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WO2017004797A1 - Composés pyrrolidinone - Google Patents

Composés pyrrolidinone Download PDF

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Publication number
WO2017004797A1
WO2017004797A1 PCT/CN2015/083514 CN2015083514W WO2017004797A1 WO 2017004797 A1 WO2017004797 A1 WO 2017004797A1 CN 2015083514 W CN2015083514 W CN 2015083514W WO 2017004797 A1 WO2017004797 A1 WO 2017004797A1
Authority
WO
WIPO (PCT)
Prior art keywords
compound
mmol
salt
pharmaceutically acceptable
oxo
Prior art date
Legal status (The legal status 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 status listed.)
Ceased
Application number
PCT/CN2015/083514
Other languages
English (en)
Inventor
Koc Kan Ho
Weiguo QUAN
Jingye Zhou
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Lilly China Research and Development Co Ltd
Eli Lilly and Co
Original Assignee
Lilly China Research and Development Co Ltd
Eli Lilly and Co
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 Lilly China Research and Development Co Ltd, Eli Lilly and Co filed Critical Lilly China Research and Development Co Ltd
Priority to PCT/CN2015/083514 priority Critical patent/WO2017004797A1/fr
Priority to PCT/CN2016/084464 priority patent/WO2017005069A1/fr
Publication of WO2017004797A1 publication Critical patent/WO2017004797A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings

Definitions

  • This invention relates to pyrrolidinone compounds, or a pharmaceutically acceptable salt thereof, and therapeutic use thereof.
  • Compounds of this invention are inhibitors of methionine aminopeptidase 2 (MetAP2) and dipeptidyl peptidase-4 (DPP-4) .
  • 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.
  • DPP-4 inhibitors are an established drug class to improve glycemic control in patients with type 2 diabetes mellitus. Compounds with dual inhibitory activity in both MetAP2 and DPP-4 are desired.
  • the present invention provides novel compounds with dual MetAP2 and DPP-4 inhibition. These dual inhibitor compounds can be useful in the treatment of a MetAP2 mediated condition.
  • the present invention provides a compound of the Formula I
  • R is selected from the group consisting of and
  • the compound is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • the compound is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • the compound is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • the compound is selected from the group consisting of 1- [2- [4- [ (3R, 5S, 6R) -5-Amino-6- (2, 5-difluorophenyl) tetrahydropyran-3-yl] piperazin-1-yl] pyrimidin-5-yl] -N- [ (3-chloro-5-fluoro-phenyl) methyl] -3-hydroxy-2-oxo-pyrrolidine-3-carboxamide, isomer 1 and 1- [6- [ (3R, 5S, 6R) -5-amino-6- (2, 5-difluorophenyl) tetrahydropyran-3-yl] -5, 7-dihydropyrrolo [3, 4-b] pyridin-3-yl] -N- [ (3-chloro-5-fluoro-phenyl) methyl] -3-hydroxy-2-oxo-pyrrolidine-3-carboxamide, isomer 1, or a pharmaceutically acceptable salt
  • 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.
  • there is a method for treating a condition associated with MetAP2 modulation 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 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 Example below.
  • the specific synthetic steps for each of the routes described may be combined in different ways, to prepare compounds of the invention, or salts thereof.
  • the products of each step can be recovered by conventional methods well known in the art, including extraction, evaporation, precipitation, chromatography, filtration, trituration, and crystallization.
  • 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.
  • BSA Bovine Serum Albumin
  • DCM dichloromethane
  • DIPEA diisopropylethylamine
  • DMAc dimethylacetamide
  • DMF dimethylformamide
  • DIO diet induced obese
  • EDTA ethylenediaminetetraacetic acid
  • EtOAc ethyl acetate
  • F formic acid
  • HEC hydroxy ethyl cellulose
  • HPES 4- (2-hydroxyethyl) -1-piperazineethanesulfonic acid
  • HFD refers to high fat diet
  • IC 50 refers to the concentration of an agent that produces 50%of the maximal inhibitory response possible for that agent;
  • the aqueous layer is extracted with EtOAc (2 ⁇ 300 mL) and the combined organic extracts are washed with water (2 ⁇ 400 mL) , brine (2 ⁇ 400 mL) , dried over Na 2 SO 4 , filtered, and concentrated under reduced pressure.
  • the residue is slurried with MTBE (500 mL) at 15 °C for 20 minutes and filtered.
  • the filter cake is washed with MTBE (2 ⁇ 100 mL) and dried in vacuum to give the title compound (270.00 g, 944.50 mmol, 29.15%) as a white solid.
  • N- [ (3-Chloro-5-fluoro-phenyl) methyl] -2-oxo-pyrrolidine-3-carboxamide (164.38 g, 607.26 mmol) is dissolved in tert-butanol (6.00 L) at 80 °C over a period of 30 minutes.
  • the reaction mixture is cooled to 15 °C.
  • Sodium ethoxide (206.62 g, 3.04 mol) is added and the color of solution turns to yellow from colorless.
  • tert-Butyl hydroperoxide (626.98 mL, 4.25 mol, 65%purity) is added to the mixture at 25 °C. The color of solution turns to white from yellow, and a solid is precipitated.
  • the suspension is heated to 40 °C for 1 hour.
  • the white suspension is quenched with saturated aqueous Na 2 SO 3 (1500 mL) and the pH is adjusted to 7 with 4 N HCl (100 mL) and separated.
  • the aqueous layer is extracted with DCM/iPrOH (3/1, 400 mL ⁇ 2) .
  • the combined organic extracts are concentrated under reduced pressure.
  • the residue is dissolved in DCM/iPrOH (3/1, 3 L) and washed with water (500 mL) , brine (500 mL) and concentrated under reduced pressure.
  • the yellow solid is slurried with DCM (400 mL) at 15 °C for 15 minutes and filtered.
  • ES/MS m/z 286.9 (M+H) (M+H) .
  • Example 1 [2- [4-[ (3R, 5S, 6R) -5-amino-6- (2, 5-difluorophenyl) tetrahydropyran-3-yl] piperazin-1-yl]pyrimidin-5-yl] -N- [ (3-chloro-5-fluoro-phenyl) methyl] -3-hydroxy-2-oxo-pyr
  • the compounds exemplified herein are tested essentially as described below and exhibits an IC 50 for the human and mouse MetAP2 assay of lower than or equal to 1000 nM.
  • MetAP2 human and mouse proteins are generated from Sf9 cells using procedure similar to that described in Biochemistry 2003, 42, 5035-5042. MetAP2 is purified in the presence of 5 mM MnCl 2 and 2 mM CoCl 2 respectively, and stored at -78 °C before use.
  • 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 a 100 ⁇ l assay buffer (50 mM HEPES, 100 mM NaCl, 50 mg/mL BSA, 0.17 mM Triton TM X-100 at pH 7.5) for 40 minutes.
  • the levels of product and remaining substrate are quantified with a mass spectrometer.
  • the IC 50 value is calculated typically from a 10-point dose titration curve using a 4-parameter equation.
  • the IC 50 for the human and mouse MetAP2 assay for Examples 1, 2 and 3 is lower than 1000 nM.
  • An IC 50 for the human and mouse MetAP2 assay lower than 1000 nM support that the compound inhibits MetAP2.
  • Human DPP-4 (39-766) -His) and mouse DPP-4 ( (29-760) -His) are purified for use in the assay.
  • the final concentration of hDPP-4 and mDPP-4 in the assay is 0.04 nM and 0.22 nM respectively.
  • Inhibition of the catalytic activity of human and mouse DPP-4 by the compound in the present invention is monitored by the formation of product fluorescence AMC (7-amido-4-methylcoumarin hydrobromide) from substrate Gly-Pro-AMC (Sigma, G2761) on an Envision plate reader.
  • the reaction is typically conducted by incubating the enzyme, test compound, and substrate (10 ⁇ M) in a 75 ⁇ l assay buffer (0.01%BSA, 0.1 mM EDTA, 50 ⁇ M Tris-HCl, 0.01%Triton TM -X100, 0.1 M NaCl at pH 7.5) for 30 minutes.
  • the formation of fluorescent product AMC is measured on an Envision plate reader with the excitation wavelength at 355 nm and emission wavelength at 460 nm.
  • the IC 50 value is calculated typically from a 10-point dose titration curve using the 4-parameter logistic equation.
  • the IC 50 for Example 1 and 2 is lower than 1000 nM in the human and mouse DPP-4 assay and the results are shown in Table 1.
  • the compound from the invention is tested HFD feeding induced obese mouse model (DIO mice) .
  • DIO mice HFD feeding induced obese mouse 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.
  • the mice will gradually increase their 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% at 5 mL/kg) is administered orally to the obese DIO mice once or twice daily throughout the study duration.
  • the dose-dependent weight loss of obese DIO mice for Example 1 of the oral treatment at 60 mg/kg once daily is about 4.0%weight loss compared to the vehicle group at day 14.
  • the data support that the compound of Example 1 is associated with desired weight loss and could offer a therapeutic weight loss effect.
  • mice are weighed and randomized by body weight. Each mouse is dosed via oral gavage with vehicle or testing compound formulated with vehicle for up to 3 times. The first dose is administrated at 9 ⁇ 10 am on day 1. The second dose is administrated at 16: 30 ⁇ 17: 30 on day 1. The third dose is administrated at 9 ⁇ 10 am on day 2. The mice are fasted for 6 hours after the last dose before termination at ⁇ 3 pm on day 2. Blood samples are collected at 1 hour after the first dosing and upon termination. EDTA-K 2 at final concentration of 5 mM is used as an anticoagulant. Plasma, isolated from the blood samples, is used to determine the plasma DPP-4 enzyme activity.
  • Plasma DPP-4 enzyme activity in the present invention is monitored by the formation rate of fluorescence AMC from substrate Gly-Pro-AMC (Sigma, G2761) via Envision plate reader.
  • the reaction is typically conducted by incubating the plasma (20 ⁇ l) and substrate (10 ⁇ M) in a 40 ⁇ L assay buffer (0.01%BSA, 0.1 mM EDTA, 50 ⁇ M Tris-HCl, 0.01%Triton TM -X100, 0.1 M NaCl at pH 7.5) . Fluorescence signal is read immediately after the start of the reaction in kinetic model in Envision plate reader.
  • the excitation wavelength is set at 355 nm and emission wavelength is set at 460 nm.
  • the plasma DPP-4 activity is calculated from reaction velocity.
  • the percentage plasma DPP- 4 inhibition is normalized against plasma DPP-4 activity in the vehicle group, which is set as 0%inhibition.
  • the plasma DPP-4 inhibition for Example 2 and under the assay condition is 92%for 1 hour after the first dosing and 92%at 6 hours upon termination.
  • the plasma DPP-4 inhibition for Example 3 under the assay condition is 91%for 1 hour after the first dosing and 92%at 6 hours upon termination.
  • the data support that the compounds of Example 2 and Example 3 are associated with desired DPP-4 inhibition that could yield therapeutic glycemic control.
  • 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 amounts effective to treat obesity.
  • the pharmaceutical composition is administered to a patient in need thereof in amounts effective to provide desired weight loss.
  • An appropriate amount or dose effective to treat a patient can be determined by a health care provider.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Plural Heterocyclic Compounds (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/CN2015/083514 2015-07-08 2015-07-08 Composés pyrrolidinone Ceased WO2017004797A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
PCT/CN2015/083514 WO2017004797A1 (fr) 2015-07-08 2015-07-08 Composés pyrrolidinone
PCT/CN2016/084464 WO2017005069A1 (fr) 2015-07-08 2016-06-02 Composés pyrrolidinone

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/CN2015/083514 WO2017004797A1 (fr) 2015-07-08 2015-07-08 Composés pyrrolidinone

Publications (1)

Publication Number Publication Date
WO2017004797A1 true WO2017004797A1 (fr) 2017-01-12

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
USD838910S1 (en) 2017-04-04 2019-01-22 Dentek Oral Care, Inc. Interdental pick set with frame
USD838909S1 (en) 2017-04-04 2019-01-22 Dentek Oral Care, Inc. Interdental pick

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20060019831A1 (en) * 2002-10-18 2006-01-26 Basf Aktiengesellschaft 1-phenylpyrrolidine-2-one-3-carboxamides
WO2007015767A1 (fr) * 2005-07-20 2007-02-08 Eli Lilly And Company Dérivés de pyridine en tant qu'inhibiteurs de dipeptedyl peptidase
US7238724B2 (en) * 2002-09-19 2007-07-03 Abbott Laboratories Pharmaceutical compositions as inhibitors of dipeptidyl peptidase-IV (DPP-IV)
US20070238753A1 (en) * 2004-02-27 2007-10-11 Madar David J Pharmaceutical Compositions as Inhibitors of Dipeptidyl Peptidase-IV (DPP-IV)
CN103153951A (zh) * 2010-10-13 2013-06-12 默克专利股份公司 作为MetAP-2抑制剂的吡咯烷酮
WO2014056938A1 (fr) * 2012-10-09 2014-04-17 Sanofi Dérivés de pyrrolidinone à titre de modulateurs de gpr119 pour le traitement du diabète, de l'obésité, de la dyslipidémie et autres affections apparentées

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7238724B2 (en) * 2002-09-19 2007-07-03 Abbott Laboratories Pharmaceutical compositions as inhibitors of dipeptidyl peptidase-IV (DPP-IV)
US20060019831A1 (en) * 2002-10-18 2006-01-26 Basf Aktiengesellschaft 1-phenylpyrrolidine-2-one-3-carboxamides
US20070238753A1 (en) * 2004-02-27 2007-10-11 Madar David J Pharmaceutical Compositions as Inhibitors of Dipeptidyl Peptidase-IV (DPP-IV)
WO2007015767A1 (fr) * 2005-07-20 2007-02-08 Eli Lilly And Company Dérivés de pyridine en tant qu'inhibiteurs de dipeptedyl peptidase
CN103153951A (zh) * 2010-10-13 2013-06-12 默克专利股份公司 作为MetAP-2抑制剂的吡咯烷酮
WO2014056938A1 (fr) * 2012-10-09 2014-04-17 Sanofi Dérivés de pyrrolidinone à titre de modulateurs de gpr119 pour le traitement du diabète, de l'obésité, de la dyslipidémie et autres affections apparentées

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
USD838910S1 (en) 2017-04-04 2019-01-22 Dentek Oral Care, Inc. Interdental pick set with frame
USD838909S1 (en) 2017-04-04 2019-01-22 Dentek Oral Care, Inc. Interdental pick

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