Imidazolo-, oxazolo-, and thiazolopyrimidine modulators of TRPV1

• US 9,440,978 B2
• Filed: 12/19/2013
• Issued: 09/13/2016
• Est. Priority Date: 12/17/2007
• Status: Active Grant

• Current Assignee: Janssen Pharmaceutica NV (Johnson & Johnson)
• Original Assignee: Janssen Pharmaceutica NV (Johnson & Johnson)
• Inventors: Branstetter, Bryan James, Breitenbucher, J. Guy, Lebsack, Alec D., Liu, Jing, Rech, Jason C., Xiao, Wei
• Primary Examiner(s): Moore, Susanna
• Application Number:
  US14/133,848
• Publication Number:
  US 20140107098A1
• Time in Patent Office: 999 Days
• US Class Current: 1/1
• CPC Class Codes: A61K 31/497 containing further heterocyclic rings
• CPC Class Codes: A61K 31/519 ortho- or peri-condensed with heterocyclic rings
• CPC Class Codes: A61K 31/5377 not condensed and containing further heterocyclic rings, e.g. timolol
• CPC Class Codes: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
• CPC Class Codes: A61P 1/04 for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 11/06 Antiasthmatics
• CPC Class Codes: A61P 11/10 Expectorants
• CPC Class Codes: A61P 11/14 Antitussive agents
• CPC Class Codes: A61P 13/00 Drugs for disorders of the urinary system
• CPC Class Codes: A61P 13/02 of urine or of the urinary tract, e.g. urine acidifiers
• CPC Class Codes: A61P 17/04 Antipruritics
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/02 for peripheral neuropathies
• CPC Class Codes: A61P 25/04 Centrally acting analgesics, e.g. opioids
• CPC Class Codes: A61P 25/28 for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• CPC Class Codes: A61P 27/16 Otologicals
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 29/02 without antiinflammatory effect
• CPC Class Codes: A61P 7/00 : Drugs for disorders of the blood or the extracellular fluid
• CPC Class Codes: A61P 9/00 : Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/10 : for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: C07D 473/16 : two nitrogen atoms
• CPC Class Codes: C07D 473/18 : one oxygen and one nitrogen atom, e.g. guanine
• CPC Class Codes: C07D 473/24 : one nitrogen and one sulfur atom
• CPC Class Codes: C07D 473/34 : attached in position 6, e.g. adenine
• CPC Class Codes: C07D 498/04 : Ortho-condensed systems
• CPC Class Codes: C07D 513/04 : Ortho-condensed systems

Abstract

Certain TRPV1-modulating imidazolo-, oxazolo-, and thiazolopyrimdine compounds are described. The compounds may be used in pharmaceutical compositions and methods for treating disease states, disorders, and conditions mediated by TRPV1 activity, such as pain, arthritis, itch, cough, asthma, or inflammatory bowel disease.

Claims

1. A compound selected from the group consisting of:

(a) compounds of Formula (I);

2. A compound as defined in claim 1 selected from the group consisting of:

(a) the compounds of Formula (I) wherein R¹ is —

H, methyl, —

OC_1-4alkyl, —

SC_1-4alkyl, or —

SO₂—

C_1-6alkyl;

and (b) pharmaceutically acceptable salts of said compounds.

3. A compound as defined in claim 1 selected from the group consisting of:

(a) the compounds of Formula (I) wherein R¹ is —

H;

and (b) pharmaceutically acceptable salts of said compounds.

4. A compound as defined in claim 1 selected from the group consisting of:

(a) the compounds of Formula (I) wherein R¹ is —

NR^aR^b;

and (b) pharmaceutically acceptable salts of said compounds.

5. A compound as defined in claim 1 selected from the group consisting of:

(a) the compounds of Formula (I) wherein R¹ is isopropylamino, isobutylamino, diisopropylamino, 2-hydroxy-1-methyl-ethylamino, 2-morpholin-4-yl-ethyl, 2-pyrrolidin-1-yl-ethyl, cyclopropylmethylamino, azetidinyl, pyrrolidinyl, 2-methylpyrrolidinyl, 2-isopropyl-pyrrolidinyl, 2-methoxymethyl-pyrrolidinyl, piperidinyl, 4-pyrrolidin-1-yl-piperidin-1-yl, piperazinyl, 4-methyl-piperazinyl, 4-isopropyl-piperazinyl, 4-isobutyl-piperazinyl, 4-cyclopentyl-piperazinyl, or morpholinyl;

and (b) pharmaceutically acceptable salts of said compounds.

6. A compound as defined in claim 1 selected from the group consisting of:

(a) the compounds of Formula (I) wherein R^a and R^b are each independently —

H;

methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, or hexyl;

an ethyl or propyl group substituted with an —

OH or —

NR^eR^f substituent;

or a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopropylmethyl, cyclopentylmethyl, pyridylmethyl, pyrrolidinylmethyl, or piperidinylmethyl group, each unsubstituted or substituted with a methyl, methoxy, or fluoro substituent;

and (b) pharmaceutically acceptable salts of said compounds.

7. A compound as defined in claim 1 selected from the group consisting of:

(a) the compounds of Formula (I) wherein R^a and R^b taken together with the nitrogen of attachment form an azetidinyl, pyrrolidinyl, piperidinyl, 2-oxo-piperidin-1-yl, piperazinyl, oxo-piperazinyl, morpholinyl, thiomorpholinyl, 1,1-dioxo-1λ

⁶-thiomorpholin-4-yl, or azepanyl group, each unsubstituted or substituted with a —

C_1-4alkyl, —

OH, —

CH₂—

OC_1-2alkyl, —

CO₂H, or monocyclic cycloalkyl substituent;

and (b) pharmaceutically acceptable salts of said compounds.

8. A compound as defined in claim 1 selected from the group consisting of:

(a) the compounds of Formula (I) wherein R² is a phenyl group unsubstituted or substituted with one or two R^g substituents;

and (b) pharmaceutically acceptable salts of said compounds.

9. A compound as defined in claim 1 selected from the group consisting of:

(a) the compounds of Formula (I) wherein R² is a thiadiazolyl, pyridinyl, or pyrazinyl ring substituted with —

CF₃ or tert-butyl;

and (b) pharmaceutically acceptable salts of said compounds.

10. A compound as defined in claim 1 selected from the group consisting of:

(a) the compounds of Formula (I) wherein each R^g substituent is independently methyl, isopropyl, tert-butyl, —

OCH₃, —

SO₂CH₃, —

SO₂CF₃, —

SO₂NH₂, —

SO₂(morpholinyl), —

SO₂(piperazinyl), fluoro, chloro, —

CF₃, —

OCF₃, —

CO₂CH₃, —

C(CH₃)₂—

CN, —

C(CH₃)₂—

CO₂CH₃, —

C(CH₃)₂—

CONH₂, or —

C(CH₃)₂—

OH;

or two adjacent R^g substituents taken together form —

OC_1-2alkylO-;

and (b) pharmaceutically acceptable salts of said compounds.

11. A compound as defined in claim 1 selected from the group consisting of:

(a) the compounds of Formula (I) wherein each R^g substituent is independently tert-butyl or —

CF₃;

and (b) pharmaceutically acceptable salts of said compounds.

12. A compound as defined in claim 1 selected from the group consisting of:

(a) the compounds of Formula (I) wherein R³ is —

H, chloro, iodo, methyl, —

CF₃, —

CN, or —

S—

Si(iPr)₃;

and (b) pharmaceutically acceptable salts of said compounds.

13. A compound as defined in claim 1 selected from the group consisting of:

(a) the compounds of Formula (I) wherein R³ is —

H, chloro, or —

CF₃;

and (b) pharmaceutically acceptable salts of said compounds.

14. A compound as defined in claim 1 selected from the group consisting of:

(a) the compounds of Formula (I) wherein R⁴ is —

H, —

CN, —

C(O)N(Rⁿ)R^o, —

CH₂OH, or —

CH₂N(Rⁿ)R^o;

and (b) pharmaceutically acceptable salts of said compounds.

15. A compound as defined in claim 1 selected from the group consisting of:

(a) the compounds of Formula (I) wherein R⁴ is —

H or chloro;

and (b) pharmaceutically acceptable salts of said compounds.

16. A compound as defined in claim 1 selected from the group consisting of:

(a) the compounds of Formula (I) wherein R⁵ is —

H, chloro, or —

CF₃;

and (b) pharmaceutically acceptable salts of said compounds.

17. A compound selected from the group consisting of:

[8-(2,6-Dichloro-benzyl)-9H-purin-6-yl]-(4-trifluoromethyl-phenyl)-amine;

(4-tert-Butyl-phenyl)-[8-(2,6-dichloro-benzyl)-9H-purin-6-yl]-amine;

[8-(2,6-Dimethyl-benzyl)-9H-purin-6-yl]-(4-trifluoromethyl-phenyl)-amine;

[8-(2-Methyl-benzyl)-9H-purin-6-yl]-(4-trifluoromethyl-phenyl)-amine;

[8-(2,6-Dimethyl-benzyl)-2-methyl-9H-purin-6-yl]-(4-trifluoromethyl-phenyl)-amine;

[8-(2,6-Dichloro-benzyl)-2-methylsulfanyl-9H-purin-6-yl]-(4-trifluoromethyl-phenyl)-amine;

[8-(2,6-Dichloro-benzyl)-2-methanesulfonyl-9H-purin-6-yl]-(4-trifluoromethyl-phenyl)-amine;

[8-(2,6-Dichloro-benzyl)-2-methoxy-9H-purin-6-yl]-(4-trifluoromethyl-phenyl)-amine;

[8-(2,6-Dichloro-benzyl)-2-(4-methyl-piperazin-1-yl)-9H-purin-6-yl]-(4-trifluoromethyl-phenyl)-amine;

[8-(2,6-Dichloro-benzyl)-2-(4-isobutyl-piperazin-1-yl)-9H-purin-6-yl]-(4-trifluoromethyl-phenyl)-amine;

[8-(2,6-Dichloro-benzyl)-2-morpholin-4-yl-9H-purin-6-yl]-(4-trifluoromethyl-phenyl)-amine;

[8-(2,6-Dichloro-benzyl)-2-piperidin-1-yl-9H-purin-6-yl]-(4-trifluoromethyl-phenyl)-amine;

8-(2,6-Dichloro-benzyl)-N²-isobutyl-N⁶-(4-trifluoromethyl-phenyl)-9H-purine-2,6-diamine;

8-(2,6-Dichloro-benzyl)-N²-isopropyl-N⁶-(4-trifluoromethyl-phenyl)-9H-purine-2,6-diamine; and

[8-(2,6-Dichloro-benzyl)-2-pyrrolidin-1-yl-9H-purin-6-yl]-(4-trifluoromethyl-phenyl)-amine;

and pharmaceutically acceptable salts thereof.

18. A pharmaceutical composition, comprising:

(a) an effective amount of at least one agent selected from compounds of Formula (I) and pharmaceutically acceptable salts of said compounds of Formula (I);

19. A pharmaceutical composition comprising a pharmaceutically acceptable excipient and an effective amount of at least one agent selected from the group consisting of:

[8-(2,6-Dichloro-benzyl)-9H-purin-6-yl]-(4-trifluoromethyl-phenyl)-amine;

(4-tert-Butyl-phenyl)-[8-(2,6-dichloro-benzyl)-9H-purin-6-yl]-amine;

[8-(2,6-Dimethyl-benzyl)-9H-purin-6-yl]-(4-trifluoromethyl-phenyl)-amine;

[8-(2-Methyl-benzyl)-9H-purin-6-yl]-(4-trifluoromethyl-phenyl)-amine;

[8-(2,6-Dimethyl-benzyl)-2-methyl-9H-purin-6-yl]-(4-trifluoromethyl-phenyl)-amine;

[8-(2,6-Dichloro-benzyl)-2-methylsulfanyl-9H-purin-6-yl]-(4-trifluoromethyl-phenyl)-amine;

[8-(2,6-Dichloro-benzyl)-2-methanesulfonyl-9H-purin-6-yl]-(4-trifluoromethyl-phenyl)-amine;

[8-(2,6-Dichloro-benzyl)-2-methoxy-9H-purin-6-yl]-(4-trifluoromethyl-phenyl)-amine;

[8-(2,6-Dichloro-benzyl)-2-(4-methyl-piperazin-1-yl)-9H-purin-6-yl]-(4-trifluoromethyl-phenyl)-amine;

[8-(2,6-Dichloro-benzyl)-2-(4-isobutyl-piperazin-1-yl)-9H-purin-6-yl]-(4-trifluoromethyl-phenyl)-amine;

[8-(2,6-Dichloro-benzyl)-2-morpholin-4-yl-9H-purin-6-yl]-(4-trifluoromethyl-phenyl)-amine;

[8-(2,6-Dichloro-benzyl)-2-piperidin-1-yl-9H-purin-6-yl]-(4-trifluoromethyl-phenyl)-amine;

8-(2,6-Dichloro-benzyl)-N²-isobutyl-N⁶-(4-trifluoromethyl-phenyl)-9H-purine-2,6-diamine;

8-(2,6-Dichloro-benzyl)-N²-isopropyl-N⁶-(4-trifluoromethyl-phenyl)-9H-purine-2,6-diamine; and

[8-(2,6-Dichloro-benzyl)-2-pyrrolidin-1-yl-9H-purin-6-yl]-(4-trifluoromethyl-phenyl)-amine;

and pharmaceutically acceptable salts thereof.