Vanilloid receptor ligands and their use in treatments

• US 20060030618A1
• Filed: 04/05/2005
• Published: 02/09/2006
• Est. Priority Date: 12/10/2001
• Status: Abandoned Application

• Current Assignee: Amgen Inc.
• Original Assignee: Amgen Inc.
• Inventors: 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., Norman, Mark Henry
• Application Number:
  US11/100,272
• Publication Number:
  US 20060030618A1
• Time in Patent Office: Days
• US Class Current: 514/452
• 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:

R¹ is a naphthyl, the naphthyl is substituted by 0, 1, 2 or 3 substituents independently selected from R⁵, R⁶ and R⁷;

R² is H, hydroxy, halo, C_1-6alkyl substituted by 0, 1 or 2 substituents selected from R¹⁰,

or a saturated or unsaturated 5- or 6-membered ring heterocycle containing 1, 2 or 3 heteroatoms independently selected from N, O and S, wherein no more than 2 of the ring members are O or S, wherein the heterocycle is optionally fused with a phenyl ring, and the heterocycle or fused phenyl ring is substituted by 0, 1, 2 or 3 substituents independently selected from R⁵, R⁶ and R⁷; and

R³ is H or C_1-4alkyl.

3. A compound according to claim 2, wherein R² is

4. A compound according to claim 3, wherein R² is

5. A compound according to claim 3, wherein R² is a saturated or unsaturated 5- or 6-membered ring heterocycle containing 1, 2 or 3 heteroatoms independently selected from N, O and S, wherein no more than 2 of the ring members are O or S, wherein the heterocycle is optionally fused with a phenyl ring, and the heterocycle or fused phenyl ring is substituted by 0, 1, 2 or 3 substituents independently selected from R⁵, R⁶ and R⁷.

6. A compound according to claim 2, wherein:

R⁴is

R^b is H, C_1-6alkyl, —

C(═

O)C_1-6alkyl, C_1-6alkyl-O^Ra; and

Y² is —

NR^a—

or —

O—

.

7. A compound according to claim 2, wherein:

R⁴is

L³ is a 2- or 3-atom, saturated or unsaturated, bridge containing 1, 2 or 3 carbon atoms and 0 or 1 atoms independently selected from O, N and S, wherein the each of the carbon atoms in the bridge is substituted by H, ═

O, —

OR^a, —

C_1-6alkylOR^a, —

C_1-6alkyl, —

NR^aR^a, —

C_1-6alkylNR^Ra, —

C(═

O)OR^a, —

C(═

O)NR^aR^a, —

C_1-3alkylC(═

O)OR^a, —

C_1-3alkylC(═

O)NR^aR^a, —

OC(═

O)C_1-6alkyl, —

NR^aC(═

O)C_1-6alkyl, —

C_1-3alkylOC(═

O)C_1-6alkyl or —

C_1-3alkylNR^aC(═

O)C_1-6alkyl, and any nitrogen atoms in the bridge are substituted by H, —

C_1-6alkylOR^a, —

C_1-6alkyl, —

C_1-6alkylNR^aR^a, —

C_1-3alkylC(═

O)OR^a, —

C_1-3alkylC(═

O)NR^aR^a, —

C_1-3alkylOC(═

O)C_1-6alkyl, —

C_1-3alkylNR^aC(═

O)C_1-6alkyl, —

C(═

O)R^c or —

C_1-3alkylR^c;

R^b is H, C_1-6alkyl, —

C(═

O)C_1-6alkyl, C_1-6alkyl-O—

R^a; and

Y² is —

NR^b—

or —

O—

.

8. A compound according to claim 2, wherein:

R⁴is

L³ is a 2- or 3-atom, saturated or unsaturated, bridge containing 1, 2 or 3 carbon atoms and 0, 1 or 2 atoms independently selected from O, N and S, wherein the each of the carbon atoms in the bridge is substituted by H, ═

O, —

OR^a, —

C_1-6alkylOR^a, —

C_1-6alkyl, —

NR^aR^a, —

C_1-6alkylNR^aR^a, —

C(═

O)OR^a, —

C(═

O)NR^aR^a, —

C_1-3alkylC(═

O)OR^a, —

C_1-3alkylC(═

O)NR^aR^a, —

OC(═

O)C_1-6alkyl, —

NR^aC(═

O)C_1-6alkyl, —

C_1-3alkylOC(═

O)C_1-6alkyl or —

C_1-3alkylNR^aC(═

O)C_1-6alkyl, and any nitrogen atoms in the bridge are substituted by H, —

C_1-6alkylOR^a, —

C_1-6alkyl, —

C_1-6alkylNR^aR^a, —

C_1-3alkylC(═

O)OR^a, —

C_1-3alkylC(═

O)NR^aR^a, —

C_1-3alkylOC(═

O)C_1-6alkyl, —

C_1-3alkylNR^aC(═

O)C_1-6alkyl, —

C(═

O)R^c or —

C_1-3alkylR^c;

R^b is H, C_1-6alkyl, —

C(═

O)C_1-6alkyl, C_1-6alkyl-O—

R^a; and

Y² is —

NR^b or —

O—

.

9. A compound according to claim 2, wherein:

R⁴ is

L³ is a 2- or 3-atom, saturated or unsaturated, bridge containing 1, 2 or 3 carbon atoms and 0, 1 or 2 atoms independently selected from O, N and S, wherein the each of the carbon atoms in the bridge is substituted by H, ═

O, —

OR^a, —

C_1-6alkylOR^a, —

C_1-6alkyl, —

NR^aR^a, —

C_1-6alkylNR^aR^a, —

C(═

O)OR^a, —

C(═

O)NR^aR^a, —

C_1-3alkylC(═

O)OR^a, —

C_1-3alkylC(═

O)NR^aR^a, —

OC(═

O)C_1-6alkyl, —

NR^aC(═

O)C_1-6alkyl, —

C_1-3alkylOC(═

O)C_1-6alkyl or —

C_1-3alkylNR^aC(′

O)C_1-6alkyl, and any nitrogen atoms in the bridge are substituted by H, —

C_1-6alkylOR^a, —

C_1-6alkyl, —

C_1-6alkylNR^aR^a, —

C_1-3alkylC(═

O)OR^a, —

C_1-3alkylC(═

O)NR^aR^a, —

C_1-3alkylOC(═

O)C_1-6alkyl, —

C_1-3alkylNR^aC(═

O)C_1-6alkyl, —

C(═

O)R^c or —

C_1-3alkylR^c;

R^b is H, C_1-6alkyl, —

C(═

O)C_1-6alkyl, C_1-6alkyl-O—

R^a; and

Y² is —

NR^a—

or —

O—

.

10. A compound according to claim 2, wherein:

R⁴is

R^b is H, C_1-6alkyl, —

C(═

O)C_1-6alkyl, C_1-6alkyl-O—

R^a; and

Y² is —

NR^a—

or —

O—

.

11. A compound according to claim 2, wherein:

R⁴ is 10-membered bicyclic ring comprising fused 6-membered rings, containing 0, 1, 2, 3 or 4 N atoms with the remainder being carbon atoms, with at least one of the 6-membered rings being aromatic, wherein the carbon atoms are substituted by H, halo, OR^a, NR^aR^a, C_1-6alkyl and C_1-3haloalkyl; and

saturated carbon atoms may be additionally substituted by ═

O.

12. A compound according to claim 2, wherein:

R⁴is

R¹⁰ is independently, at each instance, H, C_1-9alkyl, —

C_1-3alkylOR^a, C_1-4haloalkyl, halo, nitro, cyano, —

OR^a, —

S(═

O)_nC_1-6alkyl, —

O—

C_1-4haloalkyl, —

O—

C_1-6alkylNR^aR^a, —

O—

C_1-6alkylOR^a, —

O—

C_1-6alkylC(═

O)OR^a, —

NR^aR^a, —

NR^a—

C_1-4haloalkyl, —

NR^a—

C_1-6alkylNR^aR^a, —

NR^a—

C_1-6alkylOR^a, —

C(═

O)C_1-6alkyl, —

C(═

O)OC_1-6alkyl, —

OC(═

O)C_1-6alkyl, —

C(═

O)NR^aC_1-6alkyl or —

NR^aC(═

O)C_1-6alkyl;

R¹¹ is independently, at each instance, H, C_1-9alkyl, —

C_1-3alkylOR^a, C_1-4haloalkyl, halo, nitro, cyano, —

OR^a, —

S(═

O)_nC_1-6alkyl, —

O—

C_1-4haloalkyl, —

O—

C_1-6alkylNR^aR^a, —

O—

C_1-6alkylR^c, —

O—

C_1-6alkylOR^a, —

O—

C_1-6alkylC(═

O)OR^a, —

N^aR^a, —

NR^a—

C_1-4haloalkyl, —

NR^a—

C_1-6alkylNR^aR^a, —

NR^a—

C_1-6alkylOR^a, —

C(═

O)C_1-6alkyl, —

C(═

O)OC_1-6alkyl, —

OC(═

O)C_1-6alkyl, —

C(═

O)NR^aC_1-6alkyl or —

NR^aC(═

O)C_1-6alkyl;

C_1-6alkylNR^aR^a;

R¹² is independently, at each instance, H, C_1-9alkyl, —

C_1-3alkylOR^a, C_1-4haloalkyl, halo, nitro, cyano, —

OR^a, —

S(═

O)_nC_1-6alkyl, —

O—

C_1-4haloalkyl, —

O—

C_1-6alkylNR^aR^a, —

O—

C₆alkylOR^a, —

O—

C_1-6alkylC(═

O)OR^a, —

NR^aR^a, —

NR^a—

C_1-4haloalkyl, —

NR^a—

C_1-6alkylNR^aR^a, —

NR^a—

C_1-6alkylOR^a, —

C(═

O)C_1-6alkyl, —

C(═

O)OC_1-6alkyl, —

OC(═

O)C_1-6alkyl, —

C(═

O)NR^aC_1-6alkyl or —

NR^aC(═

O)C_1-6alkyl;

R¹³ is independently, at each instance, H, C_1-9alkyl, —

C_1-3alkylOR^a, C_1-4haloalkyl, halo, nitro, cyano, —

OR^a, —

S(═

O)_nC_1-6alkyl, —

O—

C_1-4haloalkyl, —

O—

C_1-6alkylNR^aR^a, —

O—

C_1-6alkylOR^a, —

O—

C_1-6alkylC(═

O)OR^a, NR^aR^a, —

NR^aC_1-4haloalkyl, —

NR^a—

C_1-6alkylNR^aR^a, —

NR^a—

C_1-6alkylOR^a, —

C(═

O)C_1-6alkyl, —

C(═

O)OC_1-6alkyl, —

OC(═

O)C_1-6alkyl, —

C(═

O)NR^aC_1-6alkyl or —

NR^aC(═

O)C_1-6alkyl; and

R¹⁴ is independently, at each instance, H, C_1-9alkyl, —

C_1-3alkylOR^a, C_1-4haloalkyl, halo, nitro, cyano, —

OR^a, —

S(═

O)_nC_1-6alkyl, —

O—

C_1-4haloalkyl, —

O—

C_1-6alkylNR^aR^a, —

O—

C_1-6alkylOR^a, —

O—

C_1-6alkylC(═

O)OR^a, —

NR^aR^a, —

NR^a—

C_1-4haloalkyl, —

NR^a—

C_1-6alkylNR^aR^a, —

NR^a—

C_1-6alkylOR^a, —

C(═

O)C_1-6alkyl, —

C(═

O)OC_1-6alkyl, —

OC(═

O)C_1-6alkyl, —

C(═

O)NR^a—

C_1-6alkyl or —

NR^aC(═

O)C_1-6alkyl;

wherein one of R¹⁰ and R¹² is not H.

13. A compound according to claim 2, wherein R⁴ is a saturated or unsaturated 5- or 6-membered ring heterocycle containing 1, 2 or 3 heteroatoms independently selected from N, O and S, wherein no more than 2 of the ring members are O or S, wherein the heterocycle is optionally fused with a phenyl ring, and the heterocycle or fused phenyl ring is substituted by 0, 1, 2 or 3 substituents selected from halo, C_1-4haloalkyl, —

OR^a and —

NR^aR^a.

14. A compound according to claim 1, or a pharmaceutically-acceptable salt thereof, wherein the compounds is selected from:

15. A method of treating 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, comprising the step of administering a compound according to claim 1.

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