Methods and Compositions for the Treatment of Cancer and Related Hyperproliferative Disorders

Patent metadata

Field	Value
Publication number	US-2016136164-A1
Application number	US-201514940584-A
Country	US
Kind code	A1
Filing date	Nov 13, 2015
Priority date	Feb 2, 2007
Publication date	May 19, 2016
Grant date	—

Abstract

The present invention relates to methods of treating a disease related to cell hyper-proliferation via administration of a therapeutically effective amount of a compound having a general tripartite structure A-B—C. In the tripartite structure A, B, and C are identical or non-identical structures, for example, but not limited to, heterocyclic, phenyl or benzyl ring structures with or without substitutions and are described in detail herein. The methods may utilize particular compounds, for example, having a piperidinyl, a pyrrolinyl or pyridinyl A ring, a thiazole B ring, and a phenyl C ring which may be further substituted independently.

First claim

What is claimed is:

1 . A method for treating a disease related to cell hyper-proliferation in a patient in need thereof, comprising the step of administering to the patient, in a pharmaceutically acceptable medium, a therapeutically effective amount of a compound having a structure:
A-B—C
wherein A is a pyridine or a substituted pyridine, a piperidine or a substituted piperidine, a pyrrolidine or a substituted pyrrolidine, a thiazole or a substituted thiazole, a phenyl ring or a substituted phenyl ring; B is a thioazole or a substituted thioazole, a piperazine or a substituted piperazine, a phenyl ring or a substituted phenyl ring; and C is a phenyl ring or a substituted phenyl ring, a pyridine or a substituted pyridine, a thioazole or a substituted thioazole; or a pharmaceutically acceptable salt or a stereoisomer thereof or a combination thereof.

2 . The method of claim 1 , wherein the chemical structure of the compound is:

wherein R 1 is H, halogen, —OH, C 1-3 alkyl, —OR 3 , —NHR 5
R 3 is C 1 -C 3 alkyl, Bz or —OCH 2 —C(O)OR 4 ;
R 4 is H or C 1 -C 3 alkyl;
R 5 is H, C 1 -C 4 alkyl, methylcyclopropane, cyclohexane, benzyl, —NHC(O)R 6 , or —SO 2 —R 7 ;
R 6 is C 1 -C 3 alkyl or —O-tert-butyl;
R 7 is methyl, thiophenyl or quinolinyl;
R 2 is C 2 -C 4 alkyl or —C(O)OR 8 , and
R 8 is C 3 -C 5 alkyl or aryl; or

a pharmaceutically acceptable salt or a stereoisomer thereof or a combination thereof.

3 . The method of claim 2 , wherein said halogen is bromine.

4 . The method of claim 2 , wherein the compound is:
4-(4-bromophenyl)-2-(pyrrolidin-2-yl)thiazole, 4-(4-bromophenyl)-2-(1-propylpyrrolidin-2-yl)thiazole, tert-butyl 2-(4-(4-bromophenyl)thiazol-2-yl)pyrrolidine-1-carboxylate, benzyl 2-(4-(4-bromophenyl)thiazol-2-yl)pyrrolidine-1-carboxylate, or benzyl(R)-2-(4-(4-(methylsulfonamido)phenyl)thiazol-2-yl)pyrrolidine-1-carboxylate.

5 . The method of claim 1 , wherein the chemical structure of the compound is:

wherein R 1 is H, halogen, —OH, C 1-3 alkyl, —OR 3 , or —NHR 5 ;
R 3 is C 1 -C 3 alkyl, Bz or —OCH 2 —C(O)OR 4 ;
R 4 is H or C 1 -C 3 alkyl;
R 5 is H, C 1 -C 4 alkyl, methylcyclopropane, cyclohexane, benzyl, —C(O)R 6 , or —SO 2 —R 7 ;
R 6 is C 1 -C 3 alkyl or —O-tert-butyl;
R 7 is methyl, thiophenyl or quinolinyl;
R 2 is C 2 -C 4 alkyl or —C(O)OR 8 , and
R 8 is C 3 -C 5 alkyl or aryl; or
a pharmaceutically acceptable salt or a stereoisomer thereof or a combination thereof.

6 . The method of claim 5 , wherein said halogen is bromine.

7 . The method of claim 5 , wherein the compound is:
3-(4-(4-bromophenyl)thiazol-2-yl)-1-propylpiperidine, tert-butyl 3-(4-(4-bromophenyl)thiazol-2-yl)piperidine-1-carboxylate, benzyl 3-(4-(4-bromophenyl)thiazol-2-yl)piperidine-1-carboxylate, benzyl 4-(4-(4-bromophenyl)thiazol-2-yl)piperidine-1-carboxylate, benzyl 3-(4-(4-(methylsulfonamido)phenyl)thiazol-2-yl)piperidine-1-carboxylate, or benzyl 4-(4-(4-(methylsulfonamido)phenyl)thiazol-2-yl)piperidine-1-carboxylate.

8 . The method of claim 1 , wherein the chemical structure of the compound is:

wherein R 9 is H, halogen, —OH, —OR 11 or —NHR 13 ;
R 11 is C 1 -C 3 alkyl, Bz or —OCH 2 —C(O)OR 12 ;
R 12 is H or C 1 -C 3 alkyl;
R 13 is H, C 1 -C 4 alkyl, methylcyclopropane, cyclohexane, benzyl, or —C(O)R 14 , or —SO 2 —R 15 ;
R 14 is C 1 -C 3 alkyl or —O-tert-butyl;
R 15 is methyl, thiophenyl, quinolinyl, or phenylR 16 ;
R 16 is 4-chloro, 4-methyl or 3-chloro-4-methyl;
R 10 is nitrogen or methylene,
n is 0 or 1 and when n is 1, Z is —C═O; and
A is

wherein R 17 is H or C 1 -C 3 alkyl group; or
a pharmaceutically acceptable salt or a stereoisomer thereof or a combination thereof.

9 . The method of claim 8 , wherein the compound is:
3-chloro-4-methyl-N-(6-(4-(3-(trifluoromethyl)benzyl)piperazin-1-yl)pyridin-3-yl)benzene sulfonamide, (4-(5-chloro-2-methylphenyl)piperazin-1-yl)(4-(tosylamino)phenyl)methanone, 4-(4-((1-methyl-1H-benzo[d]imidazole-2-yl)methyl)piperazin-1-yl)-N-tosylbenzenamine, or 4-chloro-N-(4-(4-((1-methyl-1H-benzo[d]imidazol-2-yl)methyl)piperazin-1-yl)phenyl)benzenesulfonamide.

10 . The method of claim 1 , wherein the chemical structure of the compound is:

The method of claim 10 , wherein the compound is:
4-(3-(pyridin-2-yl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)-N-tosylbenzenamine;
(Z)-4-(3-cyano-3-(4-(2,4-dimethylphenyl)thiazol-2-yl)allyl)-N-(thiazol-2-yl)benzenesulfonamide;
N-(3-(H-imidazo[1,2-a]pyridine-2-yl)phenyl)-4-methyl-2-phenylthiazole-5-carboxamide;
N-(3-(benzo[d]thiazol-2-yl)phenyl)isonicotinamide;
3-(4-chlorophenyl)-4,5-dihydro-1-phenyl-5-(2-phenylthiazol-4-yl)-1H-pyrazole;
N-(4-(6-methylbenzo[d]thiazol-2-yl)phenyl)-2-(N-m-tolylmethylsulfonamido)acetamide; or
N-(4-(6-methylbenzo[d]thiazol-2-yl)phenyl)-2-(N-p-tolylmethylsulfonamido)acetamide.

11 . The method of claim 1 , wherein the disease related to cell hyper-proliferation is cancer.

12 . The method of claim 11 , wherein the cancer is a cancer of the breast, respiratory tract, brain, reproductive organs, prostate, digestive tract, urinary tract, eye, liver, skin, head and neck, thyroid, parathyroid, lymphoma, sarcoma, melanoma, leukemia or a distant metastasis of a solid tumor.

13 . A method for treating a cancer in a patient in need thereof, comprising the step of administering to the patient, in a pharmaceutically acceptable medium, a therapeutically effective amount of a compound having the chemical structure:

wherein R is H, isopropyl, benzyl, cyclohexyl, cyclopropylmethyl, —COMe, tert-butyloxycarbonyl, or methylsulfonyl, or a pharmaceutically acceptable salt or a stereoisomer thereof or a combination thereof.

14 . The method of claim 13 , wherein the chemical structure of the compound is:

15 . The method of claim 13 , wherein the compound is:
4-(4-bromophenyl)-2-(1-propylpyrrolidin-2-yl)thiazole, N-(4-(2-(2-propylpyridin-4-yl)thiazol-4-yl)phenyl)methanesulfonamide, 4-(2-(2-propylpyridin-4-yl)thiazol-4-yl)benzenamine, N-isopropyl-4-(2-(2-propylpyridin-4-yl)thiazol-4-yl)benzenamine, N-(4-(2-(2-propylpyridin-4-yl)thiazol-4-yl)phenyl)acetamide, N-(cyclopropylmethyl)-4-(2-(2-propylpyridin-4-yl)thiazol-4-yl)benzenamine, N-benzyl-4-(2-(2-propylpyridin-4-yl)thiazol-4-yl)benzenamine, N-cyclohexyl-4-(2-(2-propylpyridin-4-yl)thiazol-4-yl)benzenamine, 4-(3-(pyridin-2-yl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)-N-tosylbenzenamine, (Z)-4-(3-cyano-3-(4-(2,4-dimethylphenyl)thiazol-2-yl)allyl)-N-(thiazol-2-yl)benzenesulfonamide, N-(4-(6-methylbenzo[d]thiazol-2-yl)phenyl)-2-(N-m-tolylmethyls

Assignees

• Uesugi Motonari
• Wakil Salih J
• Abu-Elheiga Lutfi
• Watanabe Mizuki
• Baylor College Medicine

Inventors

• Uesugi Motonari
• Wakil Salih J
• Abu-Elheiga Lutfi
• Watanabe Mizuki

Classifications

• A61K31/4709

  Non-condensed quinolines and containing further heterocyclic rings · CPC title

• A61K31/5025 Primary

  ortho- or peri-condensed with heterocyclic ring systems · CPC title

• A61K31/426

  1,3-Thiazoles · CPC title

• C07D487/04

  Ortho-condensed systems · CPC title

• A61K31/44

  Non condensed pyridines; Hydrogenated derivatives thereof · CPC title