IP Library › Granted Patent US 7,528,165

Granted Patent B2

US 7,528,165 · App. 11/195,531 · Granted May 5, 2009

Indole compounds

Assignee: National Health Research Institutes

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Quick Facts

Patent No.: US 7,528,165
App. No.: 11/195,531
Granted: May 5, 2009
Kind: B2

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Abstract

This invention relates to methods of inhibiting tubulin polymerization and treating cancer and other angiogenesis-related disorders with indole compounds of the formula: wherein L 1 , L 2 , R 1 , R 2 , R a , R b , R c , R d , and R e are defined herein.

Claims (243)

1. A method for treating cancer selected from the group consisting of gastric carcinoma, cervical carcinoma, leukemia, breast cancer, colon carcinoma, liver cancer, lung cancer, oropharynx cancer, hypopharynx cancer, and oral epidermoid carcinoma, comprising administering to a subject in need thereof an effective amount of a compound of the following formula:

wherein

L 1 is C(O), and L 2 is a bond, C(O), O, S, NR, SO 2 , or CH 2 ; in which if L 2 is a bond, the other one is C(O), O, S, NR, SO 2 , or CH 2 ;

R 1 is 5, 6, or 7-member aryl tri-substituted with alkoxy, and R 2 is R, halogen, nitro, nitroso, cyano, azide, isothionitro, OR, OC(O)R, OC(O)OR, OC(O)NRR′, SO 2 R, SO 3 R, SO 2 NRR′, SR, NRR′, NRSO 2 NR′R″, NRSO 2 R′, NRSO 3 R′, NRC(O)R′, NRC(O)NR′R″, NRC(O)OR′, NRC(N)NR′R″, C(O)R, C(O)OR, C(O)NRR′;

each of R a , R b , R c , and R d , independently, is R, halogen, nitro, nitroso, cyano, azide, isothionitro, OR, OC(O)R, OC(O)OR, OC(O)NRR′, SO 2 R, SO 3 R, SO 2 NRR′, SR, NRR′, NRSO 2 NR′R″, NRSO 2 R′, NRSO 3 R′, NRC(O)R′, NRC(O)NR′R″, NRC(O)OR′, NRC(N)NR′R″, C(O)R, C(O)OR, C(O)NRR′, or R b and R c , R a and R b , or R c and R d taken together are O(CH 2 ) n O; and

R e is H, alkyl, alkenyl, alkynyl, heteroaryl, cyclyl, heterocyclyl, halogen, nitro, nitroso, cyano, azide, isothionitro, OR, OC(O)R, OC(O)OR, OC(O)NRR′, SO 2 R, SO 3 R, SO 2 NRR′, SR, NRR′, NRSO 2 NR′R″, NRSO 2 R′, NRSO 3 R′, NRC(O)R′, NRC(O)NR′R″, NRC(O)OR′, NRC(N)NR′R″, C(O)R, C(O)OR, or C(O)NRR′;

in which each of R, R′, and R″, independently, is H, alkyl, alkenyl, alkynyl, aryl, heteroaryly, cyclyl, or heterocyclyl; and n is 1, 2, 3, 4, or 5.

2. The method of claim 1 , wherein R 1 is 3,4,5-trimethoxylphenyl.

3. The method of claim 1 , wherein L 2 is a bond; and R 2 is alkyl, alkenyl, alkynyl, cyclyl, or heterocyclyl.

4. The method of claim 1 , wherein L 2 is a bond.

5. The method of claim 1 , wherein L 2 is a bond; R 2 is COR′″; R′″ is H, alkyl, alkenyl, alkynyl, heteroaryl, cyclyl, or heterocyclyl; and n is 1, 2, 3, 4, or 5.

6. The method of claim 1 , wherein the compound is

(6-methoxy-1H-indol-3-yl)-(3,4,5-trimethoxy-phenyl)-methanone;

(6-methyl-1H-indol-3-yl)-(3,4,5-trimethoxy-phenyl)-methanone;

(6-methoxy-1-pyridin-4-ylmethyl-1H-indol-3-yl)-(3,4,5-trimethoxy-phenyl)-methanone;

(1-allyl-6-methoxy-1H-indol-3-yl)-(3,4,5-trimethoxy-phenyl)-methanone;

[6-methoxy-1-(pyridine-2-carbonyl)-1H-indol-3-yl]-(3,4,5-trimethoxy-phenyl)-methanone;

6-methoxy-3-(3,4,5-trimethoxy-benzoyl)-indole-1-carboxylic acid tert-butyl ester;

(1-methanesulfonyl-6-methoxy-1H-indol-3-yl)-(3,4,5-trimethoxy-phenyl)-methanone;

[6-methoxy-1-(morpholine-4-carbonyl)-1H-indol-3-yl]-(3,4,5-trimethoxy-phenyl)-methanone;

[6-methoxy-1-(2-piperidin-1-yl-ethyl)-1H-indol-3-yl]-(3,4,5-trimethoxy-phenyl)-methanone;

(6-methoxy-1-prop-2-ynyl-1H-indol-3-yl)-(3,4,5-trimethoxy-phenyl)-methanone;

6-methoxy-3-(3,4,5-trimethoxy-benzoyl)-indole-1-carboxylic acid dimethylamide;

1-[6-methoxy-3-(3,4,5-trimethoxy-benzoyl)-indol-1-yl]-3-phenyl-propenone;

6-methoxy-3-(3,4,5-trimethoxy-benzoyl)-indole-1-carboxylic acid phenyl ester;

[1-(5-dimethylamino-naphthalene-1-sulfonyl)-6-methoxy-1H-indol-3-yl]-(3,4,5-trimethoxy-phenyl)-methanone;

[1-(2-dimethylamino-ethyl)-6-methoxy-1H-indol-3-yl]-(3,4,5-trimethoxy-phenyl)-methanone;

(6-methoxy-1-methyl-1H-indol-3-yl)-(3,4,5-trimethoxy-phenyl)-methanone;

[1-(2-amino-ethyl)-6-methoxy-1H-indol-3-yl]-(3,4,5-trimethoxy-phenyl)-methanone;

[1-(furan-2-carbonyl)-6-methoxy-1H-indol-3-yl]-(3,4,5-trimethoxy-phenyl)-methanone;

(1-ethyl-6-methoxy-1H-indol-3-yl)-(3,4,5-trimethoxy-phenyl)-methanone;

[6-methoxy-1-(2-morpholin-4-yl-ethyl)-1H-indol-3-yl]-(3,4,5-trimethoxy-phenyl)-methanone;

[1-(4-chloro-benzyl)-6-methoxy-1H-indol-3-yl]-(3,4,5-trimethoxy-phenyl)-methanone;

(1-benzyl-6-methoxy-1H-indol-3-yl)-(3,4,5-trimethoxy-phenyl)-methanone;

(6-fluoro-1H-indol-3-yl)-(3,4,5-trimethoxy-phenyl)-methanone;

(6-bromo-1H-indol-3-yl)-(3,4,5-trimethoxy-phenyl)-methanone;

(4,5,6-trimethoxy-1H-indol-3-yl)-(3,4,5-trimethoxy-phenyl)-methanone;

(5,6-dimethoxy-1H-indol-3-yl)-(3,4,5-trimethoxy-phenyl)-methanone;

(1,6-dimethyl-1H-indol-3-yl)-(3,4,5-trimethoxy-phenyl)-methanone;

(1-ethyl-6-methyl-1H-indol-3-yl)-(3,4,5-trimethoxy-phenyl)-methanone;

(1-allyl-6-methyl-1H-indol-3-yl)-(3,4,5-trimethoxy-phenyl)-methanone;

(5-ethyl-5H-[1,3]dioxolo[4,5-f]indol-7-yl)-(3,4,5-trimethoxy-phenyl)-methanone;

(5-methyl-5H-[1,3]dioxolo[4,5-f]indol-7-yl)-(3,4,5-trimethoxy-phenyl)-methanone;

(5-allyl-5H-[1,3]dioxolo[4,5-f]indol-7-yl)-(3,4,5-trimethoxy-phenyl)-methanone;

(6-methoxy-2-methyl-1H-indol-3-yl)-(3,4,5-trimethoxy-phenyl)-methanone;

6-methoxy-3-(3,4,5-trimethoxy-phenylsulfanyl)-1H-indole;

(6-ethoxy-1H-indol-3-yl)-(3,4,5-trimethoxy-phenyl)-methanone;

(7-methoxy-1H-indol-3-yl)-(3,4,5-trimethoxy-phenyl)-methanone;

(4-methoxy-1H-indol-3-yl)-(3,4,5-trimethoxy-phenyl)-methanone;

(5-methoxy-4-methyl-1H-indol-3-yl)-(3,4,5-trimethoxy-phenyl)-methanone;

(4,7-dimethoxy-1H-indol-3-yl)-(3,4,5-trimethoxy-phenyl)-methanone;

(4,6-dimethoxy-1H-indol-3-yl)-(3,4,5-trimethoxy-phenyl)-methanone;

(5,7-dimethoxy-1H-indol-3-yl)-(3,4,5-trimethoxy-phenyl)-methanone;

{6-methoxy-1-[4-(4-nitro-phenyl)-furan-2-ylmethyl]-1H-indol-3-yl}-(3,4,5-trimethoxy-phenyl)-methanone;

(6-hydroxy-1H-indol-3-yl)-(3,4,5-trimethoxy-phenyl)-methanone;

6-methoxy-3-(3,4,5-trimethoxy-benzenesulfonyl)-1H-indole;

[1-(2-dimethylamino-ethyl)-4,5,6-trimethoxy-1H-indol-3-yl]-(3,4,5-trimethoxy-phenyl)-methanone;

4-[6-methoxy-3-(3,4,5-trimethoxy-benzoyl)-indole-1-sulfonyl]-benzoic acid;

(5H-[1,3]dioxolo[4,5-f]indol-7-yl)-(3,4,5-trimethoxy-phenyl)-methanone;

{2-[6-methoxy-3-(3,4,5-trimethoxy-benzoyl)-indol-1-yl]-2-oxo-ethyl}-carbamic acid 9H-fluoren-9-yl-methyl ester;

[6-methoxy-1-(pyridine-3-carbonyl)-1H-indol-3-yl]-(3,4,5-trimethoxy-phenyl)-methanone;

[6-methoxy-1-(thiophene-2-carbonyl)-1H-indol-3-yl]-(3,4,5-trimethoxy-phenyl)-methanone;

(1-benzoyl-6-methoxy-1H-indol-3-yl)-(3,4,5-trimethoxy-phenyl)-methanone;

[6-methoxy-1-(thiophene-2-carbonyl)-1H-indol-3-yl]-(3,4,5-trimethoxy-phenyl)-methanone;

(6-propoxy-1H-indol-3-yl)-(3,4,5-trimethoxy-phenyl)-methanone;

(6-isopropoxy-1H-indol-3-yl)-(3,4,5-trimethoxy-phenyl)-methanone;

[6-(3-morpholin-4-yl-propoxy)-1H-indol-3-yl]-(3,4,5-trimethoxy-phenyl)-methanone;

(6-{2-[2-(2-hydroxy-ethoxy)-ethoxy]-ethoxy}-1H-indol-3-yl)-(3,4,5-trimethoxy-phenyl)-methanone;

[6-methoxy-3-(3,4,5-trimethoxy-benzoyl)-indol-1-yl]-acetic acid;

3-[6-methoxy-3-(3,4,5-trimethoxy-benzoyl)-indol-1-yl]-propionic acid;

(5H-[1,3]dioxolo[4,5-f]indol-7-yl)-(3,4,5-trimethoxy-phenyl)-methanone;

(5-methoxy-2-methyl-1H-indol-3-yl)-(3,4,5-trimethoxy-phenyl)-methanone;

(6-amino-1H-indol-3-yl)-(3,4,5-trimethoxy-phenyl)-methanone;

2-methyl-3-(3,4,5-trimethoxy-phenoxy)-1H-indole;

5-methoxy-2-methyl-3-(3,4,5-trimethoxy-phenoxy)-1H-indole;

6-methoxy-2-methyl-3-(3,4,5-trimethoxy-phenoxy)-1H-indole;

4-methoxy-2-methyl-3-(3,4,5-trimethoxy-phenoxy)-1H-indole;

5-fluoro-2-methyl-3-(3,4,5-trimethoxy-phenoxy)-1H-indole;

6-fluoro-2-methyl-3-(3,4,5-trimethoxy-phenoxy)-1H-indole;

4-fluoro-2-methyl-3-(3,4,5-trimethoxy-phenoxy)-1H-indole; or

(6-dimethylamino-1H-indol-3-yl)-(3,4,5-trimethoxy-phenyl)-methanone.

7. A method for inhibiting tubulin polymerization, comprising administering to a subject in need thereof an effective amount of a compound of the following formula:

wherein

L 1 is C(O), and L 2 , is a bond, C(O), O, S, NR, SO 2 , or CH 2 ; in which if L 2 is a bond, the other one is C(O), O, S, NR, SO 2 , or CH 2 ;

R 1 is aryl, and R 2 , is R, halogen, nitro, nitroso, cyano, azide, isothionitro, OR, OC(O)R, OC(O)OR, OC(O)NRR′, SO 2 R, SO 3 R, SO 2 NRR′, SR, NRR′,NRSO 2 NR′R″, NRSO 2 R′, NRSO 3 R′, NRC(O)R′, NRC(O)NR′R″, NRC(O)OR′, NRC(N)NR′R″, C(O)R, C(O)OR, C(O)NRR′;

R e is H, alkyl, alkenyl, alkynyl, heteroaryl, halogen, nitro, nitroso, cyano, azide, isothionitro, OR, OC(O)R, OC(O)OR, OC(O)NRR′, SO 2 R, SO 3 R, SO 2 NRR′, SR, NRR′, NRSO 2 NR′R″, NRSO 2 R′, NRSO 3 R′, NRC(O)R′, NRC(O)NR′R″, NRC(O)OR′, NRC(N)NR′R″, C(O)R, C(O)OR, or C(O)NRR′;

in which each of R, R′, and R″, independently, is H, alkyl, alkenyl, alkynyl, aryl, heteroaryl, cyclyl, or heterocyclyl; and n is 1, 2, 3, 4, or 5.

8. The method of claim 7 , wherein R 1 is 3,4,5-trimethoxylphenyl.

9. The method of claim 7 , wherein L 2 is a bond; and R 2 is alkyl, alkenyl, alkynyl, cyclyl, or heterocyclyl.

10. The method of claim 7 , wherein L 2 is a bond.

11. The method of claim 7 , wherein L 2 is a bond; and R 2 is COR′″; R′″ is H, alkyl, alkenyl, alkynyl, heteroaryl, cyclyl, or heterocyclyl; and n is 1, 2, 3, 4, or 5.

12. The method of claim 7 , wherein the compound is