Indole derivatives and use thereof

• US 10,730,866 B2
• Filed: 04/07/2015
• Issued: 08/04/2020
• Est. Priority Date: 04/07/2014
• Status: Active Grant

• Current Assignee: Purdue Pharma L.P.
• Original Assignee: Purdue Pharma L.P.
• Inventors: Lynch, Stephen M., Yao, Jiangchao, Park, Jae Hyun, Tafesse, Laykea
• Primary Examiner(s): Havlin, Robert H
• Application Number:
  US14/680,086
• Publication Number:
  US 20150284383A1
• Time in Patent Office: 1,946 Days
• CPC Class Codes: C07D 401/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 403/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 403/14 containing three or more hetero rings
• CPC Class Codes: C07D 405/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 413/14 containing three or more hetero rings
• CPC Class Codes: C07D 417/14 containing three or more hetero rings

Abstract

The Invention provides indole derivatives of Formula I:

and pharmaceutically acceptable salts and solvates thereof, wherein R^1e, R^1f, A, X, Y, Z, and W₄ are defined as set forth in the specification. The Invention also provides the use of compounds of Formula I and the pharmaceutically acceptable salts and solvates thereof to treat pain. In certain embodiments, the Compounds of the Invention are effective in treating a disorder responsive to blockade of one or more sodium channels.

Claims

1. A compound of Formula IV:

3. A pharmaceutical composition comprising the compound of claim 1, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier.

4. A method for treating pain in a mammal, comprising administering an effective amount of a compound as claimed in claim 1, or a pharmaceutically acceptable salt or solvate thereof, to a mammal in need of such treatment.

5. The method of claim 4, wherein said pain is selected from the group consisting of chronic pain, inflammatory pain, neuropathic pain, acute pain, and surgical pain.

6. A method of modulating Nav1.7 sodium channels in a mammal, comprising administering to the mammal at least one compound as claimed in claim 1, or a pharmaceutically acceptable salt or solvate thereof.

7. A compound as claimed in claim 1, or a pharmaceutically acceptable salt or solvate thereof, wherein the compound is ³H, ¹¹C, or ¹⁴C radiolabeled.

2. A compound selected from the group consisting of:

6-(1-methyl-3-(3-(trifluoromethyl) phenyl)-1H-indol-5-yl)picolinamide;

6-(1-methyl-3-(4-(trifluoromethyl) phenyl)-1H-indol-5-yl)picolinamide;

6-(1-(2-(diethylamino)ethyl)-3-(4-fluorophenyl)-1H-indol-6-yl)picolinamide;

6-(1H-indol-5-yl)-N-(4-(trifluoromethyl)phenyl)picolinamide;

6-(1-(4-(trifluoromethyl)benzyl)-1H-indol-5-yl)picolinamide;

6-(1-((4-(trifluoromethyl)phenyl)sulfonyl)-1H-indol-5-yl)picolinamide;

6-(1H-indol-5-yl)picolinamide;

6-(1-methyl-1H-indol-5-yl)-N-(4-(trifluoromethyl)phenyl)picolinamide;

N-cyclohexyl-6-(1H-indol-5-yl)picolinamide;

(S)-6-(1H-indol-5-yl)-4-((2-oxopyrrolidin-3-yl)amino)-N-(4-(trifluoromethyl)-phenyl)picolinamide;

6-(1-(cyclohexylmethyl)-1H-indol-5-yl)picolinamide;

6-(benzofuran-5-yl)-N-(4-(trifluoromethyl)phenyl)picolinamide;

5-(6-((4-(trifluoromethyl)phenyl)carbamoyl)pyridin-2-yl)-1H-indole-3-carboxamide;

5-(6-((4-(trifluoromethyl)phenyl)carbamoyl)pyridin-2-yl)-1H-indole-3-carboxylic acid;

(S)-2-(5-(6-((4-(trifluoromethyl)phenyl)carbamoyl)pyridin-2-yl)-1H-indole-3-carboxamido)pentanediamide;

5-(6-carbamoylpyridin-2-yl)-1-(4-(trifluoromethyl)benzyl)-1H-indole-3-carboxamide;

(S)—

N-(1-amino-1-oxopropan-2-yl)-5-(6-carbamoylpyridin-2-yl)-1-(4-(trifluoromethyl)benzyl)-1H-indole-3-carboxamide;

N-(cyclohexylmethyl)-6-(1H-indol-5-yl)picolinamide;

6-(1-(4-fluorobenzyl)-1H-indol-5-yl)picolinamide;

N-cyclopentyl-6-(1H-indol-5-yl)picolinamide;

6-(1-(2-cyclohexylethyl)-1H-indol-5-yl)picolinamide;

6-(1H-indol-5-yl)-N-(1H-tetrazol-5-yl)picolinamide;

6-(1-((2-methylthiazol-4-yl)methyl)-1H-indol-5-yl)picolinamide;

6-(1-isobutyl-1H-indol-5-yl)picolinamide;

6-(1-(4-m ethylbenzyl)-1H-indol-5-yl)picolinamide;

6-(1-(pyridin-4-ylmethyl)-1H-indol-5-yl)picolinamide;

6-(1-(cyclohexylsulfonyl)-1H-indol-5-yl)picolinamide;

6-(1-(2-morpholinoethyl)-1H-indol-5-yl)picolinamide;

(S)-6-(3-(((2-oxopyrrolidin-3-yl)amino)methyl)-1-(4-(trifluoromethyl)benzyl)-1H-indol-5-yl)picolinamide;

6-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-indol-5-yl)picolinamide;

(S)-6-(1-(cyclohexylmethyl)-3-(((2-oxopyrrolidin-3-yl)amino)methyl)-1H-indol-5-yl)picolinamide;

(R)-4-(1,2-dihydroxyethyl)-6-(1-(4-(trifluoromethyl)benzyl)-1H-indol-5-yl)picolinamide;

(S)-4-(1,2-dihydroxyethyl)-6-(1-(4-(trifluoromethyl)benzyl)-1H-indol-5-yl)picolinamide;

(S)-4-(1,2-dihydroxyethyl)-6-(1-isobutyl-1H-indol-5-yl)picolinamide;

(R)-4-(1,2-dihydroxyethyl)-6-(1-isobutyl-1H-indol-5-yl)picolinamide;

and a pharmaceutically acceptable salt or solvate thereof.

8. A pharmaceutical composition comprising the compound of claim 2, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier.