Thyroid hormone receptor antagonists for cardiac and metabolic disorders II

• US 7,319,096 B2
• Filed: 04/15/2002
• Issued: 01/15/2008
• Est. Priority Date: 05/15/2001
• Status: Expired due to Fees

• Current Assignee: Karo Pharma AB
• Original Assignee: Karo Pharma AB
• Inventors: Ericsson, Thomas, Malm, Johan, Brandt, Peter, Gordon, Sandra, Edvinsson, Karin
• Primary Examiner(s): Saeed; Kamal A.
• Assistant Examiner(s): Cheng; Karen
• Application Number:
  US10/477,676
• Publication Number:
  US 20040220147A1
• Time in Patent Office: 2,101 Days
• Field of Search: 562/465, 562/472, 562/108, 562/621, 514/79, 514/366, 514/374, 514/576, 514/617, 548/203, 548/247
• US Class Current: 514/79
• CPC Class Codes: A61P 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• 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 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• 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: C07C 229/36 with at least one amino group and one carboxyl group bound to the same carbon atom of the carbon skeleton
• 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: C07D 213/30 Oxygen atoms
• CPC Class Codes: C07D 261/08 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

Abstract

This invention relates to novel compounds which are thyroid receptor ligands, preferably antagonists, and to methods for using such compounds in the treatment of cardiac and metabolic disorders, such as cardiac arrhythmias, thyrotoxicosis, subclinical hyperthyrodism and liver diseases.

Claims

1. A compound according to formula I:

2. A compound according to claim 1 wherein R₅ is —

CO₂H.

3. A compound according to claim 2 wherein n is 1.

4. A compound according to claim 2 wherein R₃ and R₄ are bromine.

5. A compound according to claim 1 wherein R₃ and R₄ are bromine, and n is 1.

6. A compound according to claim 4 wherein n is 1.

7. A compounds according to claim 1 which is:

2-Amino-3-[3,5-dibromo-4-(3-bromobenzyloxy)phenyl]propionic acid;

2-Amino-3-[3,5-dibromo-4-(3-trifluormethylbenzyloxy)phenyl]propionic acid;

2-Amino-3-[3,5-dibromo-4-(3,5-dimethylbenzyloxy)phenyl]propionic acid;

3-[3,5-Dibromo-4-(naphthalen-2-ylmethoxy)phenyl]-2-hydroxypropionic acid;

3-[3,5-Dibromo-4-(3-bromobenzyloxy)phenyl]-2-hydroxypropionic acid;

3-[3,5-Dibromo-4-(3-bromobenzyloxy)phenyl]-2-chloropropionic acid;

3-[3,5-Dibromo-4-(pyridin-2-ylmethoxy)phenyl]-2-hydroxypropionic acid;

2-Amino-3-[4-(bistrifluoromethylbenzyloxy)-3,5-dibromophenyl]propionic acid;

2-Amino-3-[3,5-dibromo-4-(pyridin-2-ylmethoxy)phenyl]propionate triethylammonium;

2-Amino-3-[3,5-dibromo-4-(3-trifluoromethoxybenzyloxy)phenyl]propionate triethylammonium;

2-Amino-3-[3,5-dibromo-4-(3-fluoro-5-trifluoromethoxybenzyloxy)phenyl]propionate triethylammonium;

2-Amino-3-[3,5-dibromo-4-(3-fluorobenzyloxy)phenyl]propionate triethylammonium;

2-Amino-3-[3,5-dibromo-4-(3,5-difluorobenzyloxy)phenyl]propionate triethylammonium;

2-Amino-3-[3,5-dibromo-4-[3-(difluoromethoxy)benzyloxy]phenyl]propionate triethylammonium;

2-Amino-3-[3,5-dibromo-4-(pyridin-4-ylmethoxy)phenyl]propionate triethylammonium;

2-Amino-3-[3,5-dibromo-4-(5-methylisoxazol-3-ylmethoxy)phenyl]propionic acid;

2-Amino-3-[3,5-dibromo-4-(3,5-dichlorobenzyloxy)phenyl]propionate triethyl ammonium;

2-Amino-3-[3,5-dibromo-4-(2-fluorobenzyloxy)phenyl]propionic acid;

2-Amino-3-[3,5-dibromo-4-(2-methylthiazol-4-ylmethoxy)phenyl]propionate triethylammonium;

2-Amino-3-[3,5-dibromo-4-(3-chlorobenzyloxy)phenyl]propionate triethylammonium;

2-Amino-3-[3,5-dibromo-4-(2-chlorobenzyloxy)phenyl]propionate triethylammonium;

2-Amino-3-[3,5-dibromo-4-(3-iodobenzyloxy)phenyl]propionic acid;

and pharmaceutically acceptable salts, bioisosters, and stereoisomers thereof.

8. A compound according to claim 1, which has one or more asymmetric centers and can exist in the form of a racemate, single or multiple enantiomer, or as a diastereomer.

9. A pharmaceutical composition comprising an effective amount of a compound according to claim 1 together with a pharmaceutically acceptable carrier.

10. The compound of Formula I, wherein said prodrug ester form is pivaloyloxymethyl.

11. The compound of Formula I, wherein said prodrug ester form is dioxolenylmethyl.