Phenyl naphthol ligands for thyroid hormone receptor

• US 20050038122A1
• Filed: 09/21/2004
• Published: 02/17/2005
• Est. Priority Date: 12/07/2001
• Status: Active Grant

• Current Assignee: Jon J. Hangeland
• Original Assignee: Jon J. Hangeland
• Inventors: Hangeland, Jon J.
• Granted Patent: US 6,951,844 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

1-6. -6. (Canceled)

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

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 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.

13-21. -21. Cancel