| Sonstiges: |
- Nachgewiesen in: USPTO Patent Grants
- Sprachen: English
- Patent Number: 8,618,286
- Publication Date: December 31, 2013
- Appl. No: 13/360029
- Application Filed: January 27, 2012
- Assignees: NeurAxon, Inc. (Mississauga, CA)
- Claim: 1. A method of treating a condition selected from the group consisting of headache, neuropathic pain, chronic inflammatory pain, visceral pain, neuroinflammation, medication-induced hyperalgesia and/or allodynia, acute pain, chronic pain, and bone cancer pain in a mammal, wherein said method comprises administering an effective amount of a compound [chemical expression included] wherein, Q is S—(CHR 6) 1 ; R 1 and each R 6 is, independently, H, optionally substituted C 1-6 alkyl, optionally substituted C 1-4 alkaryl, optionally substituted C 1-4 alkheterocyclyl, optionally substituted C 2-9 heterocyclyl, optionally substituted C 3-8 cycloalkyl, optionally substituted C 1-4 alkcycloalkyl, or —(CR 1A R 1B) n NR 1C R 1D ; R 1A and R 1B are, independently, H, hydroxy, halo, optionally substituted C 1-6 alkyl, optionally substituted C 1-6 alkoxy, optionally substituted C 1-4 alkcycloalkyl, optionally substituted C 1-4 alkaryl, optionally substituted C 1-4 alkheterocyclyl, optionally substituted C 1-4 alkheteroaryl, optionally substituted C 3-8 cycloalkyl, or optionally substituted C 2-9 heterocyclyl, or R 1A and R 1B combine to form ═O; R 1C and R 1D are, independently, H, optionally substituted C 1-6 alkyl, optionally substituted C 1-6 alkoxy, optionally substituted C 1-4 alkcycloalkyl, optionally substituted C 1-4 alkaryl, optionally substituted C 1-4 alkheterocyclyl, optionally substituted C 1-4 alkheteroaryl, optionally substituted C 3-8 cycloalkyl, optionally substituted C 2-9 heterocyclyl, or an N-protecting group selected from the group consisting of formyl, acetyl, propionyl, pivaloyl, t-butylacetyl, 2-chloroacetyl, 2-bromoacetyl, trifluoroacetyl, trichloroacetyl, o-nitrophenoxyacetyl, α-chlorobutyryl, benzoyl, 4-chlorobenzoyl, 4-bromobenzoyl, 4-nitrobenzoyl, alaninyl, leucinyl, phenylalaninyl, benzenesulfonyl, p-toluenesulfonyl, benzyloxycarbonyl, p-chlorobenzyloxycarbonyl, p-methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl, p-bromobenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl, 3,5-dimethoxybenzyloxycarbonyl, 2,4-dimethoxybenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 2-nitro-4,5-dimethoxybenzyloxycarbonyl, 3,4,5-trimethoxybenzyloxycarbonyl, 1-(p-biphenylyl)-1-methylethoxycarbonyl, α,α-dimethyl-3,5-dimethoxybenzyloxycarbonyl, benzhydryloxy carbonyl, t-butyloxycarbonyl, diisopropylmethoxycarbonyl, isopropyloxycarbonyl, ethoxycarbonyl, methoxycarbonyl, allyloxycarbonyl, 2,2,2,-trichloroethoxycarbonyl, phenoxycarbonyl, 4-nitrophenoxy carbonyl, fluorenyl-9-methoxycarbonyl, cyclopentyloxycarbonyl, adamantyloxycarbonyl, cyclohexyloxycarbonyl, phenylthiocarbonyl, benzyl, triphenylmethyl, benzyloxymethyl, and trimethylsilyl, or R 1C and R 1D combine to form an optionally substituted C 2-9 heterocyclyl; n is an integer between 1-6; each of R 2 and R 3 is, independently, H, hal, optionally substituted C 1-6 alkyl, optionally substituted C 6-10 aryl, optionally substituted C 1-6 alkaryl, optionally substituted C 2-9 heterocyclyl, hydroxy, optionally substituted C 1-6 alkoxy, optionally substituted C 1-6 thioalkoxy, (CH 2) r2 NHC(NH)R 2A , or (CH 2) r2 NHC(S)NHR 2B , or optionally substituted C 1-4 alkheterocyclyl, wherein r2 is an integer from 0 to 2, R 2A is optionally substituted C 1-6 alkyl, optionally substituted C 6-10 aryl, optionally substituted C 1-4 alkaryl, optionally substituted C 2-9 heterocyclyl, optionally substituted C 1-4 alkheterocyclyl, optionally substituted C 1-6 thioalkoxy, optionally substituted C 1-4 thioalkaryl, optionally substituted aryloyl, optionally substituted C 1-4 thioalkheterocyclyl, or; and R 2B is optionally substituted C 1-4 alkaryl, optionally substituted C 2-9 heterocyclyl, substituted C 1-4 alkheterocyclyl, optionally substituted C 1-6 thioalkoxy, optionally substituted C 1-4 thioalkaryl, optionally substituted aryloyl, optionally substituted C 1-4 thioalkheterocyclyl, or optionally substituted amino; and each of R 4 and R 5 is independently H, hal, (CH 2) r2 NHC(NH)R 2A , or (CH 2) r2 NHC(S)NHR 2B ; wherein Y 1 and Y 2 are each H, or Y 1 and Y 2 together are ═O, or Y 1 and Y 2 are independently H, optionally substituted C 1-6 alkyl, optionally substituted C 6-10 aryl, optionally substituted C 1-6 alkaryl, optionally substituted C 2-9 heterocyclyl, hydroxy, optionally substituted C 1-6 alkoxy, optionally substituted C 1-6 thioalkoxy, or optionally substituted C 1-4 alkheterocyclyl; wherein one and only one of R 2 , R 3 , R 4 , and R 5 is (CH 2) r2 NHC(NH)R 2A or (CH 2) r2 NHC(S)NHR 2B ; or a pharmaceutically acceptable salt thereof to said mammal.
- Claim: 2. The method of claim 1 , wherein said mammal is a human.
- Claim: 3. The method of claim 1 , wherein said headache is migraine headache (with or without aura), chronic tension type headache (CTTH), migraine with allodynia, medication overuse headache, cluster headache, chronic headache, or transformed migraine.
- Claim: 4. The method of claim 1 , wherein said headache is a headache with central sensitization.
- Claim: 5. The method of claim 1 , wherein said chronic pain has components of central sensitization.
- Claim: 6. The method of claim 1 , wherein said chronic pain is neuropathic pain.
- Claim: 7. The method of claim 1 , wherein R 1 and each R 6 is, independently, H, optionally substituted C 1-6 alkyl, optionally substituted C 1-4 alkaryl, optionally substituted C 1-4 alkheterocyclyl, or optionally substituted C 2-9 heterocyclyl.
- Claim: 8. The method of claim 1 , wherein R 2 , R 3 , R 4 , or R 5 has the formula: [chemical expression included]
- Claim: 9. The method of claim 8 , wherein R 2A has the formula: [chemical expression included] and each of X 1 , X 2 , X 4 , and X 5 is independently selected from O, S, NR 7 , N, or CR 8 ; X 3 is selected from N or C; R 7 is H or optionally substituted C 1-6 alkyl; R 8 is H, hal, optionally substituted C 1-6 alkyl, hydroxy, optionally substituted C 1-6 alkoxy, or optionally substituted C 1-6 thioalkoxy, wherein at least one of X 1 , X 2 , X 4 , and X 5 is not CR 8 .
- Claim: 10. The method of claim 9 , wherein R 2A has the formula: [chemical expression included] and each of X 1 and X 2 is independently selected from O, S, NH, N, or CH; and wherein at least one of X 1 and X 2 is not CH.
- Claim: 11. The method of claim 1 , wherein said compound has a structure selected from [chemical expression included] and wherein one of R 4 and R 5 has the following structure: [chemical expression included] wherein X 2 is O or S.
- Claim: 12. The method of claim 1 , wherein Y 1 and Y 2 are each H or together are ═O.
- Claim: 13. The method of claim 1 , wherein R 1 is optionally substituted C 1-6 alkyl, optionally substituted C 2-9 heterocyclyl, or optionally substituted C 1-4 alkheterocyclyl.
- Claim: 14. The method of claim 13 , wherein R 1 is optionally substituted aminoC 1-6 alkyl or optionally substituted C 1-4 alkheterocyclyl, wherein said heterocyclyl is a 5- or 6-membered cyclic amine.
- Claim: 15. The method of claim 14 , wherein said cyclic amine is substituted with a carboxyl, C 1-6 alkoxycarbonyl, or carbamoyl group.
- Claim: 16. The method of claim 13 , wherein said heterocyclyl is optionally substituted pyrrolidinyl or optionally substituted piperidinyl.
- Claim: 17. The method of claim 16 , wherein R 1 is [chemical expression included] wherein R 9 is H, optionally substituted C 1-6 alkyl, or optionally substituted C 1-4 alkaryl.
- Claim: 18. The method of claim 1 , wherein R 1 is an optionally substituted C 3 -C 8 cycloalkyl.
- Claim: 19. The method of claim 18 , wherein said C 3 -C 8 cycloalkyl is substituted by an amino.
- Claim: 20. The method of claim 1 , wherein R 1 is —(CR 1A R 1B) n NR 1C R 1D .
- Claim: 21. The method of claim 20 , wherein R 1A and R 1B are each H, and n is 2 or 3.
- Claim: 22. The method of claim 20 , wherein R 1C is H, and R 1D is —CH 3 , —CH 2 CH 3 , —(CH 2) 2 OH, or —CH 2 CO 2 H; or R 1C and R 1D combine to form optionally substituted pyrrolidinyl or optionally substituted piperidinyl.
- Claim: 23. The method of claim 20 , wherein R 1 is —CH 2 CH 2 N(CH 3) 2 or —CH 2 CH 2 NHCH 3 .
- Claim: 24. The method of claim 1 , wherein one of R 4 or R 5 is H or F.
- Claim: 25. A method of treating a condition selected from the group consisting of headache, neuropathic pain, chronic inflammatory pain, visceral pain, neuroinflammation, medication-induced hyperalgesia and/or allodynia, acute pain, chronic pain, and bone cancer pain in a mammal, wherein said method comprises administering an effective amount of the compound selected from the group consisting of: [chemical expression included] [chemical expression included] [chemical expression included] [chemical expression included] [chemical expression included] or a pharmaceutically acceptable salt thereof to said mammal.
- Claim: 26. The method of claim 25 , wherein said headache is migraine headache (with or without aura), chronic tension type headache (CTTH), migraine with allodynia, medication overuse headache, cluster headache, chronic headache, or transformed migraine.
- Current U.S. Class: 544/51
- Patent References Cited: 5521145 May 1996 Takano et al. ; 6914059 July 2005 Rehwinkel et al. ; 7141595 November 2006 Ramnauth et al. ; 2006/0258721 November 2006 Maddaford et al. ; 2207628 June 1996 ; 2494323 February 2004 ; 2607219 February 2007 ; 2643822 October 2007 ; 198 44 291 March 2000 ; WO 00/63197 October 2000 ; WO 01/81323 November 2001 ; WO 2007/024949 March 2007 ; WO 2008/100463 August 2008
- Other References: Abdel-Majid et al., “Reductive Amination of Aldehydes and Ketones with Sodium Triacetoxyborohydride. Studies on Direct and Indirect Reductive Amination Procedures,” J. Org. Chem. 61(11):3849-3862, 1996. cited by applicant ; Chapter II Demand from International Application No. PCT/CA2009/00092, filed Jan. 5, 2010. cited by applicant ; European Search Report from European Application No. EP 09771883, dated Mar. 5, 2012 (date of completion of search). cited by applicant ; Geneste et al., “Synthesis and SAR of Highly Potent and Selective Dopamine D3-receptor Antagonists: Quinolin(di)one and Benzazepin(di)one Derivatives,” Bioorg. Med. Chem. Lett. 16(3):658-662, 2006. cited by applicant ; Grice et al., “The SAR of 4-substituted (6,6-bicyclic) Piperidine Cathepsin S Inhibitors,” Bioorg. Med. Chem. Lett. 16(8):2209-2212, 2006. cited by applicant ; Hanson et al., “The Bromination and Nitration of Some (2H)-1 ,4-Benzoxazin-3(4H)-ones,” J. Chem. Res. 2003(11 ):681, 2003. cited by applicant ; Hartwig, “Evolution of a Fourth Generation Catalyst for the Amination and Thioetherification of Aryl Halides,” Acc. Chem. Res. 41(11):1534-1544, 2008. cited by applicant ; Huang and Buchwald, “New Ammonia Equivalents for the Pd-Catalyzed Amination of Aryl Halides,” Org. Lett. 3(21):3417-3419, 2001. cited by applicant ; International Preliminary Report on Patentability from International Application No. PCT/CA2009/000923, mailed Oct. 21, 2010. cited by applicant ; International Search Report and Written Opinion from International Application No. PCT/CA2009/000923, mailed Sep. 8, 2009. cited by applicant ; Kamila et al., “Regioselective One Pot Synthesis of 2-Alkyl/Aryl-4H-benzo[1,4]thiazine-3-one via Microwave Irradiation,” J. Heterocyclic Chem. 43(6):1641-1646, 2006. cited by applicant ; Luci et al., “Phenylpiperidine-Benzoxazinones as Urotensin-II Receptor Antagonists: Synthesis, SAR, and In Vivo Assessment,” Bioorg. Med. Chem. Lett. 17(23):6489-6492, 2007. cited by applicant ; Mizar et al., “Synthesis of Substituted 4-(3-alky1-1,2,4-oxadiazol-5-ylmethyl)-3,4-dihydro-2H-1,4-benzoxazines and 4-(1H-benzimidazol-2-ylmethyl)-3,4-dihydro-2H-1,4-benzoxazines,” Tetrahedron Lett. 47(44):7823-7826, 2006. cited by applicant ; Ram et al., “Synthesis and Biological Activity of Some New 1-Aryl-3-Benzoxazinyldihydro-Pyrimidinediones,” Indian J. Chem. 29B:697-699, 1990. cited by applicant ; Shridhar et al., “Synthesis & Hypoglycemic Activity of (3-0xo-3,4-Dihydro-2H-1 ,4-Benzoxazin-6/7-yl)Biguanidine Hydrochlorides,” Indian J. Chern. 24B:1293-1294, 1985. cited by applicant ; Wolfe et al., “Simple, Efficient Catalyst System for the Palladium-Catalyzed Amination of Aryl Chlorides, Bromides, and Triflates,” J. Org. Chem. 65(4):1158-1174, 2000. cited by applicant ; Zhou et al., “Studies toward the Discovery of the Next Generation of Antidepressant. Part 5: 3,4-Dihydro-2H-benzo[1,4]oxazine Derivatives with Dual 5-HT1A Receptor and Serotonin Transporter Affinity,” Bioorg. Med. Chem. Lett. 16(5):1338-1341, 2006. cited by applicant ; Hanson et al., “The Bromination and Nitration of Some (2H)-1,4-Benzoxazin-3(4H)-ones,” J. Chem. Res. 2003(11):681, 2003. cited by applicant ; Shridhar et al., “Synthesis & Hypoglycemic Activity of (3-Oxo-3,4-Dihydro-2H-1,4-Benzoxazin-6/7-yl)Biguanidine Hydrochlorides,” Indian J. Chem. 24B:1293-1294, 1985. cited by applicant ; International Search Report and Written Opinion for PCT/CA2009/000923 (mailed Sep. 8, 2009). cited by applicant ; Chapter II Demand (PCT/CA2009/000923), filed Jan. 5, 2010. cited by applicant ; International Preliminary Report on Patentability (PCT/CA2009/000923), mailed Oct. 21, 2010. cited by applicant
- Primary Examiner: McDowell, Brian
- Attorney, Agent or Firm: Clark & Elbing LLP
|
