Claims
- 1. A compound of Formula (I)
- 2. A compound according to claim 1, wherein Ar is pyridyl; R, R1, R2, R3, R4, and R8 are hydrogen; X is oxygen; Y is a direct bond; and R5 is a five- or six-membered ring heterocycle selected from the group consisting of dihydropyridazinonyl, imidazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolinyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinonyl, pyridazinyl, pyridyl, pyrimidinonyl, pyrimidyl, thiadiazolyl, thiazolinyl, thiazolyl, triazinyl, and triazolyl.
- 3. A compound according to claim 2 selected from the group consisting of:
(R)-2-{2-[4-(4-benzofuran-2-yl-thiazol-2-yl)-phenoxy]-ethylamino}-1-pyridin-3-yl-ethanol; (R)-2-{2-[4-(2-benzyloxymethyl-oxazol-4-yl)-phenoxy]-ethylamino}-1-pyridin-3-yl-ethanol; (R)-2-{2-[4-(2-butyl-thiazol-4-yl)-phenoxy]-ethylamino}-1-pyridin-3-yl-ethanol; (R)-2-{2-[4-(2-tert-butyl-thiazol-4-yl)-phenoxy]-ethylamino}-1-pyridin-3-yl-ethanol; (R)-2-{2-[4-(2-cyclopentyl-thiazol-4-yl)-phenoxy]-ethylamino}-1-pyridin-3-yl-ethanol; (R)-2-{2-[4-(2,5-dimethyl-oxazol-4-yl)-phenoxy]-ethylamino}-1-pyridin-3-yl-ethanol; (R)-2-(2-{4-[2-(2-ethyl-pyridin-4-yl)-thiazol-4-yl]-phenoxy}-ethylamino)-1-pyridin-3-yl-ethanol; (R)-2-{2-[4-(2-ethyl-oxazol-4-yl)-phenoxy]-ethylamino}-1-pyridin-3-yl-ethanol; (R)-2-{2-[4-(4-ethyl-thiazol-2-yl)-phenoxy]-ethylamino}-1-pyridin-3-yl-ethanol; (R)-2-{2-[4-(2-ethyl-thiazol-4-yl)-phenoxy]-ethylamino}-1-pyridin-3-yl-ethanol; (R)-2-{2-[4-(2-hydroxymethyl-oxazol-4-yl)-phenoxy]-ethylamino}-1-pyridin-3-yl-ethanol; (R)-6-{4-[2-(2-hydroxy-2-pyridin-3-yl-ethylamino)-ethoxy]-phenyl}-4,5-dihydro-2H-pyridazin-3-one; (R)-2-[2-(4-imidazol-1-yl-phenoxy)-ethylamino]-1-pyridin-3-yl-ethanol; (R)-2-{2-[4-(2-isopropyl-1H-imidazol-4-yl)-phenoxy]-ethylamino}-1-pyridin-3-yl-ethanol; (R)-2-{2-[4-(2-isopropyl-oxazol-4-yl)-phenoxy]-ethylamino}-1-pyridin-3-yl-ethanol; (R)-2-{2-[4-(2-isopropyl-thiazol-4-yl)-phenoxy]-ethylamino}-1-pyridin-3-yl-ethanol; (R)-2-{2-[4-(2-methoxymethyl-oxazol-4-yl)-phenoxy]-ethylamino}-1-pyridin-3-yl-ethanol; (R)-2-(2-{4-[2-(4-methoxy-phenyl)-thiazol-4-yl]-phenoxy}-ethylamino)-1-pyridin-3-yl-ethanol; (R)-2-{2-[4-(2-methyl-1H-imidazol-4-yl)-phenoxy]-ethylamino}-1-pyridin-3-yl-ethanol; (R)-2-{2-[4-(5-methyl-[1,3,4]oxadiazol-2-yl)-phenoxy]-ethylamino}-1-pyridin-3-yl-ethanol; (R)-2-{2-[4-(2-methyl-oxazol-4-yl)-phenoxy]-ethylamino}-1-pyridin-3-yl-ethanol; (R)-2-{2-[4-(5-methyl-oxazol-4-yl)-phenoxy]-ethylamino}-1-pyridin-3-yl-ethanol; (R)-2-(2-{4-[2-(2-methyl-propane-2-sulfonylmethyl)-thiazol-4-yl]-phenoxy)-ethylamino)-1-pyridin-3-yl-ethanol; (R)-2-{2-[4-(1-methyl-1H-pyrazol-3-yl)-phenoxy]-ethylamino}-1-pyridin-3-yl-ethanol; (R)-2-{2-[4-(4-methyl-thiazol-2-yl)-phenoxy]-ethylamino}-1-pyridin-3-yl-ethanol; (R)-2-{2-[4-(2-methyl-thiazol-4-yl)-phenoxy]-ethylamino}-1-pyridin-3-yl-ethanol; (R)-2-{2-[4-(5-methyl-4H-[1,2,4]triazol-3-yl)-phenoxy]-ethylamino}-1-pyridin-3-yl-ethanol; (R)-2-{2-[4-(2′-methyl-[2,4′]bithiazolyl-4-yl)-phenoxy]-ethylamino}-1-pyridin-3-yl-ethanol; (R)-2-[2-(4-oxazol-4-yl-phenoxy)-ethylamino]-1-pyridin-3-yl-ethanol; (R)-2-[2-(4-oxazol-5-yl-phenoxy)-ethylamino]-1-pyridin-3-yl-ethanol; (R)-2-{2-[4-(2-phenyl-1H-imidazol-4-yl)-phenoxy]-ethylamino}-1-pyridin-3-yl-ethanol; (R)-2-{2-[4-(2-phenyl-thiazol-4-yl)-phenoxy]-ethylamino}-1-pyridin-3-yl-ethanol; (R)-2-{2-[4-(4-phenyl-thiazol-2-yl)-phenoxy]-ethylamino}-1-pyridin-3-yl-ethanol; (R)-2-{2-[4-(2-propyl-thiazol-4-yl)-phenoxy]-ethylamino}-1-pyridin-3-yl-ethanol; (R)-2-{2-[4-(1H-pyrazol-3-yl)-phenoxy]-ethylamino}-1-pyridin-3-yl-ethanol; (R)-1-pyridin-3-yl-2-{2-[4-(2-pyridin-3-yl-1H-imidazol-4-yl)-phenoxy]-ethylamino}-ethanol; (R)-1-pyridin-3-yl-2-{2-[4-(2-pyridin-4-yl-1H-imidazol-4-yl)-phenoxy]-ethylamino}-ethanol; (R)-1-pyridin-3-yl-2-{2-[4-(2-pyridin-3-yl-thiazol-4-yl)-phenoxy]-ethylamino}-ethanol; (R)-1-pyridin-3-yl-2-{2-[4-(2-pyridin-4-yl-thiazol-4-yl)-phenoxy]-ethylamino}-ethanol; (R)-1-pyridin-3-yl-2-[2-(4-thiazol-2-yl-phenoxy)-ethylamino]-ethanol (R)-1-pyridin-3-yl-2-[2-(4-thiazol-4-yl-phenoxy)-ethylamino]-ethanol; (R)-1-pyridin-3-yl-2-{2-[4-(2-thiophen-2-yl-1H-imidazol-4-yl)-phenoxy]-ethylamino}-ethanol; (R)-1-pyridin-3-yl-2-{2-[4-(2-thiophen-2-yl-thiazol-4-yl)-phenoxy]-ethylamino)-ethanol; (R)-1-pyridin-3-yl-2-{2-[4-(4-p-tolyl-thiazol-2-yl)-phenoxy]-ethylamino}-ethanol; (R)-1-pyridin-3-yl-2-{2-[4-(2-p-tolyl-thiazol-4-yl)-phenoxy]-ethylamino}-ethanol; (R)-1-pyridin-3-yl-2-{2-[4-(2-trifluoromethyl-1H-imidazol-4-yl)-phenoxy]-ethylamino}-ethanol; (R)-1-pyridin-3-y-2-(2-{4-[2-(4-trifluoromethyl-phenyl)-thiazol-4-yl]-phenoxy}-ethylamino)-ethanol; (R)-1-pyridin-3-yl-2-{2-[4-(4-trifluoromethyl-thiazol-2-yl)-phenoxy]-ethylamino)-ethanol; and (R)-1-pyridin-3-yl-2-{2-[4-(2-trifluoromethyl-thiazol-4-yl)-phenoxy]-ethylamino}-ethanol; a stereoisomer or prodrug thereof, or a pharmaceutically acceptable salt of said compound, stereoisomer, or prodrug.
- 4. A compound according to claim 3 selected from the group consisting of:
(R)-2-{2-[4-(ethyl-thiazol-2-yl)-phenoxy]-ethylamino}-1-pyridin-3-yl-ethanol; (R)-2-{2-[4-(2-methoxymethyl-oxazol-4-yl)-phenoxy]-ethylamino}-1-pyridin-3-yl-ethanol; (R)-2-{2-[4-(2-methyl-oxazol-4-yl)-phenoxy]-ethylamino}-1-pyridin-3-yl-ethanol; (R)-2-{2-[4-(2-methyl-thiazol-4-yl)-phenoxy]-ethylamino}-1-pyridin-3-yl-ethanol; (R)-2-[2-(4-oxazol-4-yl-phenoxy)-ethylamino]-1-pyridin-3-yl-ethanol; (R)-2-{2-[4-(1H-pyrazol-3-yl)-phenoxy]-ethylamino}-1-pyridin-3-yl-ethanol; (R)-1-pyridin-3-yl-2-[2-(4-thiazol-2-yl-phenoxy)-ethylamino]-ethanol; (R)-1-pyridin-3-yl-2-[2-(4-thiazol-4-yl-phenoxy)-ethylamino]-ethanol; and (R)-1-pyridin-3-yl-2-{2-[4-(4-trifluoromethyl-thiazol-2-ethylamino}-ethanol; a stereoisomer or prodrug thereof, or a pharmaceutically acceptable salt of said compound, stereoisomer, or prodrug.
- 5. A compound according to claim 1 wherein Ar is phenyl; R is —NR9SO2R10; R1 is hydrogen, hydroxy, or halogen; R2, R3, R4, and R8 are hydrogen; X is oxygen; Y is a direct bond; and R5 is a five- or six-membered ring heterocycle selected from the group consisting of dihydropyridazinonyl, imidazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolinyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinonyl, pyridazinyl, pyridyl, pyrimidinonyl, pyrimidyl, thiadiazolyl, thiazolinyl, thiazolyl, triazinyl, and triazolyl.
- 6. A compound according to claim 5 selected from the group consisting of:
(R)-N-[2-chloro-5-(2-{2-[4-(2-ethyl-oxazol-4-yl)-phenoxy]-ethylamino}-1-hydroxy-ethyl)-phenyl]-methanesulfonamide; (R)-N-[2-chloro-5-(2-{2-[4-(2-ethyl-thiazol-4-yl)-phenoxy]-ethylamino}-1-hydroxy-ethyl)-phenyl]-methanesulfonamide; (R)-N-[2-chloro-5-(1-hydroxy-2-{2-[4-(2-isopropyl-1H-imidazol-4-yl)-phenoxy]-ethylamino}-ethyl)-phenyl]-methanesulfonamide; (R)-N-[2-chloro-5-(1-hydroxy-2-{2-[4-(2-isopropyl-oxazol-4-yl)-phenoxy]-ethylamino}-ethyl)-phenyl]-methanesulfonamide; (R)-N-[2-chloro-5-(1-hydroxy-2-{2-[4-(2-methyl-oxazol-4-yl)-phenoxy]-ethylamino}-ethyl)-phenyl]-methanesulfonamide; (R)-N-[2-chloro-5-(1-hydroxy-2-{2-[4-(2-methyl-1H-imidazol-4-yl)-phenoxy]-ethylamino}-ethyl)-phenyl]-methanesulfonamide; (R)-N-[2-chloro-5-(1-hydroxy-2-{2-[4-(2-methyl-thiazol-4-yl)-phenoxy]-ethylamino}-ethyl)-phenyl]-methanesulfonamide; (R)-N-(2-chloro-5-{1-hydroxy-2-[2-(4-oxazol-4-yl-phenoxy)-ethylamino]-ethyl}-phenyl)-methanesulfonamide; (R)-N-[2-chloro-5-(1-hydroxy-2-{2-[4-(2-phenyl-1H-imidazol-4-yl)-phenoxy]-ethylamino}-ethyl)-phenyl]-methanesulfonamide; (R)-N-[2-chloro-5-(1-hydroxy-2-{2-[4-(2-pyridin-3-yl-1H-imidazol-4-yl)-phenoxy]-ethylamino}-ethyl)-phenyl]-methanesulfonamide; (R)-N-[2-chloro-5-(1-hydroxy-2-{2-[4-(2-pyridin-4-yl-1H-imidazol-4-yl)-phenoxy]-ethylamino}-ethyl)-phenyl]-methanesulfonamide; (R)-N-(2-chloro-5-{1-hydroxy-2-[2-(4-thiazol-4-yl-phenoxy)-ethylamino]-ethyl}-phenyl)-methanesulfonamide; and (R)-N-[2-chloro-5-(1-hydroxy-2-{2-[4-(2-trifluoromethyl-1H-imidazol-4-yl)-phenoxy]-ethylamino}-ethyl)-phenyl]-methanesulfonamide; a stereoisomer or prodrug thereof, or a pharmaceutically acceptable salt of said compound, stereoisomer, or prodrug.
- 7. A compound according to claim 6 selected from the group consisting of:
(R)-N-[2-chloro-5-(2-{4-(2-ethyl-oxazol-4-yl)-phenoxy]-ethylamino}-1-hydroxy-ethyl)-phenyl]-methanesulfonamide; (R)-N-[2-chloro-5-(2-{4-(2-ethyl-thiazol-4-yl)-phenoxy]-ethylamino}-1-hydroxy-ethyl)-phenyl]-methanesulfonamide; (R)-N-[2-chloro-5-(1-hydroxy-2-{2-(4-(2-methyl-thiazol-4-yl)-phenoxy]-ethylamino}-ethyl)-phenyl]-methanesulfonamide; (R)-N-(2-chloro-5-{1-hydroxy-2-[2-(4-thiazol-4-yl-phenoxy)-ethylamino]-ethyl}-phenyl)-methanesulfonamide; (R)-N-[2-chloro-5-(1-hydroxy-2-{2-[4-(2-methyl-oxazol-4-yl)-phenoxy]-ethylamino}-ethyl)-phenyl]-methanesulfonamide; and (R)-N-(2-chloro-5-{1-hydroxy-2-[2-(4-oxazol-4-yl-phenoxy)-ethylamino]-ethyl}-phenyl)-sulfonamide; a stereoisomer or prodrug thereof, or a pharmaceutically acceptable salt of said compound, stereoisomer, or prodrug.
- 8. A method of treating a β3 adrenergic receptor-mediated disease, condition, or disorder in a mammal in need of such treatment which method comprises administering to said mammal a therapeutically effective amount of a compound of claim 1, a stereoisomer or prodrug thereof, or a pharmaceutically acceptable salt of said compound, stereoisomer, or prodrug.
- 9. A method according to claim 8 wherein said β3 adrenergic receptor-mediated disease, condition, or disorder is selected from the group consisting of obesity, diabetes, irritable bowel syndrome, inflammatory bowel disease, esophagitis, duodenitis, Crohn's Disease, proctitis, asthma, intestinal motility disorder, ulcer, gastritis, hypercholesterolemia, cardiovascular disease, urinary incontinence, depression, prostate disease, dyslipidemia, and airway inflammatory disorder.
- 10. A method of increasing lean meat content in an edible animal which method comprises administering to said edible animal a lean meat increasing amount of a compound of claim 1, a stereoisomer, or prodrug thereof, or a pharmaceutically acceptable salt of the compound, stereoisomer, or prodrug.
- 11. A pharmaceutical composition which comprises a compound of claim 1, a stereoisomer or prodrug thereof, or a pharmaceutically acceptable salt of said compound, stereoisomer, or prodrug, and a pharmaceutically acceptable carrier, vehicle, or diluent.
- 12. A method of treating a β3 adrenergic receptor-mediated disease, condition, or disorder in a mammal in need of such treatment which method comprises administering to said mammal a therapeutically amount of a composition of claim 11.
- 13. A method according to claim 12 wherein said β3 adrenergic receptor-mediated disease, condition, or disorder is selected from the group consisting of obesity, diabetes, irritable bowel syndrome, inflammatory bowel disease, esophagitis, duodenitis, Crohn's Disease, proctitis, asthma, intestinal motility disorder, ulcer, gastritis, hypercholesterolemia, cardiovascular disease, urinary incontinence, depression, prostate disease, dyslipidemia, and airway inflammatory disorder.
- 14. A method of increasing lean meat content in an edible animal which method comprises administering to said edible animal a lean meat increasing amount of a pharmaceutical composition of claim 11.
- 15. A pharmaceutical composition which comprises a compound of claim 1, a stereoisomer or prodrug thereof, or a pharmaceutically acceptable salt of said compound, stereoisomer, or prodrug; an anti-obesity agent; and a pharmaceutically acceptable carrier, vehicle, or diluent.
- 16. A composition according to claim 15 wherein said anti-obesity agent is selected from the group consisting of an apo-B/MTP inhibitor, an MCR-4 agonist, a CCK-A agonist, a monoamine reuptake inhibitor, a sympathomimetic agent, a serotoninergic agent, a dopamine agonist, a melanocyte-stimulating hormone receptor analog, a cannabinoid receptor antagonist, a melanin concentrating hormone antagonist, leptin, a leptin analog, a leptin receptor agonist, a galanin antagonist, a lipase inhibitor, a bombesin agonist, a Neuropeptide-Y antagonist, a thyromimetic agent, dehydroepiandrosterone or an analog thereof, a glucocorticoid receptor agonist or antagonist, an orexin receptor antagonist, a urocortin binding protein antagonist, a glucagon-like peptide-1 receptor agonist, and a ciliary neurotrophic factor, or AGRP.
- 17. A composition according to claim 16 wherein said anti-obesity agent is selected from the group consisting of phentermine, ephedrine, leptin, phenylpropanolamine, and pseudoephedrine; said monoamine reuptake inhibitor is sibutramine; said serotoninergic agent is fenfluramine or dexfenfluramine; said dopamine agonist is bromocriptine; said lipase inhibitor is orlistat; and said anorectic agent is a bombesin agonist.
- 18. A method of treating β3 adrenergic receptor-mediated disease, condition, or disorder in a mammal in need of such treatment which method comprises administering to said mammal a therapeutically effective amount of a composition of claim 15.
- 19. A method according to claim 18 wherein said β3 adrenergic receptor-mediated disease, condition, or disorder is selected from the group consisting of obesity, diabetes, irritable bowel syndrome, inflammatory bowel disease, esophagitis, duodenitis, Crohn's Disease, proctitis, asthma, intestinal motility disorder, ulcer, gastritis, hypercholesterolemia, cardiovascular disease, urinary incontinence, depression, prostate disease, dyslipidemia, and airway inflammatory disorder.
- 21. A method of increasing lean meat content in an edible animal which method comprises administering to said edible animal a lean meat increasing amount of a pharmaceutical composition of claim 15.
- 22. A compound of the formula
- 23. A compound according to claim 22 selected from the group consisting of:
2-[4-(4-benzofuran-2-yl-thiazol-2-yl)-phenoxy]-ethylamine; 2-[4-(2-benzyloxymethyl-oxazol-4-yl)-phenoxy]-ethylamine; 2-[4-(2-tert-butyl-thiazol-4-yl)-phenoxy]-ethylamine; 2-[4-(2-butyl-thiazol-4-yl)-phenoxy]-ethylamine; 2-[4-(2-cyclopentyl-thiazol-4-yl)-phenoxy]-ethylamine; 2-[4-(2,5-dimethyl-oxazol-4-yl)-phenoxy]-ethylamine; 2-[4-(2-ethyl-oxazol-4-yl)-phenoxy]-ethylamine; 2-{4-[2-(2-ethyl-pyridin-4-yl)-thiazol-4-yl]-phenoxy}-ethylamine; 2-[4-(4-ethyl-thiazol-2-yl)-phenoxy]-ethylamine; 2-[4-(4-ethyl-thiazol-4-yl)-phenoxy]-ethylamine; 2-[4-(2-hydroxymethyl-oxazol-4-yl)-phenoxy]-ethylamine; 2-[4-(2-isopropyl-oxazol-4-yl)-phenoxy]-ethylamine; 2-[4-(2-isopropyl-thiazol-4-yl)-phenoxy]-ethylamine; 2-[4-(2-methoxymethyl-oxazol-4-yl)-phenoxy]-ethylamine; 2-{4-[2-(4-methoxy-phenyl)-thiazol-4-yl]-phenoxy}-ethylamine; 2-[4-(2-methyl-oxazol-4-yl)-phenoxy]-ethylamine; 2-[4-(5-methyl-oxazol-4-yl)-phenoxy]-ethylamine; 2-(3-methyl-4-oxazol-4-yl)-phenoxy]-ethylamine; 2-{4-[2-(2-methyl-propane-2-sulfonylmethyl)-thiazol-4-yl]-phenoxy}-ethylamine; 2-[4-(l1-methyl-1H-pyrazol-3-yl)-phenoxy]-ethylamine; 2-[4-(2-methyl-thiazol-4-yl)-phenoxy]-ethylamine; 2-[4-(4-methyl-thiazol-2-yl)-phenoxy]-ethylamine; 2-[4-(2′-methyl-[2,4′]bithiazolyl-4-yl)-phenoxy]-ethylamine; 2-[4-(5-methyl-[1,3,4]oxadiazol-2-yl)-phenoxy]-ethylamine; 2-(4-[1,3,5]oxadiazol-2-yl-phenoxy)-ethylamine; 2-(4-oxazol-2-yl-phenoxy)-ethylamine; 2-(4-oxazol-4-yl-phenoxy)-ethylamine; 2-(4-oxazol-5-yl-phenoxy)-ethylamine; 2-[4-(2-phenethyl-thiazol-4-yl)-phenoxy]-ethylamine; 2-[4-(5-phenyl-[1,3,4]oxadiazol-2-ylmethyl)-phenoxy]-ethylamine; 2-[4-(4-phenyl-thiazol-2-yl)-phenoxy]-ethylamine; 2-[4-(2-phenyl-thiazol-4-yl)-phenyl]-ethylamine; 2-[4-(2-propyl-thiazol-4-yl)-phenoxy]-ethylamine; 2-(4-pyrazol-1-yl-phenoxy)-ethylamine; 2-[4-(1H-pyrazol-3-yl)-phenoxy]-ethylamine; 2-[4-(2-pyridin-3-yl-thiazol-4-yl)-phenoxy]-ethylamine; 2-4-(2-pyridin-4-yl-thiazol-4-yl)-phenoxy]-ethylamine; 2-(4-[1,2,3]thiadiazol-5-yl-phenoxy)-ethylamine; 2-(4-thiazol-2-yl-phenoxy)-ethylamine; 2-(4-thiazol-4-yl-phenoxy)-ethylamine; 2-[4-(2-thiophen-2-ylthiazol-4-yl)-phenoxy]-ethylamine; 2-[4-(2-p-tolyl-thiazol-4-yl)-phenoxy]-ethylamine; 2-[4-(4-p-tolyl-thiazol-2-yl)-phenoxy]-ethylamine; 2-[4-(2-trifluoromethyl-thiazol-4-yl)-phenoxy]-ethylamine; 2-{4-[2-(4-trifluoromethyl-phenyl)-thiazol-4-yl]-phenoxy}-ethylamine; 2-[4-(4-trifluoromethyl-thiazol-2-yl)-phenoxy]-ethylamine; and 2-[4-(5-trifluoromethyl-2H-pyrazol-3-yl)-phenoxy]-ethylamine; or an acid addition salt thereof.
CROSS REFERENCE TO RELATED APPLICATION
[0001] This application claims the benefit of U.S. Provisional Application No. 60/242,274 filed Oct. 20, 2000.
Provisional Applications (1)
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Number |
Date |
Country |
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60242274 |
Oct 2000 |
US |
Divisions (1)
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Number |
Date |
Country |
Parent |
09981551 |
Oct 2001 |
US |
Child |
10379976 |
Mar 2003 |
US |