THYROID RECEPTOR LIGANDS

• US 20100298276A1
• Filed: 05/21/2009
• Published: 11/25/2010
• Est. Priority Date: 04/18/2003
• Status: Active Grant

• Current Assignee: Bristol-Myers Squibb Company
• Original Assignee: Bristol-Myers Squibb Company
• Inventors: Sanin, Andrei, Doweyko, Arthur M.P., Friends, Todd J., Caringal, Yolanda V., Dejneka, Tamara, Ryono, Denis E., Malm, Johan, Devasthale, Pratik, Hangeland, Jon J., Zhang, Minsheng
• Granted Patent: US 8,263,659 B2
• Time in Patent Office: Days
• US Class Current: 514/140
• 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 31/4439 containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole nicotine A61K31/465
• CPC Class Codes: A61K 31/662 Phosphorus acids or esters thereof having P—C bonds, e.g. foscarnet, trichlorfon
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: C07C 205/38 the oxygen atom of at least one of the etherified hydroxy groups being further bound to a carbon atom of a six-membered aromatic ring, e.g. nitrodiphenyl ethers
• CPC Class Codes: C07C 217/58 with amino groups and the six-membered aromatic ring, or the condensed ring system containing that ring, bound to the same carbon atom of the carbon chain
• CPC Class Codes: C07C 233/29 having the carbon atom of the carboxamide group bound to an acyclic carbon atom of a carbon skeleton containing six-membered aromatic rings
• CPC Class Codes: C07C 235/34 having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
• CPC Class Codes: C07C 235/42 having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton
• CPC Class Codes: C07C 235/46 having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
• CPC Class Codes: C07C 235/52 having the nitrogen atom of at least one of the carboxamide groups bound to an acyclic carbon atom of a hydrocarbon radical substituted by carboxyl groups
• CPC Class Codes: C07C 235/60 having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
• CPC Class Codes: C07C 235/62 having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a ring other than a six-membered aromatic ring
• CPC Class Codes: C07C 235/64 having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a six-membered aromatic ring
• CPC Class Codes: C07C 2601/02 with a three-membered ring
• CPC Class Codes: C07C 2601/14 The ring being saturated
• CPC Class Codes: C07C 2602/08 the other ring being five-membered, e.g. indane
• CPC Class Codes: C07C 2603/18 Fluorenes; Hydrogenated fluorenes
• CPC Class Codes: C07C 311/37 having the sulfur atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
• CPC Class Codes: C07C 311/46 : Y being a hydrogen or a carbon atom
• CPC Class Codes: C07C 43/29 : containing halogen
• CPC Class Codes: C07C 43/295 : containing hydroxy or O-metal groups
• CPC Class Codes: C07C 59/68 : the oxygen atom of the ether group being bound to a non-condensed six-membered aromatic ring
• CPC Class Codes: C07C 59/72 : containing six-membered aromatic rings and other rings
• CPC Class Codes: C07C 65/24 : polycyclic
• CPC Class Codes: C07C 65/26 : containing rings other than six-membered aromatic rings
• CPC Class Codes: C07C 69/16 : of dihydroxylic compounds
• CPC Class Codes: C07C 69/736 : the hydroxy group of the ester being etherified with a hydroxy compound having the hydroxy group bound to a carbon atom of a six-membered aromatic ring
• CPC Class Codes: C07C 69/94 : of polycyclic hydroxy carboxylic acids, the hydroxy groups and the carboxyl groups of which are bound to carbon atoms of six-membered aromatic rings
• CPC Class Codes: C07D 213/30 : Oxygen atoms
• CPC Class Codes: C07D 239/26 : with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
• CPC Class Codes: C07D 257/04 : Five-membered rings
• CPC Class Codes: C07D 263/14 : with radicals substituted by oxygen atoms
• CPC Class Codes: C07D 263/32 : with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
• CPC Class Codes: C07D 277/24 : Radicals substituted by oxygen atoms
• CPC Class Codes: C07D 285/06 : 1,2,3-Thiadiazoles; Hydrogenated 1,2,3-thiadiazoles
• CPC Class Codes: C07D 307/42 : Singly bound oxygen atoms
• CPC Class Codes: C07D 307/52 : Radicals substituted by nitrogen atoms not forming part of a nitro radical
• CPC Class Codes: C07D 307/87 : Benzo [c] furans; Hydrogenated benzo [c] furans
• CPC Class Codes: C07D 317/58 : Radicals substituted by nitrogen atoms nitro radicals C07D317/52
• CPC Class Codes: C07D 317/60 : Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
• CPC Class Codes: C07D 333/32 : Oxygen atoms
• CPC Class Codes: C07F 9/306 : Arylalkanephosphinic acids, e.g. Ar-(CH2)n-P(=X)(R)(XH), (X = O,S, Se; n>=1)
• CPC Class Codes: C07F 9/3241 : Esters of arylalkanephosphinic acids
• CPC Class Codes: C07F 9/4056 : Esters of arylalkanephosphonic acids C07F9/4025 takes precedence

Abstract

Thyroid receptor ligands are provided which have the general formula I

wherein:

• • R₁ is

• • R₂ and R₃ are the same or different and are hydrogen, halogen, alkyl of 1 to 4 carbons or cycloalkyl of 3 to 5 carbons, provided that at least one of R₂ and R₃ is other than hydrogen;
  • R₄ is

• • R₅ and R₆ are the same or different and are selected from hydrogen, aryl, heteroaryl, alkyl, cycloalkyl, aralkyl or heteroaralkyl.
  • R₇ is aryl, heteroaryl, alkyl, aralkyl, or heteroaralkyl;
  • R₈ is aryl, heteroaryl, or cycloalkyl;
  • R₉ is R₇ or hydrogen;
  • R₁₀ is hydrogen, halogen, cyano or alkyl;
  • R₁₁ and R₁₂ are each independently selected from the group consisting of hydrogen, halogen, alkoxy, hydroxy (—OH) cyano, and alkyl;
  • R₁₃ is carboxylic acid (COOH) or esters thereof, phosphonic and phosphinic acid or esters thereof, sulfonic acid, tetrazole, hydroxamic acid, thiazolidinedione, acylsulfonamide, or other carboxylic acid surrogates known in the art;
  • R₁₄ and R₁₅ may be the same or different and are selected from hydrogen and alkyl, or R₁₄ and R₁₅ may be joined together forming a chain of 2 to 5 methylene groups [—(CH2)m-, m=2, 3, 4 or 5], thus forming 3- to 6-membered cycloalkyl rings;
  • R₁₆ is hydrogen or alkyl of 1 to 4 carbons;
  • R₁₇ and R₁₈ are the same or different and selected from hydrogen, halogen and alkyl;
  • n is 0 or an integer from 1 to 4;
  • X is oxygen (—O—), sulfur (—S—), sulfonyl (—SO₂—), sulfenyl (—SO—) selenium (—Se—), carbonyl (—CO—), amino (—NH—) or methylene (—CH2-); wherein the substituents are as described herein.

In addition, a method is provided for preventing, inhibiting or treating diseases or disorders associated with metabolism 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

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

3. A pharmaceutical composition comprising a compound as defined in claim 2 and at least one additional therapeutic agent selected from the group consisting of 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.

4. The pharmaceutical composition of claim 3 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, GLP-1, a dipeptidyl peptidase IV inhibitor and insulin.

5. The pharmaceutical composition of claim 3 wherein said additional therapeutic agent is an antidiabetic agent selected from the group consisting of metformin, glyburide, glimepiride, glipyride, glipizide, chlorpropamide, gliclazide, acarbose, miglitol, troglitazone, pioglitazone, englitazone, darglitazone, rosiglitazone and insulin

6. The pharmaceutical composition of claim 3 wherein said additional therapeutic agent is an anti-obesity agent is selected from the group consisting of 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.

7. The pharmaceutical composition of claim 3 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 and a nicotinic acid.

8. 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.

9. 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.

10. The method according to claim 9 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.

11. The method according to claim 9 further comprising administering, concurrently or sequentially, a therapeutically effective amount of at least one additional therapeutic agent selected from the group consisting of 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.

12. 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.

13. 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.

14. A method according to claim 13 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.

15. A method according to claim 14 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 agents and anorectic agents.

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

17. A compound selected from the group consisting of:

(4-{3-[(Benzo[1,3]dioxol-5-ylmethyl)-carbamoyl]-4-hydroxy-phenoxy}-3,5-dibromo-phenyl)-acetic acid;

{4-[3-(2-Benzo[1,3]dioxol-5-yl-ethylcarbamoyl)-4-hydroxy-phenoxy]-3,5-dibromo-phenyl}-acetic acid;

{3,5-Dibromo-4-[4-hydroxy-3-(4-[1,2,3]thiadiazol-4-yl-benzylcarbamoyl)-phenoxy]-phenyl}-acetic acid;

(3,5-Dibromo-4-{3-[(furan-2-ylmethyl)-carbamoyl]-4-hydroxy-phenoxy}-phenyl)-acetic acid;

{3,5-Dibromo-4-[4-hydroxy-3-(phenethylamino-methyl)-phenoxy]-phenyl}-acetic acid;

{3,5-Dibromo-4-[4-hydroxy-3-(thiophen-3-yloxy)-phenoxy]-phenyl}-acetic acid;

[3,5-Dichloro-4-(4-hydroxy-3-pyridin-3-yl-phenoxy)-phenyl]-acetic acid;

[3,5-Dichloro-4-(4-hydroxy-3-pyridin-4-yl-phenoxy)-phenyl]-acetic acid;

[3,5-Dichloro-4-(4-hydroxy-3-pyrimidin-5-yl-phenoxy)-phenyl]-acetic acid;

{3,5-Dichloro-4-[4-hydroxy-3-(4-methyl-pyridin-2-yl)-phenoxy]-phenyl}-acetic acid;

{3,5-Dichloro-4-[4-hydroxy-3-(6-methyl-pyridin-2-yl)-phenoxy]-phenyl}-acetic acid;

[3,5-Dichloro-4-(4-hydroxy-3-pyridin-2-yl-phenoxy)-phenyl]-acetic acid;

[3,5-Dichloro-4-(4-hydroxy-3-thiazol-2-yl-phenoxy)-phenyl]-acetic acid;

(S)-{3,5-Dibromo-4-[4-hydroxy-3-(4-phenyl-4,5-dihydro-oxazol-2-yl)-phenoxy]-phenyl}-acetic acid;

(R)-{3,5-Dibromo-4-[4-hydroxy-3-(4-isopropyl-4,5-dihydro-oxazol-2-yl)-phenoxy]-phenyl}-acetic acid;

(S)-{3,5-Dibromo-4-[4-hydroxy-3-(4-isopropyl-4,5-dihydro-oxazol-2-yl)-phenoxy]-phenyl}-acetic acid;

(R)-{3,5-Dibromo-4-[4-hydroxy-3-(4-phenyl-4,5-dihydro-oxazol-2-yl)-phenoxy]-phenyl}-acetic acid;

(R)-{3,5-Dibromo-4-[4-hydroxy-3-(4-methyl-4,5-dihydro-oxazol-2-yl)-phenoxy]-phenyl}-acetic acid;

(S)-{3,5-Dibromo-4-[4-hydroxy-3-(4-methyl-4,5-dihydro-oxazol-2-yl)-phenoxy]-phenyl}-acetic acid;

{3,5-Dibromo-4-[3-(4,5-dihydro-oxazol-2-yl)-4-hydroxy-phenoxy]-phenyl}-acetic acid;

{3,5-Dibromo-4-[4-hydroxy-3-(4-phenyl-oxazol-2-yl)-phenoxy]-phenyl}-acetic acid;

{3,5-Dibromo-4-[4-hydroxy-3-(4-isopropyl-oxazol-2-yl)-phenoxy]-phenyl}-acetic acid;

{3,5-Dibromo-4-[4-hydroxy-3-(4-methyl-oxazol-2-yl)-phenoxy]-phenyl}-acetic acid;

3,5-Dibromo-4-(3-furan-2-yl-4-hydroxy-5-isopropyl-phenoxy)-benzoic acid; and

5-[2,6-Dichloro-4-(1H-tetrazol-5-ylmethyl)-phenoxy]-biphenyl-2-ol.

18. A compound selected from the group consisting of

{3,5-Dibromo-4-[4-hydroxy-3-(4-sulfamyl-benzylcarbamoyl)-phenoxyl]-phenyl}-acetic acid;

3,5-Dibromo-4-(6-hydroxy-5-isopropyl-biphenyl-3-yloxy)-benzoic acid; and

3-[3,5-Dibromo-4-(6-hydroxy-5-isopropyl-biphenyl-3-yloxy)-phenyl]-propionic acid.