Title:
ISOXAZOLE DERIVATIVE, PREPARATION METHOD THEREFOR, AND USE THEREOF
Document Type and Number:
WIPO Patent Application WO/2019/120088
Kind Code:
A1
Abstract:
The present invention generally relates to an isoxazole derivative, a preparation therefor, and a use thereof. In particular, the present invention provides a farnesoid X receptor (FXR) agonist compound, and a stereoisomer, a tautomer, a polymorph, a solvate (e.g., a hydrate), a pharmaceutically acceptable salt, an ester, a metabolite, and an N-oxide, and the chemically protected forms and prodrugs thereof. The present invention further provides a preparation method for the compound, an intermediate thereof, and a pharmaceutical composition and kit containing the same and used thereof for treating FXR-mediated diseases or conditions.
Inventors:
LIU JINMING (CN)
CAI JIAQIANG (CN)
WU YONGYONG (CN)
YIN WEI (CN)
WANG LICHUN (CN)
WANG JINGYI (CN)
CAI JIAQIANG (CN)
WU YONGYONG (CN)
YIN WEI (CN)
WANG LICHUN (CN)
WANG JINGYI (CN)
Application Number:
PCT/CN2018/119715
Publication Date:
June 27, 2019
Filing Date:
December 07, 2018
Export Citation:
Assignee:
SICHUAN KELUN BIOTECH BIOPHARMACEUTICAL CO LTD (CN)
International Classes:
C07D413/12; A61K31/422; C07D413/14
Domestic Patent References:
WO2012087521A1 | 2012-06-28 | |||
WO2012087519A1 | 2012-06-28 |
Other References:
KUIPERS, F. ET AL.: "The Farnesoid X Receptor (FXR) as Modulator of Bile Acid Metabolism", REV. ENDOCRINE METAB. DISORDERS, vol. 5, 2004, pages 319 - 326
KALAANY, N. Y.MANGELSDORF, D. J.: "LXRS and FXR: the yin and yang of cholesterol and fat metabolism", ANNU. REV. PHYSIOL., vol. 68, 2006, pages 159 - 191, XP002731239, DOI: 10.1146/annurev.physiol.68.033104.152158
CALKIN, A. C.TONTONOZ, P.: "Transcriptional integration of metabolism by the nuclear sterol-activated receptors LXR and FXR", NAT. REV. MOL. CELL BIOL., vol. 13, 2012, pages 213 - 224
T. INAGAKI ET AL.: "Fibroblast growth factor 15 functions as an enterohepatic signal to regulate bile acid homeostasis", CELL METAB., vol. 2, no. 4, 2005, pages 217 - 225, XP055000838, DOI: 10.1016/j.cmet.2005.09.001
MAKISHIMA, M.: "Nuclear Receptors as Targets for Drug Development: Regulation of Cholesterol and Bile Acid Metabolism by Nuclear Receptors", J. PHARMACOL. SCI., vol. 97, 2005, pages 177 - 183
MODICA, S.GADALETA, R. M.MOSCHETTA, A.: "Deciphering the nuclear bile acid receptor FXR paradigm", NUCL. RECEPT. SIGNAL., vol. 8, 2010, pages e005
MUDALIAR, S.HENRY, R. R.SANYAL, A. J. ET AL.: "Efficacy and safety of the farnesoid X receptor agonist obeticholic acid in patients with type 2 diabetes and nonalcoholic fatty liver disease", GASTROENTEROLOGY, vol. 145, 2013, pages 574 - 582
NEVENS, F.ANDREONE, P.MAZZELLA, G. ET AL.: "The first primary biliary cirrhosis (PBC) phase 3 trial in two decades - an international study of the FXR agonist obeticholic acid in PBC patients", J. HEPATOL., vol. 60, 2014, pages S525 - S526
"McGraw-Hill Dictionary of Chemical Terms", 1984, MCGRAW-HILL BOOK COMPANY
ELIEL, E.WILEN, S.: "Stereochemistry of Organic Compounds", 1994, JOHN WILEY & SONS, INC.
T. L. GILCHRIST, COMPREHENSIVE ORGANIC SYNTHESIS, vol. 7, pages 748 - 750
M. TISLERB. STANOVNIK: "Protective Groups in Organic Chemistry", vol. 3, 1973, PERGAMON PRESS, pages: 18 - 20
T. W. GREENEP. G. M. WUTS: "Protective Groups in Organic Synthesis", 1991, JOHN WILEY & SONS
"Design of Prodrugs", 1985, ELSEVIER
"Remington's Pharmaceutical Sciences", 1990
See also references of EP 3730491A4
KALAANY, N. Y.MANGELSDORF, D. J.: "LXRS and FXR: the yin and yang of cholesterol and fat metabolism", ANNU. REV. PHYSIOL., vol. 68, 2006, pages 159 - 191, XP002731239, DOI: 10.1146/annurev.physiol.68.033104.152158
CALKIN, A. C.TONTONOZ, P.: "Transcriptional integration of metabolism by the nuclear sterol-activated receptors LXR and FXR", NAT. REV. MOL. CELL BIOL., vol. 13, 2012, pages 213 - 224
T. INAGAKI ET AL.: "Fibroblast growth factor 15 functions as an enterohepatic signal to regulate bile acid homeostasis", CELL METAB., vol. 2, no. 4, 2005, pages 217 - 225, XP055000838, DOI: 10.1016/j.cmet.2005.09.001
MAKISHIMA, M.: "Nuclear Receptors as Targets for Drug Development: Regulation of Cholesterol and Bile Acid Metabolism by Nuclear Receptors", J. PHARMACOL. SCI., vol. 97, 2005, pages 177 - 183
MODICA, S.GADALETA, R. M.MOSCHETTA, A.: "Deciphering the nuclear bile acid receptor FXR paradigm", NUCL. RECEPT. SIGNAL., vol. 8, 2010, pages e005
MUDALIAR, S.HENRY, R. R.SANYAL, A. J. ET AL.: "Efficacy and safety of the farnesoid X receptor agonist obeticholic acid in patients with type 2 diabetes and nonalcoholic fatty liver disease", GASTROENTEROLOGY, vol. 145, 2013, pages 574 - 582
NEVENS, F.ANDREONE, P.MAZZELLA, G. ET AL.: "The first primary biliary cirrhosis (PBC) phase 3 trial in two decades - an international study of the FXR agonist obeticholic acid in PBC patients", J. HEPATOL., vol. 60, 2014, pages S525 - S526
"McGraw-Hill Dictionary of Chemical Terms", 1984, MCGRAW-HILL BOOK COMPANY
ELIEL, E.WILEN, S.: "Stereochemistry of Organic Compounds", 1994, JOHN WILEY & SONS, INC.
T. L. GILCHRIST, COMPREHENSIVE ORGANIC SYNTHESIS, vol. 7, pages 748 - 750
M. TISLERB. STANOVNIK: "Protective Groups in Organic Chemistry", vol. 3, 1973, PERGAMON PRESS, pages: 18 - 20
T. W. GREENEP. G. M. WUTS: "Protective Groups in Organic Synthesis", 1991, JOHN WILEY & SONS
"Design of Prodrugs", 1985, ELSEVIER
"Remington's Pharmaceutical Sciences", 1990
See also references of EP 3730491A4
Attorney, Agent or Firm:
NTD UNIVATION INTELLECTUAL PROPERTY AGENCY LTD (CN)
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