Substituted indol-5-ol derivatives and their therapeutical applications

Patent metadata

Field	Value
Publication number	US-10160749-B2
Application number	US-201615285234-A
Country	US
Kind code	B2
Filing date	Oct 4, 2016
Priority date	Nov 5, 2012
Publication date	Dec 25, 2018
Grant date	Dec 25, 2018

Abstract

The present invention relates generally to the use of compounds to treat a variety of disorders, diseases and pathologic conditions and more specifically to the use of substituted indol-5-ol derivatives to modulate protein kinases and for treating protein kinase-mediated diseases.

First claim

What is claimed is:

1. A method of treating cancer comprising a tumor cell, comprising contacting the tumor cell with a composition comprising a compound of formula (I):

or its pharmaceutically acceptable salts, hydrates, solvates, and individual diastereomers thereof, wherein R is selected from the group consisting of:
(i) hydrogen, amino, and alkyl amino;
(ii) C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl;
(iii) K—Ar, wherein:
Ar represents heteroaryl or aryl, each of which is substituted with from 0 to 4 substituents independently chosen from the group consisting of:
(1) halogen, hydroxy, amino, amide, cyano, —COOH, —SO 2 NH 2 , oxo, nitro and alkoxycarbonyl; and
(2) C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 3 -C 10 cycloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 2 -C 6 alkanoyl, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, mono- and di- (C 1 -C 6 alkyl)amino, C 1 -C 6 alkylsulfonyl, mono- and di-(C 1 -C 6 alkyl) sulfonamido and mono- and di-(C 1 -C 6 alkyl)aminocarbonyl; phenylC 0 -C 4 alkyl and (4- to 7-membered heterocycle)C 0 -C 4 alkyl, each of which is substituted with from 0 to 4 secondary substituents independently chosen from halogen, hydroxy, cyano, oxo, imino, C 1 -C 4 alkyl, C 1 -C 4 alkoxy and C 1 -C 4 haloalkyl;

K is selected from the group consisting of:
1) O, S, SO, and SO 2 ;
2) (CH 2 ) m , m=0-3, —O(CH 2 ) p , p=1-3, —S(CH 2 ) p , p=1-3, —N(CH 2 )p, p=1-3, and —(CH 2 ) p O, p=1-3; and
3) NR 1 , wherein R 1 is selected from the group consisting of hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, alkylthio, aryl, and arylalkyl; and

(iv) groups of the formula (Ia):

 wherein:
R 2 is selected from the group consisting of hydrogen, C 1 -C 4 alkyl, and oxo; and
X is CH, when R 3 is hydrogen; or X—R 3 is O; or X is N;
R 3 is selected from the group consisting of hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 10 aryl and heteroaryl, (C 3 -C 7 cycloalkyl)C 1 -C 4 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkylthio, C 2 -C 6 alkanoyl, C 1 -C 6 alkoxycarbonyl, C 2 -C 6 alkanoyloxy, mono- and di-(C 3 -C 8 cycloalkyl)amino C 0 -C 4 alkyl, (4- to 7-membered heterocycle)C 0 -C 4 alkyl, C 1 -C 6 alkylsulfonyl, mono- and di-(C 1 -C 6 alkyl) sulfonamido, and mono- and di-(C 1 -C 6 alkyl)aminocarbonyl, each of which is substituted with from 0 to 4 substituents independently chosen from halogen, hydroxy, cyano, amino,—COOH or oxo; and

Het is selected from any heterocycle, which is substituted with from 0 to 4 substituents independently chosen from the group consisting of:
(i) C 1 C 6 alkyl, C 2 C 6 alkenyl, and C 2 C 6 alkynyl;
(ii) halogen, hydroxy, amino, amide, cyano, —COOH, —SO 2 NH 2 , oxo, nitro and alkoxycarbonyl; and
(iii) aryl;

R 11 and R 12 are independently selected from the group consisting of Hydrogen, F, Cl, Br, CN, C 1 -C 4 alkyl, and C 1 -C 6 alkoxy; and
R 13 , R 14 and R 15 are independently selected from the group consisting of Hydrogen, C 1 -C 4 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 10 aryl or heteroaryl, C 1 -C 6 alkoxy, C 1 -C 6 alkylthio, C 2 -C 6 alkanoyl, C 1 -C 6 alkoxycarbonyl, and C 2 -C 6 alkanoyloxy.

2. The method of claim 1 , in which the concentration of the compound in the pharmaceutical composition results in administration to a patient of a dosage of between 0.01-100 mg/kg body weight/day.

3. The method of claim 1 , wherein the cancer is breast cancer, gastric cancer, chronic myelogenous leukemia, acute myelogenous leukemia, pancreatic carcinoma, thyroid cancer or endometrial carcinoma.

4. A method of claim 3 , in which the cancer is chronic myeogenous leukemia (CML).

5. A method of treating cancer comprising a tumor cell, comprising contacting the tumor cell with a composition comprising a compound having the formula:

or its pharmaceutically acceptable salts, solvates, and individual diastereomers thereof.

6. The method of claim 5 , in which the concentration of the compound in the pharmaceutical composition results in administration to a patient of a dosage of between 0.01-100 mg/kg body weight/day.

7. The method of claim 5 , wherein the cancer is breast cancer, gastric cancer, chronic myelogenous leukemia, acute myelogenous leukemia, pancreatic carcinoma, thyroid cancer or endometrial carcinoma.

8. A method of claim 7 , in which the cancer is chronic myeogenous leukemia (CML).

9. A method of treating cancer comprising a tumor cell, comprising contacting the tumor cell with a composition comprising a compound having the formula:

or its pharmaceutically acceptable salts, hydrates, solvates, and individual diastereomers thereof.

10. The method of claim 9 , in which the concentration of the compound in the pharmaceutical composition results in administration to a patient of a dosage of between 0.01-100 mg/kg weight/day.

11. The method of claim 9 , wherein the cancer is breast cancer, gastric cancer, chronic myelogenous leukemia, acute myelogenous leukemia, pancreatic carcinoma, thyroid cancer or endometrial carcinoma.

12. A method of claim 11 , in which the cancer is chronic myeogenous leukemia (CML).

13. A method of claim 11 , in which the cancer is pancreatic carcinoma.

14. A method of claim 7 , in which the cancer is pancreatic carcinoma.

Assignees

• Nantbioscience Inc
• Nantbio Inc

Inventors

• Tao Chunlin
• Wang Qinwei
• Ho David
• Polat Tulay
• Nallan Laxman
• Soon-Shiong Patrick

Classifications

• A61K31/541

  Non-condensed thiazines containing further heterocyclic rings · CPC title

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• C07D403/14 Primary

  containing three or more hetero rings · CPC title

• A61K45/06

  Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca · CPC title