Thyroid receptor ligands, pharmaceutical compositions comprising them and their use in the treatment of disorders influenced by thyroid hormones

• US 20040097589A1
• Filed: 04/22/2003
• Published: 05/20/2004
• Est. Priority Date: 06/21/2000
• Status: Active Grant

• Current Assignee: Karo Pharma AB
• Original Assignee: Karo Pharma AB
• Inventors: Malm, Johan, Garg, Neeraj, Yi-Lin, Li, Collazo, Ana Maria Garcia, Litten, Chris
• Granted Patent: US 7,199,265 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 31/40 having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
• CPC Class Codes: A61K 31/41 having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
• 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 19/10 for osteoporosis
• CPC Class Codes: A61P 25/24 Antidepressants
• 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 233/25 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 233/27 : having the carbon atom of the carboxamide group bound to a carbon atom of an acyclic unsaturated carbon skeleton
• 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 233/75 : with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a six-membered aromatic ring
• 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 237/40 : having the nitrogen atom of the carboxamide group bound to a carbon atom of a six-membered aromatic ring
• CPC Class Codes: C07C 2601/04 : with a four-membered ring
• CPC Class Codes: C07C 2601/14 : The ring being saturated
• CPC Class Codes: C07C 2601/18 : with a ring being at least seven-membered
• CPC Class Codes: C07C 311/08 : having the nitrogen atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
• CPC Class Codes: C07C 311/13 : the carbon skeleton containing six-membered aromatic rings
• CPC Class Codes: C07C 311/21 : having the nitrogen atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
• CPC Class Codes: C07C 311/24 : of an acyclic saturated carbon skeleton
• CPC Class Codes: C07C 311/29 : 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 335/18 : being further substituted by singly-bound oxygen atoms
• CPC Class Codes: C07D 209/34 : in position 2
• CPC Class Codes: C07D 209/42 : 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 213/70 : Sulfur atoms
• CPC Class Codes: C07D 215/48 : Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
• CPC Class Codes: C07D 217/26 : Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
• CPC Class Codes: C07D 265/36 : condensed with one six-membered ring
• CPC Class Codes: C07D 295/15 : to an acyclic saturated chain

Abstract

This invention relates to compounds of the formula (I) which are thyroid receptor ligands, and are preferably selective for the thyroid hormone receptor β, to methods of preparing such compounds and to methods for using such compounds such as in the regulation of metabolism.

Claims

1. Compounds of the general formula:

2. The compounds as defined in claim 1 wherein:

R₁ is selected from C_6-10 aryl, C_5-9 heteroaryl, C_1-10 alkyl, C_2-10 alkenyl or C_2-10 alkynyl or C_3-10 cycloalkyl;

R₂ is selected from hydrogen, halogen, C_6-10 aryl or C_1-4 alkyl;

R₃ and R₄ is selected from halogen and C_1-3 alkyl;

Z is —

(CH₂)_n—

or —

CH═

CH—

;

R₅ is —

CO₂H or a carboxylic acid amide —

COR′

R″

.

3. The compounds as defined in claim 1 wherein:

R₁ is selected from C_6-10 aryl, C_5-9 heteroaryl, C_3-10 alkyl, C_3-1alkenyl or C_3-10 alkynyl or C_3-10 cycloalkyl;

R₂ is selected from hydrogen, halogen or C_1-2 alkyl;

R₃ and R₄ is selected from chlorine;

Z is —

(CH₂)_n—

or —

CH═

CH—

;

R₅ is —

CO₂H;

R^a is hydrogen, halogen, —

CO₂H, C₆ aryl, —

N(C_1-4 alkyl)₂;

R^b is hydrogen, halogen, —

CO₂H, C_1-4 alkoxy, —

N(C_1-4 alkyl)₂;

n is 1 or 2.

4. The compounds as defined in claim 1 wherein:

R₁ is selected from;

C_3-8 alkyl

R₂ is selected from;

hydrogen, halogen or C₁ alkyl;

R₃ and R₄ is selected from chlorine;

Z is —

(CH₂)_n—

or —

CH═

CH—

R₅ is —

CO₂H;

R^a is hydrogen or fluorine;

n is 1 or 2;

Q is —

CO—

.

5. A compound according to any one of claims 1 to 4, which have one or more assymetric centers and can exist in the form of racemates, single and multiple enantiomers, as individual diastereomers, with all possible isomers, and mixtures thereof.

6. The compounds as defined in claim 1-5 which is:

3,5-Dichloro-4-(3-bromo-4-isobutyramidophenoxy)phenylacetic acid;

3,5-Dichloro-4-(4-isobutyramidophenoxy)phenylacetic acid;

3,5-Dichloro-4-(3-phenyl-4-isobutyramidophenoxy)phenylacetic acid;

3,5-Dichloro-4-(3-bromo-4-[3-methylcrotonylamido]phenoxy)phenylacetic acid;

3,5-Dichloro-4-(3-isopropylidene-1,3-dihydro-2-oxy-5-indoloxy)phenylacetic acid

3,5-Dichloro-4-(3-isopropyl-1,3-dihydro-2-oxy-5-indoloxy)phenylacetic acid;

3,5-Dichloro-4-(3-bromo-4-acetamidophenoxy)phenylacetic acid;

3,5-Dichloro-4-(4-acetamido-3-phenylphenoxy)phenylacetic acid;

N-[3,5-dichloro-4-(4-isobutyramidophenoxy)phenylacetyl]glycine;

L-N-[3,5-dichloro-4-(4-isobutyramidophenoxy)phenylacetyl]alanine;

L-N-[3,5-dichloro-4-(4-isobutyramidophenoxy)phenylacetyl]valine;

N-[3,5-dichloro-4-(4-isobutyramido-3-bromophenoxy)phenylacetyl]glycine;

L-Methyl-N-[3,5-dichloro-4-(4-isobutyramido-3-bromophenoxy)phenylacetyl]alanine;

L-N-[3,5-Dichloro-4-(4-isobutyramido-3-bromophenoxy)phenylacetyl]valine;

3,5-Dichloro-4-(4-isobutyramido-3-methylphenoxy)phenylacetic acid;

3,5-Dichloro-4-(4-trifluoroacetamido-3-bromophenoxy)phenylacetic acid;

3,5-Dichloro-4-(4-[2-chloropropionamido]-3-bromophenoxy)phenylacetic acid;

3,5-Dichloro-4-(4-p-fluorobenzamido-3-bromophenoxy)phenylacetic acid;

3,5-Dichloro-4-(4-isobutyramido-3-trifluoromethylphenoxy)phenylacetic acid;

3,5-Dichloro-4-(3chloro-4-isobutyramidophenoxy)phenylacetic acid;

3,5-Dichloro-4-(1,3-dihydro-2-oxy-5-imidazoloxy)phenylacetic acid;

3,5-Dichloro-4-(3-bromo-4-isobutyramidophenoxy)phenylcinnamic acid;

3,5-Dichloro-4-(3-bromo-4-[2-chloropropionamido]phenoxy)phenylcinnamic acid;

3,5-Dichloro-4-(3-bromo-4-isobutyramidophenoxy)phenylpropionic acid;

3,5-Dichloro-4-(3-bromo-4-p-fluorobenzamidophenoxy)phenylpropionic acid;

3,5-Dichloro-4-(3-bromo-4-[2-chloropropionamido]phenoxy)phenylpropionic acid;

3,5-Dichloro-4-(4-isobutyramidophenoxy)phenylpropionic acid;

3,5-Dichloro-4-(4-[2-chloropropionamido]phenoxy)phenylcinnamic acid;

3,5-Dibromo-4-(3-methyl-1,3-dihydro-2-oxy-5-indoloxy)phenylcinnamic acid;

3,5-Dibromo-4-(3-methyl-1,3-dihydro-2-oxy-5-indoloxy)phenoxyacetic acid;

3,5-Diisopropyl-4-(7-2H-1,4-benzoxazinoxy-3(4H)-one)phenylpropionic acid;

3,5-Dichloro-4-[3-((E)-2-carboxyvinyl)-4-isobutyramidophenoxy]phenylacetic acid;

3,5-Dichloro-4-(3-bromo-4-isobutyramidophenoxy)benzoyl phenylsulfonamide;

and the compounds showed in the table below,

R₁—

Q—

R₂H H H H H H H H H H H H H H H H H H H H H H H H Br Br Br Br Br Br Br H B H H H H H H H H H H H H H H H

7. A compound according to any one of claims 1 to 6 for use in medical therapy.

8. A pharmaceutical composition comprising an effective amount of a compound according to claim 1 to 6 or a pharmaceutically effective salt thereof, together with a pharmaceutically acceptable carrier.

9. A process for making a pharmaceutical composition comprising combining a compound according to any one of claims 1 to 6 and a pharmaceutically acceptable carrier.

10. A method for preventing inhibiting or treating a disease dependent on the expression of a T₃ regulated gene or associated with metabolic dysfunction, which method comprises administering to a patient a therapeutically effective amount of a compound as defined in claims 1 to 6.

11. The method as defined in claim 10, wherein the disease is obesity, hypercholesterolemia, atherosclerosis, depression, osteoporosis, hypothyroidism, goiter, thyroid cancer, glaucoma, cardiac arrhythmia, congestive heart failure, or a skin disorders or disease.

12. The method according to claim 11, 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 and skin scarring.

13. The use of a compound according to claims 1 to 6 in the preparation of a medicament for the treatment of a disease or disorder which is dependent on the expression of a T₃ regulated gene.

14. The use of a compound according to claims 1 to 6 in which the disease or disorder is obesity, hypercholesterolemia, atherosclerosis, depression, osteoporosis, hypothyroidism, goiter, thyroid cancer, or another endocrine disorder related to thyroid hormone.

15. The use of a compound according to claims 1 to 6 in which the disease or disorder is a skin disorder, glaucoma, cardiovascular disease, or congestive heart failure.

16. The use according to claim 15, 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 and skin scarring.

17. A method to treat a skin disorder or disease by the use of a compound of claims 1 to 6 in a combination with a retinoid or a Vitamin D anal g.