Aniline-derived ligands for the thyroid receptor

• US 7,109,164 B2
• Filed: 08/30/2004
• Issued: 09/19/2006
• Est. Priority Date: 02/17/2000
• Status: Expired due to Fees

• Current Assignee: Karo Pharma AB
• Original Assignee: Bristol-Myers Squibb Company
• Inventors: Friends, Todd J., Ryono, Denis E., Zhang, Minsheng
• Primary Examiner(s): Gupta, Anish
• Application Number:
  US10/930,360
• Publication Number:
  US 20050032890A1
• Time in Patent Office: 750 Days
• Field of Search: None
• US Class Current: 514/4.8
• 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 31/167 having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
• 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 17/16 Emollients or protectives, e.g. against radiation
• 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 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
• 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

Abstract

New thyroid receptor ligands are provided which have the general formula

in which:

• • X is —O—, —S—, —CH₂—, —CO—, or —NH—;
  • Y is —(CH₂)_n— where n is an integer from 1 to 5, or cis- or trans-ethylene;
  • 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 different and are hydrogen, halogen, alkyl of 1 to 4 carbons or cycloalkyl of 3 to 6 carbons, at least one of R₂ and R₃ being other than hydrogen;
  • R₄ is hydrogen or lower alkyl;
  • R₅ is hydrogen or lower alkyl;
  • R₆ is carboxylic acid, or esters or prodrugs;
  • R₇ is hydrogen or an alkanoyl or an aroyl.

In addition, a method is provided for preventing, inhibiting or treating a disease associated with metabolism dysfunction or which is dependent 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 method for treating obesity, hypercolesterolemia atherosclerosis, depression, osteoporosis, hypothyroidism, goiter, glaucoma, cardiac arrhythmia, congestive heart failure, or a skin disorder or disease, which comprises administering to a patient in need of treatment a therapeutically effective amount of a compound of the formula

5. The method as defined in claim 1 where in the compound administered X is oxygen, R₅ is hydrogen, R₁ is isopropyl, R₄ is hydrogen or methyl, R₂ and R₃ are each independently halogen or an alkyl group or hydrogen.

6. The method as defined in claim 5 where in the compound administered one of R₂ and R₃ is halogen and the other is an alkyl group, or wherein one of R₂ and R₃ is halogen and the other is hydrogen, or wherein one of R₂ and R₃ is alkyl and the other is hydrogen.

7. The method as defined in claim 5 where in the compound administered R₂ and R₃ are independently Cl, Br, methyl or ethyl.

8. The method as defined in claim 5 where in the compound administered Y is

—

(CH₂)_n—

where n is 1 or 2 or wherein Y is cis- or trans-ethylene.

9. The method as defined in claim 5 where the compound administered has the structure

10. The method as defined in claim 1 wherein the compound administered has the structure

11. The method as defined in claim 1 wherein the compound administered has the structure

12. The method as defined in claim 1 wherein the compound administered has the structure

2. A pharmaceutical composition comprising an effective amount of a compound of the formula

3. A method to treat skin disorder or disease by the use of a compound of the formula

4. The method according to claim 3, 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, Dernier'"'"'s disease, eczema, atopic dermatitis, chloracne, pityriasis and skin scarring.