Coumarin derivative having antitumor activity

• US 7,897,792 B2
• Filed: 02/09/2007
• Issued: 03/01/2011
• Est. Priority Date: 02/09/2006
• Status: Active Grant

• Current Assignee: Chugai Seiyaku Kabushiki Kaisha (Roche Holding AG), Sakai Toshiyuki
• Original Assignee: Chugai Seiyaku Kabushiki Kaisha (Roche Holding AG), Sakai Toshiyuki
• Inventors: Watanabe, Fumio, Furuichi, Noriyuki, Aoki, Toshihiro, Tomii, Yasushi, Harada, Naoki, Takanashi, Kenji, Hyoudoh, Ikumi, Iikura, Hitoshi, Matsushita, Masayuki, Sakaitani, Masahiro, Ozawa, Sawako, Ho, Pil-Su
• Primary Examiner(s): Chandrakumar; Nizal S
• Application Number:
  US12/161,256
• Publication Number:
  US 20100004233A1
• Time in Patent Office: 1,481 Days
• Field of Search: 549/289
• US Class Current: 549/289
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: C07D 311/18 substituted otherwise than in position 3 or 7
• CPC Class Codes: C07D 405/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 417/12 linked by a chain containing hetero atoms as chain links

Abstract

The present invention provides a compound represented by general formula (1) below or a pharmaceutically acceptable salt thereof:

wherein: X is selected from heteroaryl etc., Y¹ and Y² are selected from —N═ etc., Y³ and Y⁴ are selected from —CH═ etc., A is selected from sulfamide etc., R¹ is selected from hydrogen etc., and R² is selected from C_1-6 alkyl etc. The compound or salt has sufficiently high antitumor activity, and is useful in the treatment of cell proliferative disorders, particularly cancers. The present invention also provides a pharmaceutical composition containing the compound or salt as an active ingredient.

Claims

1. A compound represented by general formula (11) below or a pharmaceutically acceptable salt thereof:

2. The compound or pharmaceutically acceptable salt thereof according to claim 1, wherein the compound represented by general formula (11) is a compound represented by general formula (1) below:

3. The compound or pharmaceutically acceptable salt thereof according to claim 2, wherein R¹ is a hydrogen atom, a halogen atom or a C_1-6 alkyl group.

4. The compound or pharmaceutically acceptable salt thereof according to claim 2, wherein R⁵ or R⁸ is a hydrogen atom.

5. The compound or pharmaceutically acceptable salt thereof according to claim 2, wherein R³, R⁴, R⁶, R⁷, R⁹ and R¹⁰ are each independently a hydrogen atom or a C_1-6 alkyl group.

6. The compound or pharmaceutically acceptable salt thereof according to claim 2, wherein X is a thiazol-2-yl group, a pyrimidin-2-yl group, a 2-pyridyl group or R³R⁴NCO—

(where R³ and R⁴ have the same definitions as above).

7. The compound or pharmaceutically acceptable salt thereof according to claim 6, wherein both R³ and R⁴ are a methyl group.

8. The compound or pharmaceutically acceptable salt thereof according to claim 2, wherein R² is a C_1-6 alkyl group optionally substituted with a fluorine atom.

9. The compound or pharmaceutically acceptable salt thereof according to claim 8, wherein R² is —

CH₃, —

CH₂F or —

CH₂CH₃.

10. The compound or pharmaceutically acceptable salt thereof according to claim 2, which is selected from:

dimethylcarbamic acid 4-methyl-3-{2-(methylaminosulfonyl)aminopyridin-4-ylmethyl}-2-oxo-2H-1-benzopyran-7-yl ester,

dimethylcarbamic acid 4-methyl-3-{2-(methylaminosulfonyl)aminopyridin-4-ylmethyl}-6-fluoro-2-oxo-2H-1-benzopyran-7-yl ester,

dimethylcarbamic acid 4-methyl-3-{2-(methylaminosulfonyl)aminopyridin-4-ylmethyl}-6-chloro-2-oxo-2H-1-benzopyran-7-yl ester,

dimethylcarbamic acid 4-methyl-3-{6-(methylaminosulfonyl)aminopyridin-2-ylmethyl}-2-oxo-2H-1-benzopyran-7-yl ester,

dimethylcarbamic acid 4-methyl-3-{6-(methylaminosulfonyl)aminopyridin-2-ylmethyl}-6-fluoro-2-oxo-2H-1-benzopyran-7-yl ester,

dimethylcarbamic acid 4-methyl-3-{6-(methylaminosulfonyl)aminopyridin-2-ylmethyl}-6-chloro-2-oxo-2H-1-benzopyran-7-yl ester,

3-{2-(methylaminosulfonyl)aminopyridin-4-ylmethyl}-4-methyl-7-(pyrimidin-2-yloxy)-2-oxo-2H-1-benzopyran,

3-{2-(methylaminosulfonyl)aminopyridin-4-ylmethyl}-4-methyl-7-(pyrimidin-2-yloxy)-6-chloro-2-oxo-2H-1-benzopyran,

3-{2-(methylaminosulfonyl)amino-3-fluoropyridin-4-ylmethyl}-4-methyl-7-(pyrimidin-2-yloxy)-2-oxo-2H-1-benzopyran,

3-{2-(ethylaminosulfonyl)amino-3-fluoropyridin-4-ylmethyl}-4-methyl-7-(pyrimidin-2-yloxy)-2-oxo-2H-1-benzopyran,

3-{2-(isopropylaminosulfonyl)amino-3-fluoropyridin-4-ylmethyl}-4-methyl-7-(pyrimidin-2-yloxy)-2-oxo-2H-1-benzopyran,

3-{2-(methylaminosulfonyl)amino-3-fluoropyridin-4-ylmethyl}-4-methyl-6-fluoro-7-(pyrimidin-2-yloxy)-2-oxo-2H-1-benzopyran,

3-{2-(cyclopropylaminosulfonyl)amino-3-fluoropyridin-4-ylmethyl}-4-methyl-6-fluoro-7-(pyrimidin-2-yloxy)-2-oxo-2H-1-benzopyran, 3-{2-(methylaminosulfonyl)amino-3-fluoropyridin-4-ylmethyl}-4-methyl-6-chloro-7-(pyrimidin-2-yloxy)-2-oxo-2H-1-benzopyran,

3-{2-(methylaminosulfonyl)amino-3-fluoropyridin-4-ylmethyl}-4-methyl-6-methyl-7-(pyrimidin-2-yloxy)-2-oxo-2H-1-benzopyran,

3-{2-(methylaminosulfonyl)amino-3-fluoropyridin-4-ylmethyl}-4-ethyl-6-methyl-7-(pyrimidin-2-yloxy)-2-oxo-2H-1-benzopyran,

3-{2-(cyclopropylaminosulfonyl)amino-3-fluoropyridin-4-ylmethyl}-4-methyl-6-methyl-7-(pyrimidin-2-yloxy)-2-oxo-2H-1-benzopyran,

3-{2-(cyclopropylaminosulfonyl)amino-3-fluoropyridin-4-ylmethyl}-4-methyl-7-(pyrimidin-2-yloxy)-2-oxo-2H-1-benzopyran,

3-{2-(methylaminosulfonyl)amino-3-chloropyridin-4-ylmethyl}-4-methyl-7-(pyrimidin-2-yloxy)-2-oxo-2H-1-benzopyran,

3-{2-(methylaminosulfonyl)aminopyridin-4-ylmethyl}-4-methyl-6-chloro-7-(thiazol-2-yloxy)-2-oxo-2H-1-benzopyran,

3-{2-(methylaminosulfonyl)amino-3-fluoropyridin-4-ylmethyl}-4-methyl-6-methyl-7-(thiazol-2-yloxy)-2-oxo-2H-1-benzopyran,

3-{2-(cyclopropylaminosulfonyl)amino-3-fluoropyridin-4-ylmethyl}-4-methyl-6-methyl-7-(thiazol-2-yloxy)-2-oxo-2H-1-benzopyran,

3-{2-(methylaminosulfonyl)aminopyridin-4-ylmethyl}-4-methyl-6-methyl-7-(thiazol-2-yloxy)-2-oxo-2H-1-benzopyran,

3-{2-(methylaminosulfonyl)amino-3-chloropyridin-4-ylmethyl}-4-methyl-6-methyl-7-(thiazol-2-yloxy)-2-oxo-2H-1-benzopyran,

3-{2-(methylaminosulfonyl)amino-3-fluoropyridin-4-ylmethyl}-4-methyl-7-(5-fluoropyrimidin-2-yloxy)-2-oxo-2H-1-benzopyran,

3-{2-(methylaminosulfonyl)amino-3-fluoropyridin-4-ylmethyl}-4-methyl-7-(4-chloropyrimidin-2-yloxy)-2-oxo-2H-1-benzopyran,

3-{2-(methylaminosulfonyl)amino-3-fluoropyridin-4-ylmethyl}-4-methyl-7-(2,4-dimethoxypyrimidin-6-yloxy)-2-oxo-2H-1-benzopyran,

3-{2-(methylaminosulfonyl)amino-3-fluoropyridin-4-ylmethyl}-4-methyl-7-(benzothiazol-2-yloxy)-2-oxo-2H-1-benzopyran,

3-{2-(methylaminosulfonyl)amino-3-fluoropyridin-4-ylmethyl}-4-methyl-7-(5-bromothiazol-2-yloxy)-2-oxo-2H-1-benzopyran,

3-{2-(methylaminosulfonyl)amino-3-fluoropyridin-4-ylmethyl}-4-methyl-7-(pyrazin-2-yloxy)-2-oxo-2H-1-benzopyran, and

3-{2-(methylaminosulfonyl)amino-3-fluoropyridin-4-ylmethyl}-4-methyl-7-(pyridin-2-yloxy)-2-oxo-2H-1-benzopyran.

11. A pharmaceutical composition comprising the compound or pharmaceutically acceptable salt thereof according to claim 1 as an active ingredient.

12. A pharmaceutical composition comprising the compound or pharmaceutically acceptable salt thereof according to claim 2 as an active ingredient.

13. The compound or pharmaceutically acceptable salt thereof according to claim 2, which is 3-{2-(methylaminosulfonyl)amino-3-fluoropyridin-4-ylmethyl}-4-methyl-7-(pyrimidin-2-yloxy)-2-oxo-2H-1-benzopyran.