Bita3 adrenergic receptor agonists and uses thereof

• US 20020052392A1
• Filed: 10/17/2001
• Published: 05/02/2002
• Est. Priority Date: 10/20/2000
• Status: Active Grant

• Current Assignee: Jennifer A. Lafontaine, Robert F. Day
• Original Assignee: Jennifer A. Lafontaine, Robert F. Day
• Inventors: Lafontaine, Jennifer A., Day, Robert F.
• Granted Patent: US 6,566,377 B2
• Time in Patent Office: Days
• US Class Current: 514/345
• 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 1/06 Anti-spasmodics, e.g. drugs for colics, esophagic dyskinesia
• CPC Class Codes: A61P 1/12 Antidiarrhoeals
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 11/04 for throat disorders
• CPC Class Codes: A61P 11/06 Antiasthmatics
• CPC Class Codes: A61P 13/00 Drugs for disorders of the urinary system
• CPC Class Codes: A61P 13/02 of urine or of the urinary tract, e.g. urine acidifiers
• CPC Class Codes: A61P 13/04 for urolithiasis
• CPC Class Codes: A61P 13/08 of the prostate
• CPC Class Codes: A61P 25/24 Antidepressants
• 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 3/00 Drugs for disorders of the metabolism of the blood or the extracellular fluid A61P7/00
• CPC Class Codes: A61P 3/04 Anorexiants; Antiobesity agents
• CPC Class Codes: A61P 3/06 Antihyperlipidemics
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 31/18 for HIV
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/10 for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: C07D 231/12 : with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
• CPC Class Codes: C07D 233/56 : with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
• CPC Class Codes: C07D 233/64 : with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
• CPC Class Codes: C07D 249/08 : 1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
• CPC Class Codes: C07D 263/32 : with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
• CPC Class Codes: C07D 271/06 : 1,2,4-Oxadiazoles; Hydrogenated 1,2,4-oxadiazoles
• CPC Class Codes: C07D 271/10 : 1,3,4-Oxadiazoles; Hydrogenated 1,3,4-oxadiazoles
• CPC Class Codes: C07D 277/24 : Radicals substituted by oxygen atoms
• CPC Class Codes: C07D 285/06 : 1,2,3-Thiadiazoles; Hydrogenated 1,2,3-thiadiazoles
• 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 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 417/04 : directly linked by a ring-member-to-ring-member bond
• 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

Abstract

The instant invention provides β₃ adrenergic receptor agonists of structural Formula (I),

the stereoisomers and prodrugs thereof, and the pharmaceutically acceptable salts of the compounds, stereoisomers and prodrugs, wherein Ar, R, R₁, R₂, R₃, R₄, R₅, R₆, R₇, R₈, X, and Y, are as defined herein.

The invention further provides intermediates useful in the preparation of the compounds of Formula (I), to combinations of the compounds of Formula (I), the stereoisomers and prodrugs thereof, and the pharmaceutically acceptable salts of the compounds, stereoisomers and prodrugs, with anti-obesity agents; to pharmaceutical compositions comprising the compounds of Formula (I), the stereoisomers and prodrugs thereof, and the pharmaceutically acceptable salts of the compounds, stereoisomers and prodrugs, or pharmaceutical compositions comprising the compounds of Formula (I), the stereoisomers and prodrugs thereof, and the pharmaceutically acceptable salts of the compounds, stereoisomers and prodrugs, and anti-obesity agents; and methods of treating β₃ adrenergic receptor-mediated diseases, conditions, or disorders in a mammal which methods comprise administering to the mammal an effective amount of a compound of Formula (I), a stereoisomer or prodrug thereof, or a pharmaceutical composition thereof; or a combination of a compound of Formula (I), a pharmaceutically acceptable salt of the compound, stereoisomer, or prodrug, and an anti-obesity agent, or a pharmaceutical composition thereof.

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-oxazol4-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)-phenoxyl-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)-phenoxyl-ethylamino}-ethanol;

(R)-1-pyridin-3-yl-2-{2-[4-(2-pyridin-3-yl-thiazol4-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-yl-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-thiazol4-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-yl)-phenoxy]-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-{l -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 β

₃ 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 β

₃ 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 β

₃ 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 β

₃ 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 MCR4 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 β

₃ 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 β

₃ 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-(1-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.