Novel thyroid receptor ligands and method II

• US 20050282872A1
• Filed: 07/26/2005
• Published: 12/22/2005
• Est. Priority Date: 12/24/1998
• Status: Active Grant

• Current Assignee: Ana Maria Garcia Collazo, Chris Litten, Denis Ryono, Johan Malm, Jon Hangeland, Konrad Koehler, Minsheng Zhang, Neeraj Garg, Ye Liu, Yi-Lin Li, Yolanda Caringal
• Original Assignee: Ana Maria Garcia Collazo, Chris Litten, Denis Ryono, Johan Malm, Jon Hangeland, Konrad Koehler, Minsheng Zhang, Neeraj Garg, Ye Liu, Yi-Lin Li, Yolanda Caringal
• Inventors: Liu, Ye, Malm, Johan, Garg, Neeraj, Li, Yi-Lin, Zhang, Minsheng, Caringal, Yolanda, Koehler, Konrad, Hangeland, Jon, Collazo, Ana Maria Garcia, Ryono, Denis, Litten, Chris
• Granted Patent: US 7,288,571 B2
• Time in Patent Office: Days
• US Class Current: 514/362
• 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 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 3/04 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 9/06 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 235/32 the carbon skeleton containing six-membered aromatic rings
• 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 307/06 having nitrogen atoms of the sulfamide groups bound to acyclic carbon atoms
• CPC Class Codes: C07C 311/51 Y being a hydrogen or a carbon atom
• CPC Class Codes: C07C 323/41 Y being a hydrogen or an acyclic carbon atom
• CPC Class Codes: C07C 323/60 with the carbon atom of at least one of the carboxyl groups bound to nitrogen atoms
• CPC Class Codes: C07D 207/09 : Radicals substituted by nitrogen atoms, not forming part of a nitro radical
• CPC Class Codes: C07D 207/27 : with substituted hydrocarbon radicals directly attached to the ring nitrogen atom
• CPC Class Codes: C07D 211/24 : by sulfur atoms to which a second hetero atom is attached
• CPC Class Codes: C07D 211/34 : with hydrocarbon 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 211/58 : attached in position 4
• CPC Class Codes: C07D 211/96 : Sulfur atom
• CPC Class Codes: C07D 213/40 : Acylated substituent nitrogen atom
• CPC Class Codes: C07D 223/12 : Nitrogen atoms not forming part of a nitro radical
• CPC Class Codes: C07D 231/38 : Nitrogen atoms nitro radicals C07D231/16
• CPC Class Codes: C07D 233/64 : with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
• CPC Class Codes: C07D 257/04 : Five-membered rings
• CPC Class Codes: C07D 285/06 : 1,2,3-Thiadiazoles; Hydrogenated 1,2,3-thiadiazoles
• CPC Class Codes: C07D 285/135 : Nitrogen atoms
• CPC Class Codes: C07D 295/13 : to an acyclic saturated chain
• CPC Class Codes: C07D 295/185 : from aliphatic carboxylic acids
• CPC Class Codes: C07D 333/20 : by nitrogen atoms nitro, nitroso radicals C07D333/12

Abstract

New thyroid receptor ligands are provided which have general formula (I) in which: n is an integer from 0 to 4; R₁ is halogen, trifluoromethyl, or alkyl of 1 to 6 carbons or cycloalkyl of 3 to 7 carbons; R₂ and R₃ are the same or differential hydrogen, halogen, alkyl of 1 to 4 carbons or cycloalkyl of 3 to 5 carbons, at least one of R₂ and R₃ being other than hydrogen; R₄ is a carboxylic acid thereof; or when n is equal to or greater than one, R₄ may be heteroaromatic moiety which may be substituted or unsubstituted, or an amine (NR′R″). R₅ is hydrogen or an acyl (such as acetyl or benzoyl) or other group capable of bioconversion to generate the free phenol structure (wherein R₅—H). In addition, a method is provided for preventing, inhibiting or treating a disease associated with metabolism dysfunction or which is dependant upon the expression of a T₃ regulated gene, wherein a compound as described above is administered in a therapeutically effective amount. Examples of such diseases associated with metabolism dysfunction or are dependent upon the expression of a T₃ regulated gene include obesity, hypercholesterolemia, atherosclerosis, cardiac arrhythmias, depression, osteoporosis, hypothyroidism, goiter, thyroid cancer as well as glaucoma, congestive heart failure and skin disorders.

Claims

1. A compound having the formula

2. A compound as defined in claim 1 where R₄ is a carboxylic acid amide (CONR′

R″

) in which the amine portion of the carboxylic amide can be derived from an achiral or a L or D alpha amino acid such as when the general structure —

CONR′

R″

can be represented by

3. The compound as defined in claim 2 where R′

and R* are connected to form a 4 to 8-membered ring.

4. The compound as defined in claim 2 where R′

and R* comprise consecutive —

(CH₂)—

groups to form proline or homoproline.

5. The compound as defined in claim 1 where n is 0 or 1 or 2.

6. The compound as defined in claim 1 wherein R₂ and R₃ are each independently halogen.

7. The compound as defined in claim 1 wherein R₂ and R₃ are each independently an alkyl group.

8. The compound as defined in claim 1 wherein one of R₂ and R₃ is halogen and the other is an alkyl group.

9. The compound as defined in claim 1 wherein one of R₂ and R₃ is halogen and the other is hydrogen.

10. The compound as defined in claim 1 wherein one of R₂ and R₃ is alkyl and the other is hydrogen.

11. The compound as defined in claim 1 wherein R₂ and R₃ are independently Cl, Br, methyl or ethyl.

12. The compound as defined in claim 1 wherein R₁ is isopropyl.

13. The compound as defined in claim 1 wherein R₄ is heteroaromatic hydrocarbon, carboxylic acid amide, or an acylsulphonamide.

14. The compound as defined in claim 1 wherein R₅ is hydrogen.

15. The compound as defined in claim 1 which is

3,5-Dimethyl-4-(4-hydroxy-3-isopropylphenoxy)benzyltetrazole,

3,5-Dichloro-4-(4-hydroxy-3-isopropylphenoxy)benzyltetrazole,

2-[3,5-Dibromo-4-(4-hydroxy-3-isopropylphenoxy)benzyl]-4-thiazole acetic acid,

2-[3,5-Dibromo-4-(4-hydroxy-3-isopropylphenoxy)benzyl]-4-methylthiazole,

16. The compound as defined in claim 1 which is

3,5-Dibromo-4-(4-hydroxy-3-isopropylphenoxy)benzoyl-5-hydroxy-1-naphthalenesulphon-amide,

3,5-Dibromo-4-(4-hydroxy-3-isopropylphenoxy)benzoyl-4-toluenesulphonamide,

3,5-Dibromo-4-(4-hydroxy-3-isopropylphenoxy)benzoyl-4-nitrobenzenesulphonamide,

3,5-Dibromo-4-(4-hydroxy-3-isopropylphenoxy)benzoyl sulfamide,

3,5-Dibromo-4-(4-hydroxy-3-isopropylphenoxy)benzoyl-5-dimethylamino-1-naphthalenesulp honamide,

3,5-Dibromo-4-(4-hydroxy-3-isopropylphenoxy)benzoyl-4-aminobenzenesulphonamide,

Methyl-[3,5-Dibromo-4-(4-hydroxy-3-isopropylphenoxy)benzoyl-2-sulphonamide] benzoate,

3,5-Dibromo-4-(4-hydroxy-3-isopropylphenoxy)benzoyl-2-aminobenzenesulphonamide,

3,5-Dibromo-4-(4-hydroxy-3-isopropylphenoxy)benzoyl-2-toluenesulphonamide,

3,5-Dibromo-4-(4-hydroxy-3-isopropylphenoxy)benzoyl-4-(2-aminoethyl)benzenesulphonam ide,

3,5-Dibromo-4-(4-hydroxy-3-isopropylphenoxy)benzoyl-(2-aminomethyl)benzenesulphona mide,

3,5-Dibromo-4-(4-hydroxy-3-isopropylphenoxy)benzoyl-3-nitrobenzenesulphonamide,

3,5-Dibromo-4-(4-hydroxy-3-isopropylphenoxy)benzoyl-4-chlorobenzenesulphonamide,

and the compounds shown below,

17. The compound as defined in claim 1 which is in the table below,

18. The compound as defined in claim 1 which is

D-N-[3,5-Dibromo-4-(4-hydroxy-3-isopropylphenoxy)benzoyl]valine,

D-N-[3,5-Dibromo-4-(4-hydroxy-3-isopropylphenoxy)benzoyl]leucine,

L-S-Benzyl, N-[3,5-dibromo-4-(4-hydroxy-3-isopropylphenoxy)benzoyl]cysteine,

D-N-[3,5-Dibromo-4-(4-hydroxy-3-isopropylphenoxy)benzoyl]tyrosine,

L-N-d-(2,2,5,7,8-Pentamethylchroman-6-sulfonyl),

N-[3,5-dibromo-4-(4-hydroxy-3-isopropylphenoxy)benzoyl]arginine,

L-N-[3,5-Dibromo-4-(4-hydroxy-3-isopropylphenoxy)benzoyl]aminobutyric acid,

L-N-[3,5-Dibromo-4-(4-hydroxy-3-isopropylphenoxy)benzoyl]valine,

L-N-[3,5-Dibromo-4-(4-hydroxy-3-isopropylphenoxy)benzoyl]leucine,

L-N-[3,5-Dibromo-4-(4-hydroxy-3-isopropylphenoxy)benzoyl]proline,

L-N-[3,5-Dibromo-4-(4-hydroxy-3-isopropylphenoxy)benzoyl]cysteine,

N-[3,5-Dibromo-4-(4-hydroxy-3-isopropylphenoxy)benzoyl]glycine,

L-N-a-[3,5-Dibromo-4-(4-hydroxy-3-isopropylphenoxy)benzoyl]lysine,

D-N-a-[3,5-Dibromo-4-(4-hydroxy-3-isopropylphenoxy)benzoyl]lysine,

N-[3,5-Dibromo-4-(4-hydroxy-3-isopropylphenoxy)benzoyl]aminoisobutyric acid,

L-N-[3,5-Dibromo-4-(4-hydroxy-3-isopropylphenoxy)benzoyl]phenylglycine,

D-N-[3,5-Dibromo-4-(4-hydroxy-3-isopropylphenoxy)benzoyl]phenylglycine,

N-[3,5-Dibromo-4-(4-hydroxy-3-isopropylphenoxy)benzoyl]sarcosine,

DL-N-[3,5-Dibromo-4-(4-hydroxy-3-isopropylphenoxy)benzoyl]-a-methylphenylalanine,

L-N-[3,5-Dibromo-4-(4-hydroxy-3-isopropylphenoxy)benzoyl]isoleucine,

D-N-[3,5-Dibromo-4-(4-hydroxy-3-isopropylphenoxy)benzoyl]methionine,

L-N-[3,5-Dibromo-4-(4-hydroxy-3-isopropylphenoxy)benzoyl]methionine,

L-N-[3,5-Dibromo-4-(4-hydroxy-3-isopropylphenoxy)benzoyl]phenylalanine,

D-N-3,5-Dibromo-4-(4-hydroxy-3-isopropylphenoxy)benzoyl]phenylalanine,

L-N-[3,5-Dibromo-4-(4-hydroxy-3-isopropylphenoxy)benzoyl]cyclohexylalanine,

L-N-e-(Benzyloxycarbonyl), N-a-[3,5-dibromo-4-(4-hydroxy-3-isopropylphenoxy)-benzoyl]lysine,

D-N-e-(Benzyloxycarbonyl), N-a-[3,5-dibromo-4-(4-hydroxy-3-isopropylphenoxy)-benzoyl]lysine,

D-N-[3,5-Dibromo-4-(4-hydroxy-3-isopropylphenoxy)benzoyl]homoserine,

N-[3,5-Dichloro-4-(4-hydroxy-3-isopropylphenoxy)benzoyl]glycine,

N-[3,5-Dichloro-4-(4-hydroxy-3-isopropylphenoxy)benzoyl]sarcosine,

3,5-Dichloro-4-(4-hydroxy-3-isopropylphenoxy)phenylformylimino diacetic acid,

N-[3,5-Dibromo-4-(4-hydroxy-3-isopropylphenoxy)benzoyl]-beta-alanine,

N-[3,5-Dichloro-4-(4-hydroxy-3-isopropylphenoxy)benzoyl]-beta-alanine,

D-N-[3,5-Dichloro-4-(4-hydroxy-3-isopropylphennoxy)benzoyl]methionine.

L-N-[3,5-Dichloro-4-(4-hydroxy-3-isopropylphenoxy)benzoyl]serine

D-N-[3,5-Dichloro-4-(4-hydroxy-3-isopropylphenoxy)benzoyl]serine

N-[3,5-Dichloro-4-(4-hydroxy-3-bromophenoxy)benzoyl]glycine

N-[3,5-Dichloro-4-(4-hydroxy-3-methylphenoxy)benzoyl]glycine

N-[3,5-Dichloro-4-(4-hydroxy-3-ethylphenoxy)benzoyl]glycine

19. The compound as defined in claim 1 which is

D-N-[3,5-Dibromo-4-(4-hydroxy-3-isopropylphenoxy)phenylacetyl]methionine,

L-N-[3,5-Dibromo-4-(4-hydroxy-3-isopropylphenoxy)phenylacetyl]methionine,

D-N-[3,5-Dibromo-4-(4-hydroxy-3-isopropylphenoxy)phenylacetyl] a-methylalanine,

D-N-[3,5-Dibromo-4-(4-hydroxy-3-isopropylphenoxy)phenylacetyl]aspargine,

L-Methyl-N-[3,5-dibromo-4-(4-hydroxy-3-isopropylphenoxy)phenylacetyl]alanine,

L-N-[3,5-dibromo-4-(4-hydroxy-3-isopropylphenoxy)phenylacetyl]alanine,

L-Dimethyl-N-[3,5-dibromo-4-(4-hydroxy-3-isopropylphenoxy)phenylacetyl]glutamate,

L-Dimethyl-N-[3,5-dibromo-4-(4-hydroxy-3-isopropylphenoxy)phenylacetyl]glutarnate,

L-(O-tert-butyl)methyl-N-[3,5-dibromo-4-(4-hydroxy-3-isopropylphenoxy)phenylacetyl]glutamate,

L-N-[3,5-dibromo-4-(4-hydroxy-3-isopropylphenoxy)phenylacetyl]glutamic acid,

L-N-[3,5-Dichloro-4-(4-hydroxy-3-isopropylphenoxy)phenylacetyl]aspartic acid,

D-di-tert-butyl-N-[3,5-dibromo-4-(4-hydroxy-3-isopropylphenoxy)phenylacetyl]glutamate,

D-N-[3,5-Dibromo-4-(4-hydroxy-3-isopropylphenoxy)phenylacetyl]glutamic acid,

L-O-tert-Butyl-N-[3,5-dibromo-4-(4-hydroxy-3-isopropylphenoxy)phenylacetyl]glutamine,

L-N-[3,5-Dibromo-4-(4-hydroxy-3-isopropylphenoxy)phenylacetyl]glutamine,

D-N-[3,5-Dibromo-4-(4-hydroxy-3-isopropylphenoxy)phenylacetyl]glutamine,

L-O-Benzyl-N-[3,5-dibromo-4-(4-hydroxy-3-isopropylphenoxy)phenylacetyl]aspartic acid,

L-O-tert-Butyl-N-[3,5-dibromo-4-(4-hydroxy-3-isopropylphenoxy)phenylacetyl]asparagine,

L-MethyL-N-[3,5-dibromo-4-(4-hydroxy-3-isopropylphenoxy)phenylacetyl]homoserine,

L-N-[3,5-Dibromo-4-(4-hydroxy-3-isopropylphenoxy)phenylacetyl]homoserine,

D-Methyl-N-[3,5-dibromo-4-4-hydroxy-3-isopropylphenoxy)phenylacetyl]homoserine,

and the compounds showed in the table below,

RMol FormelL-ValC22H25Br2NO5L-ValC22H25Br2NO5L-TyrC26H25Br2NO6C23H27Br2NO5 C27H27Br2NO5S D-LeuC23H27Br2NO5D-TyrC26H25Br2NO6D-TrpC28H26Br2N2O5L-ArgC23H28Br2N4O5L-AbuC21H23Br2NO5 C20H21Br2NO5 C20H21Br2NO5 L-LeuC23H27Br2NO5 C25H23Br2NO5 D-ProC22H23Br2NO5L-IleC23H27Br2NO5 C23H25Br2NO5 L-PheC26H25Br2NO5L-LysC23H28Br2N2O5 C23H25Br2NO5 L-ProC22H23Br2NO5 C25H23Br2NO5

20. The compounds as defined in claim 1 having the structures

21. The compounds as defined in claim 1 having the structures

22. The compounds as defined in claim 1 having the structures

23. A method for treating a disease associated with metabolism dysfunction, or which is dependent on the expression of a T₃ regulated gene, which comprises administering to a patient in need of treatment a therapeutically effective amount of a compound as defined in claim 1.

24. The method as defined in claim 23 wherein the disease associated with metabolism dysfunction or which is dependent on the expression of a T₃ regulated gene is obesity, hypercholesterolemia, atherosclerosis, depression, osteoporosis, hypothyroidism, goiter, thyroid cancer, glaucoma, cardiac arrhythmia, congestive heart failure, or skin disorders.

25. The use of a compound according to claim 1 in the preparation of a medicament for the treatment of a disease or disorders which is dependent on the expression of a T₃ regulated gene.

26. The use of a compound according to claim 1 in which the disease or disorder is selected from hypothyroidism, hypercholesterolemia, obesity, skin disorders, glaucoma, cardiovascular disease, congestive heart failure and other endocrine disorders related to thyroid hormone.

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

28. The method according to claim 24 in which 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, Demier'"'"'s disease, eczema, atopic dermatitis, chloracne, pityriasis and skin scarring.

29. A method to treat skin disorder or disease by the use of a compound of claim 1 in combination with a retinoid or a vitamin D analog.