Patent EA-004930-B1 (EA)
Title: A pharmaceutical composition for treatment of acute, chronic pain and/or neuropathic pain and migraines
Inventor: COE JOTHAM WADSWORTH
IPC: A61K36/81
Filed: 2001-03-16
Abstract: 1. A pharmaceutical composition for the treatment of acute, chronic and/or neuropathic pain and migraine comprising (a) a nicotine receptor partial agonist or a pharmaceutical acceptable salt thereof; (b) an analgesic agent or pharmaceutically acceptable salt thereof and (c) a pharmaceutical acceptable carrier; wherein the active agents "a" and "b" above are present in amounts that render the composition effective in treating acute, chronic and/or neuropathic pain, and migraine. 2. The pharmaceutical composition according to Claim 1, wherein said analgesic agent is selected from opioid analgesics, NMDA antagonists, substance P antagonists, COX 1 and COX 2 inhibitors, tricyclic antidepressants (TCA), selective serotonin reuptake inhibitors (SSRI), capsaicin receptor agonists, anesthetic agents, benzodiazepines, skeletal muscle relaxants, migraine therapeutic agents, anti-convulsants, anti-hypertensives, anti-arrythmics, antihistamines, steroids, caffeine, N-type calcium channel antagonists, and botulinum toxin. 3. The pharmaceutical composition according to Claim 2, wherein said opioid analgesic agent is selected from propoxyphene (Darvon), meperidine (Demerol), hydromorphone (Dilaudid), hydrocodone (Lortab), morphine, codeine and tramodol; their pharmaceutical active salts and their optical isomers. 4. The pharmaceutical composition according to Claim 2 wherein said NMDA antagonist analgesic agent is selected from-2-piperdino-1alkanol derivates, dextromethorphan, eliprodil, and ifenprodil, their pharmaceutically active salts and their optical isomers. 5. The pharmaceutical composition according to Claim 2, wherein the substance P antagonist analgesic agent is selected from (6-Methoxy-3-trifluoromethyl-benzo[d]isoxazol-5-ylmethyl)-(2-phenyl-piperidin-3-yl)-amine; 6-Methoxy-1-methyl-7-[(2-phenyl-1-propyl-piperidin-3-ylamino)-methyl]-3,4-dihydro-1H-quinolin-2-one; 6-Methoxy-1-methyl-7-{[1-(5-oxo-2,5-dihydro-1H-[1,2,4]triazol-3-ylmethyl)-2-phenypiperidin-3-ylamino]-methyl}-3,4-dihydro-1H-quinolin-2-one; 3-(2-Methoxy-5-trifluoromethoxy-phenyl)-6-phenyl-1,7-diaza-spiro[4,5]decane; 6-Methoxy-1-methyl-7-[(2-phenyl-piperidin-3-ylamino)-methyl]-3,4-dihydro-1H-quinolin-2-one; [2-Methoxy-5-(2,2,2-trifiuoro-1-trifluoromethyl-ethyl)-benzyl]-(2-phenyl-piperidin-3-yl)-amine; [5-(1,1-Dimethyl-prop-2-ynyl)-2-methoxy-benzyl]-(2-phenyl-piperidin-3-yl)-amine; 7-Methoxy-1-methyl-6-[(2-phenyl-piperidin-3-ylamino)-methyl]-3,4-dihydro-1H quinolin-2-one; [2-Methoxy-5-(2,2,2-trifiuoro-1,1-dimethyl-ethyl)-benzyl]-(2-phenyl-piperidin-3-yl)-amine; (7-Methoxy-4-methyl-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethyl)-(2-phenyl-piperidin-3-yl)-amine; [2-Methoxy-5-(1-methyl-1-trifluoromethyl-prop-2-ynyl)-benzyl]-(2-phenyl-piperidin-3-yl)-amine; (6-Methoxy-1-mehyl-1-trifluoromethyl-isochroman-7-ylmethyl)-(2-phenyl-piperidin-3-yl)-amine; 2-{3-[(2-Benzhydryl-1-aza-bicyclo[2.2.2]oct-3-ylamino)-methyl]-4-methoxy-phenyl}-methyl-propan-1-ol; (2S,3S)-N-[(5-oxo-1H,4H-1,2,4-triazolo)methyl]-2-(4-fluorophenyl)-3-(3,5-ditrifluoromethyl)benzyloxymorpholine; 3-(3,5-Bis-trifluoromethyl-benzyloxy)-2-phenyl-piperidine; 5-[2-(3,5-Bis-trifluoromethyl-benzyloxy)-3-phenyl-morpholin-4-ylmethyl]-2,4-dihydro-[1,2,4]triazol-3-one; (2S,3S)-3-(2-Methoxy-5-(trifluoromethoxy)benzyl)amino-2-phenylpiperidine; (2S,3S)-N-(5-isopropyl-2-methoxyphenyl)methyl-2-diphenylmethyl-1-azabicyclo[2,2,2]-octan-3-amine; (2S,3S)-N-(5-tert-butyl-2-methoxyphenyl)methyl-2-diphenytmethyl-1azabicyclo[2,2,2]-octane-3-amine; (2S,3S)-N-(5-ethyl-2-methoxyphenyl)methyl-2-diphenylmethyl-1-azabicyclo[2,2,2]octan-3-amine; and (2S,3S)-N-(5-n-propyl-2-methoxyphenyl)methyl-2-diphenyimethyl-1-azabicyclo[2,2,2]octane-3-amine, their pharmaceutically active salts and their optical isomers. 6. The pharmaceutical composition according to Claim 2 wherein the COX 2 inhibitor analgesic agent is selected from rofecoxib and celecoxib their pharmaceutical active salts and their optical isomers. 7. The pharmaceutical composition according to Claim 2 wherein the anesthetic analgesic agent is selected from nitrous oxide, halothane, lidocaine, etidocaine, ropivacaine, chloroprocaine, sarapin and bupivacaine their pharmaceutical active salts and their optical isomers. 8. The pharmaceutical composition according to Claim 2 wherein the benzodiazepine analgesic agent is selected from diazepam, chlordiazepoxide, alprazolam, and lorazepam their pharmaceutical active salts and their optical isomers. 9. The pharmaceutical composition according to Claim 2 wherein the skeletal muscle relaxant analgesic agent is selected from flexeril, carisoprodol, robaxisal, norgesic and dantrium their pharmaceutical active salts and their optical isomers. 10. The pharmaceutical composition according to Claim 2 wherein the migraine therapeutic agent is selected from elitriptan, sumatriptan, rizatriptan, zolmitriptan, and naratriptan their pharmaceutical active salts and their optical isomers. 11. The pharmaceutical composition according to Claim 2 wherein the anticonvulsant analgesic agent is selected from gabapentin, pregabalin, carbamazepine, and topiramate and valproic acid their pharmaceutically active salts and their optical isomers. 12. The pharmaceutical composition according to Claim 2 wherein the COX 1 inhibitor analgesic agent is selected from salycylic acid, acetominophen, diclofenac, piroxican indomethacin, ibuprofen, and naproxen their pharmaceutically active salts and their optical isomers. 13. The pharmaceutical composition according to Claim 2 wherein the tricyclic antidepressant analgesic agent is selected fromamitriptyline, desipramine, perphenazine, protriptyline, and tranylcypromine their pharmaceutically active salts and their optical isomers. 14. The pharmaceutical composition according to Claim 1 wherein the analgesic agent is chosen from baclofen, clonidine, mexilitene, diphenyl-hydramine, hydroxysine, caffeine, prednisone, methylprednisone, decadron, paroxetine, sertraline, fluoxetine, tramodol, Ziconotide ( and levodopa their pharmaceutically active salts and their optical isomers. 15. The pharmaceutically composition according to Claim 1, wherein said nicotine receptor partial agonist is selected from 9-brom-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido [1,2-a] [1,5]diazocin-8-one; 9-chloro-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido [1,2-a] [1,5]diazocin-8-one; 9-fluoro-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido [1,2-a] [1,5]diazocin-8-one; 9-ethyl-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido [1,2-a] [1,5]diazocin-8-one; 9-methyl-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido [1,2-a] [1,5] diazocin-8-one; 9-phenyl-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido [1,2-a] [1,5] diazocin-8-one; 9-vinyl-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido [1,2-a] [1,5]diazocin-8-one; 9-bromo-3-methyl-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido [1,2-a] [1,5]diazocin-8-one; 3-benzyl-9-bromo-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido [1,2-a] [1,5]diazocin-one; 3-benzyl-9-chloro-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2-a] [1,5]diazocin-8-one; 9-acetyl-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido [1,2-a] [1,5]diazocin-8-one; 9-iodo-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido [1,2-a] [1,5] diazocin-8-one; 9-cyano-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido [1,2-a] [1,5] diazocin-8-one; 9-ethynyl-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido [1,2-a] [1,5] diazocin-8-one; 9-(2-propenyl)-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido [1,2-a] [1,5] diazocin-8-one; 9-(2-propyl)-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido [1,2-a] [1,5] diazocin-8-one; 9-carbomethoxy-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido [1,2-a] [1,5]diazocin-8-one; 9-carboxyaldehyde-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido [1,2-a] [1,5] diazocin-8-one; 9-(2,6-difluorophenyl)-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2-a] [1,5]diazocin-8-one; 9-phenyl-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido [1,2-a] [1,5]diazocin-8-one; 9-(2-fluorophenyl)-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido [1,2-a] [1,5]diazocin-8-one; 9-(4-flurophenyl)-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido [1,2-a] [1,5]diazocin-8-one; 9-(3-fluorophenyl)-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2-a] [1,5]diazocin-8-one; 9-(3,5-difluorophenyl)-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2-a] [1,5]diazocin-8-one; 9-(2,4-difluorophenyl)-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2-a] [1,5]diazocin-one; 9-(2,5-difluorophenyl)-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2-a] [1,5]diazocin-8-one; 6-methyl-5-oxo-6,13-diazatetracyclo [9.3.1.0<2,10>.0<4,8>]pentadeca-2(10),3,8-trien; 5-oxo-6,13-diazatetracyclo [9.3.1.0<2,10>.0<4,8>]pentadeca-2(10),3,8-triene; 6-oxo-5,7,13-triazatetracyclo [9.3.1.0<2,10>.0<4,8>]pentadeca-2(10),3,8-triene; 4,5-difluoro-10-aza-tricyclo [6.3.1.0<2,7>] dodeca-2(7),3,5-trine; 5-fluoro-10-aza-tricyclo [6.3.1.0<2,7>] dodeca-2(7),3,5-triene-4-carbonitrile; 4-ethynyl-5-fluoro-10-aza-tricyclo [6.3.1.0<2.7>] dodeca-2(7),3,5-triene; 5-ethynyl-10-aza-tricyclo [6.3.1.0<2,7>]dodeca-2(7),3,5-triene-4-carbonitrile; 6-methyl-5-thia-5-dioxa-6,13-diazatetracyclo [9.3.1.0<2,10>.0<4,8>]pentadeca-2(10),3,8triene; 10-aza-tricyclo [6.3.1.0<2,7>]dodeca-2(7),3,5-triene; 4-fluoro-10-aza-tricyclo [6.3.1.0<2,7>]dodeca-2(7),3,5-triene; 4-methyl-10-aza-tricyclo [6.3.1.0<2,7>] dodeca-2(7),3,5-triene; 4-trifluoromethyl-10-aza-tricyclo [6.3.1.0<2,7>] dodeca-2(7),3,5-triene; 4-nitro-10-azatricyclo [6.3.1.0<2,7>] dodeca-2(7),3,5-triene; 7-methyl-5,7,13-triazatetracyclo [9.3.1.0<2,10>.0<4,8>]pentadeca-2(10),3,5,8-tetraene; 6-methyl-5,7,13-triazatetracyclo [9.3.1.0<2,10>.0<4,8>]pentadeca-2(10),3,5,8-tetraene; 6,7-dimethyl-5,7,13-triazatetracyclo [9.3.1.0<2,10>.0<4,8>]pentadeca-2(10),3,5,8-tetraene; 6-methyl-7-phenyl-5,7,13-triazatetracyclo [9.3.1.0<2,10>.0<4,8>]pentadeca-2(10),3,5,8-tetraene; 6,7-dimethyl-5,8,14-triazatetracyclo[10.3.1.0<2,11>.0<4,9>] hexadeca-2(11),3,5,7,9-pentaene; 5,8,14-triazatetracyclo [10.3.1.0<2,11>.0<4,9>] hexadeca-2(11),3,5,7,9-pentaene; 14-methyl-5,8,14-triazatetracyclo[10.3.1.0<2,11>.0<4,9>]hexadeca-2(11),3,5,7,9-pentaene; 5-oxa-7,13-diazatetracyclo [9.3.1.0<2,10