Title:
INHIBITORS OF THE FARNESOID X RECEPTOR AND USES IN MEDICINE
Document Type and Number:
WIPO Patent Application WO/2015/017813
Kind Code:
A3
Abstract:
Disclosed are inhibitors of the farnesoid X receptor, for example of formula (I), wherein R1, R2, R4, X, Y, Z, m, and n are as defined herein, which are useful in treating or preventing obesity, type 2 diabetes/insulin resistance and non alcoholic fatty liver disease in a mammal in need thereof. Also disclosed is a composition comprising a pharmaceutically suitable carrier and at least one compound of the invention, a method of method of inhibiting a farnesoid X receptor in a mammal, and a method of treating or preventing obesity in a mammal.
Inventors:
GONZALEZ FRANK J (US)
JIANG CHANGTAO (US)
XIE CEN (US)
PATTERSON ANDREW D (US)
LI FEI (US)
MITCHELL JAMES B (US)
AMIN SHANTU (US)
DESAI DHIMANT (US)
JIANG CHANGTAO (US)
XIE CEN (US)
PATTERSON ANDREW D (US)
LI FEI (US)
MITCHELL JAMES B (US)
AMIN SHANTU (US)
DESAI DHIMANT (US)
Application Number:
PCT/US2014/049460
Publication Date:
April 02, 2015
Filing Date:
August 01, 2014
Export Citation:
Assignee:
US HEALTH (US)
PENN STATE RES FOUND (US)
PENN STATE RES FOUND (US)
International Classes:
C07J9/00; A61K31/575; A61P1/16; A61P3/04; A61P3/10; C07J41/00
Domestic Patent References:
| WO2003030612A2 | 2003-04-17 | |||
| WO1994024147A1 | 1994-10-27 | |||
| WO2000037077A1 | 2000-06-29 | |||
| WO2010014836A2 | 2010-02-04 | |||
| WO2011022838A1 | 2011-03-03 | |||
| WO2002094865A1 | 2002-11-28 | |||
| WO1990000175A1 | 1990-01-11 | |||
| WO1987002367A2 | 1987-04-23 | |||
| WO2009136396A2 | 2009-11-12 |
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SATO HIROYUKI ET AL: "Novel potent and selective bile acid derivatives as TGR5 agonists: biological screening, structure-activity relationships, and molecular modeling studies", JOURNAL OF MEDICINAL CHEMISTRY, AMERICAN CHEMICAL SOCIETY, US, vol. 51, no. 6, 27 March 2008 (2008-03-27), pages 1831 - 1841, XP002520339, ISSN: 0022-2623, [retrieved on 20080229], DOI: 10.1021/JM7015864
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DATABASE CA [online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; HIRATA, KOJI: "Influence of bile salts on carbohydrate metabolism. II. Influence of bile salts on the amount of glucose, pyruvate, citrate, and .alpha.-ketoglutarate in the blood of normal and alloxan-", XP002731167, retrieved from STN Database accession no. 1960:119943
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J. R. SWANN ET AL: "Systemic gut microbial modulation of bile acid metabolism in host tissue compartments", PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES, vol. 108, no. Supplement_1, 13 September 2010 (2010-09-13), pages 4523 - 4530, XP055146363, ISSN: 0027-8424, DOI: 10.1073/pnas.1006734107
SAMA I. SAYIN ET AL: "Gut Microbiota Regulates Bile Acid Metabolism by Reducing the Levels of Tauro-beta-muricholic Acid, a Naturally Occurring FXR Antagonist", CELL METABOLISM, vol. 17, no. 2, 1 February 2013 (2013-02-01), pages 225 - 235, XP055145995, ISSN: 1550-4131, DOI: 10.1016/j.cmet.2013.01.003
ALDO RODA ET AL: "Synthesis and Physicochemical, Biological, and Pharmacological Properties of New Bile Acids Amidated with Cyclic Amino Acids +", JOURNAL OF MEDICINAL CHEMISTRY, vol. 39, no. 11, 1 January 1996 (1996-01-01), pages 2270 - 2276, XP055146671, ISSN: 0022-2623, DOI: 10.1021/jm9508503
BAO-ZHU YU ET AL: "Effect of Guggulsterone and Cembranoids of Commiphora mukul on Pancreatic Phospholipase A 2 : Role in Hypocholesterolemia", JOURNAL OF NATURAL PRODUCTS, vol. 72, no. 1, 23 January 2009 (2009-01-23), pages 24 - 28, XP055145997, ISSN: 0163-3864, DOI: 10.1021/np8004453
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FIORUCCI S ET AL: "Development of FXR, PXR and CAR agonists and antagonists for treatment of liver disorders", vol. 12, no. 6, 1 March 2012 (2012-03-01), pages 605 - 624, XP008173991, ISSN: 1568-0266, Retrieved from the Internet DOI: 10.2174/156802612799436678
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PETER I. DOSA ET AL: "Synthesis and Evaluation of Water-Soluble Prodrugs of Ursodeoxycholic Acid (UDCA), an Anti-apoptotic Bile Acid", CHEMMEDCHEM, vol. 8, no. 6, 2 May 2013 (2013-05-02), pages 1002 - 1011, XP055160064, ISSN: 1860-7179, DOI: 10.1002/cmdc.201300059
LACK L ET AL: "The ileal bile salt transport system: Effect of the charged state of the substrate on activity", BIOCHIMICA ET BIOPHYSICA ACTA (BBA) - BIOMEMBRANES, ELSEVIER, AMSTERDAM, NL, vol. 135, no. 5, 1 November 1967 (1967-11-01), pages 1065 - 1068, XP023353689, ISSN: 0005-2736, [retrieved on 19671101], DOI: 10.1016/0005-2736(67)90078-8
DATABASE CA [online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; SHEN, YUMEI ET AL: "99mTc-labeled bile acid derivative and its reference standard, and preparation method and medical application thereof as imaging agent", XP002734126, retrieved from STN Database accession no. 2010:1477293
SATO HIROYUKI ET AL: "Novel potent and selective bile acid derivatives as TGR5 agonists: biological screening, structure-activity relationships, and molecular modeling studies", JOURNAL OF MEDICINAL CHEMISTRY, AMERICAN CHEMICAL SOCIETY, US, vol. 51, no. 6, 27 March 2008 (2008-03-27), pages 1831 - 1841, XP002520339, ISSN: 0022-2623, [retrieved on 20080229], DOI: 10.1021/JM7015864
DATABASE CA [online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; KOBAYASHI, JIRO: "Influence of bile salts on fat metabolism. I. Lipotropic action of bile salts", XP002731165, retrieved from STN Database accession no. 1956:37341
DATABASE CA [online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; JANI, RAJENDRAKUMAR HARIPRASAD ET AL: "Treatment for nonalcoholic fatty liver disease", XP002731166, retrieved from STN Database accession no. 2012:266494
DATABASE CA [online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; HIRATA, KOJI: "Influence of bile salts on carbohydrate metabolism. II. Influence of bile salts on the amount of glucose, pyruvate, citrate, and .alpha.-ketoglutarate in the blood of normal and alloxan-", XP002731167, retrieved from STN Database accession no. 1960:119943
DATABASE CA [online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; KITANI, K: "The protective effect of hydrophilic bile acids on bile acid hepatotoxicity in the rat", XP002731168, retrieved from STN Database accession no. 1996:68392
J. R. SWANN ET AL: "Systemic gut microbial modulation of bile acid metabolism in host tissue compartments", PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES, vol. 108, no. Supplement_1, 13 September 2010 (2010-09-13), pages 4523 - 4530, XP055146363, ISSN: 0027-8424, DOI: 10.1073/pnas.1006734107
SAMA I. SAYIN ET AL: "Gut Microbiota Regulates Bile Acid Metabolism by Reducing the Levels of Tauro-beta-muricholic Acid, a Naturally Occurring FXR Antagonist", CELL METABOLISM, vol. 17, no. 2, 1 February 2013 (2013-02-01), pages 225 - 235, XP055145995, ISSN: 1550-4131, DOI: 10.1016/j.cmet.2013.01.003
ALDO RODA ET AL: "Synthesis and Physicochemical, Biological, and Pharmacological Properties of New Bile Acids Amidated with Cyclic Amino Acids +", JOURNAL OF MEDICINAL CHEMISTRY, vol. 39, no. 11, 1 January 1996 (1996-01-01), pages 2270 - 2276, XP055146671, ISSN: 0022-2623, DOI: 10.1021/jm9508503
BAO-ZHU YU ET AL: "Effect of Guggulsterone and Cembranoids of Commiphora mukul on Pancreatic Phospholipase A 2 : Role in Hypocholesterolemia", JOURNAL OF NATURAL PRODUCTS, vol. 72, no. 1, 23 January 2009 (2009-01-23), pages 24 - 28, XP055145997, ISSN: 0163-3864, DOI: 10.1021/np8004453
DATABASE CA [online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; PAOLINI, MORENO ET AL: "Anticholestatic bile acids as inducers of the cytochrome P450-dependent system", XP002734124, retrieved from STN Database accession no. 2002:481189
FIORUCCI S ET AL: "Development of FXR, PXR and CAR agonists and antagonists for treatment of liver disorders", vol. 12, no. 6, 1 March 2012 (2012-03-01), pages 605 - 624, XP008173991, ISSN: 1568-0266, Retrieved from the Internet
DATABASE CA [online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; KATAGIRI, KENJI ET AL: "Tauromuricholic acid for treatment of bile acid secretory disorders", XP002734125, retrieved from STN Database accession no. 1990:604829
PETER I. DOSA ET AL: "Synthesis and Evaluation of Water-Soluble Prodrugs of Ursodeoxycholic Acid (UDCA), an Anti-apoptotic Bile Acid", CHEMMEDCHEM, vol. 8, no. 6, 2 May 2013 (2013-05-02), pages 1002 - 1011, XP055160064, ISSN: 1860-7179, DOI: 10.1002/cmdc.201300059
LACK L ET AL: "The ileal bile salt transport system: Effect of the charged state of the substrate on activity", BIOCHIMICA ET BIOPHYSICA ACTA (BBA) - BIOMEMBRANES, ELSEVIER, AMSTERDAM, NL, vol. 135, no. 5, 1 November 1967 (1967-11-01), pages 1065 - 1068, XP023353689, ISSN: 0005-2736, [retrieved on 19671101], DOI: 10.1016/0005-2736(67)90078-8
DATABASE CA [online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; SHEN, YUMEI ET AL: "99mTc-labeled bile acid derivative and its reference standard, and preparation method and medical application thereof as imaging agent", XP002734126, retrieved from STN Database accession no. 2010:1477293
Attorney, Agent or Firm:
PILLAI, Xavier et al. (Voit & Mayer Ltd.,Two Prudential Plaza, Sutie 4900,180 N. Stetson Avenu, Chicago Illinois, US)
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