Urea derivatives and their use as vanilloid receptor antagonists in the treatment of pain

• US 20060276447A1
• Filed: 03/04/2004
• Published: 12/07/2006
• Est. Priority Date: 03/07/2003
• Status: Active Grant

• Current Assignee: Glaxo Group Limited (Glaxosmithkline Holdings Ltd.)
• Original Assignee: Glaxo Group Limited (Glaxosmithkline Holdings Ltd.)
• Inventors: Rami, Harshad Kantial, Thompson, Mervyn, Witty, David Richard, Fell, Stephen Christopher Martin
• Granted Patent: US 7,514,562 B2
• Time in Patent Office: Days
• US Class Current: 514/210.200
• CPC Class Codes: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
• CPC Class Codes: A61P 1/02 Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
• 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 11/08 Bronchodilators
• CPC Class Codes: A61P 13/02 of urine or of the urinary tract, e.g. urine acidifiers
• CPC Class Codes: A61P 13/10 of the bladder
• CPC Class Codes: A61P 15/00 Drugs for genital or sexual disorders for disorders of sex hormones A61P5/24; Contraceptives
• CPC Class Codes: A61P 17/02 for treating wounds, ulcers, burns, scars, keloids, or the like
• CPC Class Codes: A61P 17/04 Antipruritics
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 19/08 for bone diseases, e.g. rachitism, Paget's disease
• CPC Class Codes: A61P 21/00 Drugs for disorders of the muscular or neuromuscular system
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/04 Centrally acting analgesics, e.g. opioids
• CPC Class Codes: A61P 25/06 Antimigraine agents
• 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 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 3/10 : for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 31/18 : for HIV
• CPC Class Codes: A61P 35/00 : Antineoplastic agents
• CPC Class Codes: A61P 43/00 : Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• 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 401/04 : directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 401/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 401/14 : containing three or more hetero rings
• CPC Class Codes: C07D 403/12 : linked by a chain containing hetero atoms as chain links

Abstract

Compounds of formula (I),

or a pharmaceutically acceptable salt or solvate thereof, wherein P, P′, W, R¹, R², n, p, q, r, s and t are as defined in the specification, processes for preparing such compounds, pharmaceutical compositions comprising such compounds and their use in therapy.

Claims

1. A compound of formula (I),

2. A compound according to claim 1 wherein P represents phenyl, naphthyl, quinolinyl, cinnolinyl or isoquinolinyl.

3. A compound according to claim 1 wherein P′

represents phenyl, pyrimidinyl or pyridyl.

4. A compound according to claim 1 wherein R¹ represents halo, —

CF₃ or alkyl.

5. A compound according to claim 1 wherein p represents 1 or 2.

6. A compound according to claim 1 wherein n represents 0 or 1.

7. A compound according to claim 6 wherein n represents 0.

8. A compound according to claim 1 wherein R² represents halo, alkyl, alkoxy, —

CN or —

CF₃.

9. A compound according to claim 1 wherein q represents 0, 1 or 2.

10. A compound according to claim 1 wherein q represents 2, P′

represents a 6-membered aromatic ring and when W is a bond, R² is 3-trifluoromethyl, 4-trifluoromethyl, 5-trifluoromethyl, 6-trifluoromethyl, 6-methyl-4-trifluoromethyl or 6-methyl-5-trifluoromethyl; and

when W is CH or (CH₂)CH, R² is hydrogen or halo.

11. A compound according to claim 1 wherein r+s represents 1.

12. A compound according to claim 11 wherein r=0 and s=1.

13. A compound according to claim 1 wherein W represents a bond or CH.

14. A compound according to claim 1 wherein r=0, s=1 and P′

represents phenyl or 2-pyridyl.

15. A compound according to claim 1 as defined in any one of Examples 1-41 or a pharmaceutically acceptable salt or solvate thereof.

16. A compound according to claim 1 selected from:

N-(2-Trifluoromethylphenyl)-N′

-[(1-(6-trifluoromethyl-2-pyridyl)azetidin-3-yl)]urea;

N-(2-Bromophenyl)-N′

-[(1-(6-methyl-4-trifluoromethyl-2-pyridyl)azetidin-3-yl)]urea;

N-(2-Chlorophenyl)-N′

-[(1-(6-methyl-4-trifluoromethyl-2-pyridyl)azetidin-3-yl)]urea;

N-(2,3-Dichlorophenyl)-N′

-[(1-(6-methyl-4-trifluoromethyl-2-pyridyl)azetidin-3-yl)]urea; and

N-(1-Methylisoquinolin-5-yl)-N′

-(1-diphenylmethylazetidin-3-yl)-urea;

or a pharmaceutically acceptable salt or solvate of any one thereof.

17. A compound according to claim 1 or a pharmaceutically acceptable salt or solvate thereof for use as an active therapeutic substance.

18. A pharmaceutical composition comprising a compound according to claim 1 or a pharmaceutically acceptable salt or solvate thereof and a pharmaceutically acceptable carrier or excipient.

19. A method for the treatment or prophylaxis of disorders in which antagonism of the Vanilloid (VR1) receptor is beneficial in mammal, which method comprises administering to a mammal in need thereof a therapeutically acceptable amount of a compound according to claim 1 or a pharmaceutically acceptable salt or solvate thereof.

21. The method according to claim 19 wherein the disorder is selected from pain, chronic pain, neuropathic pain, postoperative pain, postrheumatoid arthritic pain, osteoarthritic pain, back pain, visceral pain, cancer pain, algesia, neuralgia, dental pain, headache, migraine, neuropathies, carpal tunnel syndrome, diabetic neuropathy, HIV-related neuropathy, post-herpetic neuralgia, fibromyalgia, neuritis, sciatica, nerve injury, ischaemia, neurodegeneration, stroke, post stroke pain, multiple sclerosis, respiratory diseases, asthma, cough, COPD, broncho constriction, inflammatory disorders, oesophagitis, heart burn, Barrett'"'"'s metaplasia, dysphagia, gastroeosophageal relux disorder (GERD), stomach and duodenal ulcers, functional dyspepsia, irritable bowel syndrome, inflammatory bowel disease, colitis, Crohn'"'"'s disease, pelvic hypersensitivity, pelvic pain, menstrual pain, renal colic, urinary incontinence, cystitis, burns, itch, psoriasis, pruritis and emesis.

22. A process for the production of a compound according to claim 1 which process comprises coupling a compound of formula (II):

23. A compound of formula (IIIA):

24. A compound according to claim 23 selected from:

1-(5-Trifluoromethylpyridin-2-yl)azetidin-3-ylamine;

1-(3-Trifluoromethylpyridin-2-yl)azetidin-3-ylamine;

1-(4-Trifluoromethylpyridin-2-yl)azetidin-3-ylamine;

1-(6-Trifluoromethylpyridin-2-yl)azetidin-3-ylamine;

1-(6-Methyl-4-trifluoromethylpyridin-2-yl)azetidin-3-ylamine;

1-(6-Methyl-5-trifluoromethylpyridin-2-yl)azetidin-3-ylamine;

3-Amino-1-diphenylmethylazetidine; and

3-Amino-1-di-(4-fluorophenyl)methylazetidine.

20. (canceled)