6649626 November 2003 Dodd et al. 2005/0054651 March 2005 Natarajan et al. 2005/0070570 March 2005 Garcia et al. 2009/0082358 March 2009 Nishimura et al. 0 801 067 October 1997 48-034180 May 1973 48-048479 July 1973 WO 01/29030 April 2001 WO 2004/007468 January 2004 WO 2005/070929 August 2005 WO 2005/087743 September 2005 WO 2006/035280 April 2006 WO 2007/098608 September 2007 WO2008/062282 May 2008 WO 2009/038812 March 2009 WO 2012/004722 January 2012 |
| Other References: | International Search Report for parent PCT Application No. PCT/US2008/013375, mailed on Mar. 25, 2009. cited by applicant Written Opinion for parent PCT Application No. US2008/013375, dated Mar. 25, 2009. cited by applicant International Preliminary Report on Patentability for parent PCT Application No. PCT/US2008/013375, dated Jun. 8, 2010. cited by applicant Bach et al., “α-Arylation of Cyclic Amines by Aryl Transfer in Lithiated Ureas”, Synlett (2009), pp. 421-424, 3, USA. cited by applicant Colandrea, et al., “Synthesis and Regioselective Alkylation of 1,6- and 1,7-naphthyridines,” Tet. Lett., (2000), pp. 8053-8057, 41 (42), USA. cited by applicant Database Chemcats, Chemical Abstracts Service, Columbus, OH, US Jun. 13, 2008 XP002519324 Order No. kam-021285 & “Aurora Screening Library”, Jun. 13, 2008, Aurora Fine Chemicals LLC, San Diego, CA 92126, USA. cited by applicant Gitto et al., “Solution-phase parallel synthesis and evaluation of anticonvulsant activity of N-substituted-3,4-dihydroisoquinoline-2(1H)-carboxamides”, European J. Med. Chem., (2009), pp. 1349-1354, 44(3). cited by applicant Ivanov et al., “Synthesis and contractile activity of substituted 1,2,3,4-tetrahydroisoquinolines”, Molecules (2011), pp. 7019-7042, 16. cited by applicant Naito, R. et al., “Synthesis and Antimuscarinic Properties of Quinuclidin-3-yl 1, 2, 3, 4-Tetrahydroisoquinoline-2-carboxylate Derivatives as Novel Muscarinic Receptor Antagonists,” J. Med. Chem. (2005), pp. 6597-6606, 48(21), USA. cited by applicant Tamayo et al., “Fused Piperidines as a Novel Class of Potent and Orally Available Transient Receptor Potential Melastatin Type 8 (TRPM8) Antagonists”, J. Med. Chem., (2012), pp. 1593-1611, 55(4). cited by applicant Venkov, A. P. et al., “New Modification of the Intramolecular α-Amidoalkylation for the Synthesis of 2-Acyl-1,2,3,4-tetrahydroisoquinolines,” Synthesis, (1989), pp. 59-61, 1, DE. cited by applicant Venkov, A. P. et al., “Synthesis of 1-Phenyl-2-acyl-tetrahydroisoquinolines by Intermolecular α-Amidoalkylation reaction,” Synthetic Comm. (1992), pp. 125-134, 22(1), Great Britain. cited by applicant Zara-Kaczian et al., “Synthesis of 1-aryl-2-carbamoyl-1,4-dihydro-3(2H)-isoquinolinones from 2-tritylcarbamoyl derivatives”, Acta Chimica Hungarica (1984), pp. 89-94, 116(1). cited by applicant Zara-Kaczian et al., “Selective reduction of 2-carbamoyl-1-phenyl-1,4-dihydroisoquinolin-3(2H)-ones”, J. Chem. Research, Synopses (1984), pp. 282,(9). cited by applicant Zhang et al., “Unprecedented FeCl3•6 H2O-Promoted Skeleton Rearrangement of 1-Aryl-2,3,4,5-tetrahydro-1H-3-benzazepines: A New Strategy for the Synthesis of Cl Quaternary Tetrahydroisoquinolines”, Chem. A Euro. J., (2009), pp. 11119-11122, S11119/1-S11119/71, 15(42). cited by applicant English Language Abstract for Zhou, Z. et al, “Syntheses of 1,2-Disubstituted Tetrahydroisoquinoline Derivatives and their Antiarrhythmic Effects” XP 002519323 retrieved from STN Database CA [Online] Chemical Abstracts Service, Columbus, OH, Database Accession No. 1988;94357. Shanghai Yike Daxue Xuebao (1987) 14(1), pp. 15-20, Coden: Sydxee; ISSN: 0257-8131, China. cited by applicant |
| Primary Examiner: | Davis, Zinna Northington |
| Attorney, Agent or Firm: | Friedrichsen, Bernard P. |
| رقم الانضمام: | edspgr.08476297 |
| قاعدة البيانات: | USPTO Patent Grants |
| الوصف غير متاح. |