Phenyl naphthol ligands for thyroid hormone receptor

• US 6,951,844 B2
• Filed: 09/21/2004
• Issued: 10/04/2005
• Est. Priority Date: 12/07/2001
• Status: Expired due to Fees

• Current Assignee: Bristol Myers Squibb Co.
• Original Assignee: Bristol Myers Squibb Co.
• Inventors: Hangeland, Jon J.
• Primary Examiner(s): Wilson, James O.
• Assistant Examiner(s): Tucker, Zachary C.
• Application Number:
  US10/946,162
• Publication Number:
  US 20050038122A1
• Time in Patent Office: 378 Days
• Field of Search: 514/43, 514/54, 514/369, 514/532, 514/534, 514/535, 514/563, 514/565, 514/569, 514/592
• US Class Current: 514/43
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/195 having an amino group
• CPC Class Codes: A61K 31/198 Alpha-amino acids, e.g. alanine or edetic acid [EDTA] betaine A61K31/205; proline A61K31/401; tryptophan A61K31/405; histidine A61K31/4172; peptides not degraded to individual amino acids A61K38/00
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: C07C 229/18 the nitrogen atom of the amino group being further bound to carbon atoms of six-membered aromatic rings
• CPC Class Codes: C07C 233/25 having the carbon atom of the carboxamide group bound to a hydrogen atom or to a carbon atom of an acyclic saturated carbon skeleton
• CPC Class Codes: C07C 233/56 having carbon atoms of carboxamide groups bound to carbon atoms of carboxyl groups, e.g. oxamides
• CPC Class Codes: C07C 59/56 containing halogen

Abstract

New thyroid receptor ligands are provided which have the general formula I

• • wherein
  • R₁ is halogen, trifluoromethyl, substituted or unsubstituted aryl, substituted or unsubstituted C_1-6 alkyl, or substituted or unsubstituted C_3-7 cycloalkyl;
  • R₂ and R₃ are each independently hydrogen, halogen, substituted or unsubstituted C_1-4 alkyl, or substituted or unsubstituted C_3-6 cycloalkyl, wherein at least one of R₂ and R₃ is other than hydrogen;
  • R₄ is a carboxylic acid selected from the group consisting of (CH₂)_nCOOH, (CH)₂COOH, NHCO(CH₂)_nCOOH, CONH(CH₂)_nCOOH and NH(CH₂)_mCOOH;
  • n is an integer from 0 to 4; and
  • m is an integer from 1 to 4.

In addition, a method is provided for preventing, inhibiting or treating a disease associated with metabolism dysfunction or which is dependent upon the expression of a T₃ regulated gene, wherein a compound as described above is administered in a therapeutically effective amount.

Claims

1. A pharmaceutical composition comprising a compound of the formula I

wherein

R₃ is selected from the group consisting of halogen, trifluoromethyl, aryl, C_1-6 alkyl and C_3-7 cycloalkyl, wherein

the aryl group may optionally be substituted with one or more substituent selected from the group consisting of hydrogen, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, trifluoromethyl, trifluoromethoxy, alkynyl, hydroxy, amino, nitro, cyano, aryl, cycloalkyl, heteroaryl, carboxyl or an alkyl ester thereof, and carboxamide;

the C_1-6 alkyl group may optionally be substituted with one or more substituent selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heteroaryl, hydroxy, cyano, nitro, amino, halogen, carboxyl or an alkyl ester thereof, and carboxamide;

the C_3-7 cycloalkyl group may optionally be substituted with one or more substituent selected from the group consisting of hydrogen, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, trifluoromethyl, trifluoromethoxy, alkynyl, hydroxy, amino, nitro, cyano, aryl, cycloalkyl, heteroaryl, carboxyl or an alkyl ester thereof, and carboxamide;

R₂ and R₃ are each independently selected from the group consisting of hydrogen, halogen, C_1-4 alkyl and C_3-6 cycloalkyl, wherein at least one of R₂ and R₃ is other than hydrogen, and wherein

the C_1-6 alkyl group may optionally be substituted with one or more substituent selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heteroaryl, hydroxy, cyano, nitro, amino, halogen, carboxyl or an alkyl ester thereof, and carboxamide;

the C_3-7 cycloalkyl group may optionally be substituted with one or more substituent selected from the group consisting of hydrogen, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, trifluoromethyl, trifluoromethoxy, alkynyl, hydroxy, amino, nitro, cyano, aryl, cycloalkyl, heteroaryl, carboxyl or an alkyl ester thereof, and carboxaide;

R₄ is selected from the group consisting of (CH₂)_nCOOH, (CH)₂COOH, NHCO(CH₂)_nCOOH, CONH(CH₂)_nCOOH and NH(CH₂)_mCOOH, or esters thereof;

n is an integer from 0 to 4; and

m is an integer from 1 to 4,

including all stereolsomers thereof, prodrug esters thereof, and pharmaceutically acceptable salts thereof, and at least one additional therapeutic agent selected from the group consisting of other compounds of formula I, metformin, phenformin, glimepiride, glyburide, glicazide, chlorpropamide, glipizide, troglitazone, darglitazone, englitazone, rosiglitazone, pioglitazone, insulin, acarbose, miglitol, GLP-1, alendronate, risedronate, raloxifene, calcitonin, orlistat, sibutramine, topiramate, axokine, dexamphetamine, phentermine, phenylpropanolamine, mazindol, diethylstilbestrol, theophylline, enkephalins, sulbenox, GHRP-6, GHRP-2, GHRP-1, IGF-1, IGF-2, clonidine, sumatriptan, physostigmine, pyndostigmine, parathyroid hormone, estrogen, testosterone, tamoxifen, levonorgestrel, medroxyprogesterone acetate, prednisone, dexamethasone, aspirin, indomethacin, ibuprofen, piroxicam, mycophenolate, infliximab, budesonide, clofazimine, priliximab, diazepam, lorazepam, buspirone, oxazepam, hydroxyzine pamoate, citalopram, fluoxetine, nefazodone, sertraline, tretinoin, diltiazem, verapamil, nifedipine, amlodipine, mybefradil, chlorothiazide, hydrochlorothiazide, flumethiazide, hydroflumethiazide, bendroflumethiazide, methylchlorothiazide, trichloromethiazide, polythiazide, benzthiazide, ethacrynic acid, chlorthalidone, furosemide, musolimine, bumetanide, triamterene, amiloride, spironolactone, captopril, zofenapril, pentopril, quinapril, ramipril, lisinopril, losartan, irbesartan, valsartan, sitaxsentan, atrasentan, omaprilat, gemopatrilat, digitalis, ouabain, 9-[4-[4-[[2-(2,2,2-trifluoroethoxy)benzoyl]amino]-1-piperidinyl]butyl]-N-(2,2,2-trifluoroethyl)-9H-fluorene-9-carboxamide, mevastatin, lovastatin, pravastatin, fluvastatin, atorvastatin, cholestyramine, colestipol, imanixil, tetrahydrolipostatin, istmastanylphosphorylcholine, melinamide, nicotinic acid, acipimox, acifran, neomycin, p-aminosalicylic, thyrotropin, polythyroid and dronedarone.

2. The pharmaceutical composition of claim 1 wherein said antidiabetic agent is selected from the group consisting of metformin, glyburide, glimepiride, glipyride, glipizide, chlorpropamide, gliclazide, acarbose, miglitol, troglitazone, pioglitazone, englitazone, darglitazone, rosiglitazone, and insulin.