Quinoline derivatives as anti-cancer agents

Patent metadata

Field	Value
Publication number	US-9493419-B2
Application number	US-201113334073-A
Country	US
Kind code	B2
Filing date	Dec 22, 2011
Priority date	Aug 21, 2007
Publication date	Nov 15, 2016
Grant date	Nov 15, 2016

Abstract

Quinoline derivatives showing anticancer activities against cancer cell lines of hepatocellular carcinoma (Hep3B), lung carcinoma (A549), esophageal squamous cell carcinoma (HKESC-1, HKESC-4 and KYSE150). The quinoline derivatives have a backbone structure of the following formulas:

First claim

What is claimed is:

1. A quinoline derivative, comprising a structure of the following formula:

wherein R 1 and R 3 are independently of each other H or Br;
wherein each of R 2 , R 7 and R 8 is H;
wherein R 4 is CN, 2-(piperdin-1-yl)ethoxy, biphenyl-3-ylmethoxy, OH, OAc, or OR′, wherein R′ is a phenyl group having the following formula:

wherein R a is CH 2 or SO 2 ; R b and R c independently are H, Cl, F, OCH 3 , CH 3 , Ph, NO 2 , CF 3 or OCF 3 ;
wherein R 5 is H or COCH 3 ;
wherein R 6 is CH 3 , OH, CH 2 OH, CH 2 CH 2 Ph, CH 2 CH 3 , OBn, COOH, CHO, 3,4-dimethoxyphenethyl or a phenyl group having the following formula:

wherein R a is CH 2 NH; R b and R c independently of each other are H, C(CH 3 ) 3 , OCH 3 , OPh, COH 2 Ph or morpholinyl;
provided that when R 2 , R 5 , R 7 and R 8 are H, and R 4 is OH, then R 6 is not CH 3 ;
provided that when R 1 , R 2 , R 3 , R 7 and R 8 are H, R 6 is CH 3 , and R 4 is an alkoxy, then R 5 is not H; and
provided that when R 1 is Br, R 2 , R 3 , R 5 , R 7 and R 8 are H, and R 6 is CH 3 , then R 4 is not OH;
and salts thereof.

2. The quinoline derivative of claim 1 , wherein R 6 is selected from the group consisting of CH 3 , CH 2 OH, CH 2 CH 2 Ph, and OH; and wherein R 4 is OH, OAc or OR′ wherein R′ is a phenyl group having the following formula:

wherein R a is CH 2 or SO 2 , R b and R c independently are H, Cl, F, OCH 3 , CH 3 , Ph, NO 2 , CF 3 or OCF 3 .

3. The quinoline derivative of claim 1 , wherein R 6 is selected from the group consisting of CH 2 CH 3 , OBn, COOH and CHO; and R 4 is OH, OAc or OR′ wherein R′ is a phenyl group having the following formula:

wherein R a is CH 2 or SO 2 , R b and R c independently are H, Cl, F, OCH 3 , CH 3 , Ph, NO 2 , CF 3 or OCF 3 .

4. The quinoline derivative of claim 2 , wherein R 6 is CH 3 .

5. The quinoline derivative of claim 2 , wherein R 4 is OH; and wherein R 6 is OH.

6. The quinoline derivative of claim 3 , wherein R 4 is OAc; and wherein R 6 is COOH.

7. The quinoline derivative of claim 1 , wherein R 1 and R 3 are H; wherein R 6 is CH 3 ; and wherein R 4 is OR′ wherein R′ is a phenyl group of the following formula:

and
wherein Ra is CH 2 , Rb is H, OCH 3 , NO 2 or Ph, and Rc is H, Ph, F, Cl, OCF 3 , CF 3 , CN, OCH 3 or NO 2 .

8. The quinoline derivative of claim 7 , wherein Rb is H and Rc is OCH 3 , NO 2 , F, Cl, CF 3 or OCF 3 .

9. A quinoline derivative having a structure of the following formula:

wherein R 2 , R 5 , R 7 , and R 8 are H;
wherein R 1 and R 3 are Br;
wherein R 6 is CH 3 ; and
wherein R 4 is OAc or OH; and
wherein, when R 4 is OH and when the quinoline derivative comprises the following formula:

* represents a chiral center of the quinoline derivative;
and salts thereof.

10. A method of treating cancer in a mammal, the method comprising the step of administering to the mammal a quinoline derivative of claim 1 in an amount from about 8 to about 12 mg/kg/day body weight with a pharmaceutically acceptable carrier.

11. The method of claim 10 , wherein said quinoline derivative is administered over a continuous period of between 5 to 10 days.

12. The method of claim 10 , wherein said cancer is breast carcinoma, hepatocellulor carcinoma, or chronic myelogenous leukemia.

13. The method of claim 10 , wherein said quinoline derivative is a chiral or non-chiral tetrahydroquinoline derivative.

14. A quinoline derivative, wherein said quinoline derivative is a substituted quinoline selected from the group consisting of 5,7-dibromo-1,2,3,4-tetrahydro-2-methylquinolin-8-ol and 1,2,3,4-tetrahydro-2-(hydroxymethyl)quinolin-8-ol.

15. The quinoline derivative of claim 1 , wherein said quinoline derivative is selected from the group consisting of 2-methyl-1,2,3,4-tetrahydroquinolin-8-yl acetate, and 1-acetyl-2-methyl-1,2,3,4-tetrahydroquinoline-8-yl acetate.

16. The quinoline derivative of claim 1 , wherein said quinoline derivative is selected from the group consisting of 8-(2-(piperidin-1-yl)ethoxy)-1,2,3,4-tetrahydro-2-methylquinoline, 8-(benzyloxy)-1,2,3,4-tetrahydro-2-methylquinoline, 8-(3-nitrobenzyloxy)-1,2,3,4-tetrahydro-2-methylquinoline, 8-(4-nitrobenzyloxy)-1,2,3,4-tetrahydro-2-methylquinoline, 8-(4-methoxybenzyloxy)-1,2,3,4-tetrahydro-2-methylquinoline, 8-(3-methoxybenzyloxy)-1,2,3,4-tetrahydro-2-methylquinoline, 4-((1,2,3,4-tetrahydro-2-methylquinolin-8-yloxy)methyl)benzonitrile, 8-(biphenyl-3-ylmethoxy)-2-methyl-1,2,3,4-tetrahydroquinoline, 8-(4-(trifluoromethoxy)benzyloxy)-1,2,3,4-tetrahydro-2-methylquinoline, 8-(4-fluorobenzyloxy)-1,2,3,4-tetrahydro-2-methylquinoline, 8-(4-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydro-2-methylquinoline, 8-(4-chlorobenzyloxy)-1,2,3,4-tetrahydro-2-methylquinoline, 8-(benzyloxy)-1,2,3,4-tetrahydro-2-phenethylquinoline, 2-(3,4-dimethoxyphenethyl)-1,2,3,4-tetrahydroquinoline, 5,7-dibromo-2-methyl-8-(4-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydroquinoline, and 5,7-dibromo-2-methyl-8-(4-(trifluoromethoxy)benzyloxy)-1,2,3,4-tetrahydroquinoline.

17. The quinoline derivative of claim 1 ,
wherein R 1 and R 3 are H;
wherein R 6 is CH 3 ; and
wherein R 4 is 4-(trifluoromethyl)benzyloxy.

18. The quinoline derivative of claim 1 , wherein R 4 is OR′ wherein R′ is a phenyl group of the following formula:

and
wherein Ra is CH 2 , Rb is H, OCH 3 , NO 2 or Ph, and Rc is H, Ph, F, Cl, OCF 3 , CF 3 , CN, OCH 3 or NO 2 .

19. A method of treating cancer in a mammal, the method comprising the step of administering to the mammal a pharmaceutical composition comprising
(i) the quinoline derivative of claim 14 ; and
(ii) a pharmaceutically acceptable carrier.

20. The method according to claim 19 , wherein the step of administering comprises administering the quinoline derivative in an amount from about 8 to about 12 mg per kg body weight of the mammal.

21. The method according to claim 19 , wherein the quinoline derivative is administered to the mammal daily over a continuous period of between 5 to 10 days.

22. The method according to claim 19 , wherein the cancer is breast carcinoma, hepatocellulor carcinoma, or chronic myelogenous leukemia.

Assignees

• Tang Johnny Cheuk-On
• Chan Albert Sun Chi
• Lam Kim Hung
• Chan Sau Hing
• Univ Hong Kong Polytechnic

Inventors

• Tang Johnny Cheuk-On
• Chan Albert Sun Chi
• Lam Kim Hung
• Chan Sau Hing

Classifications

• C07D215/14

  Radicals substituted by oxygen atoms · CPC title

• C07D215/227

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

• A61P35/02

  specific for leukemia · CPC title

• C07D215/22

  attached in position 2 or 4 · CPC title

• A61P35/00

  Antineoplastic agents · CPC title