| Title: |
CIS-CYCLOHEXYL SUBSTITUTED PYRIMIDINONE DERIVATIVES |
| Document Number: |
20100008866 |
| Publication Date: |
January 14, 2010 |
| Appl. No: |
12/436587 |
| Application Filed: |
May 06, 2009 |
| Abstract: |
Cis-cyclohexyl substituted pyrimidinone derivatives are provided, of the Formula: [chemical expression included] wherein variables are as described herein. Such compounds are ligands that may be used to modulate specific receptor activity in vivo or in vitro, and are particularly useful in the treatment of conditions associated with pathological receptor activation in humans, domesticated companion animals and livestock animals. Pharmaceutical compositions and methods for using such compounds to treat such disorders are provided, as are methods for using such ligands for receptor localization studies. |
| Inventors: |
Blum, Charles A. (Westbrook, CT, US); Ghosh, Manuka (Madison, CT, US); Martinez, Isamir (Guilford, CT, US); Zhang, Xuechun (Guilford, CT, US); Zheng, Xiaozhang (Newton, MA, US) |
| Assignees: |
Neurogen Corporation (Branford, CT, US) |
| Claim: |
1. A compound of the formula: [chemical expression included] or a pharmaceutically acceptable salt or hydrate thereof, wherein: [chemical expression included] represents a fused 5- or 6-membered heteroaryl that contains 1, 2 or 3 heteroatoms independently chosen from O, N and S, with the remaining ring atoms being carbon, wherein the fused heteroaryl is substituted with from 0 to 2 substituents independently chosen from (i) amino and hydroxy; and (ii) C1-C6alkyl, (C3-C7cycloalkyl)C0-C2alkyl, C1-C6haloalkyl, C1-C6alkoxy, C2-C6alkyl ether, C1-C6alkanoyloxy, C1-C6alkylsulfonylamino, C1-C6alkanonylamino, and mono- or di-(C1-C6alkyl)amino, each of which is substituted with from 0 to 2 substituents independently chosen from hydroxy, amino, C1-C4alkyl and C1-C4alkoxy; Ar is a 6- to 10-membered aryl or a 5- to 10-membered heteroaryl, each of which is substituted with from 0 to 4 or from 0 to 3 substituents that are independently chosen from halogen, cyano, amino, nitro, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6alkoxy, C1-C6haloalkoxy, (C3-C7cycloalkyl)C0-C4alkyl, and mono- or di-(C1-C6alkyl)amino; and Rx is C1-C6alkyl, (C3-C7cycloalkyl)C0-C4alkyl or C1-C6haloalkyl, each of which is substituted with from 0 to 2 substituents independently chosen from halogen, cyano, amino, hydroxy and C1-C6alkyl. |
| Claim: |
2. A compound or salt or hydrate thereof according to claim 1, wherein the compound is represented by the structure: [chemical expression included] wherein: X is N or CH; and R1 represents from 0 to 3 substituents independently chosen from halogen, cyano, amino, nitro, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6alkoxy, C1-C6haloalkoxy, (C3-C7cycloalkyl)C0-C4alkyl, and mono- or di-(C1-C6alkyl)amino. |
| Claim: |
3. A compound or salt or hydrate thereof according to claim 1, wherein: [chemical expression included] is a 5-membered heteroaryl that is substituted with from 0 to 2 substituents independently chosen from C1-C4alkyl, (C3-C5cycloalkyl)C0-C2alkyl, and C1-C4haloalkyl. |
| Claim: |
4. A compound or salt or hydrate thereof according to claim 3, wherein: [chemical expression included] wherein R2 is hydrogen, C1-C4alkyl, C1-C4haloalkyl or (C3-C5cycloalkyl)C0-C2alkyl. |
| Claim: |
5. A compound or salt or hydrate thereof according to claim 1, wherein [chemical expression included] is a 6-membered heteroaryl that is substituted with from 0 to 2 substituents independently chosen from hydroxy, C1-C4alkyl, (C3-C5cycloalkyl)C0-C2alkyl, C1-C4haloalkyl, C1-C4hydroxyalkyl, C1-C4alkoxy and C1-C4haloalkoxy. |
| Claim: |
6. A compound or salt or hydrate thereof according to claim 5, wherein: [chemical expression included] wherein R4 represents from 0 to 3 substituents independently chosen from hydroxy, C1-C4alkyl, (C3-C5cycloalkyl)C0-C2alkyl, C1-C4haloalkyl, C1-C4hydroxyalkyl, C1-C4alkoxy and C1-C4haloalkoxy. |
| Claim: |
7. A compound or salt or hydrate thereof according to claim 1, wherein R1 represents from 1 to 3 substituents independently chosen from halogen, cyano, C1-C4alkyl and C1-C4haloalkyl. |
| Claim: |
8. A compound or salt or hydrate thereof according to claim 7, wherein one substituent represented by R1 is a halogen or cyano at the para position. |
| Claim: |
9. A compound or salt or hydrate thereof according to claim 1, wherein R1 represents exactly one substituent. |
| Claim: |
10. A compound or salt or hydrate thereof according to claim 9, wherein the compound has the formula: [chemical expression included] wherein: R2 is hydrogen, C1-C4alkyl, C1-C4haloalkyl or C3-C5cycloalkyl; R3 is halogen, cyano, C1-C4alkyl or C1-C4haloalkyl; and R4 represents from 0 to 2 substituents independently chosen from C1-C4alkyl, (C3-C5cycloalkyl)C0-C2alkyl and C1-C4haloalkyl. |
| Claim: |
11. A compound or salt or hydrate thereof according to claim 10, wherein R3 is halogen or CN. |
| Claim: |
12. A compound or salt or hydrate thereof according to claim 1, wherein Rx is C1-C4alkyl or C1-C4haloalkyl. |
| Claim: |
13. A compound or salt or hydrate thereof according to claim 12, wherein Rx is methyl, ethyl, isopropyl, t-butyl, difluoromethyl or trifluoromethyl. |
| Claim: |
14. A compound or salt or hydrate thereof according to claim 1, wherein the compound is: 1-(4-chlorophenyl)-9-methyl-2-[cis-4-(trifluoromethyl)cyclohexyl]-1,9-dihydro-6H-purin-6-one; 1-(4-fluorophenyl)-9-methyl-2-[cis-4-(trifluoromethyl)cyclohexyl]-1,9-dihydro-6H-purin-6-one; 3-(4-fluorophenyl)-7-methyl-2-[cis-4-(trifluoromethyl)cyclohexyl]thieno[3,2-d]pyrimidin-4(3H)-one; 3-(4-chlorophenyl)-7-methyl-2-[cis-4-(trifluoromethyl)cyclohexyl]thieno[3,2-d]pyrimidin-4(3H)-one; 9-cyclopropyl-1-(4-fluorophenyl)-2-[cis-4-(trifluoromethyl)cyclohexyl]-1,9-dihydro-6H-purin-6-one; 4-{9-methyl-6-oxo-2-[cis-4-(trifluoromethyl)cyclohexyl]-6,9-dihydro-1H-purin-1-yl}benzonitrile; 1-(4-chlorophenyl)-9-cyclopropyl-2-[cis-4-(trifluoromethyl)cyclohexyl]-1,9-dihydro-6H-purin-6-one; 9-ethyl-1-(4-fluorophenyl)-2-[cis-4-(trifluoromethyl)cyclohexyl]-1,9-dihydro-6H-purin-6-one; 6-(4-chlorophenyl)-5-[cis-4-(trifluoromethyl)cyclohexyl][1,3]thiazolo[5,4-d]pyrimidin-7(6H)-one; 3-(4-chlorophenyl)-2-[cis-4-(trifluoromethyl)cyclohexyl]pyrido[3,2-d]pyrimidin-4(3H)-one; 3-(6-chloropyridin-3-yl)-7-methyl-2-[cis-4-(trifluoromethyl)cyclohexyl]thieno[3,2-d]pyrimidin-4(3H)-one; 1-(4-chlorophenyl)-9-ethyl-2-(cis-4-isopropylcyclohexyl)-1,9-dihydro-6H-purin-6-one; 4-{9-ethyl-6-oxo-2-[cis-4-(trifluoromethyl)cyclohexyl]-6,9-dihydro-1H-purin-1-yl}benzonitrile; 1-(6-chloropyridin-3-yl)-9-ethyl-2-[cis-4-(trifluoromethyl)cyclohexyl]-1,9-dihydro-6H-purin-6-one; 4-{4-oxo-2-[cis-4-(trifluoromethyl)cyclohexyl]pyrido[3,2-d]pyrimidin-3(4H)-yl}benzonitrile; 3-(4-fluorophenyl)-2-[cis-4-(trifluoromethyl)cyclohexyl]pyrido[3,2-d]pyrimidin-4(3H)-one; 9-ethyl-1-(6-methylpyridin-3-yl)-2-[cis-4-(trifluoromethyl)cyclohexyl]-1,9-dihydro-6H-purin-6-one; 9-ethyl-1-(6-cyanopyridin-3-yl)-2-[cis-4-(trifluoromethyl)cyclohexyl]-1,9-dihydro-6H-purin-6-one; 3-(6-chloropyridin-3-yl)-2-[cis-4-(trifluoromethyl)cyclohexyl]pyrido[3,2-d]pyrimidin-4(3H)-one; 1-(4-chlorophenyl)-9-ethyl-8-(methylamino)-2-[cis-4-(trifluoromethyl)cyclohexyl]-1,9-dihydro-6H-purin-6-one; 5-{4-oxo-2-[cis-4-(trifluoromethyl)cyclohexyl]pyrido[3,2-d]pyrimidin-3(4H)-yl}pyridine-2-carbonitrile; 1-(benzo[d]thiazol-6-yl)-9-methyl-2-((1s,4s)-4-(trifluoromethyl)cyclohexyl)-1H-purin-6(9H)-one; or 3-(benzo[d]thiazol-6-yl)-2-((1s,4s)-4-(trifluoromethyl)cyclohexyl)pyrido[3,2-d]pyrimidin-4(3H)-one. |
| Claim: |
15. (canceled) |
| Claim: |
16. (canceled) |
| Claim: |
17. A pharmaceutical composition, comprising at least one compound or salt or hydrate thereof according to claim 1 in combination with a physiologically acceptable carrier or excipient. |
| Claim: |
18. A pharmaceutical composition according to claim 17, wherein the composition is formulated as an injectible fluid, an aerosol, a cream, an oral liquid, a tablet, a gel, a pill, a capsule, a syrup, or a transdermal patch. |
| Claim: |
19.-28. (canceled) |
| Claim: |
29. A method for treating a condition responsive to capsaicin receptor modulation in a patient, comprising administering to the patient a therapeutically effective amount of at least one compound or salt or hydrate thereof according to claim 1, and thereby alleviating the condition in the patient. |
| Claim: |
30. A method according to claim 29, wherein the patient is suffering from (i) exposure to capsaicin, (ii) burn or irritation due to exposure to heat, (iii) burns or irritation due to exposure to light, (iv) burn, bronchoconstriction or irritation due to exposure to tear gas, infectious agents, air pollutants or pepper spray, or (v) burn or irritation due to exposure to acid. |
| Claim: |
31. A method according to claim 29, wherein the condition is asthma or chronic obstructive pulmonary disease. |
| Claim: |
32. A method for treating pain in a patient, comprising administering to a patient suffering from pain a therapeutically effective amount of at least one compound or salt or hydrate thereof according to claim 1, and thereby alleviating pain in the patient. |
| Claim: |
33. A method according to claim 32, wherein the patient is suffering from neuropathic pain. |
| Claim: |
34. A method according to claim 32, wherein the pain is associated with a condition selected from: postmastectomy pain syndrome, stump pain, phantom limb pain, oral neuropathic pain, toothache, postherpetic neuralgia, diabetic neuropathy, reflex sympathetic dystrophy, trigeminal neuralgia, osteoarthritis, rheumatoid arthritis, fibromyalgia, Guillain-Barre syndrome, meralgia paresthetica, burning-mouth syndrome, bilateral peripheral neuropathy, causalgia, neuritis, neuronitis, neuralgia, AIDS-related neuropathy, MS-related neuropathy, spinal cord injury-related pain, surgery-related pain, musculoskeletal pain, back pain, headache, migraine, angina, labor, hemorrhoids, dyspepsia, Charcot's pains, intestinal gas, menstruation, cancer, venom exposure, irritable bowel syndrome, inflammatory bowel disease and trauma. |
| Claim: |
35. A method according to claim 32, wherein the patient is a human. |
| Claim: |
36. A method for treating pain in a patient, comprising administering to a patient suffering from pain a therapeutically effective amount of a combination of (i) at least one compound or salt or hydrate thereof according to claim 1, and (ii) ibuprofen, and thereby alleviating pain in the patient. |
| Claim: |
37. A method for treating itch in a patient, comprising administering to a patient a therapeutically effective amount of a compound or salt or hydrate thereof according to claim 1, and thereby alleviating itch in the patient. |
| Claim: |
38. A method for treating cough or hiccup in a patient, comprising administering to a patient a therapeutically effective amount of a compound or salt or hydrate thereof according to claim 1, and thereby alleviating cough or hiccup in the patient. |
| Claim: |
39. A method for treating urinary incontinence or overactive bladder in a patient, comprising administering to a patient a therapeutically effective amount of a compound or salt or hydrate thereof according to claim 1, and thereby alleviating urinary incontinence or overactive bladder in the patient. |
| Claim: |
40. A method for treating symptoms of menopause in a patient, comprising administering to a patient a therapeutically effective amount of a compound or salt or hydrate thereof according to claim 1, and thereby alleviating symptoms of menopause in the patient. |
| Claim: |
41. (canceled) |
| Claim: |
42. (canceled) |
| Claim: |
43. (canceled) |
| Claim: |
44. (canceled) |
| Claim: |
45. A packaged pharmaceutical preparation, comprising: (a) a pharmaceutical composition according to claim 17 in a container; and (b) instructions for using the composition to treat pain. |
| Claim: |
46. A packaged pharmaceutical preparation, comprising: (a) a pharmaceutical composition according to claim 17 in a container; and (b) instructions for using the composition to treat cough or hiccup. |
| Claim: |
47.-50. (canceled) |
| Current U.S. Class: |
424/45 |
| Current International Class: |
61; 12; 01; 61; 61; 07; 07; 07; 61; 61; 61; 61 |
| Accession Number: |
edspap.20100008866 |
| Database: |
USPTO Patent Applications |
