# US 9,040,568 B2 · Pharmaceutical compositions for the treatment of pain

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- Number: US 9,040,568 B2
- Document ID: US9040568B2
- Status: Granted
- Kind: B2
- Application number: 12/787,937
- Filed: 2010-05-26
- Published: 2010-12-02
- Granted: 2015-05-26
- Earliest claimed: 2009-05-29
- Assignees: AbbVie Inc.
- Applicants: Murali Gopalakrishnan; Chih-Hung Lee; Jianguo Ji; Tao Li; Kevin B. Sippy
- Inventors: Murali Gopalakrishnan; Chih-Hung Lee; Jianguo Ji; Tao Li; Kevin B. Sippy
- Web page: https://patentgrep.com/patent/US9040568B2

## CPC

- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61K 31/4245: Oxadiazoles
- A61K 31/4427: containing further heterocyclic ring systems
- A61P 9/10: for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
- A61P 19/02: for joint disorders, e.g. arthritis, arthrosis
- A61P 25/04: Centrally acting analgesics, e.g. opioids
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P 35/00: Antineoplastic agents
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

This invention discloses a method of treatment of osteoarthritis pain by administration of a composition containing a nicotinic acetylcholine receptor ligand and a nicotinic acetylcholine receptor subtype α4β2 allosteric modulator. The present application also relates to compositions comprising such compounds for use in treating pain and related disorders mediated by controlling neurotransmitter release in a subject.

## Claims

### Claim 1

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 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.

### Claim 2 (depends on 1)

The composition of claim 1, wherein the nicotinic acetylcholine receptor ligand is a nicotinic acetylcholine receptor subtype α4β2 ligand demonstrating a Ki value of about 0.001 nanomolar to about 100 micromolar, as measured by [3H]-cytisine binding assay (Ki Cyt).

### Claim 3 (depends on 1)

The composition of claim 1, wherein the nicotinic acetylcholine receptor ligand is a nicotinic acetylcholine receptor subtype α4β2 agonist or partial agonist.

### Claim 4 (depends on 1)

The composition of claim 1, wherein the nicotinic acetylcholine receptor ligand is a compound selected from:
5-[(2R)-azetidin-2-ylmethoxy]-2-chloropyridine;
(3R)-1-pyridin-3-ylpyrrolidin-3-amine;
2-methyl-3-(2-(S)-pyrrolidinylmethoxy)pyridine;
3-(5,6-dichloro-pyridin-3-yl)-1(S),5(S)-3,6-diazabicyclo[3.2.0]heptane; and
(R,R)-1-(pyridin-3-yl)octahydro-pyrrolo[3,4-b]pyrrole;
or is a pharmaceutically acceptable salt thereof.

### Claim 5

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.

### Claim 6 (depends on 1)

The composition of claim 1, further comprising an effective amount of at least one of a non-steroid anti-inflammatory agent and an opioid.

### Claim 7 (depends on 1)

A pharmaceutical composition comprising a therapeutically effective amount of a composition of claim 1 and a pharmaceutically acceptable carrier or excipient.

### Claim 8 (depends on 1)

A method for treating a mammalian subject suffering from a pain condition, the method comprising administering a therapeutically effective amount of the composition of claim 1, wherein the pain condition is nociceptive pain, neuropathic pain or a combination thereof.

### Claim 9 (depends on 8)

A method for treating a pain condition comprising administering a therapeutically effective amount of the composition of claim 8, wherein the nociceptive pain is selected from post-operative pain, osteoarthritis pain, rheumatoid arthritis pain, musculoskeletal pain, burn pain, ocular pain, pain due to inflammation and bone fracture.

### Claim 10

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.

### Claim 11

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.

### Claim 12 (depends on 11)

The composition of claim 11, wherein the nicotinic acetylcholine receptor ligand is a nicotinic acetylcholine receptor subtype α4β2 ligand demonstrating a Ki value of about 0.001 nanomolar to about 100 micromolar, as measured by [3H]-cytisine binding assay (Ki Cyt).

### Claim 13 (depends on 11)

The composition of claim 11, wherein the nicotinic acetylcholine receptor ligand is a nicotinic acetylcholine receptor subtype α4β2 agonist or partial agonist.

### Claim 14 (depends on 11)

The composition of claim 11, wherein the nicotinic acetylcholine receptor ligand is a compound selected from:
5-[(2R)-azetidin-2-ylmethoxy]-2-chloropyridine;
(3R)-1-pyridin-3-ylpyrrolidin-3-amine;
2-methyl-3-(2-(S)-pyrrolidinylmethoxy)pyridine;
3-(5,6-dichloro-pyridin-3-yl)-1(S),5(S)-3,6-diazabicyclo[3.2.0]heptane; and
(R,R)-1-(pyridin-3-yl)octahydro-pyrrolo[3,4-b]pyrrole;
or is a pharmaceutically acceptable salt thereof.

### Claim 15 (depends on 11)

The composition of claim 11, further comprising an effective amount of at least one of a non-steroid anti-inflammatory agent and an opioid.

### Claim 16 (depends on 11)

A pharmaceutical composition comprising a therapeutically effective amount of a composition of claim 11 and a pharmaceutically acceptable carrier or excipient.

### Claim 17

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.