Title:
DIHYDROOROTIC ACID DEHYDROGENASE INHIBITOR
Document Type and Number:
WIPO Patent Application WO/2013/180140
Kind Code:
A1
Abstract:
The present invention provides a novel dihydroorotic acid dehydrogenase inhibitor that is applicable to various diseases. As an active ingredient, a compound represented by formula (I) (wherein X represents a halogen atom; R1 represents a hydrogen atom; R2 represents an alkyl group having 1 to 7 carbon atoms; R3 represents -CHO; and R4 represents -CH2-CH=C(CH3)-R0 (wherein R0 represents an alkyl group having 1 to 12 carbon atoms which may have a substituent on a terminal carbon atom and/or a non-terminal carbon atom, or the like)), an optical isomer of the compound, and a pharmaceutically acceptable salt of the compound or the optical isomer. The compound, the optical isomer and the pharmaceutically acceptable salt have an excellent inhibitory activity on dihydroorotic acid dehydrogenase and therefore can be used as an immunosuppressive agent, a therapeutic agent for rheumatism, an anti-cancer agent, a therapeutic agent for rejection response, an anti-viral agent, an anti-H. pylori agent, a therapeutic agent for diabetes and the like.
More Like This:
Inventors:
KITA KIYOSHI (JP)
INAOKA KEN DANIEL (JP)
SAIMOTO HIROYUKI (JP)
YAMAMOTO MASAICHI (JP)
INAOKA KEN DANIEL (JP)
SAIMOTO HIROYUKI (JP)
YAMAMOTO MASAICHI (JP)
Application Number:
PCT/JP2013/064806
Publication Date:
December 05, 2013
Filing Date:
May 28, 2013
Export Citation:
Assignee:
NAI INC (JP)
International Classes:
A61K31/11; A61K9/08; A61K31/121; A61K31/216; A61K31/222; A61K31/336; A61K31/341; A61K31/351; A61K31/357; A61K47/10; A61P1/04; A61P3/10; A61P29/00; A61P31/04; A61P31/12; A61P35/00; A61P37/06; A61P43/00; C07C47/56; C07C47/565; C07C47/575; C07C49/258; C07C69/14; C07C69/24; C07C69/738; C07D303/14; C07D307/20; C07D309/12
Domestic Patent References:
| WO2012060387A1 | 2012-05-10 | |||
| WO2000053563A1 | 2000-09-14 | |||
| WO2000035867A1 | 2000-06-22 | |||
| WO2003063849A1 | 2003-08-07 |
Foreign References:
| US3546073A | 1970-12-08 | |||
| JPH07278041A | 1995-10-24 | |||
| JP2005126343A | 2005-05-19 | |||
| JP2006213644A | 2006-08-17 |
Other References:
ZHANG, P. ET AL.: "Anti-inflammatory sesquiterpenoids from a sponge-derived fungus Acremonium sp.", JOURNAL OF NATURAL PRODUCTS, vol. 72, no. 2, 2009, pages 270 - 275, XP055090455
PROC NATL ACAD SCI USA, March 2011 (2011-03-01)
DANIEL L. DEXTER; I DAVID P. HESSON; ROBERT J. ARDECKY; GANTI V. RAO; DAVETTE L. TIPPETT; BETSY A. DUSAK; KENNETH D. PAULL; JACQUE: "Activity of a Novel 4-Quinolinecarboxylic Acid, NSC 368390 [6-Fluoro-2-(2'- fluoro-1, '-biphenyl-4-yl)-3-methyl-4-quinolinecarboxylic Acid Sodium Salt], against Experimental Tumors", CANCE RES., vol. 45, 1985, pages 5563 - 5568, XP055212656
SHIH-FONG CHEN; REGINA L. RUBEN; DANIEL L. DEXTER: "Mechanism of action of the novel anticancer agent 6-fluoro-2-(2'-fluoro-1,1'-biphenyl-4-yl)-3-methyl-4-quinolinecarbo xylic acid sodium salt (NSC 368390): inhibition of de novo pyrimidine nucleotide biosynthesis", CANCE RES., vol. 46, no. 10, 1986, pages 5014 - 5019
ARTEAGA CL; BROWN TD; KUHN JG; SHEN HS; O'ROURKE TJ; BEOUGHER K; BRENTZEL HJ; VON HOFF DD; WEISS GR: "Phase I Clinical and Pharmacokinetic Trial of Brequinar Sodium", CANCER RES., vol. 49, no. 16, 1989, pages 4648 - 4653
SCHWARTSMANN G; DODION P; VERMORKEN JB; TEN BOKKEL HUININK WW; JOGGI J; WINOGRAD B; GALL H; SIMONETTI G; VAN DER VIJGH WJ; VAN HEN: "Phase I study of Brequinar sodium (NSC 368390) in patients with solid malignancies", CANCER CHEMOTHER PHARMACOL., vol. 25, no. 5, 1990, pages 345 - 351
FORREST TL; WARE RE; HOWARD T; JAFFEE BD; DENNING SM: "Novel mechanisms of brequinar sodium immunosuppression on T cell activation", TRANSPLANTATION, vol. 58, no. 8, 1994, pages 920 - 926
WILLIAMSON RA; YEA CM; ROBSON PA; CURNOCK AP; GADHER S; HAMBLETON AB; WOODWARD K; BRUNEAU JM; HAMBLETON P; MOSS D: "Dihydroorotate dehydrogenase is a high affinity binding protein for A77 1726 and mediator of a range of biological effects of the immunomodulatory compound", JBIOL CHEM., vol. 270, no. 38, 1995, pages 22467 - 22472
DAVIS JP; CAIN GA; PITTS WJ; MAGOLDA RL; COPELAND RA: "The immunosuppressant leflunomide inhibits lymphocyte proliferation by inhibiting pyrimidine biosynthesis", BIOCHEMISTRY, vol. 35, no. 4, 1996, pages 1270 - 1273
CLEAVELAND ES; ZAHAREVITZ DW; KELLEY JA; PAULL K; COONEY DA; FORD H JR.: "Identification of a novel inhibitor (NSC 665564) of dihydroorotate dehydrogenase with a potency equivalent to brequinar", BIOCHEM BIOPHYS RES COMMUN., vol. 223, no. 3, 1996, pages 654 - 659, XP002349441, DOI: doi:10.1006/bbrc.1996.0950
BALDWIN J; MICHNOFF CH; MALMQUIST NA; WHITE J; ROTH MG; RATHOD PK; PHILLIPS MA: "High-throughput Screening for Potent and Selective Inhibitors of Plasmodium falcparum Dihydroorotate Dehydrogenase", J BIOL CHEM., vol. 280, no. 23, 2005, pages 21847 - 21853
PHILLIPS MA; GUJJAR R; MALMQUIST NA; WHITE J; EL MAZOUNI F; BALDWIN J; RATHOD PK: "Triazolopyrimidine-based dihydroorotate dehydrogenase inhibitors with potent and selective activity against the malaria parasite Plasmodium falciparum", JMED CHEM., vol. 51, no. 12, 2008, pages 3649 - 3653, XP055050943, DOI: doi:10.1021/jm8001026
COPELAND RA; MARCINKEVICIENE J; HAQUE TS; KOPCHO LM; JIANG W; WANG K; ECRET LD; SIZEMORE C; AMSLER KA; FOSTER L: "Helcobacter pylori-selective Antibacterials Based on Inhibition of pyrimidine biosynthesis", JBIOL CHEM., vol. 275, no. 43, 2000, pages 33373 - 33378
HAQUE TS; TADESSE S; MARCINKEVICIENE J; ROGERS MJ; SIZEMORE C; KOPCHO LM; AMSLER K; ECRET LD; ZHAN DL; HOBBS F: "Parallel synthesis of potent, pyrazole-based inhibitors of Helicobacter pylori dihydroorotate dehydrogenase", J MED CHEM., vol. 45, no. 21, 2002, pages 4669 - 4678, XP002470864, DOI: doi:10.1021/jm020112w
ELKE ZAMEITAT; ZORAN GOJKOVIC; WOLFGANG KNECHT; JURE PISKUR; MONIKA LO: "ffler. Biochemical characterization of recombinant dihydroorotate dehydrogenase from the opportunistic pathogenic yeast Candida albicans", FEBSJ., vol. 273, no. 14, 2006, pages 3183 - 3191, XP002539816, DOI: doi:10.1111/J.1742-4658.2006.05327.X
GUSTAFSON G; DAVIS G; WALDRON C; SMITH A; HENRY M: "Identification of a new antifungal target site through a dual biochemical and molecular-genetics approach", CURR GENET., vol. 30, no. 2, 1996, pages 159 - 165, XP009120993, DOI: doi:10.1007/s002940050115
DAVID L. EVERS; XIN WANG; SHU-MEI HUONG; KENNETH A. ANDREONI; ENG-SHANG HUANG, INHIBITION OF HUMAN CYTOMEGALOVIRUS SIGNALING AND REPLICATION BY THE IMMUNOSUPPRESSANT FK778
MIN QING; GANG ZOU; QING-YIN WANG; HAO YING XU; HONGPING DONG; ZHIMING YUAN; PEI-YONG SHI: "Characterization of Dengue Virus Resistance to Brequinar in Cell Culture", ANTIMICROB AGENTS CHEMOTHER, vol. 54, no. 9, 2010, pages 3686 - 3695
HANS-HEINRICH HOFFMANN; ANDREA KUNZA; VIVIANA A. SIMONA; PETER PALESEA; MEGAN L. SHAWA: "Broad-spectrum antiviral that interferes with de novo pyrimidine biosynthesis", PROC NATL ACED SCI U S A., 21 March 2011 (2011-03-21)
JUNE P. DAVIS; GARY A. CAIN; WILLIAM J. PITTS; RONALD L. MAGOLDA; ROBERT A. COPELAND: "The Immunosuppressive Metabolite of Leflunomide Is a Potent Inhibitor of Human Dihydroorotate Dehydrogenase", BIOCHEMISTRY, vol. 35, 1996, pages 1270 - 1273
PAPAGEORGIOU C; ALBERT R; FLOERSHEIM P; LEMAIRE M; BITCH F; WEBER HP; ANDERSEN E; HUNGERFORD V; SCHREIER MH: "Pyrazole bioisosteres of leflunomide as B-cell immunosuppressants for xenotransplantation and chronic rejection: scope and limitations", JMED CHEM., vol. 41, no. 18, 1998, pages 3530 - 3538
STOSIC-GRUJICIC S; DIMITRIJEVIC M; BARTLETT R: "Leflunomide protects mice from multiple low dose streptozotocin (MLD-SZ)-induced insulitis and diabetes", CLIN EXP IMMUNOL., vol. 117, no. 1, 1999, pages 44 - 50
ITTARAT I; ASAWAMAHASAKDA W; BARTLETT MS; SMITH JW; MESHNICK SR: "Effects of atovaquone and other inhibitors on Pneumocystis carinii dihydroorotate dehydrogenase", ANTIMICROB AGENTS CHEMOTHER., vol. 39, no. 2, 1995, pages 325 - 358, XP002069079
TETRAHEDRON, vol. 44, 1988, pages 41 - 48
H. SAIMOTO ET AL., BULL. CHEM. SOC. JPN., vol. 72, 1999, pages 279 - 284
H. SAIMOTO ET AL., BULL. CHEM. SOC. JPN., vol. 68, 1995, pages 2727 - 2734
TETRAHEDRON, vol. 59, 2003, pages 2991 - 2998
J. AM. CHEM. SOC., 2002, pages 13670 - 13671
TETRAHEDRON LETT., vol. 42, 2001, pages 2205 - 2208
K. MORI; S. TAKECHI, TETRAHEDRON, vol. 41, 1985, pages 3049 - 3062
J. BRAZ. CHEM. SOC., vol. 14, 2003, pages 975 - 981
J. AM. CHEM. SOC., vol. 99, 1977, pages 1275 - 1276
TETRAHEDRON, vol. 30, 1974, pages 715 - 718
ORG. LETT., vol. 8, 2006, pages 5649 - 5652
J. AM. CHEM. SOC., vol. 127, 2005, pages 7014 - 7024
ORG. LETT., vol. 9, 2007, pages 1461 - 1464
TETRAHEDRON, vol. 40, 1984, pages 2711 - 2720
KONG D.; T. YAMORI, BIOORGANIC & MED. CHEM., vol. 20, 2012, pages 1947 - 51
LUE J., CANCER SCI., vol. 95, no. 6, 2004, pages 547 - 552
PROC NATL ACAD SCI USA, March 2011 (2011-03-01)
DANIEL L. DEXTER; I DAVID P. HESSON; ROBERT J. ARDECKY; GANTI V. RAO; DAVETTE L. TIPPETT; BETSY A. DUSAK; KENNETH D. PAULL; JACQUE: "Activity of a Novel 4-Quinolinecarboxylic Acid, NSC 368390 [6-Fluoro-2-(2'- fluoro-1, '-biphenyl-4-yl)-3-methyl-4-quinolinecarboxylic Acid Sodium Salt], against Experimental Tumors", CANCE RES., vol. 45, 1985, pages 5563 - 5568, XP055212656
SHIH-FONG CHEN; REGINA L. RUBEN; DANIEL L. DEXTER: "Mechanism of action of the novel anticancer agent 6-fluoro-2-(2'-fluoro-1,1'-biphenyl-4-yl)-3-methyl-4-quinolinecarbo xylic acid sodium salt (NSC 368390): inhibition of de novo pyrimidine nucleotide biosynthesis", CANCE RES., vol. 46, no. 10, 1986, pages 5014 - 5019
ARTEAGA CL; BROWN TD; KUHN JG; SHEN HS; O'ROURKE TJ; BEOUGHER K; BRENTZEL HJ; VON HOFF DD; WEISS GR: "Phase I Clinical and Pharmacokinetic Trial of Brequinar Sodium", CANCER RES., vol. 49, no. 16, 1989, pages 4648 - 4653
SCHWARTSMANN G; DODION P; VERMORKEN JB; TEN BOKKEL HUININK WW; JOGGI J; WINOGRAD B; GALL H; SIMONETTI G; VAN DER VIJGH WJ; VAN HEN: "Phase I study of Brequinar sodium (NSC 368390) in patients with solid malignancies", CANCER CHEMOTHER PHARMACOL., vol. 25, no. 5, 1990, pages 345 - 351
FORREST TL; WARE RE; HOWARD T; JAFFEE BD; DENNING SM: "Novel mechanisms of brequinar sodium immunosuppression on T cell activation", TRANSPLANTATION, vol. 58, no. 8, 1994, pages 920 - 926
WILLIAMSON RA; YEA CM; ROBSON PA; CURNOCK AP; GADHER S; HAMBLETON AB; WOODWARD K; BRUNEAU JM; HAMBLETON P; MOSS D: "Dihydroorotate dehydrogenase is a high affinity binding protein for A77 1726 and mediator of a range of biological effects of the immunomodulatory compound", JBIOL CHEM., vol. 270, no. 38, 1995, pages 22467 - 22472
DAVIS JP; CAIN GA; PITTS WJ; MAGOLDA RL; COPELAND RA: "The immunosuppressant leflunomide inhibits lymphocyte proliferation by inhibiting pyrimidine biosynthesis", BIOCHEMISTRY, vol. 35, no. 4, 1996, pages 1270 - 1273
CLEAVELAND ES; ZAHAREVITZ DW; KELLEY JA; PAULL K; COONEY DA; FORD H JR.: "Identification of a novel inhibitor (NSC 665564) of dihydroorotate dehydrogenase with a potency equivalent to brequinar", BIOCHEM BIOPHYS RES COMMUN., vol. 223, no. 3, 1996, pages 654 - 659, XP002349441, DOI: doi:10.1006/bbrc.1996.0950
BALDWIN J; MICHNOFF CH; MALMQUIST NA; WHITE J; ROTH MG; RATHOD PK; PHILLIPS MA: "High-throughput Screening for Potent and Selective Inhibitors of Plasmodium falcparum Dihydroorotate Dehydrogenase", J BIOL CHEM., vol. 280, no. 23, 2005, pages 21847 - 21853
PHILLIPS MA; GUJJAR R; MALMQUIST NA; WHITE J; EL MAZOUNI F; BALDWIN J; RATHOD PK: "Triazolopyrimidine-based dihydroorotate dehydrogenase inhibitors with potent and selective activity against the malaria parasite Plasmodium falciparum", JMED CHEM., vol. 51, no. 12, 2008, pages 3649 - 3653, XP055050943, DOI: doi:10.1021/jm8001026
COPELAND RA; MARCINKEVICIENE J; HAQUE TS; KOPCHO LM; JIANG W; WANG K; ECRET LD; SIZEMORE C; AMSLER KA; FOSTER L: "Helcobacter pylori-selective Antibacterials Based on Inhibition of pyrimidine biosynthesis", JBIOL CHEM., vol. 275, no. 43, 2000, pages 33373 - 33378
HAQUE TS; TADESSE S; MARCINKEVICIENE J; ROGERS MJ; SIZEMORE C; KOPCHO LM; AMSLER K; ECRET LD; ZHAN DL; HOBBS F: "Parallel synthesis of potent, pyrazole-based inhibitors of Helicobacter pylori dihydroorotate dehydrogenase", J MED CHEM., vol. 45, no. 21, 2002, pages 4669 - 4678, XP002470864, DOI: doi:10.1021/jm020112w
ELKE ZAMEITAT; ZORAN GOJKOVIC; WOLFGANG KNECHT; JURE PISKUR; MONIKA LO: "ffler. Biochemical characterization of recombinant dihydroorotate dehydrogenase from the opportunistic pathogenic yeast Candida albicans", FEBSJ., vol. 273, no. 14, 2006, pages 3183 - 3191, XP002539816, DOI: doi:10.1111/J.1742-4658.2006.05327.X
GUSTAFSON G; DAVIS G; WALDRON C; SMITH A; HENRY M: "Identification of a new antifungal target site through a dual biochemical and molecular-genetics approach", CURR GENET., vol. 30, no. 2, 1996, pages 159 - 165, XP009120993, DOI: doi:10.1007/s002940050115
DAVID L. EVERS; XIN WANG; SHU-MEI HUONG; KENNETH A. ANDREONI; ENG-SHANG HUANG, INHIBITION OF HUMAN CYTOMEGALOVIRUS SIGNALING AND REPLICATION BY THE IMMUNOSUPPRESSANT FK778
MIN QING; GANG ZOU; QING-YIN WANG; HAO YING XU; HONGPING DONG; ZHIMING YUAN; PEI-YONG SHI: "Characterization of Dengue Virus Resistance to Brequinar in Cell Culture", ANTIMICROB AGENTS CHEMOTHER, vol. 54, no. 9, 2010, pages 3686 - 3695
HANS-HEINRICH HOFFMANN; ANDREA KUNZA; VIVIANA A. SIMONA; PETER PALESEA; MEGAN L. SHAWA: "Broad-spectrum antiviral that interferes with de novo pyrimidine biosynthesis", PROC NATL ACED SCI U S A., 21 March 2011 (2011-03-21)
JUNE P. DAVIS; GARY A. CAIN; WILLIAM J. PITTS; RONALD L. MAGOLDA; ROBERT A. COPELAND: "The Immunosuppressive Metabolite of Leflunomide Is a Potent Inhibitor of Human Dihydroorotate Dehydrogenase", BIOCHEMISTRY, vol. 35, 1996, pages 1270 - 1273
PAPAGEORGIOU C; ALBERT R; FLOERSHEIM P; LEMAIRE M; BITCH F; WEBER HP; ANDERSEN E; HUNGERFORD V; SCHREIER MH: "Pyrazole bioisosteres of leflunomide as B-cell immunosuppressants for xenotransplantation and chronic rejection: scope and limitations", JMED CHEM., vol. 41, no. 18, 1998, pages 3530 - 3538
STOSIC-GRUJICIC S; DIMITRIJEVIC M; BARTLETT R: "Leflunomide protects mice from multiple low dose streptozotocin (MLD-SZ)-induced insulitis and diabetes", CLIN EXP IMMUNOL., vol. 117, no. 1, 1999, pages 44 - 50
ITTARAT I; ASAWAMAHASAKDA W; BARTLETT MS; SMITH JW; MESHNICK SR: "Effects of atovaquone and other inhibitors on Pneumocystis carinii dihydroorotate dehydrogenase", ANTIMICROB AGENTS CHEMOTHER., vol. 39, no. 2, 1995, pages 325 - 358, XP002069079
TETRAHEDRON, vol. 44, 1988, pages 41 - 48
H. SAIMOTO ET AL., BULL. CHEM. SOC. JPN., vol. 72, 1999, pages 279 - 284
H. SAIMOTO ET AL., BULL. CHEM. SOC. JPN., vol. 68, 1995, pages 2727 - 2734
TETRAHEDRON, vol. 59, 2003, pages 2991 - 2998
J. AM. CHEM. SOC., 2002, pages 13670 - 13671
TETRAHEDRON LETT., vol. 42, 2001, pages 2205 - 2208
K. MORI; S. TAKECHI, TETRAHEDRON, vol. 41, 1985, pages 3049 - 3062
J. BRAZ. CHEM. SOC., vol. 14, 2003, pages 975 - 981
J. AM. CHEM. SOC., vol. 99, 1977, pages 1275 - 1276
TETRAHEDRON, vol. 30, 1974, pages 715 - 718
ORG. LETT., vol. 8, 2006, pages 5649 - 5652
J. AM. CHEM. SOC., vol. 127, 2005, pages 7014 - 7024
ORG. LETT., vol. 9, 2007, pages 1461 - 1464
TETRAHEDRON, vol. 40, 1984, pages 2711 - 2720
KONG D.; T. YAMORI, BIOORGANIC & MED. CHEM., vol. 20, 2012, pages 1947 - 51
LUE J., CANCER SCI., vol. 95, no. 6, 2004, pages 547 - 552
Attorney, Agent or Firm:
KOBAYASHI Hiroshi et al. (JP)
Kobayashi 浩 (JP)
Kobayashi 浩 (JP)
Download PDF: