Bibliographic Details
| Title: |
Heteroaryl Substituted Quinolin-4-Ylamine Analogues |
| Document Number: |
20080085901 |
| Publication Date: |
April 10, 2008 |
| Appl. No: |
11/795269 |
| Application Filed: |
January 13, 2006 |
| Abstract: |
Heteroaryl substituted quinolin-4-ylamine analogues of Formula I are provided. [chemical expression included] 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: |
Caldwell, Timothy M. (Guilford, CT, US); Chenard, Bertrand L. (Waterford, CT, US); Hodgetts, Kevin J. (Killingworth, CT, US) |
| Assignees: |
Neurogen Corporation (Brandford, CT, US) |
| Claim: |
1. A compound of the formula: [chemical expression included] or a pharmaceutically acceptable salt thereof, wherein: Y and Z are independently N or CR1; Each R1 is independently hydrogen, halogen, cyano, amino, C1-C4alkyl, C1-C4haloalkyl, C1-C4alkoxy, C1-C4haloalkoxy or mono- or di-(C1-C4alkyl)amino; R2 is: (i) hydrogen, halogen or cyano; (ii) a group of the formula —Rc-M-Rd—Ry, wherein: Rc is C0-C3alkylene or is joined to Ry or Rz, to form a 4- to 10-membered carbocycle or heterocycle that is substituted with from 0 to 2 substituents independently chosen from Rb; M is absent, a single covalent bond, O, S, SO, SO2, C(═O), OC(═O), C(═O)O, O—C(═O)O, C(═O)N(Rz), OC(═O)N(Rz), N(Rz)C(═O), N(Rz)C(═O)O, N(R)SO2, SO2N(Rz) or N(Rz), such that M is not N(Rz)C(═O)O if Rc is a single covalent bond; Rd is absent, a single covalent bond or C1-C8alkylene substituted with from 0 to 3 substituents independently chosen from Rb; and Ry and Rz, if present, are: (a) independently hydrogen, C1-C8alkyl, C2-C8alkyl ether, C2-C8alkenyl, a 4- to 10-membered carbocycle or heterocycle, or joined to Rc to form a 4- to 10-membered carbocycle or heterocycle, wherein each non-hydrogen Ry and Rz is substituted with from 0 to 6 substituents independently chosen from Rb; or (b) joined to form a 4- to 10-membered carbocycle or heterocycle that is substituted with from 0 to 6 substituents independently chosen from Rb; such that if Y and Z are both N, then R2 is not NH2; or (iii) taken together with R7 to form a fused 5- to 7-membered ring that is substituted with from 0 to 3 substituents independently chosen from oxo and C1-C4alkyl; R7 is hydrogen, halogen, COOH, C1-C4alkyl, C1-C4haloalkyl, C1-C4alkoxy, C1-C4alkoxycarbonyl or taken together with R2 to form a fused, optionally substituted ring; Ar1 is a 5-membered heteroaryl that is substituted with from 0 to 3 substituents independently chosen from groups of the formula LRa; Ar2 is 6- to 10-membered aryl or 5- to 10-membered heteroaryl, each of which is substituted with from 0 to 6 substituents independently chosen from oxo and groups of the formula LRa; L is independently selected at each occurrence from a single covalent bond, O, C(═O), OC(═O), C(═O)O, OC(═O)O, S(O)m, N(Rx), C(═O)N(Rx), N(Rx)C(═O), N(Rx)S(O)m, S(O)mN(Rx) and N[S(O)mRw]S(O)m; wherein m is independently selected at each occurrence from 0, 1 and 2; Rx is independently selected at each occurrence from hydrogen, C1-C6alkyl, C1-C6alkanoyl and C1-C6alkylsulfonyl; and Rw is C1-C6alkyl; Ra is independently selected at each occurrence from: (i) hydrogen, halogen, cyano and nitro, such that Ra is not hydrogen if L is a bond; and (ii) C1-C8alkyl, C2-C8alkenyl, C2-C8alkynyl, (C3-C8cycloalkyl)C0-C6alkyl, C1-C8haloalkyl, C2-C8alkyl ether, mono- and di-(C1-C8alkyl)amino and (3- to 10-membered heterocycle)C0-C6alkyl, each of which is substituted with from 0 to 6 substituents independently selected from Rb; and Rb is independently chosen at each occurrence from hydroxy, halogen, amino, aminocarbonyl, cyano, nitro, oxo, COOH, C1-C8alkyl, C1-C8alkoxy, C1-C8alkylthio, C1-C8alkanoyl, C2-C8alkanoyloxy, C1-C8alkoxycarbonyl, C1-C8alkyl ether, C1-C8hydroxyalkyl, C1-C8haloalkyl, mono- and di-(C1-C6alkyl)aminoC0-C4alkyl, C1-C8alkylsulfonyl, (3- to 7-membered carbocycle)C0-C8alkyl and (4- to 7-membered heterocycle)C0-C8alkyl. |
| Claim: |
2. A compound or salt according to claim 1, wherein Z is N. |
| Claim: |
3. A compound or salt according to claim 1 or claim 2, wherein Y is N. |
| Claim: |
4. A compound or salt according to claim 2, wherein Y is CH. |
| Claim: |
5. A compound or salt according to claim 1, wherein Y and Z are CH. |
| Claim: |
6. A compound or salt according to any one of claims 1-5, wherein Ar2 is phenyl or a 6-membered heteroaryl, each of which is substituted with from 0 to 3 substituents independently selected from (a) groups of the formula LRa and (b) groups that are taken together to form a fused, 5- to 7-membered heterocyclic ring that is substituted with from 0 to 3 substituents independently selected from Rb. |
| Claim: |
7. A compound or salt according to claim 6, wherein Ar2 is phenyl, pyridyl, pyrimidinyl, pyrazinyl or pyridazinyl, each of which is substituted with 0, 1 or 2 substituents independently selected from halogen, cyano, C1-C6alkyl, C1-C6alkoxy, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6cyanoalkyl, C1-C6alkyl ether, C1-C6alkanoyl, C1-C6alkylsulfonyl, C1-C6haloalkylsulfonyl, amino, and mono- and di-(C1-C6alkyl)amino. |
| Claim: |
8. A compound or salt according to claim 7, wherein Ar2 is phenyl, pyridyl, pyrimidinyl, pyrazinyl or pyridazinyl that is unsubstituted or substituted with halogen, cyano, C1-C4alkyl, C1-C4alkoxy, C1-C4hydroxyalkyl, C1-C4cyanoalkyl, C1-C4alkanoyl, C1-C4haloalkyl, C1-C4alkylsulfonyl, C1-C4haloalkylsulfonyl, or mono- or di-(C1-C4alkyl)amino. |
| Claim: |
9. A compound or salt according to any one of claims 1-8, wherein the compound has the formula: [chemical expression included] wherein: each dotted line represents a single or double bond, such that the ring designated [chemical expression included] is aromatic; X is CH, N, O or S; and R8 and R9 are independently hydrogen, halogen, cyano, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy or C1-C6haloalkoxy. |
| Claim: |
10. A compound or salt according to claim 9, wherein the compound has the formula: [chemical expression included] wherein X is O or S. |
| Claim: |
11. A compound or salt according to any one of claims 1-8, wherein the compound has the formula: [chemical expression included] wherein: X is CR8, N, NR8, O or S; and R8 and R9 are independently hydrogen, halogen, cyano, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy or C1-C6haloalkoxy. |
| Claim: |
12. A compound or salt according to claim 11, wherein the compound has the formula: [chemical expression included] |
| Claim: |
13. A compound or salt according to any one of claims 1-8, wherein the compound has the formula: [chemical expression included] wherein: X is O or S; and R8 and R9 are independently hydrogen, halogen, cyano, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy or C1-C6haloalkoxy. |
| Claim: |
14. A compound or salt according to any one of claims 1-8, wherein the compound has the formula: [chemical expression included] wherein: X is O or S; and R8 is hydrogen, halogen, cyano, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy or C1-C6haloalkoxy. |
| Claim: |
15. A compound or salt according to any one of claims 1-8, wherein the compound has the formula: [chemical expression included] wherein: X is O or S; and R8 is hydrogen, halogen, cyano, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy or C1-C6haloalkoxy. |
| Claim: |
16. A compound or salt according to any one of claims 1-8, wherein the compound has the formula: [chemical expression included] wherein: X is O or S; and R8 is hydrogen, halogen, cyano, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy or C1-C6haloalkoxy. |
| Claim: |
17. A compound or salt according to any one of claims 1-8, wherein the compound has the formula: [chemical expression included] wherein: X is O or S; and R8 is hydrogen, halogen, cyano, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy or C1-C6haloalkoxy. |
| Claim: |
18. A compound or salt according to any one of claims 1-17, wherein the compound has the formula: [chemical expression included] wherein Q and K are independently CH or N; J and G are independently CR11 or N; R10 is chosen from groups of the formula LRa; and Each R11 is independently chosen from hydrogen and groups of the formula LRa. |
| Claim: |
19. A compound or salt according to claim 18, wherein: at least one, and no more than two, of Q, K, J and G are N; and R10 is halogen, cyano, C1-C4alkyl, C1-C4hydroxyalkyl, C1-C4cyanoalkyl, C1-C4alkanoyl, C1-C4haloalkyl, C1-C4alkylsulfonyl or C1-C4haloalkylsulfonyl. |
| Claim: |
20. A compound or salt according to claim 18, wherein: G is carbon that is substituted with halogen, hydroxy, cyano, amino, C1-C4alkyl, C1-C4alkoxy or mono- or di-(C1-C4alkyl)amino. |
| Claim: |
21. A compound or salt according to any one of claims 1-20, wherein R2 is: (i) hydrogen, hydroxy or halogen; or (ii) C1-C6alkyl, (C3-C7cycloalkyl)C0-C4alkyl, C1-C6alkoxy, C1-C6aminoalkyl, C1-C6hydroxyalkyl, C2-C6alkyl ether, mono- or di-(C1-C6alkyl)aminoC0-C4alkyl, phenylC0-C4alkyl or (4- to 7-membered heterocycle)C0-C4alkyl, each of which is substituted with from 0 to 4 substituents independently chosen from halogen, cyano, hydroxy, amino, oxo, mono- and di-(C1-C6alkyl)amino, C1-C6alkyl C1-C6alkoxy and C1-C6haloalkyl. |
| Claim: |
22. A compound or salt according to claim 21, wherein R2 is hydrogen, C1-C6alkyl, C4-C7cycloalkyl, C2-C6alkyl ether, mono- or di-(C1-C6alkyl)amino, morpholinylC0-C2alkyl, piperazinylC0-C2alkyl, piperidinylC0-C2alkyl, azetidinylC0-C2alkyl, pyrrolidinylC0-C2alkyl, phenylC0-C2alkyl or pyridylC0-C2alkyl, each of which is substituted with from 0 to 4 substituents independently chosen from halogen, cyano, hydroxy, amino, oxo, COOH, mono- and di-(C1-C6alkyl)amino, C1-C6alkyl and C1-C6haloalkyl. |
| Claim: |
23. A compound or salt according to claim 22, wherein R2 is hydrogen. |
| Claim: |
24. A compound or salt according to any one of claims 1-23, wherein the compound exhibits no detectable agonist activity an in vitro assay of capsaicin receptor agonism. |
| Claim: |
25. A compound or salt according to any one of claims 1-23, wherein the compound has an IC50 value of 1 micromolar or less in a capsaicin receptor calcium mobilization assay. |
| Claim: |
26. A compound or salt according to claim 25, wherein the compound has an IC50 value of 100 nanomolar or less in a capsaicin receptor calcium mobilization assay. |
| Claim: |
27. A compound or salt according to claim 26, wherein the compound has an IC50 value of 10 nanomolar or less in a capsaicin receptor calcium mobilization assay. |
| Claim: |
28. A pharmaceutical composition, comprising at least one compound or salt according to any one of claims 1-23 in combination with a physiologically acceptable carrier or excipient. |
| Claim: |
29. A method for reducing calcium conductance of a cellular capsaicin receptor, comprising contacting a cell expressing a capsaicin receptor with at least one compound or salt according to any one of claims 1-20, and thereby reducing calcium conductance of the capsaicin receptor. |
| Claim: |
30. A method according to claim 29, wherein the cell is contacted in vivo in an animal. |
| Claim: |
31. A method according to claim 29, wherein the cell is a neuronal cell. |
| Claim: |
32. A method according to claim 29, wherein the cell is a urothelial cell. |
| Claim: |
33. A method according to claim 29, wherein the cell is a lung cell. |
| Claim: |
34. A method according to claim 29, wherein during contact the compound or salt is present within a body fluid of the animal. |
| Claim: |
35. A method according to claim 34, wherein the compound or salt is present in the blood of the animal at a concentration of 5 micromolar or less. |
| Claim: |
36. A method according to claim 35, wherein the compound or salt is present in the blood of the animal at a concentration of 1 micromolar or less. |
| Claim: |
37. A method according to claim 36, wherein the compound or salt is present in the blood of the animal at a concentration of 500 nanomolar or less. |
| Claim: |
38. A method according to claim 37, wherein the compound or salt is present in the blood of the animal at a concentration of 100 nanomolar or less. |
| Claim: |
39. A method according to claim 30, wherein the animal is a human. |
| Claim: |
40. A method according to claim 30, wherein the compound or salt is administered orally. |
| Claim: |
41. A method for inhibiting binding of vanilloid ligand to a capsaicin receptor in vitro, the method comprising contacting capsaicin receptor with at least one compound or salt according to any one of claims 1-23, in an amount sufficient to detectably inhibit vanilloid ligand binding to capsaicin receptor. |
| Claim: |
42. A method for inhibiting binding of vanilloid ligand to a capsaicin receptor in a patient, the method comprising contacting cells expressing capsaicin receptor with at least one compound or salt according to any one of claims 1-23, in an amount sufficient to detectably inhibit vanilloid ligand binding to cells expressing a cloned capsaicin receptor in vitro, and thereby inhibiting binding of vanilloid ligand to the capsaicin receptor in the patient. |
| Claim: |
43. A method according to claim 42, wherein the compound is present in the blood of the patient at a concentration of 5 micromolar or less. |
| Claim: |
44. A method according to claim 43, wherein the compound is present in the blood of the patient at a concentration of 1 micromolar or less. |
| Claim: |
45. A method for treating a condition responsive to capsaicin receptor modulation in a patient, comprising administering to the patient a therapeutically effective amount of a compound or salt according to any one of claims 1-23, and thereby alleviating the condition in the patient. |
| Claim: |
46. A method according to claim 45, 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, air pollutants or pepper spray, or (v) burn or irritation due to exposure to acid. |
| Claim: |
47. A method according to claim 45, wherein the condition is asthma or chronic obstructive pulmonary disease. |
| Claim: |
48. 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 according to any one of claims 1-23, and thereby alleviating pain in the patient. |
| Claim: |
49. A method according to claim 48, wherein the compound is present in the blood of the patient at a concentration of 5 micromolar or less. |
| Claim: |
50. A method according to claim 49, wherein the compound is present in the blood of the patient at a concentration of 1 micromolar or less. |
| Claim: |
51. A method according to claim 50, wherein the compound is present in the blood of the patient at a concentration of 500 nanomolar or less. |
| Claim: |
52. A method according to claim 51, wherein the compound is present in the blood of the patient at a concentration of 100 nanomolar or less. |
| Claim: |
53. A method according to claim 48, wherein the patient is suffering from neuropathic pain. |
| Claim: |
54. A method according to claim 48, wherein the patient is afflicted 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: |
55. A method according to claim 54, wherein the patient is a human. |
| Claim: |
56. A method for treating itch in a patient, comprising administering to a patient a therapeutically effective amount of a compound or salt according to any one of claims 1-23, and thereby alleviating itch in the patient. |
| Claim: |
57. A method for treating cough or hiccup in a patient, comprising administering to a patient a therapeutically effective amount of a compound or salt according to any one of claims 1-23, and thereby alleviating cough or hiccup in the patient. |
| Claim: |
58. 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 according to any one of claims 1-23, and thereby alleviating urinary incontinence or overactive bladder in the patient. |
| Claim: |
59. A method promoting weight loss in an obese patient, comprising administering to a patient a therapeutically effective amount of a compound or salt according to any one of claims 1-23, and thereby promoting weight loss in the patient. |
| Claim: |
60. A compound or salt according to any one of claims 1-23, wherein the compound or salt is radiolabeled. |
| Claim: |
61. A method for determining the presence or absence of capsaicin receptor in a sample, comprising the steps of: (a) contacting a sample with a compound or salt according to any one of claims 1-23, under conditions that permit binding of the compound to capsaicin receptor; and (b) detecting a level of the compound bound to capsaicin receptor, and therefrom determining the presence or absence of capsaicin receptor in the sample. |
| Claim: |
62. A method according to claim 61, wherein the compound is a radiolabeled compound according to claim 60, and wherein the step of detection comprises the steps of: (i) separating unbound compound from bound compound; and (ii) detecting the presence or absence of bound compound in the sample. |
| Claim: |
63. A method for identifying an agent that binds to capsaicin receptor, comprising: (a) contacting capsaicin receptor with a radiolabeled compound or salt according to claim 60, under conditions that permit binding of the VR1 modulator to capsaicin receptor, thereby generating bound, labeled VR1 modulator; (b) detecting a signal that corresponds to the amount of bound, labeled VR1 modulator in the absence of test agent; (c) contacting the bound, labeled VR1 modulator with a test agent; (d) detecting a signal that corresponds to the amount of bound labeled VR1 modulator in the presence of test agent; and (e) detecting a decrease in signal detected in step (d), as compared to the signal detected in step (b), and therefrom identifying an agent that binds to capsaicin receptor. |
| Claim: |
64. A packaged pharmaceutical preparation, comprising: (a) a pharmaceutical composition according to claim 28 in a container; and (b) instructions for using the composition to treat pain. |
| Claim: |
65. A packaged pharmaceutical preparation, comprising: (a) a pharmaceutical composition according to claim 28 in a container; and (b) instructions for using the composition to treat cough or hiccup. |
| Claim: |
66. A packaged pharmaceutical preparation, comprising: (a) a pharmaceutical composition according to claim 28 in a container; and (b) instructions for using the composition to treat obesity. |
| Claim: |
67. A packaged pharmaceutical preparation, comprising: (a) a pharmaceutical composition according to claim 28 in a container; and (b) instructions for using the composition to treat urinary incontinence or overactive bladder. |
| Claim: |
68. The use of a compound or salt according to any one of claims 1-23 for the manufacture of a medicament for the treatment of a condition responsive to capsaicin receptor modulation. |
| Claim: |
69. A use according to claim 68, wherein the condition is pain, asthma, chronic obstructive pulmonary disease, cough, hiccup, obesity, urinary incontinence or overactive bladder, exposure to capsaicin, burn or irritation due to exposure to heat, burn or irritation due to exposure to light, burn, bronchoconstriction or irritation due to exposure to tear gas, air pollutants or pepper spray, or burn or irritation due to exposure to acid. |
| Current U.S. Class: |
514250/000 |
| Current International Class: |
61; 61; 61; 07; 07; 07; 07; 61 |
| Accession Number: |
edspap.20080085901 |
| Database: |
USPTO Patent Applications |
