Claims
- 1. A method of treating neuromuscular dysfunction of the lower urinary tract in a mammal in need of such treat ment comprising administering to said mammal an effective amount of a compound having selective affinity for the mGlu5 subtype of the metabotropic glutamate receptors.
- 2. The method of claim 1 wherein said compound has an at least about 10-fold slectivity for the mGlu5 subtype of the metabotropic glutamate receptors.
- 3. The method of claim 1 wherein said compound has an at least about 25-fold slectivity for the mGlu5 subtype of the metabotropic glutamate receptors.
- 4. The method of claim 1 wherein said compound has an at least about 50-fold slectivity for the mGlu5 subtype of the metabotropic glutamate receptors.
- 5. The method of claim 1 wherein said compound has an at least about 100-fold slectivity for the mGlu5 subtype of the metabotropic glutamate receptors.
- 6. The method of claim 1 wherein said compound has an at least about 500-fold slectivity for the mGlu5 subtype of the metabotropic glutamate receptors.
- 7. The method of claim 1 wherein said compound is a selective mGlu5 receptor antagonist.
- 8. The method of claim 7 wherein said neuromuscular dysfinction is urinary urgency, overactive bladder, increased urinary frequency, decreased urinary compliance, cystitis, incontinence, urine leakage, enuresis, dysuria, urinary hesitancy or difficulty in emptying the bladder.
- 9. The method of claim 8 wherein said neuromuscular dysfunction that is decreased urinary compliance is decreased bladder storage capacity.
- 10. The method of claim 8 wherein said said neuromuscular dysfunction is interstitial cystitis.
- 11. The method of claim 1 wherein said compound is administered as a pharmaceutically acceptable composition.
- 12. The method of claim 11 wherein said compound is administered via an oral, parenteral, intranasal, sublingual, rectal or inhalatory route, or by insufflation, transdermal patches or lyophilized composition.
- 13. The method of claims 1 wherein said compound is administered in an amount of between about 0.01 to about 25 mg/kg/day.
- 14. The method of claim 13 wherein said compound is administered in an amount of between about 0.1 to about 10 mg/kg/day.
- 15. The method of claim 14 wherein said compound is administered in an amount of about 0.2 to about 5 mg/kg/day.
- 16. The method of claim 1 wherein said compound is administered at a total daily dose of about 25 to about 1000 mg.
- 17. The method of claim 16 wherein said compound is administered at a total daily dose of about 150 to about 500 mg.
- 18. The method of claim 17 wherein said compound is administered at a total daily dose of about 350 mg.
- 19. The method of claim 1 wherein said compound is administered in combination with an antimuscarinic drug.
- 20. The method of claim 19 wherein said antimuscarinic drug is selected from the group consisting of oxybutynin, tolterodine, darifenacin and temiverine.
- 21. The method of claim 1 wherein said compound is administered in combination with an α1-adrenergic antagonist.
- 22. The method of claim 21 wherein said α1-adrenergic antagonist is selected from the group consisting of prazosin, doxazosin, terazosin, alfuzosin and tamsulosin.
- 23. The method of claim 1 wherein said compound is administered in combination with a 5-HT1A receptor antagonist.
- 24. The method of claim 1 wherein said compound is administered in combination with a selective COX2 inhibitor.
- 25. The method of claim 24 wherein said selective COX2 inhibitor comprises a NO releasing group.
- 26. The method of claim 1 wherein said compound is administered in combination with a non-selective COX1/COX2 inhibitor.
- 27. The method of claim 26 wherein said non-selective COX1/COX2 inhibitor derivative comprises a NO releasing group.
- 28. The method of claim 1 wherein said mammal is a human.
- 29. The method of claim 1 wherein said compound is administered in admixture with a pharmaceutically acceptable diluent or carrier.
- 30. The method of claim 29 wherein said pharmaceutically acceptable diluent or carrier is selected from the group consisting of ethanol, water, glycerol, aloe vera gel, allantoin, glycerine, vitamin A oil, vitamin E oil, mineral oil, phosphate buffered saline, PPG2 myristyl propionate, magnesium carbonate, potassium phosphate, vegetable oil, animal oil, and solketal.
- 31. The method of claim 1 wherein said compound having selective affinity for the mGlu5 subtype of the metabotropic glutamate receptors has a general formula I
- 32. The method of claim 31 wherein said compound has a structure wherein
X1 is a (C2-4)alkenylene, (C2-4)haloalkenylene, (C2-4)alkynylene or (C2-4)haloalkynylene group, wherein each of the foregoing groups is bonded via vicinal unsaturated carbon atoms; R1 is hydrogen, (C1-4)alkyl, (C1-4)alkoxy, hydroxy(C1-4)alkyl, cyano, ethynyl, carboxy, (C1-4)alkoxycarbonyl, di(C1-4)alkylamino, (C1-6)alkylaminocarbonyl, or trifluoromethylphenylaminocarbonyl; R2 is hydrogen, hydroxy, (C1-4) alkyl, hydroxy (C1-4) alkyl, (C1-4) alkoxy, carboxy, (C2-5)alkanoyloxy, (C1-4)alkoxycarbonyl, di(C1-4)alkylamino(C1-4)alkanoyl, di(C1-4)alkylaminomethyl, 4-(4-fluorobenzoyl)-piperidin-1-yl-carbonyl, 4-tert-butyloxycarbonyl-piperazin-1-yl-carbonyl, 4-(4-azido-2-hydroxybenzoyl)-piperazin-1-yl-carbonyl or 4-(4-azido-2-hydroxy-3-iodobenzoyl)-piperazin-1-yl-carbonyl; R3 is hydrogen, (C1-4) alkyl, carboxy, (C1-4)alkoxycarbonyl, (C1-4)alkylcarbamoyl, hydroxy(C1-4)alkyl, di(C1-4)alkylaminomethyl, morpholinocarbonyl or 4-(4-fluoro-benzoyl)-piperidin-1-yl-carbonyl; R4 is hydrogen, hydroxy, (C1-4)alkoxy, carboxy, (C2-5)alkanoyloxy, (C1-4)alkoxycarbonyl, amino(C1-4)alkoxy, di(C1-4)alkylamino(C1-4)alkoxy, di(C1-4)alkylamino(C1-4)alkyl, carboxy(C1-4)alkylcarbonyl, (C1-4)alkoxycarbonyl(C1-4)alkoxy, hydroxy(C1-4)alkyl, di(C1-4)alkylamino(C1-4)alkoxy, or m-hydroxy-p-azidophenylcarbonylamino (C1-4)alkoxy; and R5 is a group of formula 14Ra and Rb independently are hydrogen, hydroxy, halogen, nitro, cyano, carboxy, (C1-4)alkyl, (C1-4)alkoxy, hydroxy(C1-4)alkyl, (C1-4)alkoxycarbonyl, (C2-7)alkanoyl, (C2-5)alkanoyloxy, (C2-5)alkanoyloxy(C1-4)alkyl, trifluoromethyl, trifluoromethoxy, trimethylsilylethynyl, (C2-5)alkynyl, amino, azido, amino(C1-4)alkoxy, (C2-5)alkanoylamino(C1-4)alkoxy, (C1-4)alkylamino(C1-4)alkoxy, di(C1-4)alkylamino(C1-4)alkoxy, (C1-4)alkylamino, di(C1-4)alkylamino, monohalobenzylamino, thienylmethylamino, thienylcarbonylamino, trifluoromethylphenylaminocarbonyl, tetrazolyl, (C2-5)alkanoylamino, benzylcarbonylamino, (C1-4)alkylaminocarbonylamino (C1-4)alkoxycarbonyl-aminocarbonylamino or (C1-4)alkylsulfonyl; Rc is hydrogen, fluorine, chlorine, bromine, hydroxy, (C1-4)alkyl, (C2-5)alkanoyloxy, (C1-4)alkoxy or cyano; and Rd is hydrogen, halogen or (C1-4)alkyl.
- 33. The method of claim 31 wherein said compound has a structure wherein
X1 is a (C2-4)alkenylene, (C2-4)haloalkenylene, (C24)alkynylene or (C2-4)haloalkynylene group, wherein each of the foregoing groups is linked via vicinal unsaturated carbon atoms; R1 is hydrogen, (C1-4)alkyl, (C1-4)alkoxy, cyano, ethynyl or di(C1-4)alkylamino; R2 is hydrogen, hydroxy, carboxy, (C1-4)alkoxycarbonyl, di(C1-4)alkylaminomethyl, 4-(4-fluorobenzoyl)-piperidin-1-yl-carbonyl, 4-tert-butyloxycarbonyl-piperazin-1-yl-carbonyl, 4-(4-azido-2-hydroxybenzoyl)-piperazin-1-yl-carbonyl or 4-(4-azido-2-hydroxy-3-iodobenzoyl)-piperazin-1-yl-carbonyl; R3 is hydrogen, (C1-4)alkyl, carboxy, (C1-4)alkoxycarbonyl, (C1-4)alkylcarbamoyl, hydroxy(C1-4)alkyl, di(C1-4)alkylaminomethyl, morpholinocarbonyl or 4-(4-fluoro-benzoyl)-piperidin-1-yl-carbonyl; R4 is hydrogen, hydroxy, carboxy, (C2-5)alkanoyloxy, (C1-4)alkoxycarbonyl, amino(C1-4)alkoxy, di(C1-4)alkylamino(C1-4)alkoxy, di(C1-4)alkylamino(C1-4)alkyl or hydroxy(C1-4)alkyl; and R5 is a group of formula 15Ra and Rb independently are hydrogen, halogen, nitro, cyano, (C1-4)alkyl, (C1-4)alkoxy, trifluoromethyl, trifluoromethoxy or (C2-5)alkynyl; Rc is hydrogen, fluorine, chlorine, bromine, hydroxy, (C1-4)alkyl, (C2-5)alkanoyloxy, (C1-4)alkoxy or cyano; and Rd is hydrogen, halogen or (C1-4)alkyl.
- 34. The method of claim 31 wherein said compound is 2-methyl-6-(phenylethynyl)pyridine (MPEP).
- 35. The method of claim 31 wherein said compound is 2-methyl-6-(2-phenylethenyl)pyridine (SIB 1893).
- 36. The method of claim 1 wherein said compound has a general formula I-A
- 37. The method of claim 1 wherein said compound has a general formula II-A
- 38. The method of claim 37 wherein B1 represents B1 and R12 represents (CH2)n—C(O)ORf, unsubstituted heteroaryl or heteroaryl substituted with one or more lower alkyl or cycloalkyl.
- 39. The method of claim 38 wherein R12 represents —C(O)O-lower alkyl.
- 40. The method of claim 1 wherein said compound has general formula II-B or II-C
- 41. The method of claim 1 wherein said compound has a general formula III
- 42. The method of claim 41 wherein said administered compound is 3-(2-methylthiazol-4-yl)ethynylpyridine (MTEP).
- 43. The method of claim 1 wherein said compound has a general formula IV
- 44. The method of claim 1 wherein said compound has general formula V-A
- 45. The method of claim 44 wherein Ar3 is selected from the group consisting of phenyl, benzyl, naphthyl, fluorenyl, anthrenyl, indenyl, phenanthrenyl and benzonaphthenyl groups.
- 46. The method of claim 44 wherein Ar2 is selected from the group consisting of thiazolyl, furyl, pyranyl, 2H-pyrrolyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, benzothiazolyl, benzimidazolyl, 3H-indolyl, indolyl, indazolyl, purinyl quinolizinyl, isoquinolyl, quinolyl, phthalizinyl, naphthyridinyl, quinazolinyl, cinnolinyl, isothiazolyl, quinoxalinyl, indolizinyl, isoindolyl, benzothienyl, benzofuranyl, isobenzofuranyl and chromenyl groups.
- 47. The method of claim 44 wherein Ar3 is selected from the group consisting of phenyl, benzyl, naphthyl, fluorenyl, anthrenyl, indenyl, phenanthrenyl and benzonaphthenyl groups and Ar2 is selected from the group consisting of thiazolyl, furyl, pyranyl, 2H-pyrrolyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, benzothiazolyl, benzimidazolyl, 3H-indolyl, indolyl, indazolyl, purinyl, quinolizinyl, isoquinolyl, quinolyl, phthalizinyl, naphthyridinyl, quinazolinyl, cinnolinyl, isothiazolyl, quinoxalinyl, indolizinyl, isoindolyl, benzothienyl, benzofuranyl, isobenzofuranyl and chromenyl groups.
- 48. The method of claim 1 wherein said compound has a general formula V-B
- 49. The method of claim 48 wherein said heterocyclic or fused heterocylic group is selected from the group consisting of quinolyl, quinazolyl, quinoxalyl, 2-pyrimidyl, 4-pyrimidyl, 5-pyrimidyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, and pyrazyl.
- 50. A method of identifying a compound useful for treating neuromuscular dysfunction of the lower urinary tract in a mammal, comprising
(a) determining the binding affinities of one or more test compound for an mGlu5 receptor and one or more of an mGlu1 receptor or Group II mGlu receptor; (b) identifying a test compound that
(1) binds to mGlu5 receptor with an affinity of at least 10−6 M; and (2) binds to mGlu5 receptor with an affinity at least 10-fold stronger than the affinity for mGlu1 receptor or Group II mGlu receptor.
- 51. The method of claim 50 further comprising
individually measuring the binding affinity of said one or more test compounds for one or more Group III mGlu receptor and identifying a test compound that binds to mGlu5 receptor with an affinity at least 10-fold stronger than the affinity for a Group III mGlu receptor.
- 52. The method of claim 50 or 51 wherein step (b) comprises identifying a test compounds that
(1) binds to mGlu5 receptor with an affinity of at least 10−6 M; and (2) binds to mGlu5 receptor with an affinity at least 10-fold stronger than the affinity for each of mGlu1 receptor and Group II mGlu receptor.
- 53. The method of claim 50 or 51 wherein step (b) comprises identifying a test compounds that
(1) binds to mGlu5 receptor with an affinity of at least 10−6 M; and (2) binds to mGlu5 receptor with an affinity at least 100-fold stronger than the affinity for a mGlu1 receptor or Group II mGlu receptor.
- 54. The method of claim 53 wherein step (b) comprises identifying a test compounds that
(1) binds to mGlu5 receptor with an affinity of at least 10−6 M; and (2) binds to mGlu5 receptor with an affinity at least 100-fold stronger than the affinity for each of mGlu1 receptor and Group II mGlu receptor.
- 55. The method of claim 50 or 51 further comprising measuring the ability of each of said identified test compound to act as an antagonist or inverse agonist at the mGlu5 receptor.
- 56. The method of claim 50 or 51 wherein said neuromuscular dysfunction is urinary urgency, overactive bladder, increased urinary frequency, decreased urinary compliance, cystitis, incontinence, urine leakage, enuresis, dysuria, urinary hesitancy or difficulty in emptying the bladder.
- 57. The method of claim 56 wherein said neuromuscular dysfunction that is decreased urinary compliance is decreased bladder storage capacity.
- 58. The method of claim 56 wherein said neuromuscular dysfunction that is cystitis is interstitial cystitis.
Priority Claims (1)
Number |
Date |
Country |
Kind |
MI2003A 000151 |
Jan 2003 |
IT |
|
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application claims priority under 35 U.S.C. § 119(e) of provisional application No. 60/506,631, filed Sep. 26, 2003, and under 35 U.S.C. § 119(a)-(d) of Italian patent application no. MI 2003 A 000151, filed Jan. 30, 2003. Each of the foregoing applications is hereby incorporated herein by reference in its entirety.
Provisional Applications (1)
|
Number |
Date |
Country |
|
60506631 |
Sep 2003 |
US |