Substituted anilide ligands for the thyroid receptor

• US 20040180940A1
• Filed: 01/23/2004
• Published: 09/16/2004
• Est. Priority Date: 01/24/2003
• Status: Active Grant

• Current Assignee: Bristol-Myers Squibb Company, Karo Pharma AB
• Original Assignee: Bristol-Myers Squibb Company
• Inventors: Washburn, William N., Meng, Wei, Ryono, Denis E., Malm, Johan, Ellsworth, Bruce A., Garg, Neeraj, Rahimi-Ghadim, Mahmoud, Ericsson, Thomas
• Granted Patent: US 7,342,127 B2
• Time in Patent Office: Days
• US Class Current: 514/357
• 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 31/277 having a ring, e.g. verapamil
• CPC Class Codes: A61K 31/44 Non condensed pyridines; Hydrogenated derivatives thereof
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 17/02 for treating wounds, ulcers, burns, scars, keloids, or the like
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 17/10 Anti-acne agents
• CPC Class Codes: A61P 19/08 for bone diseases, e.g. rachitism, Paget's disease
• CPC Class Codes: A61P 19/10 for osteoporosis
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/18 Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
• CPC Class Codes: A61P 25/24 Antidepressants
• CPC Class Codes: A61P 25/28 for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• CPC Class Codes: A61P 27/06 Antiglaucoma agents or miotics
• 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 35/00 Antineoplastic agents
• CPC Class Codes: A61P 5/14 : of the thyroid hormones, e.g. T3, T4
• CPC Class Codes: A61P 5/16 : for decreasing, blocking or antagonising the activity of the thyroid hormones
• CPC Class Codes: A61P 9/04 : Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
• CPC Class Codes: A61P 9/06 : Antiarrhythmics
• 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: 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

Abstract

Novel thyroid receptor ligands are provided having the general formula I

wherein

X, R₁, R₂, R₃, R₄, R₅, R₆, R₇, R₈, R₉, R₁₀, R₁₁, R₁₂ and R₁₃ are as defined herein.

In addition, a method is provided for preventing, inhibiting or treating diseases or disorders associated with metabolic dysfunction or which are 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 X is oxygen.

3. The compound as defined in claim 2 wherein

R₁ is hydrogen;

R₂ is C₁ to C₆ alkyl or C₃ to C₇ cycloalkyl;

R₃ is hydrogen;

R₄ is halogen or C₁ to C₄ alkyl;

R₅ is hydrogen;

R₆ and R₇ are independently bromo, chloro or methyl;

R₈ is halogen or C₁ to C₄ alkyl;

R₉ is hydrogen or halogen;

R₁₀ is hydrogen;

R₁₁ is carboxyl;

R₁₂ is hydrogen; and

R₁₃ is hydrogen.

4. The compound as defined in claim 3 wherein R₂ is isopropyl.

5. The compound as defined in claim 2 wherein

R₁ is hydrogen;

R₂ is isopropyl;

R₃ is hydrogen;

R₄ is C₁ to C₄ alkyl;

R₅ is hydrogen;

R₆ and R₇ are independently bromo, chloro or methyl;

R₈ is halogen or methyl;

R₉ is hydrogen or chloro;

R₁₀ is hydrogen;

R₁₁ is carboxyl;

R₁₂ is hydrogen; and

R₁₃ is hydrogen.

6. The compound as defined in claim 2 wherein

R₁ is hydrogen;

R₂ is isopropyl;

R₃ is hydrogen;

R₄ is methyl;

R₅ is hydrogen;

R₆ and R₇ are independently bromo or chloro;

R₈ is chloro or methyl;

R₉ is hydrogen;

R₁₀ is hydrogen;

R₁₁ is carboxyl;

R₁₂ is hydrogen; and

R₁₃ is hydrogen.

7. The compound as defined in claim 1 having the structure

8. The compound as defined in claim 1 having the structure

9. The compound as defined in claim 1 having the structure

10. The compound as defined in claim 1 having the structure

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

12. The pharmaceutical composition of claim 11 further comprising at least one additional therapeutic agent selected from 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 supressants, bone resorption inhibitors, thyroid mimetics, anabolic agents, anti-tumor agents and retinoids.

13. The pharmaceutical composition of claim 12 wherein said additional therapeutic agent is an antidiabetic agent selected from 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.

14. The pharmaceutical composition of claim 12 wherein said additional therapeutic agent is an antidiabetic agent selected from metformin, glyburide, glimepiride, glipyride, glipizide, chlorpropamide, gliclazide, acarbose, miglitol, troglitazone, pioglitazone, englitazone, darglitazone, rosiglitazone and insulin.

15. The pharmaceutical composition of claim 12 wherein said additional therapeutic agent is an anti-obesity agent selected from an aP2 inhibitor, a PPAR gamma antagonist, a PPAR delta agonist, a beta 3 adrenergic agonist, a lipase inhibitor, a serotonin reuptake inhibitor, a cannabinoid-1 receptor antagonist and an anorectic agent.

16. The pharmaceutical composition of claim 12 wherein said additional therapeutic agent is a hypolipidemic agent selected from 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 and a nicotinic acid or a derivative thereof.

17. A method for preventing, inhibiting or treating a disease associated with metabolic 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.

18. 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 mammalian patient in need of treatment a therapeutically effective amount of a compound as defined in claim 1.

19. The method according to claim 18 wherein the skin disorder or disease is dermal atrophy, post surgical bruising caused by laser resurfacing, keloids, stria, cellulite, roughened skin, actinic skin damage, lichen planus, ichtyosis, acne, psoriasis, Dernier'"'"'s disease, eczema, atopic dermatitis, chloracne, pityriasis or skin scarring.

20. The method according to claim 18 further comprising administering, concurrently or sequentially, a therapeutically effective amount of at least one additional therapeutic agent selected from 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 supressants, bone resorption inhibitors, thyroid mimetics, anabolic agents, anti-tumor agents and retinoids.

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

22. 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.

23. A method according to claim 22 further comprising administering, concurrently or sequentially, a therapeutically effective amount of at least one additional therapeutic agent selected from an anti-obesity agent or an appetite suppressant.

24. A method according to claim 23 wherein said anti-obesity agent is selected from aP2 inhibitors, PPAR gamma antagonists, PPAR delta agonists, beta 3 adrenergic agonists, lipase inhibitors, serotonin (and dopamine) reuptake inhibitors, cannabinoid-1 receptor antagonists, other thyroid receptor agents and anorectic agents.

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