Cycloalkyl containing anilide ligands for the thyroid receptor

• US 20040176425A1
• Filed: 01/23/2004
• Published: 09/09/2004
• Est. Priority Date: 01/24/2003
• Status: Abandoned Application

• Current Assignee: Bristol-Myers Squibb Company
• Original Assignee: Bristol-Myers Squibb Company
• Inventors: Washburn, William N., Meng, Wei
• Application Number:
  US10/764,118
• Publication Number:
  US 20040176425A1
• Time in Patent Office: Days
• US Class Current: 514/357
• CPC Class Codes: A61P 1/14 Prodigestives, e.g. acids, enzymes, appetite stimulants, antidyspeptics, tonics, antiflatulents
• 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 17/04 Antipruritics
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 17/16 Emollients or protectives, e.g. against radiation
• 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 25/24 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 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 5/14 of the thyroid hormones, e.g. T3, T4
• 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 233/60 : having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms
• CPC Class Codes: C07C 2601/02 : with a three-membered ring
• CPC Class Codes: C07C 2601/04 : with a four-membered ring
• CPC Class Codes: C07C 2601/08 : the ring being saturated
• CPC Class Codes: C07C 2601/14 : The ring being saturated

Abstract

Novel thyroid receptor ligands are provided having the general formula I

wherein

X, R₁, R₂, R₃, R₄, R₅, R₆, R₇, R₈, R₉, R₁₀ and R₁₁ 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 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 hydrogen, halogen or alkyl;

R₅ is hydrogen;

R₆ and R₇ are each independently bromo, chloro or C₁ to C₄ alkyl;

R₈ is hydrogen, halogen or alkyl;

R₉ is hydrogen or halogen;

R₁₀ is hydrogen;

R₁₁ is carboxyl; and

n is 2 or 3.

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 chloro or C₁ to C₄ alkyl;

R₅ is hydrogen;

R₆ and R₇ are each independently bromo, chloro or methyl;

R₈ is hydrogen, chloro or C₁ to C₄ alkyl;

R₉ is hydrogen;

R₁₀ is hydrogen;

R₁₁ is carboxyl; and

n is 2.

6. The compound as defined in claim 2 wherein

R₁ is hydrogen;

R₂ is isopropyl;

R₃ is hydrogen;

R₄ is chloro or methyl;

R₅ is hydrogen;

R₆ and R₇ are bromo;

R₈ is hydrogen or methyl;

R₉ is hydrogen;

R₁₀ is hydrogen;

R₁₁ is carboxyl; and

n is 2.

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

11. The pharmaceutical composition of claim 10 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.

12. The pharmaceutical composition of claim 11 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.

13. The pharmaceutical composition of claim 11 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.

14. The pharmaceutical composition of claim 11 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.

15. The pharmaceutical composition of claim 11 wherein said additional therapeutic agent is a hypolipidemic agent selected from 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 and a nicotinic acid or a derivative thereof.

16. 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.

17. 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.

18. The method according to claim 17 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.

19. The method according to claim 17 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.

20. 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.

21. 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.

22. A method according to claim 21 further comprising administering, concurrently or sequentially, a therapeutically effective amount of at least one additional therapeutic agent selected from an anti-obesity agent and an appetite suppressant.

23. A method according to claim 22 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.

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