Arylquinoline and analog compounds and use thereof to treat cancer

Patent metadata

Field	Value
Publication number	US-9873670-B2
Application number	US-201415036916-A
Country	US
Kind code	B2
Filing date	Nov 21, 2014
Priority date	Nov 22, 2013
Publication date	Jan 23, 2018
Grant date	Jan 23, 2018

Abstract

The subject technology relates to arylquinoline compounds and their use for treating cancer or cancer metastasis. The compounds of the subject technology promote cells to secrete a pro-apoptotic tumor suppressor, i.e., prostate apoptosis response-4 (Par-4), which in turn promote apoptosis in cancer cells or metastatic cells.

First claim

What is claimed is:

1. A method for alleviating, ameliorating, or lessening the severity of cancer in a subject in need thereof comprising administering to the subject an effective amount of the compound of formula (I):

or a pharmaceutically acceptable salt thereof;
wherein n is 1, 2, 3, 4, 5, or 6, for each NR 1 R 2 , R 1 and R 2 are independently H, alkyl, alkoxy, aryl, heteroaryl; Ar is aryl or heteroaryl, which can be further substituted with halogen, amino, alkylamino, dialkylamino, arylalkylamino, N-oxides of dialkylamino, trialkylammonium, mercapto, alkylthio, alkanoyl, nitro, nitrosyl, cyano, alkoxy, alkenyloxy, aryl, heteroaryl, sulfonyl, sulfonamide, CONR 3 R 4 , NR 3 CO(R 4 ), NR 3 COO(R 4 ), NR 3 CONR 4 R 5 where R 3 , R 4 , R 5 , are independently, H, alkyl, aryl, heteroaryl or a fluorine; X represents halogen; m is 1, 2, 3, 4, or 5,
wherein the cancer is selected from prostate cancer or lung cancer.

2. The method according to claim 1 , wherein n is 2 and one NR 1 R 2 group is at the 2 position of the quinoline ring and the another NR 1 R 2 group is at the 7 position of the quinoline ring and the Ar-Xm group is at the 3 position of the quinoline ring.

3. The method according to claim 2 , wherein m is 1 or 2, Ar is phenyl and X is selected from fluoro or chloro.

4. The method according to claim 2 , wherein Ar is heteroaryl.

5. A compound according to formula (I):

or a pharmaceutically acceptable salt thereof;
wherein n is 1, 2, 3, 4, 5, or 6, for each NR 1 R 2 , R 1 and R 2 are independently H, alkyl, alkoxy, aryl, heteroaryl; Ar is aryl or heteroaryl, which can be further substituted with halogen, amino, alkylamino, dialkylamino, arylalkylamino, N-oxides of dialkylamino, trialkylammonium, mercapto, alkylthio, alkanoyl, nitro, nitrosyl, cyano, alkoxy, alkenyloxy, aryl, heteroaryl, sulfonyl, sulfonamide, CONR 3 R 4 , NR 3 CO(R 4 ), NR 3 COO(R 4 ), NR 3 CONR 4 R 5 where R 3 , R 4 , R 5 , are independently, H, alkyl, aryl, heteroaryl or a fluorine; X represents halogen; m is 1, 2, 3, 4, or 5.

6. The compound of claim 5 , wherein n is 1 or 2; for each NR 1 R 2 , R 1 and R 2 are independently H, or a lower alkyl; Ar is phenyl; m is 1 or 2; and X is selected from fluoro or chloro.

7. The compound of claim 5 , wherein the compound is 3-(2-fluorophenyl)-N 7 ,N 7 -dimethylquinoline-2,7-diamine; 3-(3-fluorophenyl)-N 7 ,N 7 -dimethylquinoline-2,7-diamine; 3-(4-fluorophenyl)-N 7 ,N 7 -dimethylquinoline-2,7-diamine; 3-(2-fluorophenyl)-N,N-dimethylquinolin-7-amine; 3-(2-fluorophenyl)quinolin-2-amine.

8. A biotinylated derivative of the compound according to claim 5 .

9. A pharmaceutically acceptable composition comprising a compound of claim 5 and a pharmaceutically acceptable additive.

10. A method of alleviating, ameliorating, or lessening the severity of cancer in a subject in need thereof comprising administering to the subject an effective amount of a pharmaceutically acceptable composition of claim 9 ,
wherein the cancer is selected from prostate or lung cancer.

11. The method of claim 1 , wherein n is 2; R 1 and R 2 are independently H, or alkyl; Ar is aryl substituted with alkoxy; and m is 1; and wherein one NR 1 R 2 group is at the 2 position of the quinoline ring and the another NR 1 R 2 group is at the 7 position of the quinoline ring and the Ar-Xm group is a the 3 position of the quinoline ring and X is selected from the fluoro or chorlo.

12. The compound of claim 5 , wherein n is 2; R 1 and R 2 are independently H, or alkyl; Ar is aryl substituted with alkoxy; and m is 1; and wherein one NR 1 R 2 group is at the 2 position of the quinoline ring and the another NR 1 R 2 group is at the 7 position of the quinoline ring and the Ar-Xm group is at the 3 position of the quinoline ring and X is selected from fluoro or chloro.

13. The pharmaceutically acceptable composition of claim 9 , wherein n is 2; R 1 and R 2 are independently H, or alkyl; Ar is aryl substituted with alkoxy; and m is 1 ; and wherein one NR 1 R 2 group is at the 2 position of the quinoline ring and the another NR 1 R 2 group is at the 7 position of quinoline ring and the Ar-Xm group is at the 3 position of quinoline ring and X is selected from fluoro or chloro.

Assignees

• Univ Kentucky Res Found

Inventors

• Watt David S
• Liu Chunming
• Rangnekar Vivek
• Sviripa Vitaliy M
• Burikhanov Ravshan
• Zhang Wen

Classifications

• C07D215/227

  only one oxygen atom which is attached in position 2 · CPC title

• C07D215/38 Primary

  Nitrogen atoms (nitro radicals C07D215/18) · CPC title

• C07D215/36

  Sulfur atoms (C07D215/24 takes precedence) · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• C07D215/06

  having only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, attached to the ring nitrogen atom · CPC title