Pyrimidine compound and medical use thereof

• US 20060014768A1
• Filed: 06/10/2005
• Published: 01/19/2006
• Est. Priority Date: 06/11/2004
• Status: Active Grant

• Current Assignee: Japan Tobacco Inc.
• Original Assignee: Japan Tobacco Inc.
• Inventors: Abe, Hiroyuki, Sakai, Toshiyuki, Yoshida, Takayuki, Takahashi, Mitsuru, Iida, Tetsuya, Yamaguchi, Takayuki, Hori, Yoshikazu, Kikuchi, Shinichi, Kawasaki, Hisashi, Hayakawa, Kazuhide, Kurachi, Hironori, Nanayama, Toyomichi, Tamaru, Masahiro
• Granted Patent: US 7,378,423 B2
• Time in Patent Office: Days
• US Class Current: 514/269
• CPC Class Codes: A61K 31/519 ortho- or peri-condensed with heterocyclic rings
• 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 35/00 Antineoplastic agents
• CPC Class Codes: C07C 2601/16 the ring being unsaturated
• CPC Class Codes: C07C 275/30 being further substituted by halogen atoms, or by nitro or nitroso groups
• CPC Class Codes: C07C 275/50 Y being a hydrogen or an acyclic carbon atom
• CPC Class Codes: C07D 239/545 with other hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
• CPC Class Codes: C07D 239/553 with halogen atoms or nitro radicals directly attached to ring carbon atoms, e.g. fluorouracil
• CPC Class Codes: C07D 239/62 Barbituric acids
• CPC Class Codes: C07D 471/04 Ortho-condensed systems
• CPC Class Codes: C07D 471/16 Peri-condensed systems
• CPC Class Codes: C07D 487/04 Ortho-condensed systems
• CPC Class Codes: C07F 9/53 Organo-phosphine oxides; Organo-phosphine thioxides

Abstract

The present invention relates to a pyrimidine compound or a pharmaceutically acceptable salt thereof represented by the following formula [I] wherein each symbol is as defined in the specification and a method of therapeutically or prophylactically treating an undesirable cell proliferation, comprising administering such a compound. The compound of the present invention has superior activity in suppressing undesirable cell proliferation, particularly, an antitumor activity, and is useful as an antitumor agent for the prophylaxis or treatment of cancer, rheumatism, and the like. In addition, the compound of the present invention can be a more effective antitumor agent when used in combination with other antitumor agents such as an alkylating agent or metabolism antagonist.

Claims

1. A method of therapeutically or prophylactically treating an undesirable cell proliferation in a mammal comprising administering to the mammal a therapeutic or prophylactic amount of a compound represented by the following formula [I] or a pharmaceutically acceptable salt thereof:

2. The method of claim 1, wherein the compound is represented by the following formula [I-1]:

3. The method of claim 1, wherein the compound is represented by the following formula [I-2]:

4. The method of claim 1, wherein the compound is represented by the following formula [I-3]:

5. The method of claim 1, wherein R¹ is a C_1-6 alkyl group.

6. The method of claim 1, wherein R¹ is

7. The method of claim 1, wherein R¹ is a C_3-8 cycloalkyl group.

8. The method of claim 7, wherein R¹ is a cyclopropyl group.

9. The method of claim 1, wherein R² is

10. The method of claim 1, wherein R³ is a C_1-6 alkyl group.

11. The method of claim 1, wherein R⁴ is a hydrogen atom.

12. The method of claim 1, wherein R⁵ is a hydrogen atom.

13. The method of claim 1, wherein R⁶ is

14. The method of claim 1, wherein the undesirable cell proliferation causes rheumatism.

15. The method of claim 1, wherein the undesirable cell proliferation causes a tumor.

18. A commercial package comprising:

(i) a pharmaceutical composition comprising;

(a) a compound of the formula [I] of claim 1 or a pharmaceutically acceptable salt thereof, and

(b) a pharmaceutically acceptable carrier and

(ii) a written matter associated therewith, wherein the written matter states that the pharmaceutical composition can or should be used for treating a disease caused by an undesirable cell proliferation.

19. The commercial package of claim 18, wherein the disease is a tumor or rheumatism.

20. A pharmaceutical composition comprising:

(a) a compound of the formula [I] of claim 1 or a pharmaceutically acceptable salt thereof,

(b) at least one antitumor compound that is not a compound of the formula [I], and

(c) a pharmaceutically acceptable carrier.

21. A kit comprising:

(i) a pharmaceutical composition comprising;

(a) a compound of the formula [I] of claim 1 or a pharmaceutically acceptable salt thereof, and

(b) a a pharmaceutically acceptable carrier; and

(ii) a pharmaceutical composition comprising;

(a) at least one antitumor agent that is not a compound of the formula [I], and

(b) a pharmaceutically acceptable carrier.

22. A method of inhibiting MEK in a mammal comprising administering to the mammal an MEK inhibiting amount of a compound of the formula [I] of claim 1 or a pharmaceutically acceptable salt thereof, whereupon MEK is inhibited.

23. A method of inducing p15 protein in a mammal comprising administering to the mammal a p15 protein inducing amount of a compound of the formula [I] of claim 1 or a pharmaceutically acceptable salt thereof, whereupon p15 protein is induced.

24. A method of regulating cell cycle in a mammal comprising administering to the mammal a cell cycle regulating amount of a compound of the formula [I] of claim 1 or a pharmaceutically acceptable salt thereof, whereupon the cell cycle is regulated.

16. A compound represented by the following formula [I′

] or a pharmaceutically acceptable salt thereof;

17. A pharmaceutical composition which comprises:

(a) a compound of claim 16 or a pharmaceutically acceptable salt thereof, and

(b) a pharmaceutically acceptable carrier.