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(12) United States Patent (10) Patent No.: US 8,835,443 B2 Kawasaki Et Al

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(12) United States Patent (10) Patent No.: US 8,835,443 B2 Kawasaki Et Al USOO8835443B2 (12) United States Patent (10) Patent No.: US 8,835,443 B2 Kawasaki et al. (45) Date of Patent: *Sep. 16, 2014 (54) PYRIMIDINE COMPOUND AND MEDICAL (56) References Cited USE THEREOF U.S. PATENT DOCUMENTS (75) Inventors: Hisashi Kawasaki. Takatsuki (JP); 3,139,432 A 6/1964 Scarborough Hiroyuki Abe, Takatsuki (JP); Kazuhide 2004/O138285 A1 7, 2004 Okazaki Hayakawa, Takatsuki (JP); Tetsuya Iida, Takatsuki (JP); Shinichi Kikuchi, FOREIGN PATENT DOCUMENTS Takatsuki (JP); Takayuki Yamaguchi, Takatsuki (JP); Toyomichi Nanayama, A s A. 38: Takatsuki (JP); Hironori Kurachi, JP HO6-502152. A 3, 1994 Takatsuki (JP); Masahiro Tamaru, JP 2002-532414 T 10, 2002 Takatsuki (JP); Yoshikazu Hori, E. 5833. o I 1939: Takatsuki (JP); Mitsuru Takahashi, JP 2005ss4381 T 10, 2002 Takatsuki (JP); Takayuki Yoshida, JP 2002-332247 A 11, 2002 Yokohama (JP); Toshiyuki Sakai, Kyoto JP 2003-504401 T 2, 2003 (JP) JP 2004-504294 T 2, 2004 WO WOOO/35435 A1 6, 2000 WO WOOO/35436 A2 6, 2000 (73) Assignee: Japan Tobacco Inc., Tokyo (JP) WO WOOOf 40235 A2 7, 2000 WO WOOOf 40237 A1 T 2000 (*) Notice: Subject to any disclaimer, the term of this WO WOO1,05393 A2 1, 2001 patent is extended or adjusted under 35 W W 9:32, A. 38: U.S.C. 154(b) by 631 days. WO WOO2,06520 A1 1/2002 This patent is Subject to a terminal dis- (Continued) claimer. OTHER PUBLICATIONS (21) Appl. No.: 12/626,443 West, Anthony R., Solid State Chemistry and Its Applications, Wiley, New York, 1988, 358.* (22) Filed: Nov. 25, 2009 (Continued) (65) Prior Publication Data Primary Examiner — Erich A Leeser US 2010/O240613 A1 Sep. 23, 2010 (74) Attorney, Agent, or Firm — Leydig, Voit & Mayer, Ltd. (57) ABSTRACT Related U.S. Application Data The present invention relates to a pyrimidine- 0 compound or a (63) Continuation of application No. 12/053,133, filed on pharmaceutically acceptable salt thereof represented by the Mar. 21, 2008, now abandoned, which is a following formula II continuation of application No. 1 1/150,792, filed on Jun. 10, 2005, now Pat. No. 7,378,423. (60) Provisional application No. 60/630,596, filed on Nov. R R6 I 23, 2004. o NN1 (30) Foreign Application Priority Data RN ls l, 1 R4 N W X Jun. 11, 2004 (JP) ................................. 2004-174770 1. 1s Nov. 10, 2004 (JP) ................................. 2004-327111 O N1-x O (51) Int. Cl. R2 R3 A 6LX3/59 (2006.01) C07D 239/545 (2006.01) wherein each symbol is as defined in the specification and a CO7D 47L/04 (2006.01) method of therapeutically or prophylactically treating an CO7D 487/04 (2006.01) undesirable cell proliferation, comprising administering Such (52) U.S. Cl. a compound. The compound of the present invention has CPC .......... C07D 471/04 (2013.01); C07D 239/545 Superior activity in Suppressing undesirable cell proliferation, (2013.01); A61 K3 1/519 (2013.01); C07D particularly, an antitumor activity, and is useful as an antitu 48704 (2013.01) mor agent for the prophylaxis or treatment of cancer, rheu USPC ..................................... 514/262.1: 514/264.1 matism, and the like. In addition, the compound of the present (58) Field of Classification Search invention can be a more effective antitumor agent when used CPC ............. A61K31/519; C07D 239/545; C07D in combination with other antitumor agents such as an alky 471/04: CO7D 487/04 lating agent or metabolism antagonist. USPC ............................................ 514/262.1, 264.1 See application file for complete search history. 49 Claims, No Drawings US 8,835,443 B2 Page 2 (56) References Cited Burova et al., Chemistry of Heterocyclic Compounds, 5: 674-680 (1991) Translation pp. 538-544 (1991). FOREIGN PATENT DOCUMENTS Calvet, J. Am. Soc. Nephrol. 17: 1498-1500 (2006). Crees, Calif St. J. Med. V(II): 292-293 (1907). WO WO O2/O87620 A1 11, 2002 Guo et al., Leukemia, 20: 115-121 (2006). WO WO 02/094824 A1 11, 2002 Hannon et al., Nature, 371: 257-261 (Sep. 15, 1994). WO WO 03/062236 A1 T 2003 Hitomi et al., FEBS Letters, 554: 347-350 (2003). Hoshino et al., Journal of Biological Chemistry, 276(4): 2686-2692 OTHER PUBLICATIONS (Jan. 26, 2001). Khattab et al., Journal far Praktische Chemie, 338: 151-156 (1996). Khattab, et al., Ring Closure Reaction of 5-Hydroxy-pyrido2,3- Ogura et al., Chem. Pharm. Bull., 21 (9): 2014-2018 (1973). dipyrimidine-2,4,7-triones tO Benzo(bpyrimido-4,5-h1.6- Su et al., Journal of Medicinal Chemistry, 29(5): 709-715 (1986). naphthyridine-1,3,6-triones, Journal fur Praktische Chemie, vol.338, Tamir et al., Cel Growth and Differentiation, 11: 269-277 (May 151-156 (1996).* 2000). Eissa, et al., Deletion of p. 16 and p. 15 genes in Schistosomiasis Wang et al., J. Biol. Chem, 280(13): 12339-12343 (2005). associated bladder cancer (SABC), Clinica Chimica Acta 300, 159 Broom et al., J. Org. Chem., 41(7): 1095-1099 (1976). 169 (2000).* Hirota et al., J. Org. Chem., 46: 846-851 (1981). Thornber, C.W., Isosterism and Molecular Modification in Drug Khattab et al., J. prakt. Chem., 338: 151-156 (1996). Design, 563-580.* Khattab et al., Monatshefie fiur Chemie, 127: 917-925 (1996). Ogura, et al., Studies on Heterocyclic Compounds. XII. A Novel Ogura et al., Chemistry Letters, 657-658 (1972). Synthesis of 5-Oxo- and 7-Oxo-pyrido2,3-dipyrimidines, Chem. Scarborough, J. Org. Chem., 29(1): 219-221 (1964). Pharm. Bull, vol. 21, No. 7, 2014-2018 (1973).* Su et al., J. Med. Chem., 29: 709-715 (1986). Thornber, Chem. Soc. Rev., 8: 563-580 (1979).* Boultwood et al., Brit. J. of Haematol. 138:3-11 (2007). * cited by examiner US 8,835,443 B2 1. 2 PYRIMIDINE COMPOUND AND MEDICAL dence in p16 knock out mice has been demonstrated, and USE THEREOF therefore, clinical application of p 16 inducer has been tried. Under such situation, p15 protein (aka: INK4B, also sim CROSS-REFERENCE TO RELATED ply referred to as p15) has been found as a p16 family. In APPLICATIONS 1994, induction of p15 expression by TGF-B stimulation was confirmed in human keratinocyte cell (HaCaT), and p15 was This patent application is a continuation of U.S. patent considered to be one of the factors negatively regulating the application Ser. No. 12/053,133, filed Mar. 21, 2008, now cell cycle. It is known that induction of G1 phase cell cycle abandoned, which is a continuation of U.S. patent application arrest in HaCaT by TGF-B leads to the suppression of cell Ser. No. 11/150,792, filed Jun. 10, 2005, now U.S. Pat. No. 10 proliferation (Letters to Nature, Sep. 15, 1994, vol. 371, pp. 7,378,423, which claims the benefit of U.S. Provisional 257-261). Patent Application No. 60/630,596, filed Nov. 23, 2004, While the histondeacetylase (HDAC) inhibitor is known to which is incorporated by reference. arrest cell cycles at G1 phase or G2 phase in human cancer TECHNICAL FIELD 15 cell, it has been found recently that trichostatin A, which is an HDAC inhibitor, induces p15 gene in human colon cancer cell The present invention relates to a novel pyrimidine com (HCT116p21(-/-)), and the induction of p15 by trichostatin pound or a pharmaceutically acceptable salt thereofuseful as A is involved in the inhibition of the cell proliferation of the an agent for the prophylaxis or treatment of diseases caused cancer cells (FEBS Letters, 2003, vol. 554, pp. 347-350). by undesirable cell proliferation, particularly, an antitumor In this way, a compound that induces p15 and/or p27 is agent. Moreover, the present invention relates to novel use of expected to inhibit the cell proliferation of cancer cells and a certain kind of pyrimidine compound or a pharmaceutically the like. acceptable salt thereof as an agent for the prophylaxis or In the meantime, Mitogen-activated protein (MAP) treatment of a disease caused by undesirable cell prolifera Kinase/extracellular signal-regulated kinase (ERK) kinase tion, particularly, as an antitumor agent. More particularly, 25 (hereinafter to be referred to as MEK) is known to be involved the present invention relates to a pharmaceutical agent com in the regulation of cell proliferation as a kinase that mediates prising a pyrimidine compound showing a p15 protein induc Raf-MEK-ERK signal transduction pathway, and the Raf ing action and/or a p27 protein inducing action and/or an family (B-Raf, C-Rafetc.) activates the MEK family (MEK MEK inhibitory action, or a pharmaceutically acceptable salt 1. MEK-2 etc.) and the MEK family activates the ERK family thereof. 30 (ERK-1 and ERK-2). Activation of Raf-MEK-ERK signal transduction pathway BACKGROUND ART in cancer, particularly colorectal cancer, pancreatic cancer, lung cancer, breast cancer and the like, has been frequently A “cell cycle” means a cycle wherein the period for a cell observed. to divide and once again divide is one cycle, and this cycle is 35 In addition, since the signals produced by signal molecules also referred to as a “cell division cycle”. Such as growth factor, cytokine and the like converge to the A cell cycle includes four phases in a determined order. activation of MEK-ERK, inhibition of these functions is con They are DNA duplication preparation phase (G1 phase), sidered to more effectively suppress Raf-MEK-ERK signal DNA duplication phase (Sphase), division preparation phase transduction than the suppression of the function of RTK, (G2 phase) and division phase (M phase), and regulated by 40 Ras, Raf and the like in the upstream. many factors. Among them, the kinase activity of a cyclin/ Moreover, it is also known in recent years that a compound cyclindependent kinase (CDK) complex is essential for the having an MEK inhibitory activity extremely effectively regulation of the cell cycle.
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