Modulators of VR1 receptor

• US 20050004133A1
• Filed: 06/04/2004
• Published: 01/06/2005
• Est. Priority Date: 06/05/2003
• Status: Abandoned Application

• Current Assignee: Vertex Pharmaceuticals Incorporated
• Original Assignee: Vertex Pharmaceuticals Incorporated
• Inventors: Hurley, Dennis James, Termin, Andreas P., Tung, Roger D., Makings, Lewis R., Grootenhuis, Peter D.J.
• Application Number:
  US10/861,788
• Publication Number:
  US 20050004133A1
• Time in Patent Office: Days
• US Class Current: 514/252.40
• CPC Class Codes: A61K 31/416 condensed with carbocyclic ring systems, e.g. indazole
• CPC Class Codes: A61K 31/4184 condensed with carbocyclic rings, e.g. benzimidazoles
• CPC Class Codes: A61K 31/423 condensed with carbocyclic rings
• CPC Class Codes: A61K 31/428 condensed with carbocyclic rings
• CPC Class Codes: A61K 31/497 containing further heterocyclic rings
• CPC Class Codes: A61K 31/501 not condensed and containing further heterocyclic rings
• CPC Class Codes: A61K 31/506 not condensed and containing further heterocyclic rings
• 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 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 17/00 Drugs for dermatological disorders
• 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 25/06 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 27/02 : Ophthalmic agents
• 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 43/00 : Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07D 231/56 : Benzopyrazoles; Hydrogenated benzopyrazoles
• CPC Class Codes: C07D 235/06 : with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
• CPC Class Codes: C07D 235/26 : Oxygen atoms
• CPC Class Codes: C07D 241/44 : with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the hetero ring
• CPC Class Codes: C07D 263/58 : with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
• CPC Class Codes: C07D 277/68 : with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
• 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
• CPC Class Codes: C07D 405/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 405/14 : containing three or more hetero rings
• CPC Class Codes: C07D 409/14 : containing three or more hetero rings
• CPC Class Codes: C07D 413/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 417/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 417/14 : containing three or more hetero rings
• CPC Class Codes: C07D 471/04 : Ortho-condensed systems

Abstract

The present invention relates to compounds useful as modulators of the vanilloid receptor, and also provides pharmaceutically acceptable compositions comprising the compounds of the invention and methods of using the compositions in the treatment of various disorders.

Claims

1. A method for modulating VR1, comprising the step of contacting said VR1 with a compound of formula I:

2. The method according to claim 1, wherein L is —

C (O)—

NH—

(CH₂)_q—

.

3. The according to claim 2, wherein U and V are both NH, and Z is C═

O.

5. The method according to claim 1, wherein Ring A is furanyl or phenyl.

6. A compound having formula II:

4. The method according claim 2, wherein V is S, and U is NH. 12. The compound of claim 10, wherein U is —

NH—

.

7. The compound according to claim 6, wherein said compound has one or more of the following features:

(i) V₁ is NH, O, or S; and

(ii) U₁ is NH, O, or S.

10. The compound according to any one of claims 6-9, wherein A₁ is selected from any one of the following:

11. The compound according to claim 10, wherein A₁ is a or b.

12. The compound according to claim 11, wherein A₁ is i, j, k, m, o, or p.

13. The compound according to claim 6 or 8, wherein R^X and R^U each is independently R′

.

14. The compound according to claim 13, wherein R¹ is hydrogen or an optionally substituted group selected from a C₁-C₈ aliphatic group.

15. The compound according to claim 13, wherein R′

is an optionally substituted 3-6 membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

16. The compound according to claim 15, wherein R′

is selected from include optionally substituted cyclopropyl, cyclopentyl, cyclohexyl, piperidinyl, piperazinyl, morpholinyl, and pyrrolidinyl.

17. A pharmaceutical composition comprising a compound according to any one of claims 6-16, and a pharmaceutically acceptable adjuvant or carrier.

8. A compound having formula:

9. The compound according to claim 8, wherein said compound has one or more of the following features:

(i) V₂ is NH, Z₂ is N, and U₂ is CH;

(ii) V₂ is N, Z₂ is CH, and U₂ is NH;

(iii) V₂ is NH, Z₂ is CH, and U₂ is N;

or

(iv) V₂ is CH, Z₂ is N, and U₂ is NH.

18. A method of treating or lessening the severity of a disease in a patient selected from for treating or lessening the severity of one or more of the following conditions, inflammatory pain, neuropathic pain, acute pain, chronic pain, post-operative pain, migraine, arthralgia, nerve injury, neurodegeneration, neuropathies, diabetic neuropathy, hyperactive urinary bladder, hypersensitive urinary bladder, urinary incontinence, interstitial cystitis, painful bladder disorders, irritable bowel syndrome, inflammatory bowel disease, inflammatory disease, asthma, chronic obstructive pulmonary disease, digestive tract ulcer, skin irritation, or eye irritation, mucous membrane irritation, comprising the step of administering to said patient a compound of formula (I), formula (II), or formula (III).