Compounds and compositions as TPO mimetics

• US 7,816,542 B2
• Filed: 08/15/2006
• Issued: 10/19/2010
• Est. Priority Date: 08/15/2005
• Status: Expired due to Fees

• Current Assignee: IRM LLC
• Original Assignee: IRM LLC
• Inventors: Marsilje, Thomas, He, Yun, Alper, Phillip B., Mutnick, Daniel, Lu, Wenshuo
• Primary Examiner(s): STOCKTON, LAURA LYNNE
• Application Number:
  US12/063,350
• Publication Number:
  US 20080194668A1
• Time in Patent Office: 1,526 Days
• Field of Search: 548/511
• US Class Current: 548/511
• CPC Class Codes: A61P 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• CPC Class Codes: A61P 19/00 Drugs for skeletal disorders
• CPC Class Codes: A61P 31/12 Antivirals
• CPC Class Codes: A61P 31/18 for HIV
• CPC Class Codes: A61P 31/20 for DNA viruses
• CPC Class Codes: A61P 37/06 Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 7/00 Drugs for disorders of the blood or the extracellular fluid
• CPC Class Codes: A61P 7/04 Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents
• CPC Class Codes: A61P 7/06 Antianaemics
• CPC Class Codes: C07D 209/14 Radicals substituted by nitrogen atoms, not forming part of a nitro radical
• CPC Class Codes: C07D 209/18 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 235/18 with aryl radicals directly attached in position 2

Abstract

The invention provides a novel class of compounds, pharmaceutical compositions comprising such compounds and methods of using such compounds to treat or prevent diseases or disorders associated with abnormal or deregulated TPO activity, particularly diseases or disorders that involve thrombocytopenia.

Claims

1. A compound of Formula (Ia):

2. The compound of claim 1 in which R₆ is fluoro and R₂₀ is selected from fluoro, methyl and butyl.

3. The compound of claim 2 in which R₃ is selected from carboxyl, amino-carbonyl, amino-sulfonyl, methyl-sulfonyl-amino and amino;

and R₄ is selected from hydrogen, hydroxyl, nitro and amino.

4. The compound of claim 3 selected from 4-[6-(4-butyl-phenyl)-7-fluoro-1H-indol-2-yl]-benzoic acid;

4-[6-(4-butyl-phenyl)-7-fluoro-1H-indol-2-yl]-benzamide;

4-[7-fluoro-6-(4-fluoro-3-methyl-phenyl)-1H-indol-2-yl]-benzoic acid;

4-[7-fluoro-6-(4-fluoro -3-methyl-phenyl)-1H-indol-2-yl]-benzenesulfonamide;

4-[6-(4-butyl-phenyl)-3-ethyl-7-fluoro -1H-indol-2-yl]-2-hydroxy-benzoic acid;

4-[6-(4-butyl-phenyl)-7-fluoro-3-isopropyl-1H-indol-2-yl]-2-hydroxy-benzoic acid;

4-[6-(4-butyl-phenyl)-7-fluoro-1H-indol-2-yl]-2-hydroxy-benzoic acid;

4-[6-(4-butyl-phenyl)-7-fluoro-3-methyl-1H-indol-2-yl]-2-hydroxy-benzoic acid;

N-{4-[6-(4-Butyl-phenyl)-7-fluoro-1H-indol-2-yl]-phenyl }-methanesulfonamide;

N-{4-[6-(4-Butyl -phenyl)-7-fluoro-1H-indol-2-yl]-phenyl}-acetamide;

N-{4-[6-(4-Butyl-phenyl)-7-fluoro-1H -indol-2-yl]-2-chloro-phenyl}-acetamide;

4-[6-(4-Butyl-phenyl)-7-fluoro-1H-indol-2-yl]-2-chloro-phenylamine; and

2-Amino-4-[6-(4-butyl-phenyl)-7-fluoro-1H-indol-2-yl]-benzoic acid.

5. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1 in combination with a pharmaceutically acceptable excipient.

6. A method for treating thrombocytopenia in a subject in need thereof, wherein the method comprises administering to the subject a therapeutically effective amount of a compound of Formula (Ia) of claim 1.