Vanilloid receptor ligands and their use in treatments

• US 7,579,347 B2
• Filed: 04/05/2005
• Issued: 08/25/2009
• Est. Priority Date: 12/10/2001
• Status: Expired due to Fees

• Current Assignee: Amgen Inc.
• Original Assignee: Amgen Inc.
• Inventors: Norman, Mark Henry, Chen, Ning, Kelly, Michael G., Wang, Xianghong, Zhu, Jiawang, Bo, Yunxin Y., Liu, Qingyian, Han, Nianhe, Fotsch, Christopher H., Doherty, Elizabeth M., Ognyanov, Vassil I., Chakrabarti, Partha P.
• Primary Examiner(s): Balasubramanian; Venkataraman
• Application Number:
  US11/100,077
• Publication Number:
  US 20050227986A1
• Time in Patent Office: 1,603 Days
• Field of Search: 546/112, 546/113, 546/139, 546/152, 546/184, 546/193, 546/268.1, 514/311, 514/336, 514/307, 514/318, 514/231.5, 514/252.13, 544/124, 544/360
• US Class Current: 514/231.5
• 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 1/12 Antidiarrhoeals
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 11/02 Nasal agents, e.g. decongestants
• CPC Class Codes: A61P 11/06 Antiasthmatics
• CPC Class Codes: A61P 13/00 Drugs for disorders of the urinary system
• CPC Class Codes: A61P 13/10 of the bladder
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• 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 17/14 for baldness or alopecia
• 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 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 3/10 : for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 31/12 : Antivirals
• CPC Class Codes: A61P 37/08 : Antiallergic agents antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14
• 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: C07D 209/08 : with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring
• CPC Class Codes: C07D 209/12 : Radicals substituted by oxygen atoms
• CPC Class Codes: C07D 209/42 : Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
• CPC Class Codes: C07D 209/48 : with oxygen atoms in positions 1 and 3, e.g. phthalimide
• CPC Class Codes: C07D 213/26 : Radicals substituted by halogen atoms or nitro radicals
• CPC Class Codes: C07D 213/643 : 2-Phenoxypyridines; Derivatives thereof
• CPC Class Codes: C07D 213/74 : Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
• CPC Class Codes: C07D 213/75 : Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates
• CPC Class Codes: C07D 215/227 : only one oxygen atom which is attached in position 2
• CPC Class Codes: C07D 215/38 : Nitrogen atoms nitro radicals C07D215/18
• CPC Class Codes: C07D 217/04 : with hydrocarbon or substituted hydrocarbon radicals attached to the ring nitrogen atom
• CPC Class Codes: C07D 231/40 : Acylated on said nitrogen atom
• CPC Class Codes: C07D 231/56 : Benzopyrazoles; Hydrogenated benzopyrazoles
• CPC Class Codes: C07D 233/38 : with acyl radicals or hetero atoms directly attached to ring nitrogen atoms
• CPC Class Codes: C07D 237/20 : Nitrogen atoms nitro radicals C07D237/12
• CPC Class Codes: C07D 239/42 : One nitrogen atom nitro radicals C07D239/30
• CPC Class Codes: C07D 239/90 : with acyclic radicals attached in position 2 or 3
• CPC Class Codes: C07D 241/42 : with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
• CPC Class Codes: C07D 263/56 : with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
• CPC Class Codes: C07D 265/36 : condensed with one six-membered ring
• CPC Class Codes: C07D 277/62 : Benzothiazoles
• CPC Class Codes: C07D 277/82 : Nitrogen atoms
• CPC Class Codes: C07D 307/79 : with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
• CPC Class Codes: C07D 319/20 : with substituents attached to the hetero ring
• 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 407/12 : linked by a chain containing hetero atoms as chain links
• 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

Compounds having the general structure

and compositions containing them, for the treatment of acute, inflammatory and neuropathic pain, dental pain, general headache, migraine, cluster headache, mixed-vascular and non-vascular syndromes, tension headache, general inflammation, arthritis, rheumatic diseases, osteoarthritis, inflammatory bowel disorders, inflammatory eye disorders, inflammatory or unstable bladder disorders, psoriasis, skin complaints with inflammatory components, chronic inflammatory conditions, inflammatory pain and associated hyperalgesia and allodynia, neuropathic pain and associated hyperalgesia and allodynia, diabetic neuropathy pain, causalgia, sympathetically maintained pain, deafferentation syndromes, asthma, epithelial tissue damage or dysfunction, herpes simplex, disturbances of visceral motility at respiratory, genitourinary, gastrointestinal or vascular regions, wounds, burns, allergic skin reactions, pruritis, vitiligo, general gastrointestinal disorders, gastric ulceration, duodenal ulcers, diarrhea, gastric lesions induced by necrotising agents, hair growth, vasomotor or allergic rhinitis, bronchial disorders or bladder disorders.

Claims

1. A compound having the structure:

2. A compound according to claim 1, wherein:

R⁴ is

3. A compound according to claim 1, wherein:

R⁴ is

4. A compound according to claim 1, wherein:

R⁴ is

5. A pharmaceutical composition comprising a compound according to claim 1 and a pharmaceutically-acceptable diluent or carrier.

6. A compound having the structure

7. A compound according to claim 6, wherein R⁴ is a phenyl ring that is vicinally fused with an unsaturated 3-atom bridge containing 1, 2 or 3 atoms selected from O, N and S with the remaining atoms being carbon, so long as the combination of O and S atoms is not greater than 2, wherein the ring and bridge are substituted by 0, 1, 2 or 3 substituents independently selected from C_1-8alkyl, C_1-4haloalkyl, halo, cyano, nitro, —

C(═

O)Rⁿ, —

C(═

O)ORⁿ, —

C(═

O)NR^mR^m, —

C(═

NR^m)NR^mR^m, —

OR^m, —

OC(═

O)Rⁿ, —

OC(═

O)NR^mR^m, —

OC(═

O)N(R^m)S(═

O)₂Rⁿ, —

OC_2-6alkylOR^m, —

SR^m, —

S(═

O)Rⁿ, —

S(═

O)₂Rⁿ, —

S(═

O)₂NR^mR^m, —

S(═

O)₂N(R^m)C(═

O)Rⁿ, —

S(═

O)₂N(R^m)C(═

O)ORⁿ, —

S(═

O)₂N(R^m)C(═

O)NR^mR^m, —

N(R^m)C(═

O)Rⁿ, —

N(R^m)C(═

O)ORⁿ, —

N(R^m)C(═

O)NR^mR^m, —

N(R^m)C(═

NR^m)NR^mR^m, —

N(R^m)S(═

O)₂Rⁿ, —

N(R^m)S(═

O)₂NR^mR^m, —

NR^mC_2-6alkylOR^m, —

C(═

O)R^s, —

C(═

O)OR^s, —

C(═

O)NR^mR^s, —

C(═

NR^m)NR^mR^s, —

OR^s, —

OC(═

O)R^s, —

OC(═

O)NR^mR^s, —

C(═

O)N(R^m)S(═

O)₂R^s, —

OC_2-6alkylOR^s, —

SR^s, —

S(═

O)R^s, —

S(═

O)₂R^s, —

S(═

O)₂NR^mR^s, —

S(═

O)₂N(R^m)C(═

O)R^s, —

S(═

O)₂N(R^m)C(═

O)OR^s, —

S(═

O)₂N(R^m)C(═

O)NR^mR^s, —

N(R^m)C(═

O)R^s, —

N(R^m)C(═

O)OR^s, —

N(R^m)C(═

O)NR^mR^s, —

N(R^m)C(═

NR^m)NR^mR^s, —

N(R^m)S(═

O)₂R^s, —

N(R^m)S(═

O)₂NR^mR^s, —

NR^mC_2-6alkylOR^sand C_1-4alkyl substituted by 1 or 2 groups selected from C_1-2haloalkyl, halo, cyano, nitro, —

C(═

O)Rⁿ, —

C(═

O)ORⁿ, —

C(═

O)NR^mR^m, —

C(═

NR^m)NR^mR^m, —

OR^m, —

OC(═

O)Rⁿ, —

OC(═

O)NR^mR^m, —

OC(═

O)N(R^m)S(═

O)₂Rⁿ, —

OC_2-6alkylOR^m, —

SR^m, —

S(═

O)Rⁿ, —

S(═

O)₂Rⁿ, —

S(═

O)₂NR^mR^m, —

S(═

O)₂N(R^m)C(═

O)Rⁿ, —

S(═

O)₂N(R^m)C(═

O)ORⁿ, —

S(═

O)₂N(R^m)C(═

O)NR^mR^m, —

N(R^m)C(═

O)Rⁿ, —

N(R^m)C(═

O)ORⁿ, —

N(R^m)C(═

O)NR^mR^m, —

N(R^m)C(═

NR^m)NR^mR^m, —

N(R^m)S(═

O)₂Rⁿ, —

N(R^m)S(═

O)₂NR^mR^m, —

C(═

O)R^s, —

C(═

O)OR^s, —

C(═

O)NR^mR^s, —

C(═

NR^m)NR^mR^s, —

OR^s, —

OC(═

O)R^s, —

OC(═

O)NR^mR^s, —

OC(═

O)N(R^m)S(═

O)₂R^s, —

OC_2-6alkylNR^mR^s, —

OC_2-6alkylOR^s, —

SR^s, —

S(═

O)R^s, —

S(═

O)₂R^s, —

S(═

O)₂NR^mR^s, —

S(═

O)₂N(R^m)C(═

O)R^s, —

S(═

O)₂N(R^m)C(═

O)OR^s, —

S(═

O)₂N(R^m)C(═

O)NR^mR^s, —

N(R^m)C(═

O)R^s, —

N(R^m)C(═

O)OR^s, —

N(R^m)C(═

O)NR^mR^s, —

N(R^m)C(═

NR^m)NR^mR^s, —

N(R^m)S(═

O)₂R^s, and —

N(R^m)S(═

O)₂NR^mR^s, ^s, —

NR^mC_2-6alkylOR^s and —

NR^mC_2-6alkylOR^m;

and the bridge carbon atoms are substituted with 0, 1 or 2 ═

O groups.

8. A pharmaceutical composition comprising a compound according to claim 6 and a pharmaceutically acceptable diluent or carrier.

9. A compound selected from the group of: