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WO2008148279A1 - Dérivés de pyrrolidine condensés avec du cyclobutyle, leurs procédés de préparation et leur utilisation médicale - Google Patents

Dérivés de pyrrolidine condensés avec du cyclobutyle, leurs procédés de préparation et leur utilisation médicale Download PDF

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Publication number
WO2008148279A1
WO2008148279A1 PCT/CN2007/070927 CN2007070927W WO2008148279A1 WO 2008148279 A1 WO2008148279 A1 WO 2008148279A1 CN 2007070927 W CN2007070927 W CN 2007070927W WO 2008148279 A1 WO2008148279 A1 WO 2008148279A1
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WO
WIPO (PCT)
Prior art keywords
acid
tert
group
compound
butyl
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/CN2007/070927
Other languages
English (en)
Chinese (zh)
Inventor
Pengcho Tang
Zhigang Lin
Jialiang Yang
Fuqiang Zhao
Yang Wang
Qian Wang
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.)
Shanghai Hengrui Pharmaceutical Co Ltd
Original Assignee
Shanghai Hengrui Pharmaceutical 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 Shanghai Hengrui Pharmaceutical Co Ltd filed Critical Shanghai Hengrui Pharmaceutical Co Ltd
Publication of WO2008148279A1 publication Critical patent/WO2008148279A1/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
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/52—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring condensed with a ring other than six-membered
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms

Definitions

  • the present invention relates to a novel pyrrolidine and four-membered ring derivative, a process for preparing the same, and a pharmaceutical composition containing the same And its use as a therapeutic agent, in particular as a dipeptidyl peptidase inhibitor (DPPIV).
  • DPPIV dipeptidyl peptidase inhibitor
  • BACKGROUND OF THE INVENTION Diabetes is a multi-pathogenic metabolic disease characterized by chronic hyperglycemia accompanied by disorders of sugar, fat and protein metabolism caused by defects in insulin secretion and/or function. Diabetes is a very old disease. It is caused by an absolute or relative lack of insulin in the human body. The blood glucose level is increased, and then a large amount of sugar is excreted from the urine, and there are polydipsia, polyuria, polyphagia, weight loss, and dizziness. , fatigue and other symptoms.
  • DPPIV Dipeptidyl Peptidase-IV
  • DPPIV can prevent the secretion of glucagon-like peptide (GLP)-1, in particular, it can cleave the N-terminal group-propadipeptide enzyme of GLP-1 from the active form of GLP- 1 (7-36) NH 2 degraded to inactive GLP-1 (9-36) NH 2 (Endocrinology, 1999, 140: 5356 ⁇ 5363). Due to physiological conditions, the half-life of intact GLP-1 in circulating blood is very short, and the inactive metabolites after DPPIV degrades GLP-1 can bind to GLP-1 receptor antagonistic activity GLP-1, thereby shortening the physiology of GLP-1. reaction.
  • DPPIV inhibitors can completely protect endogenous and even exogenous GLP-1 from being inactivated by DPPIV, greatly increasing the physiological activity of GLP-1 (5 to 10 times), due to the secretion of insulin from pancreas by GLP-1. It is an important stimulator and can directly affect the distribution of glucose. DPPIV inhibitors play a very good role in the treatment of non-insulin-dependent diabetes mellitus (NIDDM) (US6110949). Summary of the invention
  • the present invention relates to a compound represented by the formula (I) or a pharmaceutically acceptable salt thereof:
  • R 3 is selected from the group consisting of alkyl, cycloalkyl, bicycloalkyl, tricycloalkyl, hydroxycycloalkyl, hydroxybicycloalkyl, Hydroxytricycloalkyl, aryl or heteroaryl.
  • the present invention includes a compound represented by the following formula (IA) or a pharmaceutically acceptable salt thereof:
  • R 3 is selected from the group consisting of alkyl, cycloalkyl, bicycloalkyl, tricycloalkyl, hydroxycycloalkyl, hydroxybicycloalkyl, hydroxytricycloalkyl, aryl or heteroaryl.
  • Another aspect of the invention relates to a compound of the formula (I) or a pharmaceutically acceptable salt thereof, wherein the formula ⁇ is present in the form of a pharmaceutically acceptable free form or an acid addition salt, the salt being A salt formed with an acid selected from the group consisting of hydrochloric acid, methanesulfonic acid, sulfuric acid, phosphoric acid, citric acid, acetic acid or trifluoroacetic acid, preferably hydrochloric acid or trifluoroacetic acid.
  • the compound of the formula (I) of the present invention includes the following compounds and is not limited thereto:
  • the present invention relates to a process for the preparation of a compound of the formula (I), which process comprises the steps of:
  • the obtained carboxylic pyrrolidine and four-membered ring compound is reacted with pyridine, ammonium hydrogencarbonate and di-tert-butyl dicarbonate in an acetonitrile solvent at room temperature overnight to obtain an amide pyrrolidine and a four-membered ring compound;
  • the obtained amide pyrrolidine and four-membered ring compound is reacted with a solution of hydrochloric acid in diethyl ether in an ethereal solvent to remove the amino-protecting group to obtain the hydrochloride of the aminopyrrolidine and four-membered ring compound;
  • the obtained aminopyrrolidine and four-membered ring compound hydrochloride is in an acetonitrile solvent with triethylamine,
  • R 3 is selected from the group consisting of alkyl, cycloalkyl, bicycloalkyl, tricycloalkyl, hydroxycycloalkyl, hydroxybicycloalkyl, hydroxytricycloalkyl, aryl or heteroaryl.
  • the obtained compound of the formula (I) is purified and directly subjected to an ice bath reaction in an acid dichloromethane solution to obtain an acid addition salt product.
  • the acid described therein is hydrochloric acid, methanesulfonic acid, sulfuric acid, phosphoric acid, citric acid, acetic acid or trifluoroacetic acid. It is preferably hydrochloric acid or trifluoroacetic acid.
  • the present invention relates to a compound of the formula: as an intermediate of the synthesis of the compound of the formula (I): (should be of the formula)
  • the present invention relates to a process for the preparation of an intermediate compound of the above formula, comprising the steps of:
  • ester-inverted pyrrolidine and four-membered ring compound is reacted with lithium hydroxide in an ice bath in an ice bath and then subjected to acid hydrolysis treatment with 1N hydrochloric acid to obtain a carboxylic pyrrolidine and a four-membered ring compound;
  • the obtained carboxylic pyrrolidine and four-membered ring compound is reacted with pyridine, ammonium hydrogencarbonate and di-tert-butyl dicarbonate in an acetonitrile solvent at room temperature overnight to obtain an amide pyrrolidine and a four-membered ring compound;
  • the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of a compound of the formula (I) or a salt thereof and a pharmaceutically acceptable carrier.
  • the present invention relates to the use of a compound of the formula (I) or a salt thereof for the preparation of a medicament for dipeptidyl peptidase (DPPIV) inhibitor.
  • DPPIV dipeptidyl peptidase
  • a linear or branched alkyl group preferably a linear or branched alkyl group having 1 to 10 carbon atoms, more preferably a linear or branched alkyl group having 1 to 8 carbon atoms, such as a methyl group or an ethyl group.
  • Cycloalkyl means an independent group or as part of another group, which refers to a cyclic hydrocarbon group having a saturated or partially unsaturated (having 1 or 2 double bonds), said group
  • the group has 1 to 3 rings including a monocycloalkyl group, a bicycloalkyl group, a tricycloalkyl group, and the group has 3 to 20 carbon atoms, preferably a cycloalkyl group having 3 to 10 carbon atoms, and these rings It may be a silk and a ring with 1 or 2 aromatic rings, such as an aryl group, and the group includes a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptane, a cyclooctane, a cyclodecyl group, Cyclodecyl, cyclodecyl, cyclododecyl, adam
  • Halogen means an independent group or as part of another group, and refers to chlorine, bromine, fluorine, iodine and trifluoromethyl, preferably chlorine or fluorine.
  • Aryl means an independent group or as part of another group, and refers to a monocyclic, bicyclic aromatic group having from 6 to 10 carbon atoms (eg, phenyl, naphthyl including 1-naphthalene)
  • the base, 2-naphthyl may also optionally include from 1 to 3 additional rings and carbocyclic or heterocyclic silks and (for example, aryl, cycloalkyl, heteroaryl or cycloheteroalkyl rings, such as:
  • the amino group of the group (the substituent may be selected from an alkyl group, an aryl group or other aryl compound mentioned in the definition herein), an alkyl acyl group, an ary
  • Heteroaryl means an independent group or as part of another group, and refers to a 5- or 6-membered aromatic ring having 1, 2, 3 or 4 heteroatoms such as nitrogen and oxygen. Or sulfur, these rings may be bonded to aryl, cycloalkyl, heteroaryl or cycloheterocyclohexyl and (for example: fluorenyl) and possibly N-oxide.
  • the heteroaryl group may include any of 1 to 4 substituents, such as any of the substituents defined above for the alkyl group.
  • Heteroaryl groups include the following structures:
  • the method for preparing the compound of the formula (I) or a salt thereof of the present invention comprises the following steps: Wherein the starting material (2R)-1-tert-butyl 2-ethyl 5-hydroxypyrrolidine-1,2-dicarboxylate in toluene solvent with 2,6-lutidine and N,N-dimethyl Aminopyridine and trifluoroacetic anhydride are reacted at room temperature to give (R 1-tert-butyl 2-ethyl 2,3-dihydropyrrole-1,2-dicarboxylate; (R)-l-tert-butyl 2 - a solution of ethyl 2,3-dihydropyrrole-1,2-dicarboxylate and triethylamine in cyclohexane and a solution of dichloroacetyl chloride in cyclohexane in an oil bath at 38 ° C to obtain (lR , 3R, 5S)-2-tert-butyl 3-ethyl
  • R 3 is selected from the group consisting of alkyl, cycloalkyl, bicycloalkyl, tricycloalkyl, hydroxycycloalkyl, hydroxybicycloalkyl, Hydroxytricycloalkyl, aryl or heteroaryl.
  • the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of a compound or a salt thereof and a pharmaceutical carrier, or the use of a compound of the formula of the present invention or a salt thereof for the preparation of a medicament for dipeptidyl peptidase inhibitor.
  • the present invention also provides a composition comprising a pharmaceutically effective amount of the above compound, and the use of the compound for the preparation of a dipeptidyl peptidase inhibitor.
  • the structure of the compound is determined by nuclear magnetic resonance (NMR) or mass spectrometry (MS).
  • NMR shift ( ⁇ ) is given in parts per million (ppm).
  • NMR was measured with BrukerAVANCE-400 NMR instrument, measurement solvent deuterated methanol (CD 3 OD), deuterated chloroform (CDC1 3), trimethylsilane as the internal standard (TMS), chemical shifts are 10-6 ( Ppm) is given as a unit.
  • the MS was assayed using a FINMGAN LCQAd (ESI) mass spectrometer (manufacturer: Therm, model: Finnigan LCQ advantage MAX).
  • ESI FINMGAN LCQAd
  • the average inhibition rate of the kinase and the IC 5Q value were determined using a NovoStar plate reader (BMG, Germany)
  • CD 3 OD deuterated methanol
  • Example 1 has a significant inhibitory effect on DPPIV activity, has obvious selectivity for QPP, and has different degrees of selectivity for DPP8, DPP9 and FAP.

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

Abstract

L'invention concerne un nouveau dérivé de pyrrolidine condensé avec du cyclobutyle de formule (I), les substituants étant définis dans la description, leurs procédés de préparation, leurs compositions et leur utilisation comme agent thérapeutique, en particulier comme inhibiteur de la dipeptidyle peptidase IV (DPPIV).
PCT/CN2007/070927 2007-06-04 2007-10-19 Dérivés de pyrrolidine condensés avec du cyclobutyle, leurs procédés de préparation et leur utilisation médicale Ceased WO2008148279A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN200710108915.4 2007-06-04
CNA2007101089154A CN101318925A (zh) 2007-06-04 2007-06-04 吡咯烷并四元环类衍生物、其制备方法及其在医药上的用途

Publications (1)

Publication Number Publication Date
WO2008148279A1 true WO2008148279A1 (fr) 2008-12-11

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PCT/CN2007/070927 Ceased WO2008148279A1 (fr) 2007-06-04 2007-10-19 Dérivés de pyrrolidine condensés avec du cyclobutyle, leurs procédés de préparation et leur utilisation médicale

Country Status (3)

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CN (1) CN101318925A (fr)
TW (1) TW201000096A (fr)
WO (1) WO2008148279A1 (fr)

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102260265B (zh) * 2010-05-24 2015-09-02 上海阳帆医药科技有限公司 六氢吡咯[3,4-b]吡咯衍生物、其制备方法及其用途
CN108341766B (zh) * 2017-01-24 2020-08-14 南京药石科技股份有限公司 一种3-氮杂双环[3.1.0]己烷盐酸盐的制备方法
CN108164506B (zh) * 2018-02-02 2021-03-16 上海交通大学 一种dpp-4酶抑制剂及其制备和应用

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1427826A (zh) * 2000-03-10 2003-07-02 布里斯托尔-迈尔斯斯奎布公司 基于环丙基稠合的吡咯烷二肽基肽酶iv抑制剂、它们的制备方法及用途
CN1703399A (zh) * 2002-09-19 2005-11-30 艾博特公司 作为二肽酰肽酶－iv(dpp－iv)抑制剂的药用组合物

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1427826A (zh) * 2000-03-10 2003-07-02 布里斯托尔-迈尔斯斯奎布公司 基于环丙基稠合的吡咯烷二肽基肽酶iv抑制剂、它们的制备方法及用途
CN1703399A (zh) * 2002-09-19 2005-11-30 艾博特公司 作为二肽酰肽酶－iv(dpp－iv)抑制剂的药用组合物

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
AMBROSIO J.C.L. ET AL.: "Reductive decarboxylation of bicyclic prolinic systems. A new approach to the enantioselective synthesis of the Geissman-Waiss lactone, X-ray structure determination of a key lactone intermediate", JOURNAL OF THE BRAZILIAN CHEMICAL SOCIETY, vol. 14, no. 1, 2003, pages 28 - 29, 32 - 33 *

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TW201000096A (en) 2010-01-01
CN101318925A (zh) 2008-12-10

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