Title:
4-METHYLDIHYDROPYRIMIDINONE COMPOUND AND MEDICINAL USE THEREOF
Document Type and Number:
WIPO Patent Application WO/2019/167981
Kind Code:
A1
Abstract:
The present invention relates to: a 4-methyldihydropyrimidinone compound having an ROR-γ antagonistic activity or a pharmacologically acceptable salt of the compound; a medicinal composition containing the compound or salt; and a medicinal use of the compound or salt. Provided are: the compound of formula (1) or (2) or a pharmacologically acceptable salt of the compound; a medicinal composition containing the compound or salt; and a medicinal use of the compound or salt.
Inventors:
SAKAI TAKAYUKI (JP)
IKENOGAMI TAKU (JP)
IKENOGAMI TAKU (JP)
Application Number:
PCT/JP2019/007433
Publication Date:
September 06, 2019
Filing Date:
February 27, 2019
Export Citation:
Assignee:
JAPAN TOBACCO INC (JP)
International Classes:
C07D239/22; A61K31/513; A61P3/00; A61P27/04; A61P35/00; A61P37/02; A61P37/08
Domestic Patent References:
| WO2016093342A1 | 2016-06-16 |
Foreign References:
| JP2015524449A | 2015-08-24 |
Other References:
KOENDERS ET AL.: "Potential new targets in arthritis therapy: interleukin (IL)-17 and its relation to tumour necrosis factor and IL-1 in experimental arthritis", ANN. RHEUM. DIS., vol. 65, 2006, pages iii29 - 33
SCHMIDT-WEBER ET AL.: "Thl7 cells in the big picture of immunology", J. ALLERGY CLIN. IMMUNOL., vol. 120, 2007, pages 247 - 54, XP022199073, DOI: 10.1016/j.jaci.2007.06.039
MEISSBURGER ET AL.: "Adipogenesis and insulin sensitivity in obesity are regulated by retinoid-related orphan receptor gamma", EMBO MOL. MED., vol. 3, 2011, pages 637 - 51
KELCHTERMANS ET AL.: "Effector mechanisms of interleukin-17 in collagen-induced arthritis in the absence of interferon-y and counteraction by interferon-y", ARTHRITIS RES. THER., vol. 11, no. 4, 2009, pages R122, XP021061277, DOI: 10.1186/ar2787
NAKAE ET AL.: "Suppression of Immune Induction of Collagen-Induced Arthritis in IL-17-Deficient Mice", J. IMMUNOL., vol. 171, 2003, pages 6173 - 6177
HUEBER ET AL.: "Effects of AIN457, a Fully Human Antibody to Interleukin-17A, on Psoriasis, Rheumatoid Arthritis, and Uveitis", SCI. TRANSL. MED., vol. 2, no. 52, 2010, pages 52ra72
SANFORD ET AL.: "Secukinumab: first global approval", DRUGS, vol. 75, no. 3, 2015, pages 329 - 338, XP009507136, DOI: 10.1007/s40265-015-0359-0
LEPPKES ET AL.: "RORy-Expressing Thl7 Cells Induce MurineChronic Intestinal Inflammation via Redundant Effects of IL-17A and IL-17F", GASTROENTEROLOGY, vol. 136, no. 1, 2009, pages 257 - 267
IVANOV ET AL.: "The Orphan Nuclear Receptor RORyt Directs the Differentiation Program of Proinflammatory IL-17+ T Helper Cells", CELL, vol. 126, no. 6, 2006, pages 1121 - 1133, XP008091324, DOI: 10.1016/j.cell.2006.07.035
STEINMETZ ET AL.: "The Thl7-Defining Transcription Factor RORyt Promotes Glomerulonephritis", J. AM. SOC. NEPHROL., vol. 22, no. 3, 2011, pages 472 - 483
CRISPIN ET AL.: "Interleukin-17-producing T cells in lupus", CURR. OPIN. RHEUMATOL., vol. 22, no. 5, 2010, pages 499 - 503
BAETEN ET AL.: "Anti-interleukin-17A monoclonal antibody secukinumab in treatment of ankylosing spondylitis: a randomised, double-blind, placebo-controlled trial", LANCET, vol. 382, no. 9906, 2013, pages 1705 - 1713, XP002726555, DOI: 10.1016/S0140-6736(13)61134-4
EMAMAULLEE ET AL.: "Inhibition of Thl7 Cells Regulates Autoimmune Diabetes in NOD Mice", DIABETES, vol. 58, 2009, pages 1302 - 1311, XP055052644, DOI: 10.2337/db08-1113
TILLEY ET AL.: "Retinoid-Related Orphan Receptor γ Controls Immunoglobulin Production and Thl/Th2 Cytokine Balance in the Adaptive Immune Response to Allergen", J. IMMUNOL., vol. 178, 2007, pages 3208 - 3218
"The Effects of a Single Intravenous Administration of Secukinumab (AIN457) or Canakinumab (ACZ885) in Dry Eye Patients", 4 December 2012, U.S. NATIONAL INSTITUTES OF HEALTH
MI ET AL.: "Blocking IL-17A Promotes the Resolution of Pulmonary Inflammation and Fibrosis Via TGF-(31-Dependent and -Independent Mechanisms", J. IMMUNOL., vol. 187, 2011, pages 3003 - 3014
"A Study of Efficacy and Safety of Ustekinumab in Patients With Primary Biliary Cirrhosis (PBC) Who Had an Inadequate Response to Ursodeoxycholic Acid", 2 April 2015, U.S. NATIONAL INSTITUTES OF HEALTH
FULTON ET AL.: "Attenuation of Acute Graft-versus-Host Disease in the Absence of the Transcription Factor RORyt", J. IMMUNOL., vol. 189, no. 4, 2012, pages 1765 - 1772
BRIAN G FEAGAN ET AL.: "Induction therapy with the selective interleukin-23 inhibitor risankizumab in patients with moderate-to-severe Crohn's disease: a randomised, double-blind, placebo-controlled phase 2 study", THE LANCET, vol. 389, no. 10080, 2017, pages 1699 - 1709, XP029988821, DOI: 10.1016/S0140-6736(17)30570-6
EVA HAVRDOVA ET AL.: "Activity of secukinumab, an anti-IL-17A antibody, on brain lesions in RRMS: results from a randomized, proof-of-concept study", J. NEUROL., vol. 263, no. 7, 2016, pages 1287 - 1295, XP035993925, DOI: 10.1007/s00415-016-8128-x
A. DAVID RODRIGUES ET AL.: "Oxidative Metabolism of Clarithromycin in the Presence of Human Liver Microsomes", DRUG METABOLISM AND DISPOSITION, vol. 25, no. 5, 1997, pages 623 - 630
YUKIKO SUGAYA ET AL.: "Handbook of Pharmaceutical Salts: Properties, Selection, and Use", vol. 122, 2002, YAKUGAKU ZASSHI, pages: 237 - 246
MARGARETH MARQUES: "Dissolution Media Simulating Fasted and Fed States", DISSOLUTION TECHNOLOGIES, vol. 11, no. 2, 2004, pages 16, XP055371984, DOI: 10.14227/DT110204P16
MILLER SD ET AL.: "Current Protocols in Immunology", 2010, article "Experimental autoimmune encephalomyelitis in the mouse"
FAUBER BP ET AL.: "Discovery of 1-f4-[3-fluoro-4-((3s,6r)-3-methyl-1,1-dioxo-6-phenyl-[1,2]thiazinan-2-ylmethyl)-phenyl]-piperazin-1-yl}-ethanone (GNE-3500): a potent, selective, and orally bioavailable retinoic acid receptor-related orphan receptor C (RORc or RORy) inverse agonist", J. MED. CHEM., vol. 58, no. 13, 2015, pages 5308 - 22, XP055519638, DOI: 10.1021/acs.jmedchem.5b00597
Q ZHANG ET AL.: "Targeting Thl7-IL-17 Pathway in Prevention of Micro-Invasive Prostate Cancer in a Mouse Model", PROSTATE, vol. 77, no. 8, 2017, pages 888 - 899
W SHI ET AL.: "Anti-IL-17 Antibody Improves Hepatic Steatosis by Suppressing Interleukin-17-Related Fatty Acid Synthesis and Metabolism", CLIN. DEV. IMMUNOL., vol. 2013, 2013, XP055385426, DOI: 10.1155/2013/253046
R XU ET AL.: "Neutralization of interleukin-17 attenuates high fat diet-induced non-alcoholic fatty liver disease in mice", ACTA BIOCHIM. BIOPHYS. SIN., vol. 45, no. 9, 2013, pages 726 - 733
Y.H. LIAL ET AL.: "Interleukin-17A Contributes to Myocardial Ischemia/Reperfusion Injury by Regulating Cardiomyocyte Apoptosis and Neutrophil Infiltration", J. AM. COLL. CARDIOL., vol. 59, no. 4, 2012, pages 420 - 429, XP028444164, DOI: 10.1016/j.jacc.2011.10.863
M.A. SALEH ET AL.: "Inhibition of Interleukin 17-A but not Interleukin-17F Signaling Lowers Blood Pressure and Reduces End-organ Inflammation in Angiotensin II-induced Hypertension", JACC BASIC TRANSL. SCI., vol. 1, no. 7, 2016, pages 606 - 616
N. DUTZAN ET AL.: "A dysbiotic microbiome triggers TH17 cells to mediate oral mucosal immunopathology in mice and humans", SCI. TRANSL. MED., vol. 10, no. 463, 2018, pages eaat0797
R SPEECKAERT ET AL.: "The many faces of interleukin-17 in inflammatory skin diseases", BR. J. DERMATOL., vol. 175, no. 5, 2016, pages 892 - 901
BERGE ET AL., J. PHARM. SCI., vol. 66, 1977, pages 1 - 19
PAULEKUHN ET AL., J. MED. CHEM., vol. 50, 2007, pages 6665 - 6672
See also references of EP 3760616A4
SCHMIDT-WEBER ET AL.: "Thl7 cells in the big picture of immunology", J. ALLERGY CLIN. IMMUNOL., vol. 120, 2007, pages 247 - 54, XP022199073, DOI: 10.1016/j.jaci.2007.06.039
MEISSBURGER ET AL.: "Adipogenesis and insulin sensitivity in obesity are regulated by retinoid-related orphan receptor gamma", EMBO MOL. MED., vol. 3, 2011, pages 637 - 51
KELCHTERMANS ET AL.: "Effector mechanisms of interleukin-17 in collagen-induced arthritis in the absence of interferon-y and counteraction by interferon-y", ARTHRITIS RES. THER., vol. 11, no. 4, 2009, pages R122, XP021061277, DOI: 10.1186/ar2787
NAKAE ET AL.: "Suppression of Immune Induction of Collagen-Induced Arthritis in IL-17-Deficient Mice", J. IMMUNOL., vol. 171, 2003, pages 6173 - 6177
HUEBER ET AL.: "Effects of AIN457, a Fully Human Antibody to Interleukin-17A, on Psoriasis, Rheumatoid Arthritis, and Uveitis", SCI. TRANSL. MED., vol. 2, no. 52, 2010, pages 52ra72
SANFORD ET AL.: "Secukinumab: first global approval", DRUGS, vol. 75, no. 3, 2015, pages 329 - 338, XP009507136, DOI: 10.1007/s40265-015-0359-0
LEPPKES ET AL.: "RORy-Expressing Thl7 Cells Induce MurineChronic Intestinal Inflammation via Redundant Effects of IL-17A and IL-17F", GASTROENTEROLOGY, vol. 136, no. 1, 2009, pages 257 - 267
IVANOV ET AL.: "The Orphan Nuclear Receptor RORyt Directs the Differentiation Program of Proinflammatory IL-17+ T Helper Cells", CELL, vol. 126, no. 6, 2006, pages 1121 - 1133, XP008091324, DOI: 10.1016/j.cell.2006.07.035
STEINMETZ ET AL.: "The Thl7-Defining Transcription Factor RORyt Promotes Glomerulonephritis", J. AM. SOC. NEPHROL., vol. 22, no. 3, 2011, pages 472 - 483
CRISPIN ET AL.: "Interleukin-17-producing T cells in lupus", CURR. OPIN. RHEUMATOL., vol. 22, no. 5, 2010, pages 499 - 503
BAETEN ET AL.: "Anti-interleukin-17A monoclonal antibody secukinumab in treatment of ankylosing spondylitis: a randomised, double-blind, placebo-controlled trial", LANCET, vol. 382, no. 9906, 2013, pages 1705 - 1713, XP002726555, DOI: 10.1016/S0140-6736(13)61134-4
EMAMAULLEE ET AL.: "Inhibition of Thl7 Cells Regulates Autoimmune Diabetes in NOD Mice", DIABETES, vol. 58, 2009, pages 1302 - 1311, XP055052644, DOI: 10.2337/db08-1113
TILLEY ET AL.: "Retinoid-Related Orphan Receptor γ Controls Immunoglobulin Production and Thl/Th2 Cytokine Balance in the Adaptive Immune Response to Allergen", J. IMMUNOL., vol. 178, 2007, pages 3208 - 3218
"The Effects of a Single Intravenous Administration of Secukinumab (AIN457) or Canakinumab (ACZ885) in Dry Eye Patients", 4 December 2012, U.S. NATIONAL INSTITUTES OF HEALTH
MI ET AL.: "Blocking IL-17A Promotes the Resolution of Pulmonary Inflammation and Fibrosis Via TGF-(31-Dependent and -Independent Mechanisms", J. IMMUNOL., vol. 187, 2011, pages 3003 - 3014
"A Study of Efficacy and Safety of Ustekinumab in Patients With Primary Biliary Cirrhosis (PBC) Who Had an Inadequate Response to Ursodeoxycholic Acid", 2 April 2015, U.S. NATIONAL INSTITUTES OF HEALTH
FULTON ET AL.: "Attenuation of Acute Graft-versus-Host Disease in the Absence of the Transcription Factor RORyt", J. IMMUNOL., vol. 189, no. 4, 2012, pages 1765 - 1772
BRIAN G FEAGAN ET AL.: "Induction therapy with the selective interleukin-23 inhibitor risankizumab in patients with moderate-to-severe Crohn's disease: a randomised, double-blind, placebo-controlled phase 2 study", THE LANCET, vol. 389, no. 10080, 2017, pages 1699 - 1709, XP029988821, DOI: 10.1016/S0140-6736(17)30570-6
EVA HAVRDOVA ET AL.: "Activity of secukinumab, an anti-IL-17A antibody, on brain lesions in RRMS: results from a randomized, proof-of-concept study", J. NEUROL., vol. 263, no. 7, 2016, pages 1287 - 1295, XP035993925, DOI: 10.1007/s00415-016-8128-x
A. DAVID RODRIGUES ET AL.: "Oxidative Metabolism of Clarithromycin in the Presence of Human Liver Microsomes", DRUG METABOLISM AND DISPOSITION, vol. 25, no. 5, 1997, pages 623 - 630
YUKIKO SUGAYA ET AL.: "Handbook of Pharmaceutical Salts: Properties, Selection, and Use", vol. 122, 2002, YAKUGAKU ZASSHI, pages: 237 - 246
MARGARETH MARQUES: "Dissolution Media Simulating Fasted and Fed States", DISSOLUTION TECHNOLOGIES, vol. 11, no. 2, 2004, pages 16, XP055371984, DOI: 10.14227/DT110204P16
MILLER SD ET AL.: "Current Protocols in Immunology", 2010, article "Experimental autoimmune encephalomyelitis in the mouse"
FAUBER BP ET AL.: "Discovery of 1-f4-[3-fluoro-4-((3s,6r)-3-methyl-1,1-dioxo-6-phenyl-[1,2]thiazinan-2-ylmethyl)-phenyl]-piperazin-1-yl}-ethanone (GNE-3500): a potent, selective, and orally bioavailable retinoic acid receptor-related orphan receptor C (RORc or RORy) inverse agonist", J. MED. CHEM., vol. 58, no. 13, 2015, pages 5308 - 22, XP055519638, DOI: 10.1021/acs.jmedchem.5b00597
Q ZHANG ET AL.: "Targeting Thl7-IL-17 Pathway in Prevention of Micro-Invasive Prostate Cancer in a Mouse Model", PROSTATE, vol. 77, no. 8, 2017, pages 888 - 899
W SHI ET AL.: "Anti-IL-17 Antibody Improves Hepatic Steatosis by Suppressing Interleukin-17-Related Fatty Acid Synthesis and Metabolism", CLIN. DEV. IMMUNOL., vol. 2013, 2013, XP055385426, DOI: 10.1155/2013/253046
R XU ET AL.: "Neutralization of interleukin-17 attenuates high fat diet-induced non-alcoholic fatty liver disease in mice", ACTA BIOCHIM. BIOPHYS. SIN., vol. 45, no. 9, 2013, pages 726 - 733
Y.H. LIAL ET AL.: "Interleukin-17A Contributes to Myocardial Ischemia/Reperfusion Injury by Regulating Cardiomyocyte Apoptosis and Neutrophil Infiltration", J. AM. COLL. CARDIOL., vol. 59, no. 4, 2012, pages 420 - 429, XP028444164, DOI: 10.1016/j.jacc.2011.10.863
M.A. SALEH ET AL.: "Inhibition of Interleukin 17-A but not Interleukin-17F Signaling Lowers Blood Pressure and Reduces End-organ Inflammation in Angiotensin II-induced Hypertension", JACC BASIC TRANSL. SCI., vol. 1, no. 7, 2016, pages 606 - 616
N. DUTZAN ET AL.: "A dysbiotic microbiome triggers TH17 cells to mediate oral mucosal immunopathology in mice and humans", SCI. TRANSL. MED., vol. 10, no. 463, 2018, pages eaat0797
R SPEECKAERT ET AL.: "The many faces of interleukin-17 in inflammatory skin diseases", BR. J. DERMATOL., vol. 175, no. 5, 2016, pages 892 - 901
BERGE ET AL., J. PHARM. SCI., vol. 66, 1977, pages 1 - 19
PAULEKUHN ET AL., J. MED. CHEM., vol. 50, 2007, pages 6665 - 6672
See also references of EP 3760616A4
Attorney, Agent or Firm:
YAMAO, Norihito et al. (JP)
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