Pharmaceutical compositions for the treatment of pain

A composition for treating pain in a patient, the composition comprising:

• (i) a nicotinic acetylcholine receptor ligand;
• and
• (ii) a nicotinic acetylcholine receptor subtype α4β2 positive allosteric modulator in admixture with at least one pharmaceutically acceptable excipient, wherein the nicotinic acetylcholine receptor subtype α4β2 positive allosteric modulator is selected from the group consisting of:
• 5-(2,3-difluorophenyl)-3-(pyrimidin-5-yl)-1,2,4-oxadiazole;
• 5-(pyridin-3-yl)-3-(pyrimidin-5-yl)-1,2,4-oxadiazole;
• 2-fluoro-N,N-dimethyl-4-(3-(pyrimidin-5-yl)-1,2,4-oxadiazol-5-yl)aniline;
• 3-(3-(pyrimidin-5-yl)-1,2,4-oxadiazol-5-yl)benzonitrile;
• 5-(3,4-difluorophenyl)-3-(pyridazin-4-yl)-1,2,4-oxadiazole;
• 3-(pyridazin-4-yl)-5-(pyridin-3-yl)-1,2,4-oxadiazole;
• N,N-dimethyl-N′-(4-(3-(pyrimidin-5-yl)-1,2,4-oxadiazol-5-yl)phenylsulfonyl)formimidamide;
• 5-(4-fluorophenyl)-3-(pyrimidin-5-yl)-1,2,4-oxadiazole;
• 5-(3-fluorophenyl)-3-(pyrimidin-5-yl)-1,2,4-oxadiazole;
• 3-(pyrimidin-5-yl)-5-(3,4,5-trifluorophenyl)-1,2,4-oxadiazole;
• 5-(2-chloropyridin-4-yl)-3-(pyrimidin-5-yl)-1,2,4-oxadiazole;
• 3-(Pyridin-3-yl)-5-(pyrimidin-5-yl)-1,2,4-oxadiazole;
• 5-(Pyridazin-4-yl)-3-(pyridin-3-yl)-1,2,4-oxadiazole;
• 3-(3-(pyridazin-4-yl)-1,2,4-oxadiazol-5-yl)benzonitrile;
• 5-(3-fluorophenyl)-3-(pyridazin-4-yl)-1,2,4-oxadiazole;
• 3-(pyridazin-4-yl)-5-(3,4,5-trifluorophenyl)-1,2,4-oxadiazole;
• 5-(3,5-difluorophenyl)-3-(pyridazin-4-yl)-1,2,4-oxadiazole;
• 5-(4-fluorophenyl)-3-(pyridazin-4-yl)-1,2,4-oxadiazole;
• 3-(pyridazin-4-yl)-5-(pyrimidin-5-yl)-1,2,4-oxadiazole;
• 3-(pyridazin-4-yl)-5-(2,3,6-trifluorophenyl)-1,2,4-oxadiazole;
• 3-(pyridazin-4-yl)-5-(2,3,4-trifluorophenyl)-1,2,4-oxadiazole;
• N,N-dimethyl-N′-(4-(3-(pyridazin-4-yl)-1,2,4-oxadiazol-5yl)phenylsulfonyl)formimidamide;
• 5-(3,4-difluorophenyl)-3-(pyrimidin-5-yl)-1,2,4-oxadiazole;
• 3-(3,4-difluorophenyl)-5-(pyrimidin-5-yl)-1,2,4-oxadiazole;
• 3-(pyrimidin-5-yl)-5-(2,3,4-trifluorophenyl)-1,2,4-oxadiazole;
• 3-(pyrimidin-5-yl)-5-(2,3,6-trifluorophenyl)-1,2,4-oxadiazole;
• 3-(pyrimidin-5-yl)-5-(2,3,4,5-tetrafluorophenyl)-1,2,4-oxadiazole;
• 5-(imidazo[1,5-a]pyridin-6-yl)-3-(pyridin-3-yl)-1,2,4-oxadiazole;
• 5-(1H-indol-6-yl)-3-(pyridin-3-yl)-1,2,4-oxadiazole;
• 5-(2,7-dimethylpyrazolo[1,5-a]pyrimidin-6-yl)-3-(pyridin-3-yl)-1,2,4-oxadiazole;
• 5-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-3-(pyridin-3-yl)-1,2,4-oxadiazole;
• 5-(2-methylbenzofuran-5-yl)-3-(pyridin-3-yl)-1,2,4-oxadiazole;
• 5-(benzo[d][1,2,3]thiadiazol-5-yl)-3-(pyridin-3-yl)-1,2,4-oxadiazole;
• 5-(1H-benzo[d]imidazol-5-yl)-3-(pyridin-3-yl)-1,2,4-oxadiazole;
• 5-(1H-benzo[d][1,2,3]triazol-5-yl)-3-(pyridin-3-yl)-1,2,4-oxadiazole;
• 5-(benzo[d]thiazol-5-yl)-3-(pyridin-3-yl)-1,2,4-oxadiazole;
• 3-(pyridin-3-yl)-5-(1H-pyrrolo[2,3-b]pyridin-5-yl)-1,2,4-oxadiazole;
• 5-(1H-indol-5-yl)-3-(pyridin-3-yl)-1,2,4-oxadiazole;
• 5-(benzofuran-5-yl)-3-(pyridin-3-yl)-1,2,4-oxadiazole;
• 5-(1-methyl-1H-benzo[d]imidazol-5-yl)-3-(pyridin-3-yl)-1,2,4-oxadiazole;
• 3-(imidazo[1,2-a]pyridin-6-yl)-5-(pyridin-3-yl)-1,2,4-oxadiazole;
• 5-(6-chloropyridin-3-yl)-3-(imidazo[1,2-a]pyridin-6-yl)-1,2,4-oxadiazole;
• 5-(6-fluoropyridin-3-yl)-3-(imidazo[1,2-a]pyridin-6-yl)-1,2,4-oxadiazole;
• 5-(5-fluoropyridin-3-yl)-3-(imidazo[1,2-a]pyridin-6-yl)-1,2,4-oxadiazole;
• 5-(1H-indazol-5-yl)-3-(pyridin-3-yl)-1,2,4-oxadiazole;
• 5-([1,2,4]triazolo[4,3-a]pyridin-6-yl)-3-(pyridin-3-yl)-1,2,4-oxadiazole;
• 5-(3-(pyridin-3-yl)-1,2,4-oxadiazol-5-yl)benzo[d]oxazol-2(3H)-one;
• 5-(3-(pyridin-3-yl)-1,2,4-oxadiazol-5-yl)-1H-benzo[d]imidazole-2(3H)-thione;
• 1,3-dimethyl-5-(3-(pyridin-3-yl)-1,2,4-oxadiazol-5-yl)-1H-benzo[d]imidazol-2(3H)-one;
• 6-(3-(pyridin-3-yl)-1,2,4-oxadiazol-5-yl)benzo[d]oxazol-2(3H)-one;
• 5-(3-(pyridin-3-yl)-1,2,4-oxadiazol-5-yl)-1H-benzo[d]imidazol-2(3H)-one;
• 6-(3-(Pyridin-3-yl)-1,2,4-oxadiazol-5-yl)benzo[d]oxazol-2-amine;
• 6-(3-(pyridin-3-yl)-1,2,4-oxadiazol-5-yl)benzo[d]oxazole;
• 5-(5-(pyridin-3-yl)-1,2,4-oxadiazol-3-yl)benzo[d]oxazol-2(3H)-one;
• 5-(5-(6-chloropyridin-3-yl)-1,2,4-oxadiazol-3-yl)benzo[d]oxazol-2(3H)-one;
• and
• 5-(benzo[d][1,3]dioxol-5-yl)-3-(pyridin-3-yl)-1,2,4-oxadiazole;
• or a pharmaceutically acceptable salt thereof.

An article of manufacture for the treatment of pain, comprising:

• (i) a first pharmaceutical dosage form comprising at least one nicotinic acetylcholine receptor ligand;
• and
• (ii) a second pharmaceutical dosage form comprising at least nicotinic acetylcholine receptor subtype α4β2 positive allosteric modulator;
• wherein the article contains first and second pharmaceutical dosage forms wherein the nicotinic acetylcholine receptor subtype α4β2 positive allosteric modulator is a compound of formula (II):
• or a pharmaceutically acceptable salt thereof, wherein:
• Ar2 is pyridazinyl, pyrimidinyl, triazinyl, or bicyclic heteroaryl,
• Ar3 is aryl, pyridazinyl, pyridinyl, pyrimidinyl, triazinyl, or bicyclic heteroaryl, and
• Ar2 and Ar3 are substituted independently with 0, 1, 2, 3, or 4 substituents independently selected from the group consisting of alkoxy, alkoxycarbonyl, alkoxycarbonylamino, alkoxycarbonylaminalkyl, alkyl, alkylamino, alkylcarbonyl, alkylslfonyl, amino, aminoalkyl, carboxy, dialkylamino, dialkylaminoalkyl, halo, haloalkyl, haloalkylcarbonyl, heteroaryl, heterocycle, hydroxyl, hydroxyalkyl, cyano, nitro, oxo, sulfonamide and dialkylsulfonylformimidamide.

A composition for treating pain in a patient, the composition comprising:

• (i) a nicotinic acetylcholine receptor ligand;
• and
• (ii) a nicotinic acetylcholine receptor subtype α4β2 positive allosteric modulator in admixture with at least one pharmaceutically acceptable excipient, wherein the nicotinic acetylcholine receptor subtype α4β2 positive allosteric modulator is a compound of formula (II):
• or a pharmaceutically acceptable salt thereof, wherein:
• Ar2 is aryl or pyridinyl,
• Ar3 is pyridazinyl, pyrimidinyl, triazinyl, or bicyclic heteroaryl, and
• Ar2 and Ar3 are substituted independently with 0, 1, 2, 3, or 4 substituents independently selected from the group consisting of alkoxy, alkoxycarbonyl, alkoxycarbonylamino, alkoxycarbonylaminalkyl, alkyl, alkylamino, alkylcarbonyl, alkylslfonyl, amino, aminoalkyl, carboxy, dialkylamino, dialkylaminoalkyl, halo, haloalkyl, haloalkylcarbonyl, heteroaryl, heterocycle, hydroxyl, hydroxyalkyl, cyano, nitro, oxo, sulfonamide and dialkylsulfonylformimidamide.

An article of manufacture for the treatment of pain, comprising:

• (i) a first pharmaceutical dosage form comprising at least one nicotinic acetylcholine receptor ligand;
• and
• (ii) a second pharmaceutical dosage form comprising at least nicotinic acetylcholine receptor subtype α4β2 positive allosteric modulator;
• wherein the article contains first and second pharmaceutical dosage forms wherein the nicotinic acetylcholine receptor subtype α4β2 positive allosteric modulator is a compound of formula (II):
• or a pharmaceutically acceptable salt thereof, wherein:
• Ar2 is aryl or pyridinyl,
• Ar3 is pyridazinyl, pyrimidinyl, triazinyl, or bicyclic heteroaryl, and
• Ar2 and Ar3 are substituted independently with 0, 1, 2, 3, or 4 substituents independently selected from the group consisting of alkoxy, alkoxycarbonyl, alkoxycarbonylamino, alkoxycarbonylaminalkyl, alkyl, alkylamino, alkylcarbonyl, alkylslfonyl, amino, aminoalkyl, carboxy, dialkylamino, dialkylaminoalkyl, halo, haloalkyl, haloalkylcarbonyl, heteroaryl, heterocycle, hydroxyl, hydroxyalkyl, cyano, nitro, oxo, sulfonamide and dialkylsulfonylformimidamide.