WO2016205031A1 - Composés fluoropyridyl pyrazoliques - Google Patents

Composés fluoropyridyl pyrazoliques Download PDF

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Publication number
WO2016205031A1
WO2016205031A1 PCT/US2016/036360 US2016036360W WO2016205031A1 WO 2016205031 A1 WO2016205031 A1 WO 2016205031A1 US 2016036360 W US2016036360 W US 2016036360W WO 2016205031 A1 WO2016205031 A1 WO 2016205031A1
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WO
WIPO (PCT)
Prior art keywords
compound
pharmaceutically acceptable
acceptable salt
compounds
mmol
Prior art date
Application number
PCT/US2016/036360
Other languages
English (en)
Inventor
Jiehao Chen
Kai CUI
Minmin Wang
Original Assignee
Eli Lilly And Company
Lilly China Research And Development Co., Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Eli Lilly And Company, Lilly China Research And Development Co., Ltd filed Critical Eli Lilly And Company
Publication of WO2016205031A1 publication Critical patent/WO2016205031A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics

Definitions

  • FLUOROPYRIDYL PYRAZOL COMPOUNDS This invention relates to pyrazole compounds or pharmaceutically acceptable salts thereof.
  • Compounds of this invention are inhibitors of methionine aminopeptidase 2 (MetAP2).
  • MetAP2 is a metalloproteinase that cleaves initiator methionine from nascent peptide emerging from the ribosomes.
  • WO 2010/065879 reports small molecule MetAP2 inhibitors for obesity treatment.
  • the present invention provides novel compounds with MetAP2 inhibition activity. These inhibitor compounds can be useful in the treatment of a MetAP2 mediated condition.
  • the present invention provides a compound of the Formula I
  • the compound is[3-[[3-(5-Fluoro-2-pyridyl)-1H- pyrazol-4-yl]oxy]-4-methyl-phenyl]methylurea.
  • the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of Formula I, or a pharmaceutically acceptable salt thereof, and at least one selected from the group consisting of a pharmaceutically acceptable carrier, diluent, and excipient.
  • the invention provides a method for treating type II diabetes in a mammal in need thereof, comprising administering to the mammal an effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof.
  • the invention provides a method for treating obesity in a mammal in need thereof, comprising administering to the mammal an effective amount of a compound of Formula I.
  • the invention provides a compound of Formula I, or a pharmaceutically acceptable salt thereof for use in therapy.
  • a compound of Formula I, or a pharmaceutically acceptable salt thereof, for use in the manufacture of a medicament for use in the manufacture of a medicament.
  • “Pharmaceutically-acceptable salt” refers to salts of the compound of the invention considered to be acceptable for clinical and/or veterinary use.
  • Pharmaceutically acceptable salts and common methodology for preparing them are well known in the art. See, e.g., P. Stahl, et al., Handbook of Pharmaceutical Salts: Properties, Selection and Use, (VCHA/Wiley-VCH, 2002); S.M. Berge, et al., "Pharmaceutical Salts," Journal of Pharmaceutical Sciences, Vol.66, No.1, January 1977.
  • variable protecting group may be the same or different in each occurrence depending on the particular reaction conditions and the particular transformations to be performed.
  • the protection and deprotection conditions are well known to the skilled artisan and are described in the literature (See for example“Greene’s Protective Groups in Organic Synthesis”, Fourth Edition, by Peter G.M. Wuts and Theodora W. Greene, John Wiley and Sons, Inc.2007).
  • the compounds of the present invention, or salts thereof may be prepared by a variety of procedures known in the art, some of which are illustrated in the Preparations and Examples below.
  • the specific synthetic steps for each of the routes described may be combined in different ways, or in conjunction with steps from different schemes, to prepare compounds of the invention, or salts thereof.
  • the products of each step below can be recovered by conventional methods well known in the art, including extraction, evaporation, precipitation, chromatography, filtration, trituration, and crystallization.
  • all substituents unless otherwise indicated, are as previously defined.
  • the reagents and starting materials are readily available to one of ordinary skill in the art. Others may be made by standard techniques of organic and heterocyclic chemistry which are analogous to the syntheses of known structurally-similar compounds and the procedures described in the Preparations and Examples which follow including any novel procedures.
  • Enzymatic activity assay of MetAP2 and MetAP1 The compound exemplified herein are tested essentially as described below and exhibit an IC 50 for the human and mouse MetAP2 assay of lower than 500 nM and are considered selective for MetAP2 with a MetAP1 value greater than 10 ⁇ M.
  • MetAP2 and MetAP1 Full length MetAP2 (human and mouse) and MetAP1 (human) proteins are generated from Sf9 cells using a procedure similar to that described in Biochemistry 2003, 42, 5035-5042. MetAP2 and MetAP1 are purified in the presence of 5 mM MnCl 2 and 2 mM CoCl 2 respectively, and stored at -78 °C before use.
  • Compound inhibition of the catalytic activity of human and mouse MetAP2 by compounds in the present invention is measured by monitoring the formation of the product peptide (Gly-Lys-Val-Lys-Val-Gly-Val-Asn-Gly) from the substrate peptide (Met-Gly-Lys-Val-Lys-Val-Gly-Val-Asn-Gly) via LC/MS.
  • the reaction is typically conducted by incubating the enzyme, test compound and substrate (150 ⁇ M) in assay buffer (100 ⁇ l) (50 mM HEPES, 100 mM NaCl, 50 mg/mL BSA, 0.17 mM TritonTM X- 100 at pH 7.5) for 40 minutes.
  • the levels of product and remaining substrate are quantified with a mass spectrometer.
  • the activity of human MetAP1 is monitored by the formation of the fluorescent product rhodamine-methionine from the substrate methionine-rhodamine- methionine on a spectrophotometer with the excitation light at 460 nm and emission light at 535 nm.
  • the reaction is typically conducted by incubating the enzyme, test compound and substrate (50 ⁇ M) in assay buffer (100 ⁇ l) (50 mM HEPES, 100 mM NaCl, 0.1% BSA, 0.05% Tween®-20, 50 ⁇ M CoCl 2 ) for 60 minutes.
  • the IC 50 value is calculated typically from a 10-point dose titration curve using a 4-parameter equation.
  • the IC 50 for human MetAP1 is 19.8 ⁇ M, demonstrating selective MetAP2 inhibition as compared with MetAP1.
  • Therapeutic Weight Loss Effect Measurement of Compounds To determine the therapeutic weight loss effects and improvement of metabolic parameters, compounds from the invention are tested in the HFD feeding induced obese mouse model (DIO mice). In this model, C57/Bl6J male mouse is fed with the 60% HFD (D12492i, Research Diets) for 16 ⁇ 28 weeks to establish obesity with body weight reaching around 50 g.
  • mice will gradually increase the body weight to about 50 g and maintain that weight in this obese state.
  • Test compound via the vehicle of 0.5% HEC plus 0.25% Tween-80 at 5 mL/kg is administered orally to the obese DIO mice once daily throughout the study duration.
  • the weight loss of obese DIO mice by Example 1 by at 3 mg/kg and 10 mg/kg once a day is about 3% and 8% compared to the vehicle group at day 14, respectively.
  • the data support that the compound of Example 1 is associated with desired weight loss and offers an anti-obesity effect.
  • the exemplified compounds of the present invention can be readily formulated into pharmaceutical compositions in accordance with accepted practices known in the art such as found in Remington’s“Pharmaceutical Sciences”, Gennaro, Ed., Mack Publishing Co. Easton Pa.1990 such as tablets, solid or gel filled capsules, powders, suspensions, or solutions.
  • the composition can also include one or more pharmaceutically acceptable carriers, excipients, and diluents.
  • Preferred pharmaceutical compositions are formulated as a tablet or capsule for oral administration.
  • the tablet or capsule can include a compound of the present invention in an amount effective to treat obesity.
  • the pharmaceutical composition is administered to a patient in need thereof, in amounts effective to treat obesity.
  • the pharmaceutical composition is administered to a patient in need thereof, in amounts effective to provide therapeutic weight loss.
  • An appropriate amount or dose effective to treat a patient can be determined by a health care provider.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Diabetes (AREA)
  • General Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Hematology (AREA)
  • Obesity (AREA)
  • Engineering & Computer Science (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Public Health (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Emergency Medicine (AREA)
  • Endocrinology (AREA)
  • Child & Adolescent Psychology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne des composés représentés par la formule (I) ou un sel pharmaceutiquement acceptable de ceux-ci.
PCT/US2016/036360 2015-06-18 2016-06-08 Composés fluoropyridyl pyrazoliques WO2016205031A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
PCT/CN2015/081746 WO2016201662A1 (fr) 2015-06-18 2015-06-18 Composés fluoropyridyle pyrazoliques
CNPCT/CN2015/081746 2015-06-18

Publications (1)

Publication Number Publication Date
WO2016205031A1 true WO2016205031A1 (fr) 2016-12-22

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PCT/CN2015/081746 WO2016201662A1 (fr) 2015-06-18 2015-06-18 Composés fluoropyridyle pyrazoliques
PCT/US2016/036360 WO2016205031A1 (fr) 2015-06-18 2016-06-08 Composés fluoropyridyl pyrazoliques

Family Applications Before (1)

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PCT/CN2015/081746 WO2016201662A1 (fr) 2015-06-18 2015-06-18 Composés fluoropyridyle pyrazoliques

Country Status (1)

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WO (2) WO2016201662A1 (fr)

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010065879A2 (fr) 2008-12-04 2010-06-10 Zafgen Corporation Procédés de traitement d'un sujet en surpoids ou obèse
WO2014114578A1 (fr) * 2013-01-25 2014-07-31 Boehringer Ingelheim International Gmbh Dérivés de pyrrolidine, compositions pharmaceutiques les contenant et utilisations associées
WO2014170197A1 (fr) * 2013-04-17 2014-10-23 Boehringer Ingelheim International Gmbh Dérivés de pirrolidine substitués par la pyrimidine, leurs compositions pharmaceutiques et leurs utilisations
WO2015089800A1 (fr) * 2013-12-19 2015-06-25 Eli Lilly And Company Composés fluorophényl-pyrazole

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU2002359694A1 (en) * 2001-12-14 2003-06-30 Smithkline Beecham Corporation Compounds and methods
TW201245155A (en) * 2010-09-01 2012-11-16 Du Pont Fungicidal pyrazoles

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010065879A2 (fr) 2008-12-04 2010-06-10 Zafgen Corporation Procédés de traitement d'un sujet en surpoids ou obèse
WO2014114578A1 (fr) * 2013-01-25 2014-07-31 Boehringer Ingelheim International Gmbh Dérivés de pyrrolidine, compositions pharmaceutiques les contenant et utilisations associées
WO2014170197A1 (fr) * 2013-04-17 2014-10-23 Boehringer Ingelheim International Gmbh Dérivés de pirrolidine substitués par la pyrimidine, leurs compositions pharmaceutiques et leurs utilisations
WO2015089800A1 (fr) * 2013-12-19 2015-06-25 Eli Lilly And Company Composés fluorophényl-pyrazole

Non-Patent Citations (8)

* Cited by examiner, † Cited by third party
Title
"Remington's ''Pharmaceutical Sciences", 1990, MACK PUBLISHING CO
ALDRICHIMICA ACTA, vol. 17, no. 1, 1984
BIOCHEMISTRY, vol. 42, 2003, pages 5035 - 5042
E.L. ELIEL; S.H. WILEN: "Stereochemistry of Organic Compounds", 1994, WILEY-INTERSCIENCE
J. JACQUES ET AL.: "Enantiomers, Racemates, and Resolutions", 1981, JOHN WILEY AND SONS, INC.
P. STAHL ET AL.: "Handbook of Pharmaceutical Salts: Properties, Selection and Use", 2002, VCHA/WILEY-VCH
PETER G.M. WUTS; THEODORA W. GREENE: "Greene's Protective Groups in Organic Synthesis", 2007, JOHN WILEY AND SONS, INC
S.M. BERGE ET AL.: "Pharmaceutical Salts", JOURNAL OF PHARMACEUTICAL SCIENCES, vol. 66, no. 1, January 1977 (1977-01-01), XP002675560, DOI: doi:10.1002/jps.2600660104

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