Phenyl naphthol ligands for thyroid hormone receptor

• US 20030166724A1
• Filed: 12/06/2002
• Published: 09/04/2003
• Est. Priority Date: 12/07/2001
• Status: Active Grant

• Current Assignee: Bristol-Myers Squibb Company
• Original Assignee: Bristol-Myers Squibb Company
• Inventors: Hangeland, Jon J.
• Granted Patent: US 6,831,102 B2
• Time in Patent Office: Days
• US Class Current: 514/563
• 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 compound of the formula I

2. The compound as defined in claim 1 wherein

R₁ is selected from the group consisting of halogen, substituted or unsubstituted C_1-3 alkyl and substituted or unsubstituted aryl;

R₂ and R₃ are each independently hydrogen or chloro, wherein at least one of R₂ and R₃ is chloro;

R₄ is selected from the group consisting of NHCO(CH₂)_nCOOH, NH(CH₂)_mCOOH, CONHCH₂COOH and CH₂COOH;

n is an integer from 0 to 1; and

m is an integer from 1 to 2.

3. The compound as defined in claim 1 wherein

R₁ is bromo or substituted or unsubstituted C_1-3 alkyl;

R₂ and R₃ are chloro;

R₄ is NHCO(CH₂)_nCOOH or NH(CH₂ )_mCOOH;

n is an integer from 0 to 1; and

m is an integer from 1 to 2.

4. The compound as defined in claim 1 having the structure:

5. The compound as defined in claim 1 having the structure:

6. A pharmaceutical composition comprising a compound as defined in claim 1 and a pharmaceutically acceptable carrier therefor.

7. A pharmaceutical composition comprising a compound as defined in claim 1 and at least one additional therapeutic agent selected from the group consisting of other compounds of formula I, anti-diabetic agents, anti-osteoporosis agents, anti-obesity agents, growth promoting agents, anti-inflammatory agents, anti-anxiety agents, anti-depressants, anti-hypertensive agents, cardiac glycosides, cholesterol/lipid lowering agents, appetite suppressants, bone resorption inhibitors, thyroid mimetics, anabolic agents, anti-tumor agents and retinoids.

8. The pharmaceutical composition of claim 7 wherein said additional therapeutic agent is an anti-obesity agent or appetite suppressant.

9. The pharmaceutical composition of claim 8 wherein said additional therapeutic agent is an anti-obesity agent selected from the group consisting of aP2 inhibitors, PPAR gamma antagonists, PPAR delta agonists, beta 3 adrenergic agonists, lipase inhibitors, serotonin (and dopamine) reuptake inhibitors, other thyroid receptor beta agents and anorectic agents.

10. The pharmaceutical composition of claim 7 wherein said additional therapeutic agent is a hypolipidemic agent selected from the group consisting of a thiazolidinedione, an MTP inhibitor, a squalene synthetase inhibitor, an HMG CoA reductase inhibitor, a fibric acid derivative, an ACAT inhibitor, a cholesterol absorption inhibitor, an ileal Na⁺/bile cotransporter inhibitor, a bile acid sequestrant, a nicotinic acid and a derivative thereof.

11. The pharmaceutical composition of claim 7 wherein said additional therapeutic agent is an antidiabetic agent selected from the group consisting of a biguanide, a glucosidase inhibitor, a meglitinide, a sulfonylurea, a thiazolidinedione, a PPAR-alpha agonist, a PPAR-gamma agonist, a PPAR alpha/gamma dual agonist, an SGLT2 inhibitor, a glycogen phosphorylase inhibitor, an aP2 inhibitor, a glucagon-like peptide-1 (GLP-1), a dipeptidyl peptidase IV inhibitor and insulin.

12. The pharmaceutical composition of claim 7 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.

13. A method for preventing, inhibiting or treating a disease associated with metabolism dysfunction, or which is dependent on the expression of a T₃ regulated gene, which comprises administering to a mammalian patient in need of treatment a therapeutically effective amount of a compound as defined in claim 1.

14. A method for treating or delaying the progression or onset of obesity, hypercholesterolemia, atherosclerosis, depression, osteoporosis, hypothyroidism, subclinical hyperthyroidism, non-toxic goiter, reduced bone mass, density or growth, eating disorders, reduced cognitive function, thyroid cancer, glaucoma, cardiac arrhythmia, congestive heart failure or a skin disorder or disease, which comprises administering to a mammalian patient in need of treatment a therapeutically effective amount of a compound as defined in claim 1.

15. The method according to claim 14 wherein the skin disorder or disease is dermal atrophy, keloids, stria, cellulite, roughened skin, actinic skin damage, lichen planus, ichtyosis, acne, psoriasis, Dernier'"'"'s disease, eczema, atopic dermatitis, chloracne, pityriasis or skin scarring.

16. A method according to claim 14 further comprising administering, concurrently or sequentially, a therapeutically effective amount of at least one additional therapeutic agent selected from the group consisting of other compounds of formula I, anti-diabetic agents, anti-osteoporosis agents, anti-obesity agents, growth promoting agents, anti-inflammatory agents, anti-anxiety agents, anti-depressants, anti-hypertensive agents, cardiac glycosides, cholesterol/lipid lowering agents, appetite suppressants, bone resorption inhibitors, thyroid mimetics, anabolic agents, anti-tumor agents and retinoids.

17. A method of treating or delaying the progression or onset of a skin disorder or disease which comprises administering to a mammalian patient in need of treatment a therapeutically effective amount of a compound as defined in claim 1 in combination with a retinoid or a vitamin D analog.

18. A method for treating or delaying the progression or onset of obesity which comprises administering to mammalian patient in need of treatment a therapeutically effective amount of a compound as defined in claim 1.

19. A method according to claim 18 further comprising administering, concurrently or sequentially, a therapeutically effective amount of at least one additional therapeutic agent selected from the group consisting of an anti-obesity agent and an appetite suppressant.

20. A method according to claim 18 wherein said anti-obesity agent is selected from the group consisting of aP2 inhibitors, PPAR gamma antagonists, PPAR delta agonists, beta 3 adrenergic agonists, lipase inhibitors, serotonin (and dopamine) reuptake inhibitors, other thyroid receptor beta agents and anorectic agents.

21. A pharmaceutical composition which functions as a selective agonist of the thyroid hormone receptor-beta comprising a compound as defined in claim 1.