SUBSTANCE P INHIBITORS IN COMBINATION WITH NMDA-BLOCKERS FOR TREATING PAIN
BACKGROUND OF THE INVENTION
This invention relates to an analgesic composition and method for alleviating pain. More particularly, this invention is concerned with alleviating pain by administration of an analgesic composition comprising a substance P receptor antagonist and, as a potentiator of the substance P receptor antagonist, a nontoxic N- methyl-D-aspartate (NMDA) receptor antagonist and/or nontoxic substance that blocks a major intracellular consequence of NMDA receptor activation.
The expression "substance P receptor antagonist" shall be understood to be synonymous with and/or inclusive of neurokinin-1, or NK-1, receptor antagonist. Substance P is a naturally occurring undecapeptide that belongs to the tachykinin family of peptides. Specifically, substance P is a pharmacologically active neuropeptide that is produced in mammals. Its characteristic amino acid sequence is illustrated in U.S. Patent No. 4,680,283. The neuropeptide receptors for substance P are distributed throughout the mammalian nervous system, e.g., the brain and spinal ganglia, the circulatory system and peripheral tissues such as the duodenum and jejunum. Substance P is believed to be involved in the transmission of pain. A large number of substance P receptor antagonists have been described in the patent literature as suitable for alleviating pain and/or ameliorating any of a variety of disorders that are commonly accompanied by pain. See, e.g., U.S. Patent Nos. 3,862,114, 3,912,711, 4,472,305, 4,481,139, 4,680,283, 4,839,465, 5,102,667, 5,162,339, 5,164,372, 5,166,136, 5,232,929, 5,300,648, 5,310,743, 5,338,845, 5,340,822, 5,378,803, 5,410,019, 5,411,971, 5,420,297, 5,422,354, 5,446,052,
5,451,586, 5,525,712, 5,527,811, 5,536,737, 5,541,195, 5,561,113, 5,576,317, 5,604,247, 5,624,950 and 5,635,510; World Patent Application Nos. WO 90/05525, WO 91/09844, WO.91/12266, WO 92/06079, WO 92/12151, WO 92/15585, WO 92/20661, WO 92/20676, WO 92/21677, WO 92/22569, WO 93/00330, WO 93/00331, WO 93/01159, WO 93/01160, WO 93/01165, WO 93/01169, WO 93/01170, WO 93/06099, WO 93/10073, WO 93/14084, WO 93/19064, WO 93/21155, WO 94/04496, WO 94/08997 and WO 95/11895; European Patent Application Nos. 284942, 327009, 333174, 336230, 360390, 394989, 428434, 429366, 443132, 446706, 484719, 499313, 512901, 512902, 514273, 514275, 520555, 522808, 528495 and 532456; and GB 2216529.
SUMMARY OF THE INVENTION
In accordance with the present invention, an analgesic composition is provided which comprises (a) an analgesically effective amount of at least one substance P receptor antagonist and (b) a substance P receptor antagonist-potentiating amount of at least one substance P receptor antagonist potentiator selected from the group consisting of nontoxic N-methyl-D-aspartate receptor and nontoxic substance that blocks a major intracellular consequence of N-methyl-D-aspartate receptor activation. Further in accordance with this invention, a method for alleviating pain is provided with comprises administering to a mammal exhibiting pain (a) an analgesically effective amount of at least one substance P receptor antagonist and (b) a substance P receptor antagonist-potentiating amount of at least one substance P receptor antagonist potentiator selected from the group consisting of nontoxic N-methyl-D- aspartate receptor antagonist and nontoxic substance that blocks a major intracellular consequence of N-methyl-D-aspartate receptor activation.
The expression "N-methyl-D-aspartate receptor" shall be understood to include all of the binding site subcategories associated with the NMDA receptor, e.g., the gly cine-binding .site, the phenylcyclidine (PCP)-binding site, etc., as well as the NMDA channel. Thus, the invention herein contemplates the use of nontoxic substances that block an NMDA receptor binding site, e.g., dextromethorphan, or that block the NMDA channel, e.g., a source of magnesium such as magnesium sulfate. The term "nontoxic" as used herein shall be understood in a relative sense and is intended to designate any substance that has been approved by the United States Food and Drug Administration ("FDA") for administration to humans or, in keeping with established regulatory criteria and practice, is susceptible to approval by the FDA for administration to humans. The term "nontoxic" is also used herein to distinguish the NMDA receptor antagonists, or blockers, that are useful in the practice of the present invention from NMDA receptor antagonists such as MK 801 (the compound 5-methyl-10,ll-dihydro-SH-dibenze[a,d] cyclohepten-5,10-imine), CPP (the compound 3-[2-carboxypiperazin-4-yl] propyl- 1-phosphonic acid) and PCP (the compound l-(l-phenylcyclohexyl)piperidine) whose toxicities effectively preclude their therapeutic use.
The terms "potentiate" and "potentiating" are used herein in their art- recognized sense, i.e., as referring to a significant increase in the level of analgesic activity for the combination of substance P receptor antagonist and nontoxic NMDA receptor antagonist and/or nontoxic substance that blocks a major intracellular consequence of NMDA receptor activation compared with that which could have been expected based on the activities of the substance P receptor antagonist administered alone and nontoxic NMDA receptor antagonist and/or nontoxic substance that blocks a major intracellular consequence of NMDA receptor activation administered alone.
The expression "analgesically effective amount" as applied to the substance P receptor antagonist employed in the analgesic composition and method of this invention shall be understood to mean an amount of substance P receptor antagonist which when administered by itself or in combination with the nontoxic NMDA receptor antagonist and/or substance that blocks a major intracellular consequence of NMDA receptor activation provides effective analgesia.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
Any of the substance P receptor antagonists heretofore used to treat pain and/or a disorder exhibiting a pain component, e.g., muscular pain, musculoskeletal pain, chronic pain, neuropathic pain, migraine, etc., can be used herein. Specific substance P receptor antagonists that can be used herein are disclosed in aforementioned U.S. Patent Nos. 3,862,114, 3,912,711, 4,472,305, 4,481,139, 4,680,283, 4,839,465, 5,102,667, 5,162,339, 5,164,372, 5,166,136, 5,232,929, 5,300,648, 5,310,743, 5,338,845, 5,340,822, 5,378,803, 5,410,019, 5,411,971, 5,420,297, 5,422,354, 5,446,052, 5,451,586, 5,525,712, 5,527,811, 5,536,737, 5,541,195, 5,561,113, 5,576,317, 5,604,247, 5,624,950 and 5,635,510; World Patent Application Nos. WO 90/05525, WO 91/09844, WO 91/12266, WO 92/06079, WO 92/12151, WO 92/15585, WO 92/20661, WO 92/20676, WO 92/21677, WO 92/22569, WO 93/00330, WO 93/00331, WO 93/01159, WO 93/01160, WO 93/01165, WO 93/01169, WO 93/01170, WO 93/06099, WO 93/10073, WO 93/14084, WO 93/19064, WO 93/21155, WO 94/04496, WO 94/08997 and WO 95/11895; European Patent Application Nos. 284942, 327009, 333174, 336230, 360390, 394989, 428434, 429366, 443132, 446706, 484719, 499313, 512901, 512902, 514273, 514275, 520555, 522808, 528495 and 532456; and GB 2216529, the contents of which are incorporated by reference herein.
More particularly, useful substance P receptor antagonists include the substance P analogs of U.S. Patent No. 3,862,114, e.g., compounds having the L- amino acid sequence G-L-M-NH2, O-G-L-M-NH2, F-G-L-M-NH2 and the like; the undecapeptides of U.S. Patent No. 3,912,711, e.g., L-arginyl-L-prolyl-L-lysyl-L- prolyl-L-glutøminyl-L-glutammyl-L-phenylalanyl-L-glycyl-L-leucyl-L-memionine amide and the like; the hexapeptide amides of U.S. Patent No. 4,472,305, e.g., HPro- Phe-Phe-DAla-Leu-MetNH2, HPro-Phe-MePhe-Gly-Leu-MetNH2, HPro-Phe-Phe-Gly- DLeu-MetNH2 and the like; the undecapeptides of U.S. Patent No. 4,481,139, e.g., [D-Phe5, D-Trp7, D-Trp9, Leun]-SP, [Glp5, D-Trp7, D-Trp9, Thr"]-SPs.u, [D-Ang1, D- Tip7, D-Trp9, Leuπ]-SP and the like; the substance P analogs of U.S. Patent No. 4,680,283, e.g., pyroglutamyl-ohenylalanyl-phenylalanyl-[(R)-3-amino-2-oxo-l- pyrrolidine-(S)-4-methyl-2-pentanoyl]methionine amide, pyroglutamyl-phenylalanyl-N- memyl-phenylalanyl-[(R)-3-__mino-2-oxo-l-pyrrolidine-(S)-4-methyl-2- pentanoyl] methionine amide and the like; the di-(D-tryptophyl and/or tetra- hydropyridoindolylcarbonyl)-containing peptide amides of U.S. Patent No. 4,839,465, e.g., H-trρ-Phe-trp-Leu-Met-NH2, H-Pro-trρ-Phe-trp-Leu-Phe-NH2, H-tpi-Phe-trp-Leu: Met-NH2 and the like; the isoindolones of U.S. Patent No. 5,102,667, e.g., 2-[l-imino- 2-(2-methoxyphenyl)ethyl]-7,7-diphenyl-4-perhydroisoindolone in its (3aR,7aR) or (3aR,7aRS) forms, 7,7-diphenyl-2-[2-(2-dimethylaminophenyl)acetyl]-4-perhydro- isoindolone in its (3aR,7aR) or (3aRS,7aRS) forms, 7,7-diphenyl-2-[(R)-2-(2- methoxyphenyl)propionyl]-4-perhydroisoindolone in its (3aR,7aR) or (3aRS,7aRS) forms and the like; the quinuclidines of U.S. Patent No. 5,162,339 and World Patent Application No. WO 90/05525, e.g., cis-3-[(2-chlorophenyl)methylamino]-2-benz- hydrylquinuclidine, cis-3-[(2-trifluoromethylphenyl)methylamino]-2-benzhydryl- quinuclidine, cis-3-[(2-methoxyphenyl)methylamino]-2-benzhydrylquinuclidine and the like; the peptides of U.S. Patent No. 5,164,372, e.g., the compounds of Examples 1-63 and the like; the spirolactams of U.S. Patent No. 5,166,136 and European Patent
Application No. EP 360390, e.g., 7-[(lS)-(l-methoxycarbonyl)-3-methylbutyl]-6-oxo- (5S)-l,7-diazaspiro[4.4]nonane-l-carboxylic acid, phenylmethyl ester, 7-[(lS)-(l- methoxycarbony l)-3-methy lbuty 1] -6-oxo-(5S)- 1 , 7-diazaspiro [4.4] nonane- 1 -carboxylic acid phenylmethyl ester, 7-[(lS)-(l-methoxycarbonyl)-3-methylbutyl]-6-oxo-(5S)-l,7- diazaspiro[4.4]nonane-l-carboxylic acid, (l,l-dimethyl)ethyl ester and the like; the 3- aminopiperidines and related nitrogen containing heterocycles of U.S. Patent No. 5,232,929, e.g., cis-3-(2-methoxybenzylamino)-2-phenylpiperidine, cis-l-allyl-3-(2- methoxybenzylamino)-2-phenylpiperidine, cis-l-ethyl-3-(2-methoxybenzylamino)-2- phenylpiperidine and the like; the dialkylenepiperidinos of U.S. Patent Nos. 5,300,648 and 5,446,052, e.g., N-[4-(l-benzyl-4-ρiρeridinyl)-2-(3,4-dichlorophenyl)-butyl]-4- fluoronaphtalene carboxamide hydrochloride, N-[4-[l-(fluorobenzyl)-4-piperidiny_]-2- (3,4-dichlorophenyl)-butyl]-2,4-dichlorobenzamide hydrochloride, N-methyl-N-[4-(l- benzyl-4-piperidinyl)-2-(3,4-dichlorophenyl)-butyl]3-isopropoxy-phenylacetamide hydrochloride and the like; the 1-acylpiperidines of U.S. Patent Nos. 5,310,743 and 5,541,195, e.g., (2R,4S) and (2R,4R)-2-benzyl-l-(3,5-dimethyl-benzoyl)-N-(2- phenethyl)-4-piperidinamine hydrochloride, (2R*,4S*)-2-benzyl-l-(2-naphthoyl)-N-(4- quinolylmethyl)-4-piper idinamine , (2R* ,4S *)-2-benzy 1- 1 -(3 -tri-fluoromethylbenzoy 1)- N-(4-quinolylmethyl)-4-piperidinamine and the like; the cyclic dimeric dipeptide derivatives of U.S. Patent No. 5,338,845, e.g., the compounds of Table 1 and the like; the polycyclic amines of U.S. Patent No. 5,340,822, e.g., 4-[2-(4-benzylpiperidin-l- yl)ethyl]-4-(3-methylphenyl)-l-(3-chlorophenyl)acetylpiperidine hydrochloride, 3-[2-(4- benzylpiperidin-l-yl)ethyl]-3-(3,4-dichlorophenyl)-l-phenylacetylpiperidine hydrochloride, 5-[2-(4-Benzylpiperidin-l-yl)ethyl]-5-(3,4-dichlorophenyl)-l- benzylpiperidinone hydrochloride and the like; the azole-fused peptides of U.S. Patent No. 5,378,803, e.g., the compounds of Examples 1-28 and the like; the peptides of U.S. Patent No. 5,410,019, e.g., H-Arg-Pro-Lys-Pro-Gln-Gln-Phe-Phe-Gly- Leuψ[CH2-NH]Leu-NH2, H-D-Arg-Pro-Lys-Pro-Gln-Gln-D-Trp-Phe-D-Trpψ[CH2-
NH]Leu-Nle-NH2, H-D-Arg-Pro-Lys-Pro-Gln-Gln-D-Trpψ[CH2-NH]Phe-D-Trp-Leu- Nle-NH2 and the like; the N-alkylenepiperidinos of U.S. Patent No. 5,411,971, e.g., N-[2-(3,4-dichlorophenyl)-4-(4-(2-pyridylthio)-l-piperidinyl)butyl]-2,4- dichlorobenzamide, N-[4-(4-N ' -acetylanilino- 1 -piperidinyl)-2-(3 ,4- dichlorophenyl)buty 1] -N-methylbenzamide , N-[4-( 1 -methy 1-2-imidazoly l)-4-thio- 1 - piperidinyl)-2-naphthylbutyl]-2,4-dimethoxybenzamide and the like; the peptides of U.S. Patent No. 5,420,297, e.g., Boc-Phe (p-CH3)-OH, Boc-Phe(p-F)-OH and the like; the quinuclidines of U.S. Patent No. 5,422,354, e.g., 8-(diphenylmethyl)-N-((2- methoxyphenyl)methyl))-9-azatricyclo[4.3.1.04,9]decan-7-amine, 8-(diphenylmethyl)-N- (phenylmethyl)-9-azatricyclo[4.3.1.04'9]decan-7-amine, 8-(diphenylmethyl)-N-((2- chlorophenyl)methyl))-9-azatricyclo[4.3.1.04,9]decan-7-amine and the like; the 3-aπιino- 2-arylquinuclidines of U.S. Patent No. 5,451,586, e.g., trans-2-phenyl-N-(2- methoxypheny l)methy 1)- 1 -azabicy clo [2.2.2] octan-3 -amine , cis-2-pheny l-N-(pheny 1- methy 1)- 1 -azabicy clo [2.2.2] octan-3-amine , 2-( 1 -naphthyl)-N-((2-methoxy- phenyl)methyl)-l-azabicyclo[2.2.2]octan-3-amine and the like; the isoquinolinyls of U.S. Patent No. 5,527,811, e.g., N-[(6-chloro-l,2-dihydro-2-methyl-l-oxo-4- phenylisoquinolin-3-yl)methyl]-N'-(3-isopropoxyphenyl)urea, N-[(l,2-dihydro-2,6,7- trimethy 1- 1 -oxo-4-pheny lisoquinolin-3 -y l)methyl] -N ' -(3 -methy Ipheny l)urea , N- [( 1 ,2- dihydro-2-methyl-l-oxo-4-phenylisoquinolin-3yl)methyl]-N'-(3-methylphenyl)urea and the like; the prolyl endopeptidase inhibitor compounds of U.S. Patent No. 5,536,737, e.g., (S)-2-[[(S)-2-(acetoxyacetyl)-l-pyrrolidinyl]carbonyl]-N-(phenylmethyl)-l- pyrrolidinecarboxamide , (S)-2- [[(S)-2-(hy dr oxy acetyl)- 1 -pyrrolidinyl] carbony 1] -N- (phenylmethyl)-l-pyrrolidinecarboxamide, (S)-2-[[(S)-2-[(benzoyloxyacetyl)-l- pyrrolidinyl]carbonyl]-N-(phenylmethyl)-l-pyrrolidinecarboxamide and the like; the pseudopeptides of U.S. Patent No. 5,561,113, e.g., {l-[4-(lH-tetrazol-5-yl)- butyl)indol-3-yl}carbonyl-Hyp-Nal-NMeBzl, {l-[4-(lH-tetrazol-5-yl)buty_]indol-3- yl}carbonyl-Hyp-Tna-NMeBzl, {l-[4-(lH-tetrazol-5-yl)butyl]indol-3-yl}carbonyl-Hyp-
Thn-NMeBzl and the like; the piperidines of U.S. Patent No. 5,576,317, e.g., (2S.3S)- 3-(5-tert-butyl-2-methoxybenzyl)amino-2-(3-trifluoromethoxyphenyl)piperidine (2S,3S)- 3-(2-isopropoxy-5-trifluoromethoxybenzyl)amino-2-phenyl-piperidine, (2S,3S)-3-(2- ethoxy-5-trifluoromethoxybenzyl)amino-2-phenyl-piperidine and the like; the chromone compounds of U.S. Patent No. 5,604,247, e.g., (2R,4S)-N-[l-(3,5-bis- trifluoromethylbenzoyl)-2-(4-chlorobenzyl)piperidin-4-yl]-4-oxo-4H-l-benzopyrane-2- carboxamide, (2R,4S)-N-[l-(3,5-bistrifluormethylbenzoyl)-2-benzylpiperidin-4-yl]-4- oxo-4H-l-benzopyrane-2-carboxamide, (2R,4S)-N-[l-(3,5-bistrifluoromethylbenzoyl)- 2-(4-chlorobenzy l)piperidin-4-y 1] -6-fluoro-4-oxo-4H- 1 -benzopyrane-2-carboxamide and the like; the perhydroisoindoles of U.S. Patent No. 5,624,950, e.g., 7,7-dimethyl-4-(2- methoxyphenyl)-2-[2-(S)-(2-methoxyphenyl)propionyl]-4,5-perhydroisoindolediol, 4-(2- methoxyphenyl)-2-[2-(S)-(2-methoxyphenyl)proponyl]-5-methyl-4-perhydro-isoindolol, 2-[2-(S)-(2-hydroxyphenyl)propionyl]-4-(2-methoxyphenyl)-6-methyl-4- perhydroisoindolol and the like; the substituted pyrrolidin-3-yl-alkyl-piperidines of U.S.. Patent No. 5,635,510, e.g., (+)-or(-)-l-(2-[3-(3,4-dichloro-phenyl)-l-[2-(2- methoxy-phenyl)-acetyl]-pyrrolidin-3-yl]-ethyl)-4-phenyl-piperidine-4-carboxylic.acid amide , ( + )-or (-)- 1 - [2- [3-(3 , 4-dichlorophenyl)- 1 -(2 , 6-dimethoxybenzoy l)-py rrolidin-3 - yl] -ethyl] -4-phenyl-piperidine-4-carboxy lie acid amide, (+)-or(-)-l-[2-[3-(3,4-dichloro- phenyl)- 1 (3,4 , 5-trimethoxybenzoyl)-pyrrolidin-3 -yl] -ethyl] -4-pheny l- iperidine-4- carboxy lie acid amide and the like; the 3-amino-piperidines of World Patent
Application No. WO 91/09844, e.g., cis-3-(2-chlorobenzylamino)-2-phenyl-piperidine, cis-3-(2-trifluoromethylbenzylamino)-2-phenylpiperidine, cis-3-(2- methoxybenzylamino)-2-(2-fluorophenyl)-piperidine and the like; the peptides of World Patent Application No. WO 91/12266, e.g., the compounds of Examples 1-34 and the like; the fused ring analogs of nitrogen containing heterocycles of World Patent
Application No. WO 92/06079, e.g., [lα,3 ,4α,5α]-4-(2-methoxybenzyl)-amino-3- phenyl-2-azabicyclo[3.3.0]octane, 4-(2-methoxybenzyl)amino-3-phenyl-2-
azabicy clo [4.4.0] decane , 4-(2-methoxybenzy l)amino-4-benzhydry 1-3-azabicy clo- [4.1.0]heptane and the like; the N-alkyl quinuclidinium salts of World Patent Application No. WO 92/12151, e.g., (2S,3S)-cis-l-methyl-2-(diphenylmethyl)-N-((2- methoxyphenyl)methy 1)- 1 -azabicy clo [2.2.2] octan-3 -amine iodide , (2S , 3 S)-cis- 1 -(4- carbethoxybutyl)-2-(diphenylmethyl)-N-((2-methoxyphenyl)methyl)-l-azabicyclo- [2.2.2]octan-3-amine iodide, (2S,3S)-cis-l-(4-carboethoxyphenylmethyl)-2- (diphenylmemyl)-N-((2-methoxyphenyl)methyl)-l-azabicyclo[2.2.2]ocl__m-3-amine iodide and the like; the l-azabicyclo[3.2.2]nonan-3 amines of World Patent Application No. WO 92/15585, e.g., 2-(diphenylmethyl)-N-((2-methoxyphenyl)-methyl)-l- azabicyclo[3.2.2]nonan-3-amine, 2-(diphenylmethyl)-N-((2-chlorophenyl)-methyl)-l- azabicyclo [3.2.2] nonan-3 -amine , 2-(dipheny lmethy l)-N-((2 , 4-dimethoxy- phenyl)methyl)-l-azabicyclo[3.2.2]nonan-3-amine and the like; the N,N-diacyl- piperazines of World Patent Application No. WO 92/20661, e.g., l,4-bis(N,N- diphenylcarbamoyl)piperazine-2-carboxylic acid, 1 ,4-bis(N,N-diphenylcarbamoyl)-2- methy 1-piperazine , 1 -(N , N-di-n-penty lcarbamoy l)-4-(N , N-dipheny lcarbamoy 1)- piperazine-2-carboxylic acid and the like; the substituted 3-aminoquinuclidines of World Patent Application No. WO 92/20676, e.g., (3R,4S,5S,6S)-N,N-diethyl-5-(2,5- dimethoxybenzy lamino)-6-dipheny lmethy 1- 1 -azabicy clo [2.2.2] octane-3 -carboxamide , (3R,4S,5S,6S)-5-(5-isopropyl-2-memoxybenzyl.ιmino)-6-diphenylmethyl-l-azabicyclo- [2.2.2]octane-3-carboxylic acid, (3R,4S,5S,6S)-5-(2-methoxy-2-methylthiobenzyl- amino)-6-diphenylmethyl-l-azabicyclo[2.2.2]octane-3-carboxylic acid and the like; the quinuclidines of World Patent Application No. WO 92/21677, e.g., (2S,3S)-N-(5- isopropyl-2-methoxyphenyl)methyl-2-diphenylmethyl-l-azabicyclo[2.2.2]octan-3- amine , (2S , 3S)-N-(5-ethyl-2-methoxyphenyl)methyl-2-diphenyl-methyl- 1 -azabicyclo- [2.2.2]octan-3-amine, (2S,3S)-N-(5-isopropyl-2-methoxyphenyl)methyl-2-diphenyl- methyl-l-azabicyclo[2.2.2]octan-3-amine and the like; the peptides of World Patent Application No. WO 92/22569, e.g., the compounds of Examples 1-22 and the like;
the azanorbornane compounds of World Patent Application No. WO 93/00330, e.g., (lSR,2SR,3SR,4RS)-l-aza-2-diρhenylmethyl-3-[(2-methoxyphenyl)methylamino]- bicyclo[2.2.1]heptace, (lSR,2SR,3SR,4RS)-l-aza-2-diphenylmethyl-3-[(2-methoxy-5- (l,l-dimethylethyl)phenyl)methylamino]bicyclo[2.2.1]heptane, (1SR,2SR,3SR,4RS)-1- aza-2-diphenylmethyl-3-[(2-methoxy-5-trifluoromethoxyphenyl)methylamino]bi- cyclo[2.2.1]heptane and the like; the fluoroalkoxybenzylamino derivatives of nitrogen containing heterocycles of World Patent Application No. WO 93/000331, e.g., (2S,3S)-2-phenyl-3-[2-(2,2,2-trifluoroethoxy)-benzyl]aminopiperidine, 2-(di- pheny lmethy l)-N-((2-difluoromethoxy)pheny l)methy 1- 1 -azabicy clo [2.2.2] octan-3 -amine , (2S,3S)-N-(2-methoxy-5-trifluoromethoxy-phenyl)methyl-2-diphenylmethyl-l- azabicyclo[2.2.2]octane-3-amine and the like; the fused tricyclics of World Patent Application No. WO 93/01159, e.g., l-(5H-dibe_ιzo[a,d]cyclohepten-5-y_)-2-(3,5- dimethylbenzyloxy)ethylamine, N-acetamido-l-(5H-dibenzo[a,d]cyclohepten-5-yl)-2- (3,5-dimethylbenzyloxy)ethylamine, 1-(10, 1 l-dihydro-5H-dibenzo[a,d]cyclohepten-5- yl)-2-(3,5-dimethylbenzyloxy)ethylamine and the like; the aromatic compounds of World Patent Application No. WO 93/01160, e.g., 2-ammonium-l-((3,5-dimethyl- phenyl)methyloxy)-3,3-diphenylpropane, 2-dimethylammonium-l-((3,5-dimethyl- phenyl)methyloxy)-3 ,3-diphenylpropane, 2-t-butoxycarbonylamino-3 ,3-diphenyl- propanoyl-(2-methoxyphenyl)methylamide and the like; the aromatic compounds of World Patent Application No. WO 93/01165, e.g., L-l-((3,5-bis(trifluoromethyl)- phenyl)methyloxy)-2-(t-butoxycarbonylamino)-2-phenylethane, 1 -((3 ,5-dimethyl- phenyl)methyloxy)-2(S)-2-(((carbomethoxy)methyl)amino)-2-phenylethane, (2S)-2- (((carboxamido)methyl)aπ_monium)-l-((3,5-dimethylphenyl)methyloxy)-2-phenylethane and the like; the aromatic compounds of World Patent Application No. WO 93/01169, e.g., 3,5-dimethylbenzyl 2-(l,l-dimethylethoxycarbonylaπώιo)-3-(3-indolyl)propionate, 3,5-dimethylbenzyl 2-acetamido-3-(3-indolyl)propionate; 3,5-dimethylbenzyl 2- cyclohexanecarboxamido-3-(3-indolyl)propionate and the like; the 3-aminopiperidines
of World Patent Application No. WO 93/01170, e.g., (2S,3S)-3-(4,5-difluoro-2- methoxybenzyl)amino-2-phenylpiperidine, (2S,3S)-3-(2-cyclopentyl-oxy-5- methoxybenzyl)amino-2-phenylpiperidine, (2S,3S)-3-(5-sec-butyl-2-methoxy- benzyl)amino-2-phenylpiperidine and the like; the fused tricyclic nitrogen containing heterocycles of World Patent Application No. WO 93/06099, e.g., (± tis-9- diphenylmethyl-N-((2-methoxyphenyl)methyl)- 10-azatricyclo[4.4.1. O^Jundecan-δ- amine , (+)-cis-9-diphenylmethyl-N-(2-methoxy-5-chlorophenyl)- 10-azatricyclo- [4.4.1.C^undecan-δ-amine, ( + )-cis-9-diphenylmethyl-N-(2-trifiuoromethoxypheny D- 10-azatricyclo[4.4.1.05,7]undecan-8-amine and the like; the acyclic ethylenediamines of World Patent Application No. WO 93/10073, e.g., l-amino-l-phenyl-2-[(2-methoxy)- phenylmethylamino]propane, (lR\2S -l-cyclohexylaπ_ino-l-phenyl-2-[(2-met_ιoxy)- pheny lmethy lamino] propane , 1 -N-cy clohexy 1- 1 -pheny 1-2-N ' - [(2-methoxy-5 -tr ifluoro- methoxyphenyl)methyl]-l,2-ethanediamine and the like; the piperidines of World Patent Application No. WO 93/14084, e.g., l-[2-(5-fluoro-lH-indol-3-yl)ethyl]-4-[((2- methyl)phenylsulfιnyl)methyl]-4-piperidinol, l-[2-(5-fluoro-lH-indol-3-yl)ethyl]-4-[((4- methyl)pheny lsulfiny l)methy 1] -4-piper idinol , 1 - [2-(5-fluor o- 1 H-indol-3 -y l)ethy 1] -4- [(phenylsulfιnyl)methyl]-4-piperidinol and the like; the quinuclidines of World Patent Application No. WO 93/19064, e.g., (3R,4S,5S,6S)-N-carbamoylmethyl-5-(5-iso- propy 1-2-methoxybenzy l-amino)-6-dipheny lmethy 1- 1 -azabicy clo [2.2.2] octane-3 - carboxamide, (3R,4S,5S,6S)-N-carboxymethyl-5-(5-isopropyl-2-methoxybenzylamino)- 6-diphenylmethyl- 1 -azabicyclo[2.2.2] octane-3 -carboxamide , (3R,4S ,5S , 6S)-3-(2- carbamoylpyrrolidin-l-yl)carbonyl-5-(5-isopropyl-2-methoxybenzyl_ιmino)-6- diphenylmethyl-l-azabicyclo[2.2.2]octane and the like; the perhydroisoindoles of World Patent Application No. WO 93/21155, e.g., diphenyl-7,7 (methoxy-2 phenyl)- 4[(methoxy-2 phenyl)-2 propionyl]-2 perhydroisoindolol-4, diphenyl-7,7 (methoxy-2 phenyl)-4 [(methoxy-2 phenyl)-2 propionyl]-2 perhydroisoindolediol-4,5, diphenyl-7,7 (methoxy -2 pheny l)-4 [(hydroxy-2 phenyl)-2 acetyl] -2 perhydroisoindolol-4 and the
like; the substituted benzylamino nitrogen containing non-aromatic heterocycles of World Patent Application No. WO 94/04496, e.g., (2S,3S)-N-(2-methoxy-5-methyl- sulfony lpheny l)-methy 1-2-dipheny lmethy 1- 1 -azabicy clo [2.2.2] octan-3 -amine , (2S , 3 S)-N- (2-methoxy-5-methylthiopheny l)methyl-2-dipheny lmethyl- 1 -azabicyclo[2.2.2] octan-3- amine, (2S,3S)-N-(2-methoxy-5-dimethylaminophenyl)methyl-2-diphenylmethyl-l- azabicyclo[2.2.2]octan-3-amine and the like; the substituted benzylaminoquinuclidines of World Patent Application No. WO 94/08997, e.g., (2S,3S)-N-(5-isopropenyl-2- methoxypheny l)methy 1-2-dipheny lmethy 1- 1 -azabicy clo [2,2.2] octan-3 -amine , (2S , 3 S)-N- (2-methoxy-5-viny lpheny l)methyl-2-dipheny lmethy 1- 1 -azabicy clo [2,2.2] octan-3 -amine , (2S,3S)-N-(2-methoxy-4,5-dimethylphenyl)methyl-2-diphenylmethyl-l- azabicyclo[2.2.2]octan-3-amine and the like; the N-benzoyl-4-oxy/thio-2-substituted piperidines of World Patent Application No. 95/11895, e.g., (2R*,4S*)-2-benzyl-l- (3,5-bistrifluoromethylbenzoyl)-4-(4-quinolylmethoxy)-piperidine, (2R*,4S*)-quinoline- 3-carboxylic acid [2-benzyl-l-(3 ,5-bistrifluoromethylbenzoyl)-piperidin-4-yl]ester, (2R*,4S*)-2-benzyl-l-(3,5-bistrifluoromethylbenzoyl)-4-(3-quinolylmethoxy)-piperidine and the like; the compounds of European Patent Application No. EP 327009, e.g., the compounds of Examples 1-5 and the like; the peptides of European Patent Application No. EP 333174, e.g., Boc-Gin-D-Trp(CHO)-Phe-Nmebzl, Boc-Thr-D-Trp(CHO)-Phe- NMeBzl, Boc-Glu(NMe2)-D-Trp(CHO)-Phe-NMeBzl and the like; the peptides of European Patent Application No. EP 336230, e.g., the compounds of Example 1-22 and the like; the peptides of European Patent Application No. EP 394989, e.g., the compounds of Examples 1-63 and the like; the aromatic amines of European Patent Application No. 428434, e.g., N[(benzyl-4-piperidinyl-l)-4(dichloro-3,4 phenyl)-2 butyl]-dichloro-2,4 benzamide, N[(benzyl-4 piperidinyl-l)-4(difluoro-3,4 phenyl)-2 butyl]-dichloro-2,4 benzamide, N[(benzyl-4 piperidinyl-l)-4(dichloro-3,4 phenyl)-2 butyl] fluoro-4 naphthalene- 1 carboxamide and the like; the isoindolones of European Patent Application No. EP 429366, e.g., diphenyl-7,7[dimethylamino-2 phenyl)-2
acetyl]-2 perhydroisoindolone-4, diphenyl-7,7[methoxy-2 phenyl)-2 propionyl-(R)]-2 perhydroisoindolone-4, [(5)-carboxy benzylimino-l (methoxy-2 phenyl)-2 ethyl]-2 diphenyl-7,7 perhydroisoindolone-4 and the like; the peptides of European Patent Application No. EP 443132, e.g., the compounds of Examples 1-9 and the like; the azabicyclics of European Patent Application No. EP 499313, e.g., trans-3-[3,5- bis(trifluoromethy l)benzyloxy] -2-(dipheny lmethy 1)- 1 -azabicy clo [2.2.2] octane , trans-3- [3 ,5-dimethoxybenzy loxy] -2-(dipheny lmethy 1)- 1 -azabicy clo [2.2.2] octane , trans-2- (diphenylmethyl)-3-(3-phenoxybenzyloxy)-l-azabicyclo[2.2.2]octane and the like; the polycyclic amines of European Patent Application No. EP 512901, e.g., chlorhydrate of 5-[2-(4-benzyl-l-piperidinyl)ethyl]-5-(3,4-dichlorophenyl)-l-benzyl-piperidinone, chlorohydrate of 3-[2-(4-benzyl-l-piperidinyl)ethyl]-3-(3 ,4-dichlorophenyl)-l- phenylacetylpiperidine, chlorohydrate of 3-[2-(4-benzyl-l-piperidinyl)ethyl]-3-(3,4- dichlorophenyl)-l-(3-isopropoxyphenyl)acetylazepine and the like; the dialkylenepiperidinos of European Patent Application No. EP 512902, e.g., chlorohydrate of N-[{4-[l-benzyl-piperidin-4-yl]-2-(3,4-dichlorophenyl)}-butyl]-4- fluoronaphtalenecarboxamide, chlorohydrate of N-[{2-(3,4-dichlorophenyl)-4-[l-(4- fluorobenzyl)-piperidin-4-yl]}-butyl]-2,4-dichlorobenzamide, chlorohydrate of N- methyl-N-{{4-[l-benzyl-piperidine-4-yl]-2-(3,4-dichlorophenyl)}-butyl]-3- isopropoxyphenylacetamide and the like; the perhydroisoindoles of European Patent Application No. EP 514273, e.g., {{ [(pyrrolidinyl- 1)-3 propoxy-2]phenyl}acetyl-2 diphenyl-4,4 fluoro-7 perhydroisoindole, diphenyl-4,4 fluoro-7 [(methoxy-2 phenyl)-2 propionyl-(S)]-2 perhydroisoindole, [(dimethylamino-3 propoxy)-2 phenyl] acety 1-2 diphenyl-4,4 fluoro-7 perhydroisoindole and the like; the thiopyranipyrroles of European Patent Application No. EP 514275, e.g., {[(dimethylamino-3 propoxy-2) phenyl]acetyl)-6 diphenyl-4,4-oxyde-l perhydrothiopyrano[2,3-c]pyrrole, {[(pyrrolidinyl-l)-3 propoxy-2] phenyl} acetyl}-6 diphenyl-4,4 oxyde-1 perhydrothiopyrano[2,3-c]pyrrole, [{methoxy-2 phenyl)-2 propionyl-(S)]-6 diphenyl-
4,4 oxyde-1 perhydrothiopyrano[2,3-c]pyrrole and the like; the azabicyclics of European Patent Application No. EP 520555, e.g., 3-[(3,5-dimethylphenyl)methoxy]-2- (l,2-diphenylethyl)_-l-azabicyclo[2.2.2]octane, 3-[(3,5- bistrifluoromethy lpheny l)methoxy] -2-( 1 , 2-diphenylethy 1)- 1 -azabicy clo [2.2.2] octane , 3 - [(3,5-bistrifluoromethylphenyl)methyloxy]-2-[l-(l-(4-methoxyphenyl)-2-phenyl)ethyl]- l-azabicyclo[2.2.2]octane and the like; the aromatic compounds of European Patent Application No. EP 522808, e.g., 2-ammonium-3,3-diphenylpropanoyl-(2- methoxyphenyl)methylamide, (3 ,5-dimethyl-phenyl)methyl-2-ammonium-3 ,3- diphenylpropanoate, 2-methylammonium-l-((3,5-dimethylphenyl)methyloxy)-3,3- diphenylpropane and the like; the azacyclics of European Patent Application No. EP 528495 , e. g. , cis-2-(diphenylmethyl-3-(3 ,5-dimethylbenzyloxy)- 1 -methy lpyrrolidine, cis-3-((3 ,5-dimethylphenyl)methyloxy)-2-phenylpiperidine, cis-3-((3 ,5- dimethylphenyl)methyloxy-l-methyl-2-phenylpiperidine and the like; the 1- acylpiperidins of European Patent Application No. EP 532456, e.g., (2R*,4S*)-2- benzyl- l-(2-naphthoyl)-N-(4-chinoly lmethy l)-4-piperidinamin, (2R*,4S*)-2-benzyl-l-(3- trifluoromethylbenzoyl)-N-(4-chinolylmethyl)-4-piperidinamin, (2R*,4S*)-2-benzyl-l- (3,5-bis-(trifluoromethyl)-benzoyl)-N-(4-chinolylmethyl)-4-piperidinamin and the like; and the peptides of GB 2216529, e.g., cyclo(Gln-Trρ-Phe-(R)Gly[ANC-2]Leu-Met, cyclo(Gln-Npa-Phe-(R)Gly[ANC-2]Leu-Met, cyclo(Gln-Trp-Phe-Gly-Leu-Met and the like.
Among the nontoxic substances that block the NMDA receptor and as such are useful for enhancing the analgesic activity of a substance P receptor antagonist in accordance with this invention are dextromethorphan ((+)-3-hydroxy-N- methylmorphinan) and its metabolite dextrorphan ((+)-3-hydroxy-N- methy Imorphinan), their mixtures and their pharmaceutically acceptable salts. Other useful nontoxic substances that block the NMDA receptor include amantadine (1- aminoadamantine), memantine (3,5-dimethylaminoadamantone), pyrroloquinoline
quinone and cis-4-(phosphonomethyl)-2-piperid_necarboxylic acid. Of the nontoxic NMDA receptor antagonists, dextromethorphan in the form of its hydrobromide salt is preferred for use herein due to its ready availability and its established use in over-the- counter medications where it functions as a cough suppressant. While dextrorphan and its pharmaceutically acceptable salts will also provide excellent results, it is not known to be in commercial manufacture at this time.
In addition to, or in place of, a blocker for the NMDA receptor, at least one nontoxic substance that blocks a major intracellular consequence of NMDA receptor activation can also be used. Activation of the NMDA receptor, a subtype of excitatory amino acid receptors, induces a number of changes in the functional activity of nerve cells and, in particular, their capacity for excitability or inhibition in the presence of an addictive substance via an increase in intracellular Ca+ -I- concentration. The major consequences of NMDA receptor activation include the following sequences, or cascades, of events occurring within nerve cells: a) translocation and activation of protein kinases such as protein kinase C - phosphorylation of substrate proteins such as cytosolic enzymes, channel proteins, receptor proteins, etc. → changes in functional activity; b) initiation of early gene (c-fos, c-jun, zif-26$, etc.) expression by either increased intracellular Ca+ + or Ca+ + -activated protein kinases - expression of functional genes responsible for production of cellular enzymes (such as protein kinases), receptor proteins (such as the NMDA receptor), ion channel proteins (such as K+ , Na+ , Ca+ + channels), neuropeptides (such as dynorphin), etc. - changes in functional activity; c) Ca+ +/calmodulin (or other Ca+ + binding proteins) induced activation of enzymes and other cellular components - activation of
Ca+ +/calmodulin-protein kinase systems such as Ca+ +/calmodulin kinase II -
autophosphorylation of enzymes (e.g., Ca-f- +/calmodulin kinase II) or other functional proteins - changes in functional activity; d) Ca+ +/calmodulin induced activation of constitutive nitric oxide synthase as well as induction of inducible nitric oxide synthase - production of nitric oxide → i) production of cyclic guanosine monophosphate via activation of guanosine cyclase resulting in activation of protein kinases and early gene expression; ii) direct protein modification such as enzymes, receptor and/or channel proteins; iii) lipid membrane modification and/or nucleic acid modification via scavenge of free radicals; iv) induction of neurotoxicity at higher nitric oxide levels; v) retrograde actions in adjacent neurons or glial cells such as facilitation of glutamate release/NMD A receptor activation and/or inhibition of post-synaptic NMDA receptors → changes in functional activity; e) interactions with the cyclic adenosine monophosphate/protein kinase A system, the phospholipase C-inositol triphosphate-Ca-r- +/diacylglycerol- protein kinase system, the phospholipase A2-arachidonic acid/prostanoids/ leukotrienes system - changes in functional activity induced by second messenger systems other than NMDA receptor/Ca+ +/Ca+ +-calmodulin/protein kinase systems; and, f) interactions with other excitatory amino acid receptor subtypes including non-NMDA receptors and metabotropic receptors as well as intracellular events subsequent to the activation of these excitatory amino acid receptor subtypes - changes in functional activity induced by the non-NMDA and metabotropic receptor activation.
A substance that blocks the NMDA receptor will effectively prevent all of the foregoing major intracellular sequences of events from taking place. However, even with activation of the NMDA receptor, it is still possible to alleviate pain in accordance with this invention by administering the substance P receptor antagonist and a nontoxic substance that blocks at least one of the foregoing major intra-cellular
sequences of events brought about by activation of the NMDA receptor. Thus, e.g. , a substance that interferes with translocation and activation of protein kinase C or with calmodulin induced activation of constitutive nitric oxide synthase as well as induction of inducible nitric oxide synthase is also useful for the practice of this invention. Nontoxic substances that block a major intracellular consequence of
NMDA receptor activation and are therefore useful in the practice of the invention include inhibitors of protein kinase C, e.g., gangliosides such as ganglioside GM! (monosialoganglios.de) and ganglioside GTb (trisialoganglioside); amphipathic long chain bases such as sphingosine, N,N,N-trimethylsphingosine, sphinganine and psychosine; quinolyloxazole-2-ones such as 4-methyl-5-(3-quinolinyl)-2-(3H)-oxazolone and phenyl-5-(2-quinolinyl)-2-3(3H)-oxazolone; 1 ,4-bis-(amino-hydroxyalkylamino)- anthraquinones such as l,4-bis-(3-propylamino-2-hydroxypropylamino)-9,10 anthracenedione and 1 ,4-bis-(3-benzylamino-2-hydroxypropylamino)-9, 10 anthracenedione; and, mixtures and pharmaceutically acceptable salts of any of the foregoing.
Additional nontoxic substances that block a major intracellular consequence of NMDA receptor activation and as such are useful in the practice of the invention include inhibitors of calmodulin such as the phenothiazines, in particular, chlorpromazine, chlorpromazine sulfoxide, prochlorperazine dimaleate, perphenazine, trifluoperazine, fluphenazine, fluphenazine enanthate, fluphenazine decanoate, thioridazine, mesoridazine besylate, piperacetazine, acetophenazine dimaleate, carphenazine dimaleate, butaperazine dimaleate and phenothiazine sulfoxide; naphthalenesulfonamides such as N-(6-aminohexyl)-5-chloro-l-naphthalenesulfonamide, N-(6-aminohexyl)-5-chloro-2-naphthalenesulfonamide and N-(6-aminohexyl)-5-bromo- 2-naphthalenesulfonamide ; 4-substituted-4H , 6H-pyrrolo [ 1 , 2-a] [4,1] benzoxazepines such as l,3-dihydro-l-{l-[(4-methyl-4H,6H-pyrrolo[l,2-a][4,l] benzoxazepin-4- yl)methyl]-4-piperidinyl}-2H-benzimidazol-2-one; benzhydryls such as N-
[2](diphenylmethylthioethyl]-2-(trifluoromethyl)-benzeneethanamine, N-[2-(bis(4- fluorophenyl)methylthio)- ethyl]-2-(trifluoromethyl)benzeneethanamine and N-[2-(bis(4- fluorophenyl)methylthio)ethyl]-3-(trifluoromemyl)beιιzene-ethanamine; tricyclic antidepressant drugs such as imipramine, 2-chloroimipramine and amitriptyline; penfluridol; haloperidol; pimozide; clozapine; calmidazolin; and, mixtures and pharmaceutically acceptable salts of any of the foregoing.
Of the two groups of substance P receptor antagonist potentiators the nontoxic NMDA receptor antagonists are preferred and of these, dextromethorphan is preferred for the reasons previously stated. With regard to dosage levels, the substance P receptor antagonist must be present in an analgesically effective amount, e.g., at a level corresponding to the generally recommended adult human dosages for a particular substance P receptor antagonist, and the nontoxic NMDA receptor antagonist or substance that blocks a major intracellular consequence of NMDA activation must be present at a level that potentiates the therapeutic effectiveness of the substance P receptor antagonist. Given the wide variations in dosage level of the substance P receptor antagonist which depends to a large extent on the specific substance P receptor antagonist being administered, there can similarly be a wide variation in the dosage level of the nontoxic NMDA receptor antagonist or substance that blocks a major intracellular consequence of NMDA receptor activation. These amounts can be determined for a particular drug combination in accordance with this invention employing routine experimental testing. While the substance P receptor antagonist and nontoxic NMDA receptor antagonist and/or substance that blocks a major intracellular consequence of NMDA receptor activation need not be administered together, they must both be present in the patient at effective levels at the same time. While it is within the scope of the invention to administer the substance P receptor antagonist and nontoxic NMDA receptor antagonist and/or substance that blocks a major intracellular consequence of NMDA
receptor activation separately, as a matter of convenience, it is preferred that they be coadministered as a single analgesic composition. All modes of administrations are contemplated, e.g. ^orally, rectally, parenterally, topically, or by intravenous, intramuscular, intrastemal or subcutaneous injection or in a form suitable by inhalation. The formulations may, where appropriate, be conveniently presented in discrete dosage units and may be prepared by any of the methods well known in the art of pharmacy.
An analgesic composition containing the substance P receptor antagonist and nontoxic NMDA receptor antagonist and/or substance that blocks a major intracellular consequence of NMDA receptor activation will ordinarily be formulated with one or more pharmaceutically acceptable ingredients in accordance with known and established practice. Thus, the analgesic composition can be formulated as a liquid, powder, elixir, injectable solution, etc. Formulations for oral use can be provided as tablets or hard capsules wherein the pharmacologically active ingredients are mixed with an inert solid diluent such as calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredients are mixed with water or miscible solvents such as propylene glycol; PEG's and ethanol, or an oleaginous medium, e.g., peanut oil, liquid paraffin or olive oil.
For topical administration in the mouth, the analgesic composition herein can take the form of a buccal or sublingual tablet, drops or lozenges formulated in a known or conventional manner.
For topical administration, the analgesic composition of the invention can be formulated as a cream, gel, ointment or lotion or as a transdermal patch. Such composition can, for example, be formulated with an aqueous or oily base with the addition of suitable thickening, gelling, emulsifying, stabilizing, dispersing, suspending and/or coloring agents.
The analgesic composition of the invention can also be formulated as a sustained release preparation. Such long acting formulations can be administered by
implantation (for example subcutaneously or intramuscularly) or by intramuscular injection. Thus, for example, the analgesic composition can be formulated with suitable polymeric or hydrophobic materials (for example, as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.
The analgesic composition of the invention can be formulated for parenteral administration by injection, conveniently intravenous, intramuscular or subcutaneous injection, for example, by bolus injection or continuous intravenous infusion. Formulations for injection can be presented in unit dosage, e.g., in ampoules or in multi-dose containers, with an added preservative. The analgesic composition can take a variety of forms such as a suspension, solution or emulsion in an oily or aqueous vehicle and can contain one or more formulatory agents such as suspending, stabilizing and/or dispersing agents. Alternatively, the analgesic composition can be provided in powder form for dissolution in a suitable vehicle, e.g. sterile pyrogen-free water, before administration.
The analgesic composition of the invention can also be formulated as a rectal composition, e.g., a suppository or retention enema containing conventional suppository bases such as cocoa butter or other glyceride(s).
For administration by inhalation, the analgesic composition is conveniently delivered in the form of an aerosol spray by means of a pressurized container or a nebulizer employing a suitable propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, tetrafluoro- ethane, heptafluoropropane, carbon dioxide, and the like. In the case of a pressurized aerosol delivery system, the dosage unit can be regulated by means of a metering valve.
Aqueous suspensions can include pharmaceutically acceptable excipients such as suspending agents, e.g., sodium carboxymethyl cellulose, methy lcellulose,
hy droxypropy lmethy lcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents such as naturally occurring phosphatide, e.g., lecithin, or condensation products of an alkylene oxide with fatty acids, e.g., polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, e.g, heptadecaethylene-oxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol, e.g., polyoxyethylene sorbitol monoleate or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, e.g., polyoxyethylene sorbitan monoleate. The aqueous suspensions can also contain one or more preservatives, e.g., ethyl-or-n-propyl-p-hydroxy benzoate, one or more coloring agents, one or more flavoring agents and one or more sweetening agents, such as sucrose, saccharin or sodium or calcium cyclamate.
In addition to the substance P receptor antagonist and nontoxic NMDA receptor antagonist and/or substance that blocks a major intracellular consequence of NMDA receptor activation, the analgesic composition herein can contain at least one other pharmacologically active substance, e.g., a non-narcotic analgesic such as tramadol, acetaminophen, aspirin, diclofenac, diflusinal, etodolac, fenbufen, fenoprofen, flufenisal, flurbiprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, meclofenamic acid, mefenamic acid, nabumetone, naproxen, oxaprozin, phenylbutazone, piroxicam, sulindac, tolmetin, zomepirac, and die like, or a narcotic analgesic such as codeine, oxycodone, dihydrocodeine, hydrocodone, levorphanol, morphine, and the like.
EXAMPLES 1-35 The following unit dosage forms are illustrative of the therapeutic drug combinations in accordance with the present invention:
Nontoxic NMDA Receptor Additional Active
Example Substance P Receptor Antagonist (mg . Blocker (mg . Component (mg) 1 pyroglutamyl-phenylalanyl-N-methyl- dextromethorphan pheny lalanyl-[(R)-3-amino-2-oxo- 1 - hydrobromide (30) pyrrolidine-(S)-4-methyl-2-pentanoyl] methionine amide (25) [U.S. Patent No. 4,680,283] pyroglutamyl-phenylalanyl-N-methyl- dextromethorphan acetaminophen (325) phenylalanyl-[(R)-3-amino-2-oxo-l- hydrobromide (30) pyrrolidine-(S)-4-methyl-2-pentanoyl] methionine amide (25) [U.S. Patent No. 4,680,283] pyroglutamyl-phenylalanyl-N-methyl- dextrorphan phenylalanyl-[(R)-3-amino-2-oxo- 1 - hydrobromide (30) pyrrolidine-(S)-4-methyl-2-pentanoyl] methionine amide (25) [U.S. Patent No. 4,680,283]
Nontoxic NMDA Receptor Additional Active
Example Substance P Receptor Antagonist (mg. Blw er (mg) Component (mg) 4 2-[l-imino-2-(2-methoxyρhenyl)ethyl]-7,7- dextromethorphan diphenyl-4-perhydroisoindolone in its hydrobromide (30) (3aR,3aR) or (3aR,7aRS) forms (25) [U.S. Patent No. 5,102,667] 5 2-[l-imino-2-(2-methoxyphenyl)ethyl]-7,7- dextromethorphan ibuprofen (200) diphenyl-4-perhydroisoindolone in its hydrobromide (30) (3aR,3aR) or (3aR,7aRS) forms (25) [U.S. Patent No. 5,102,667] 6 2-[l-imino-2-(2-methoxyphenyl)ethyl]-7,7- dextrorphan diphenyl-4-perhydroisoindolone in its hydrobromide (30) (3aR,3aR) or (3aR,7aRS) forms (25) [U.S. Patent No. 5,102,667] 7 2-[l-imino-2-(2-methoxyphenyl)ethyI]-7,7- amantadine (30) diphenyl-4-perhydroisoindolone in its (3aR,3aR) or (3aR,7aRS) forms (25) [U.S. Patent No. 5,102,667] 8 2-[l-imino-2-(2-methoxyphenyl)ethyl]-7,7- memantine (30) diphenyl-4-perhydroisoindolone in its (3aR,3aR) or (3aR,7aRS) forms (25) [U.S. Patent No. 5,102,667] 9 cis-3-[(2-chlorophenyl)methylamino]-2- dextromethorphan benzhydrylquinuclidine (25) hydrobromide (30) [U.S. Patent No. 5,162,339]
10 cis-3-[(2-chlorophenyl)methylamino]-2- dextromethorphan acetaminophen (325) benzhydrylquinuclidine (25) hydrobromide (30)
[U.S. Patent No. 5,162,339]
11 cis-3-[(2-chlorophenyl)methylamino]-2- dextrorphan benzhydrylquinuclidine (25) hydrobromide (30)
[U.S. Patent No. 5,162,339]
12 cis-3-[(2-chlorophenyl)methylamino]-2- amantadine (30) benzhydrylquinuclidine (25)
[U.S. Patent No. 5,162,339]
13 cis-3-[(2-chlorophenyl)methylamino]-2- memantine (30) benzhydrylquinuclidine (25)
[U.S. Patent No. 5,162,339]
Nontoxic NMDA Receptor Additional Active
Example Substance P receptor antagonist (mg . Blocker (mg. Component (mg.
14 7-[(lS)-(l-meth xycarbonyl)-3-methylbutyl]- dextromethorphan 6-oxo-(5S)-l,7-diazaspiro[4.4]nonane-l- hydrobromide (30) carboxylic acid, phenylmethyl ester (25) [U.S. Patent No. 5, 166,136]
15 7-[(lS)-(l-methoxycarbonyl)-3-methylbutyI]- dextromethorphan acetaminophen (325) 6-oxo-(5S)-l,7-diazaspiro[4.4]nonaπe-l- hydrobromide (30) carboxylic acid, phenylmethyl ester (25) [U.S. Patent No. 5,166,136]
16 7-[(lS)-(l-methoxycarbonyl)-3-methylbutyl]- dextrorphan 6-oxo-(5S)-l ,7-diazaspiro[4.4]nonane-l- hydrobromide (30) carboxylic acid, phenylmethyl ester (25) [U.S. Patent No. 5, 166,136]
17 7-[( 1 S)-( 1 -methoxycarbonyl)-3-methy lbutyl]- amantadine (30) 6-oxo-(5S)-l,7-diazaspiro[4.4]nonane-l- carboxylic acid, phenylmethyl ester (25) [U.S. Patent No. 5, 166,136]
18 7- [( 1 S)-( 1 -methoxycarbony l)-3-methy lbutyl]- memantine (30) 6-oxo-(5S)-l,7-diazaspiro[4.4]nonane-l- carboxylic acid, phenylmethyl ester (25) [U.S. Patent No. 5, 166,136]
19 cis-3-(2-methoxybenzylamino)-2- dextromethorphan phenylpiperidine (25) hydrobromide (30)
[U.S. Patent No. 5,232,929] 20 cis-3-(2-methoxyber__ylamino)-2- dextromethorphan aspirin (325) phenylpiperidine (25) hydrobromide (30) [U.S. Patent No. 5,232,929]
21 cis-3-(2-methoxybenzylamino)-2- dextrorphan phenylpiperidine (25) hydrobromide (30) [U.S. Patent No. 5,232,929]
22 cis-3-(2-methoxybenzylamino)-2- amantadine (30) phenylpiperidine (25) [U.S. Patent No. 5,232,929]
23 cis-3-(2-methoxybe___ylamino)-2- memantine (30) phenylpiperidine (25) [U.S. Patent No. 5,232,929]
24 N-[4-[l-(fluorobenzyl)-4-piperidinyl]-2- dextromethorphan (3,4-dichlorophenyl)-butyl]-2,4- hydrobromide (30) dichlorobenzamide hydrochloride (25) [U.S. Patent No. 5,300,648 and 5,446,052]
Nontoxic NMDA Receptor Additional Active
Example Substance P receptor antagonist (mg. Blocker (mg. Component (m .
25 N-[4-[l-(fluoro6enzyl)-4-piperidinyl]-2- dextromethorphan acetaminophen (325) (3,4-dichlorophenyl)-butyl]-2,4- hydrobromide (30) dichlorobenzamide hydrochloride (25) [U.S. Patent No. 5,300,648 and 5,446,052]
26 N-[4-[l-(fluorobenzyl)-4-piperidinyl]-2- dextrorphan (3,4-dichlorophenyl)-butyl]-2,4- hydrobromide (30) dichlorobenzamide hydrochloride (25) [U.S. Patent No. 5,300,648 and 5,446,052]
27 N-[4-[l-(fluorobenzyl)-4-piperidinyl]-2- amantadine (30) (3,4-dichlorophenyl)-butyl]-2,4- dichlorobenzamide hydrochloride (25) [U.S. Patent No. 5,300,648 and 5,446,052]
28 N-[4-[l-(fluorobenzyl)-4-piperidinyl]-2- memantine (30) (3,4-dichlorophenyl)-butyl]-2,4- dichlorobenzamide hydrochloride (25) [U.S. Patent No. 5,300,648 and 5,446,052]
29 3-[2-(4-Benzy lpiperidin- 1 -y l)ethyl]-3- dextromethorphan (3,4-dichlorophenyl)-l-phenylacetyl- hydrobromide (30) piperidine hydrochloride (25) [U.S. Patent No. 5,340,822]
30 3-[2-(4-Benzylpiperidin-l-yl)ethyl]-3- dextromethorphan ibuprofen (200) (3 ,4-dichloropheny 1)- 1 -phenylacetyl- hydrobromide (30) piperidine hydrochloride (25)
[U.S. Patent No. 5,340,822]
31 3-[2-(4-Benzylpiperidin- 1 -y l)ethyl]-3- dextrorphan (3,4-dichlorophenyI)-l-phenylacetyl- hydrobromide (30) piperidine hydrochloride (25)
[U.S. Patent No. 5,340,822]
32 N-[4-(4-N'-Acetylanilino-l-piperidinyl)- dextromethorphan 2-(3,4-dichlorophenyl)butyl]-N- hydrobromide (30) methylbenzamide (25) [U.S. Patent No. 5,411,971]
33 8-(diphenylmethyl)-N-((2-methoxyphenyl) dextromethorphan methyl))-9-azatricyclo[4.3.1.04 9] hydrobromide (30) decan-7-amine (25) [U.S. Patent No. 5,422,354]
Nontoxic NMDA Receptor Additional Active
Example Substance P receptor antagonist (mg . Blocker (m . Component .mg) 34 trans-2-phenyl-N-(2-methoxyphenyl) dextromethorphan methyl)-l-azabicyclo[2.2.2]octan-3- hydrobromide (30) amine (25) [U.S. Patent No. 5,451,586] 35 {l-[4-(lH-tetrazol-5-yl)butyl]indol-3-yl} dextromethorphan carbonyl-Hyp-Thn-Nmebzl (25) hydrobromide (30) [U.S. Patent No. 5,561,113]
In each of these dosage units, the nontoxic NMDA receptor antagonist dextromethorphan hydrobromide significantly potentiates the analgesic activity of the substance P receptor antagonist.