BENZYLIDENE-INDOLINONE COMPOUNDS AND THEIR MEDICAL USE

• US 20130035364A1
• Filed: 08/01/2012
• Published: 02/07/2013
• Est. Priority Date: 08/04/2011
• Status: Active Grant

• Current Assignee: National University of Singapore
• Original Assignee: National University of Singapore
• Inventors: GO, Mei Lin, HO, Han Kiat, CHEN, Xiao
• Granted Patent: US 8,877,946 B2
• Time in Patent Office: Days
• US Class Current: 514/418
• CPC Class Codes: A61K 31/404 Indoles, e.g. pindolol
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 25/28 for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 3/00 Drugs for disorders of the metabolism of the blood or the extracellular fluid A61P7/00
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 9/10 for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: C07D 209/34 in position 2
• CPC Class Codes: C07D 209/40 Nitrogen atoms, not forming part of a nitro radical, e.g. isatin semicarbazone

Abstract

Compounds of general formula I:

wherein
R^1a, R^1b, R², R^3a, R^3b and X are as defined herein are tyrosine kinase inhibitors and are useful for the treatment of various diseases and conditions, for example cancer.

Claims

1. A compound of general formula (I)

2. The compound of claim 1 wherein R^1a is hydrogen, fluoro, chloro or —

O(C_1-4alkyl).

3. The compound of claim 2 wherein:

R^1a and R^1b are both hydrogen;

or

R^1a is chloro, fluoro or methoxy and R^1b is hydrogen;

or

R^1a and R^1b are both chloro;

or

R^1a and R^1b are both fluoro.

4. The compound of claim 1 wherein R^1b is hydrogen and R^1a is at the 5- or 6-position.

5. The compound of claim 4 wherein R^1a is selected from the group consisting of chloro, fluoro or methoxy, especially 5-chloro, 5-fluoro, 6-chloro, 6-fluoro and 6-methoxy.

6. The compound of claim 1 wherein R^1a and R^1b are both halo and are at the 4- and 5-positions or at the 5- and 6-positions.

7. The compound of claim 6 wherein R^1a and R^1b are selected from the group consisting of 4,5-dichloro, 5,6-dichloro, 4,5-difluoro and 5,6-difluoro.

8. The compound of claim 1 R² is hydrogen or methyl.

9. The compound of claim 1 wherein R^3a is selected from the group consisting of hydrogen, chloro, fluoro, CN, C_1-2alkyl, —

O(C_1-2alkyl), C_1-2haloalkyl, —

O(C_1-2haloalkyl), SO₂—

(C_1-4alkyl), SO₂NH₂, SO₂NH(C_1-4alkyl) and SO₂N(C_1-2alkyl)₂; and

R^3b is hydrogen.

10. The compound of claim 9 wherein R^3a is selected from the group consisting of hydrogen, chloro, fluoro, methyl, trifluoromethyl methoxy, trifluoromethoxy, SO₂NH₂, SO₂NHCH₃, SO₂NH(ethyl), SO₂NH(n-propyl), SO₂NH(isopropyl) and SO₂N(CH₃)₂;

and R^3b is hydrogen.

11. The compound of claim 1 wherein R^1a is 6-chloro or 6-fluoro;

R^1b is H and either;

R^3b is H and R^3a is selected from the group consisting of hydrogen, 3′

-halo, 4′

-halo, 3′

-C_1-4alkyl, 4-trifluoromethyl, trifluoromethoxy, cyano, SO₂(C_1-4alkyl) and SO₂NR^4aR^4b;

where each R^4a and R^4b is independently H, methyl, ethyl, isopropyl or n-propyl;

or

R^3a is 3′

-fluoro and R^3b is 4-fluoro.

12. The compound of claim 1 wherein R^1a is 5-chloro or 5-fluoro;

R^1b is H and either;

R^3b is H and R^3a is selected from the group consisting of hydrogen, 3′

-halo, 4′

-halo C_1-4alkyl, 4-trifluoromethyl, trifluoromethoxy, cyano, SO₂(C_1-4alkyl) and SO₂NR^4aR^4b;

where each R^4a and R^4b is independently H, methyl, ethyl, isopropyl or n-propyl;

or

R^3a is 3′

-fluoro and R^3b is 4-fluoro.

13. The compound of claim 1 wherein R^1a is 6-methoxy;

R^1b is H and either;

R^3b is H and R^3a is selected from the group consisting of hydrogen, 2′

-halo, 3′

-halo, 4′

-halo, C_1-4alkyl, 2-trifluoromethyl, 4-trifluoromethyl, trifluoromethoxy, cyano, SO₂(C_1-4alkyl) and SO₂NR^4aR^4b;

where each R^4a and R^4b is independently H, methyl, ethyl, isopropyl or n-propyl;

or

R^3a is 3′

-fluoro and R^3b is 4-fluoro.

14. The compound of claim 1 wherein R^1a and R^1b are 4,5-difluoro, R^3b is hydrogen and R^3a is halo, 3′

-trifluoromethyl, trifluoromethoxy cyano or SO₂(C_1-4 alkyl), SO₂NR^4aR^4b;

where each R^4a and R^4b is independently H, methyl, ethyl, isopropyl or n-propyl.

15. The compound of claim 1 wherein R^1a and R^1b are 5,6-difluoro, R^3b is hydrogen and R^3a is 3′

-halo, 3′

-trifluoromethyl, 4′

-trifluoromethyl, trifluoromethoxy cyano or SO₂(C_1-4alkyl), SO₂NR^4aR^4b;

where each R^4a and R^4b is independently H, methyl, ethyl, isopropyl or n-propyl.

16. The compound of claim 1 wherein X is CH.

17. A compound of claim 1 selected from the group consisting of:

(E)-3-Benzylidene-6-chloro-1,3-dihydro-indol-2-one (1-1);

(E)-6-Chloro-3-(2-fluoro-benzylidene)-1,3-dihydro-indol-2-one (1-2);

(E)-6-Chloro-3-(3-fluoro-benzylidene)-1,3-dihydro-indol-2-one (1-3);

(E)-6-Chloro-3-(4-fluoro-benzylidene)-1,3-dihydro-indol-2-one (1-4);

(E)-6-Chloro-3-(3-methyl-benzylidene)-1,3-dihydro-indol-2-one (1-5);

(E)-6-Chloro-3-(2-methoxy-benzylidene)-1,3-dihydro-indol-2-one (1-6);

(E)-6-Chloro-3-(3-methoxy-benzylidene)-1,3-dihydro-indol-2-one (1-7);

(E)-6-Chloro-3-(4-methoxy-benzylidene)-1,3-dihydro-indol-2-one (1-8);

(E)-6-Chloro-3-(2-trifluoromethyl-benzylidene)-1,3-dihydro-indol-2-one (1-9);

(E)-6-Chloro-3-(4-trifluoromethyl-benzylidene)-1,3-dihydro-indol-2-one (1-11);

(E)-6-Chloro-3-(3,4-difluoro-benzylidene) 1,3-dihydro-indol-2-one (1-12);

(E)-6-Chloro-3-(2-trifluoromethoxyl-benzylidene)indol-2-one (1-13);

(E)-6-Chloro-3-(3-trifluoromethoxyl-benzylidene)indol-2-one (1-14);

(E)-6-chloro-3-(4-trifluoromethoxyl-benzylidene)indol-2-one (1-15);

(E)-6-Chloro-3-(3-methylsulfonyl-benzylidene)indol-2-one (1-16);

(E) 3-(6-Chloro-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-benzene-sulfonamide (1-17);

(E-3-(6-Chloro-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-N-methyl-benzenesulfonamide (1-18);

(E) 3-(6-Chloro-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-benzonitrile (1-19)

(E)-3-(6-Chloro-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-N,N-dimethyl-benzenesulfonamide(1-20);

(E)-4-(6-Chloro-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-N-methyl-benzenesulfonamide (1-21)

(E)-3-(6-Chloro-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-N-ethyl-benzenesulfonamide (1-22)

(E/Z)-3-(6-Chloro-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-N-propyl-benzenesulfonamide (1-23)

(E/Z)-3-(6-Chloro-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-N-isopropyl-benzenesulfonamide (1-24)

(E)-3-Benzylidene-5-chloro-1,3-dihydro-indol-2-one (2-1);

(E)-5-Chloro-3-(2-fluorobenzylidene)indol-2-one (2-2);

(E)-5-Chloro-3-(3-fluorobenzylidene)indol-2-one (2-3);

(E)-5-Chloro-3-(4-fluorobenzylidene)indol-2-one (2-4);

(E)-5-Chloro-3-(3-methoxybenzylidene)indol-2-one (2-5);

(E)-5-Chloro-3-(2-trifluoromethylbenzylidene)indol-2-one (2-6);

(E)-5-Chloro-3-(4-trifluoromethylbenzylidene)indol-2-one (2-8);

(E)-5-Chloro-3-(3,4-difluoro-benzylidene) 1,3-dihydro-indol-2-one (2-9);

(E)-5-Chloro-3-(3-trifluoromethoxyl-benzylidene)indol-2-one (2-10);

(E)-5-Chloro-3-(3-methanesulfonylbenzylidene)indol-2-one (2-11);

(E/Z)-3-(5-Chloro-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-benzenesulfonamide (2-12);

(E) 3-(5-Chloro-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-benzonitrile (2-13)

(E)-3-(5-Chloro-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-N-methyl-benzenesulphonamide (2-14);

(E)-3-Benzylidene-6-fluoroindol-2-one (3-1);

(E)-6-Fluoro-3-(2-fluorobenzylidene)indol-2-one (3-2);

(E)-6-Fluoro-3-(3-fluorobenzylidene)indol-2-one (3-3);

(E)-6-Fluoro-3-(4-fluorobenzyl idene)indol-2-one (3-4);

(E)-6-Fluoro-3-(2-trifluoromethyl-benzylidene)indol-2-one (3-5);

(E)-6-Fluoro-3-(4-trifluoromethyl-benzylidene)indol-2-one (3-7);

(E)-6-Fluoro-3-(3-trifluoromethoxyl-benzylidene)indol-2-one (3-8)

(E)-6-Fluoro-3-(3-methanesulfonylbenzylidene)indol-2-one (3-9);

(E)-3-(6-Fluoro-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-N-methyl-benzenesulphonamide (3-10);

(E)-3-(6-Fluoro-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-N-ethyl-benzenesulfonamide (3-11)

(E/Z)-3-(6-Fluoro-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-N-propyl-benzenesulfonamide (3-12)

(E)-3-(6-Fluoro-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-N-isopropyl-benzenesulfonamide (3-13)

(E)-3-Benzylidene-5-fluoro-1,3-dihydro-indol-2-one (4-1);

(E)-5-Fluoro-3-(2-fluorobenzylidene)-1,3-dihydro-indol-2-one (4-2);

(E)-5-Fluoro-3-(3-fluorobenzylidene)-1,3-dihydro-indol-2-one (4-3);

(E)-5-Fluoro-3-(4-fluorobenzylidene)-1,3-dihydro-indol-2-one (4-4);

(E)-5-Fluoro-3-(2-methylbenzylidene)-1,3-dihydro-indol-2-one (4-5);

(E)-5-Fluoro-3-(3-methylbenzylidene)-1,3-dihydro-indol-2-one(4-6);

(E)-5-Fluoro-3-(4-methylbenzylidene)-1,3-dihydro-indol-2-one (4-7);

(E)-5-Fluoro-3-(3-methoxylbenzylidene)-1,3-dihydro-indol-2-one (4-8);

(E)-5-Fluoro-3-(2-trifluoromethyl)benzylidene)-1,3-dihydro-indol-2-one (4-9);

(E)-5-Fluoro-3-(4-trifluoromethylbenzylidene)-1,3-dihydro-indol-2-one (4-11);

(E)-5-Fluoro-3-(3,4-difluorobenzylidene)-1,3-dihydro-indol-2-one (4-12);

(E)-5-Fluoro-3-(3-trifluoromethoxyl-benzylidene)-1,3-dihydro-indol-2-one (4-13);

(E)-5-Fluoro-3-(3-methanesulfonylbenzylidene)-1,3-dihydro-indol-2-one (4-14);

(E) 3-(5-Fluoro-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-benzonitrile (4-15)

(E)-3-(5-Fluoro-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-N-methyl-benzenesulphonamide (4-16);

(E)-3-Benzylidene-6-methoxy-1,3-dihydro-indol-2-one (5-1);

(E)-3-(2-Fluoro-benzylidene)-6-methoxy-1,3-dihydro-indol-2-one (5-2);

(E)-3-(3-Fluoro-benzylidene)-6-methoxy-1,3-dihydro-indol-2-one (5-3);

(E)-3-(4-Fluoro-benzylidene)-6-methoxy-1,3-dihydro-indol-2-one (5-4);

(E)-6-Methoxy-3-(2-trifluoromethyl-benzyl idene)-1,3-dihydro-indol-2-one (5-5);

(E)-6-Methoxy-3-(4-trifluoromethyl-benzylidene)-1,3-dihydro-indol-2-one (5-7);

(E)-3-(6-Methoxy-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-N-methyl-benzenesulphonamide (5-8);

(Z)-3-Benzylidene-4,5-difluoro-1,3-dihydro-indol-2-one (6-1);

(Z)-3-(2-Fluorobenzylidene)-4,5-difluoro-1,3-dihydro-indol-2-one (6-2);

(Z)-3-(3-Fluorobenzylidene)-4,5-difluoro-1,3-dihydro-indol-2-one (6-3);

(Z)-3-(4-Fluorobenzylidene)-4,5-difluoro-1,3-dihydro-indol-2-one (6-4);

(E/Z)-3-(2-Trifluoromethylbenzylidene)-4,5-difluoro-1,3-dihydro-indol-2-one (6-5);

(Z)-4,5-Difluoro-3-(3-trifluoromethyl-benzylidene)-1,3-dihydro-indol-2-one (6-6);

(Z)-4,5-Difluoro-3-(4-trifluoromethyl-benzylidene)-1,3-dihydro-indol-2-one (6-7);

(Z)-4,5-Difluoro-3-(3-trifluoromethoxyl-benzylidene)-1,3-dihydro-indol-2-one (6-8)

(E/Z)-4,5-Difluoro-3-(3-methanesulfonylbenzylidene)-1,3-dihydro-indol-2-one (6-9);

(Z)-3-(4,5-Difluoro-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-N-methyl-benzenesulphonamide (6-10);

(E)-3-Benzylidene-5,6-difluoro-1,3-dihydro-indol-2-one (7-1);

(E)-5,6-Difluoro-3-(2-fluorobenzylidene)-1,3-dihydro-indol-2-one (7-2);

(E)-5,6-Difluoro-3-(3-fluorobenzylidene)-1,3-dihydro-indol-2-one (7-3);

(E)-5,6-Difluoro-3-(4-fluorobenzylidene)-1,3-dihydro-indol-2-one (7-4);

(E)-5,6-Difluoro-3-(2-trifluoromethyl-benzylidene)-1,3-dihydro-indol-2-one (7-5);

(E)-5,6-Difluoro-3-(3-trifluoromethyl-benzylidene)-1,3-dihydro-indol-2-one (7-6)

(E)-5,6-Difluoro-3-(4-trifluoromethyl-benzylidene)-1,3-dihydro-indol-2-one (7-7);

(E)-5,6-Difluoro-3-(3-trifluoromethoxyl-benzylidene)-1,3-dihydro-indol-2-one (7-8)

(E)-5,6-Difluoro-3-(3-methanesulfonylbenzylidene)-1,3-dihydro-indol-2-one (7-9);

(E)-3-(5,6-Difluoro-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-N-ethyl-benzenesulfonamide (7-10)

(E) 3-(3-Trifluoromethyl-benzylidene)-1,3-dihydro-indol-2-one (8-1);

(E/Z) 3-(3-Trifluoromethyl-phenylimino)-1,3-dihydro-indol-2-one (8-2);

(E)-1-Methyl-3-(3-trifluoromethyl-benzylidene)-1,3-dihydro-indol-2-one (8-3);

(E/Z)) 6-Chloro-3-(3-trifluoromethyl-phenylimino)-1,3-dihydro-indol-2-one (8-4);

(E)-6-Chloro-1-methyl-3-(3-trifluoromethyl-benzylidene)-1,3-dihydro-indol-2-one (8-5);

(E/Z)-5-Chloro-3-(3-trifluoromethyl-phenylimino)-1,3-dihydro-indol-2-one (8-6);

(E/Z)-5-Fluoro-3-(3-trifluoromethyl-phenylimino)-1,3-dihydro-indol-2-one (8-7);

and pharmaceutically acceptable salts thereof.

18. A process for the preparation of a compound of general formula (I) as defined in claim 1 comprising:

a. for compounds of general formula (I) in which X is CH;

reacting a compound of general formula (II);

19. A method for the treatment or prevention of a disease or condition related to increased protein kinase activity, the method comprising administering to a patient in need of such treatment an effective amount of a compound according to claim 1.

20. A method for the treatment or prevention of cancers, atherosclerosis, arthritis, restenonsis or a metabolic disease such as diabetes, fibrotic and mesangial disorders, abnormal angiogenesis and vasculogenesis, psoriasis, diabetes mellitus, and inflammation;

neurodegenerative disorders and slow wound healing rates, the method comprising administering to a patient in need of such treatment an effective amount of a compound according to claim 1.

21. A method for the treatment of a cancer selected from the group consisting of hepatocellular carcinoma, breast cancer, colon cancer and lung cancer the method comprising administering to a patient in need of such treatment an effective amount of a compound according to claim 1.

22. A pharmaceutical composition comprising a compound according to claim 1 and a pharmaceutically acceptable excipient.

23. A pharmaceutical composition according to claim 22 which is adapted for oral, transdermal, buccal, nasal, sublingual or anal, intravenous or intramuscular administration.