CN104193731B - A kind of urea substituted biphenyl class compound and combinations thereof and purposes - Google Patents

A kind of urea substituted biphenyl class compound and combinations thereof and purposes Download PDF

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Publication number
CN104193731B
CN104193731B CN201410428191.1A CN201410428191A CN104193731B CN 104193731 B CN104193731 B CN 104193731B CN 201410428191 A CN201410428191 A CN 201410428191A CN 104193731 B CN104193731 B CN 104193731B
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compound
methyl
alkyl
acid
hydrogen
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CN104193731A (en
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杨新业
马发城
潘圣强
王晓军
张英俊
郑常春
徐景宏
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Guangdong HEC Pharmaceutical
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    • 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
    • C07D405/02—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 two hetero rings
    • C07D405/12—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 two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
    • C07D307/79—Benzo [b] furans; Hydrogenated benzo [b] furans with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

The present invention relates to biphenyl analog derivative, its preparation method and its pharmaceutical composition and in application pharmaceutically.Specifically, the present invention relates to a kind of new urea substituted biphenyl analog derivative, its medicinal composition and preparation method thereof, further to the biphenyl derivatives and or pharmaceutical composition containing the derivative as therapeutic agent, especially as GPR40 activators and the purposes in the medicine for preparing the treatment disease such as diabetes and metabolic disorder.Compound according to the present invention contains urea groups, the group unique and novelty on this class compound structure is transformed.

Description

A kind of urea substituted biphenyl class compound and combinations thereof and purposes
Technical field
The present invention relates to the compound and its pharmaceutically acceptable composition for adjusting GPR40 activity and being used for preparing The purposes of GPR40 relevant disease medicines.Particularly, the present invention relates to a kind of urea substituted biphenyl class compound, contain these chemical combination The pharmaceutical composition of thing and these compounds are being used for preparing some purposes being relevant in the active disease medicaments of GPR40.This The compound that invention is related to contains urea groups, the group unique and novelty on this class compound structure is transformed.
Background of invention
GPR40 is the member of the gene superfamilies of G- G-protein linked receptors (" GPRs ").GPRs is to be characterized by 7 to push away The memebrane protein of fixed transmembrane region, by activation to the vital Intracellular signals pipeline of various physiological-function in response to Various molecules.GPR40 is accredited as orphan receptor (that is, receiving without known ligand first from human genome DNA's fragment Body).Sawzdargo et al. (1997) Biochem.Biophys.Res.Commun.239：543-547.GPR40 is thin in pancreas islet β It is high expression in born of the same parents and insulin secretory cell system.GPR40 activation and the G of Intracellular signals transferrinqThe regulation of family Induction with adjoint elevated calcium level is associated.Part of the aliphatic acid as GPR40, and aliphatic acid adjusted by GPR40 Section insulin secretion has been known.Itoh et al. (2003) Nature 422:173-176；Briscor et al. (2003) J.Biol.Chem.278:11303-11311；Kotarsky et al. (2003) Biochem.Biophys.Res.Commun.301： 406-410.
Although the compound of many regulation GPR40 activity is disclosed, type ii diabetes, obesity, hypertension, angiocarpy Disease and the high incidence of dyslipidemia, have pointed out the demand to effectively treatment or the new treatment for preventing these diseases urgent.
The futuramic biphenyl compound being substituted of the present invention, which has the ability for adjusting GPR40, therefore describedization Compound is potentially served as treating or preventing diabetes and associated conditions.
Abstract of invention
The invention provides can be used to treat diabetes, diabetic retinopathy, diabetic neuropathy, diabetic keratopathy The elevated levels of ephrosis, insulin resistance, hyperglycaemia, hyperinsulinemia, aliphatic acid or glycerine, hyperlipidemia, obesity, height Triglyceride, X syndromes, DKA, GI, hypercholesterolemia, dyslipidemia, Metabolic syndrome Disease, angiocardiopathy, kidney trouble, thrombotic disorder, ephrosis, sex dysfunction, skin disease, indigestion, hypoglycemia, cancer The compound of disease, oedema, diabetic complication, atherosclerotic or hypertension, pharmaceutical composition and method.The present inventionization Compound or pharmaceutical composition have good adjustment effect to GPR40 acceptors.
On the one hand, the present invention relates to the alloisomerism of compound of the one kind as shown in formula (I) or the compound shown in formula (I) Body, geometric isomer, dynamic isomer, nitrogen oxides, hydrate, solvate, metabolite, pharmaceutically acceptable salt or Prodrug,
Wherein, ring A is C2-10Heterocyclic radical, C5-12Condense miscellaneous bicyclic group, C5-12The miscellaneous bicyclic group of spiral shell or C5-12The miscellaneous bicyclic group of bridge；
Each R1It independently is hydrogen, C1-6Alkyl, C1-6Haloalkyl, halogen, C1-6Alkyl sulphonyl or C1-6Alkyl sulphonyl C1-6Alkyl；Or two adjacent R1Coupled atom constitutes C together6-10Aromatic ring or C1-9Hetero-aromatic ring, wherein described C6-10Virtue Ring and C1-9Hetero-aromatic ring is optionally independently selected from hydrogen, fluorine, chlorine, bromine, hydroxyl, C by 1,2,3 or 4 independently of one another1-4Alkyl, C1-4 Haloalkyl, C1-4Alkyl sulphonyl, amino-sulfonyl or C1-4Halogenated alkyl sulfonyl substituent replaces；
R2For hydrogen or C1-6Alkyl；With
N is 1,2,3 or 4.
In certain embodiments, the present invention relates to compound of the one kind as shown in formula (II) or the compound shown in formula (II) Stereoisomer, geometric isomer, dynamic isomer, nitrogen oxides, hydrate, solvate, metabolite, pharmaceutically may be used The salt or prodrug of acceptance,
Wherein, k and m are each independently 0,1,2,3 or 4.
In certain embodiments, A rings are
In further embodiments, each R1It independently is hydrogen, C1-4Alkyl, C1-4Haloalkyl, fluorine, chlorine, bromine, C1-4Alkyl Sulfonyl or C1-4Alkyl sulphonyl C1-4Alkyl；Or two adjacent R1Coupled atom constitutes C together6-10Aromatic ring or C1-9 Hetero-aromatic ring, wherein described C6-10Aromatic ring and C1-9Hetero-aromatic ring independently of one another optionally by 1,2,3 or 4 be independently selected from hydrogen, fluorine, Chlorine, bromine, hydroxyl, C1-4Alkyl, C1-4Haloalkyl, C1-4Alkyl sulphonyl, amino-sulfonyl or C1-4Halogenated alkyl sulfonyl takes Replace for base；With
R2For hydrogen or C1-4Alkyl.
In further embodiments, each R1Independently be hydrogen, methyl, ethyl, propyl group, butyl, the tert-butyl group, trifluoromethyl, Fluorine, chlorine, bromine, methyl sulphonyl, sulfonyloxy methyl ylmethyl, methysulfonylethyl or methanesulphonylpropyl；With
R2For hydrogen, methyl, ethyl, propyl group or butyl.
In further embodiments, structure of the present invention comprising one of：
Or its stereoisomer, geometric isomer, dynamic isomer, nitrogen oxides, hydrate, solvate, metabolism product Thing, pharmaceutically acceptable salt or prodrug.
On the other hand, the invention provides a kind of pharmaceutical composition, described pharmaceutical composition includes any of the above described one kindization Compound, further comprising pharmaceutically acceptable carrier, excipient, diluent, assistant agent, medium or its combination.
In other embodiment schemes, described pharmaceutical composition further includes antidiabetic medicine, anti-high blood Sugared medicine, anti-obesity medicine, drug for hypertension, antiplatelet drug, Antiatherosclerosis medicine, fat-reducing medicament, disappear Scorching medicine or its combination.
In other embodiment schemes, described pharmaceutical composition, its are further received comprising at least one GPR40 Body activator.
On the other hand, the present invention provides a kind of compound and described pharmaceutical composition and is used for preventing, controlling in preparation Treat, mitigate or delay diabetes, diabetic retinopathy, diabetic neuropathy, nephrosis, insulin resistance, The elevated levels of hyperglycaemia, hyperinsulinemia, aliphatic acid or glycerine, hyperlipidemia, obesity, hypertriglyceridemia, X are comprehensive Close disease, DKA, GI, hypercholesterolemia, dyslipidemia, metabolic syndrome, angiocardiopathy, kidney Dirty disease, thrombotic disorder, ephrosis, sex dysfunction, skin disease, indigestion, hypoglycemia, cancer, oedema, diabetes are simultaneously Send out disease, atherosclerotic or hypertension or for increasing the purposes in hdl level medicine.
Another aspect of the present invention is related to the preparation of the compound included by formula (I) or formula (II), the method for separating and purifying.
Content noted earlier only outlines certain aspects of the invention, but in terms of being not limited to these.In terms of these and its The content of his aspect is made more specific complete description below.
The detailed description of the invention
Definition and general terms
Certain embodiments of the present invention are will now be described in more detail, the example is by the structural formula and chemical formula explanation that encloses.This Invention intention covers all of replacement, modification and equivalent technical solutions, and they are included in such as the present invention of claim definition In the range of.Those skilled in the art will appreciate that many can be used in reality with similar or equivalent method described herein and material Trample the present invention.The present invention is not limited to method described herein and material.In the document, patent and similar material for being combined one Or many different from the application or conflicting in the case of (including but not limited to defined term, term application, described Technology, etc.), be defined by the application.
It will further be appreciated that some features of the present invention, are clearly visible, carry out in multiple independent embodiments Description, but it is also possible to provide in single embodiment in combination.Conversely, the various features of the present invention, for brevity, It is described in single embodiment, but it is also possible to individually or with the sub-portfolio being arbitrarily suitable for provide.
Unless otherwise indicated, all scientific and technical terminologies used in the present invention have with those skilled in the art of the invention's It is generally understood that identical implication.All patents according to the present invention and public publication are integrally incorporated this by reference Bright.
Unless otherwise indicated, following definition used herein should be applied.For purposes of the present invention, chemical element with Periodic table of elements CAS versions, and《Handbook of Chemistry and Physics》, the 75th edition, 1994 is consistent.Additionally, organic chemistry General Principle can be joined Examine " Organic Chemistry ", Thomas Sorrell, University Science Books, Sausalito:1999, " March's Advanced Organic Chemistry " by Michael B.Smith and Jerry March, John Wiley&Sons,New York:Description in 2007, entire contents are incorporated herein by.
Term " study subject " used in the present invention refers to animal.Typically described animal is mammal.Tested right As for example also referring to primate (the such as mankind, sex), ox, sheep, goat, horse, dog, cat, rabbit, rat, little Mouse, fish, bird etc..In certain embodiments, the study subject is primate.In other embodiments, described receive Examination is to liking people.
Term " patient " used in the present invention refers to people (including adult and children) or other animals.In some enforcements In scheme, " patient " refers to people.
Stereochemical definitions used in the present invention and rule typically follow S.P.Parker, Ed., McGraw-Hill Dictionary of Chemical Terms McGraw-Hill Book Company,New York,1984；and Eliel,E.and Wilen,S.,“Stereochemistry of Organic Compounds”,John Wiley&Sons, Inc.,New York,1994.
Many organic compounds are present with optical active forms, i.e., they have rotates the plane of linearly polarized light Ability.When optically active compound is described, represent molecule with regard to one or more hand using prefix D and L or R and S The absolute configuration at property center.Prefix d and l or (+) and (-) are the symbols for linearly polarized light rotation caused by appointed compound, Wherein (-) or l represent that compound is left-handed.Prefix is dextrorotation for the compound of (+) or d.A kind of specific alloisomerism Body is enantiomter, and the mixture of this isomers is referred to as enantiomeric mixture.The 50 of enantiomter:50 mixtures Referred to as racemic mixture or racemic modification, when chemical reaction or during without stereoselectivity or during stereospecificity, May occur in which such case.
The present invention is disclosed any asymmetric atom (for example, carbon etc.) of compound and can be enriched with racemic or enantiomer In the form of, for example (R)-, (S)-or (R, S)-configuration be present.In certain embodiments, each asymmetric atom exists (R)-or (S)-configuration in terms of have at least 50% enantiomeric excess, at least 60% enantiomeric excess, at least 70% enantiomer mistake Amount, at least at least 80% enantiomeric excess, at least 90% enantiomeric excess, 95% enantiomeric excess, or at least 99% enantiomer Excessive.
According to the selection of starting material and method, the compounds of this invention can with possible isomers or they Mixture, the form of such as racemic modification and non-corresponding isomer mixture (this depends on the quantity of asymmetric carbon atom) deposits ?.Optically active (R)-or (S)-isomers can use chiral synthon or chiral reagent to prepare, or be torn open using routine techniques Point.If compound contains a double bond, substituent may be E or Z configurations；If containing dibasic cycloalkanes in compound Base, the substituent of cycloalkyl may have cis or trans configuration.
The mixture of any stereoisomer of gained can be separated into according to the difference in component physicochemical properties Pure or substantially pure geometric isomer, enantiomter, diastereoisomer, for example, by chromatography and/or fractional crystallization Method.
The racemic modification of any gained end-product or intermediate can be passed through those skilled in the art with known method Familiar method splits into optical antipode, e.g., is separated by its diastereoisomeric salt to obtaining.Racemic product Thing can also be separated by chiral chromatogram, e.g., using the high performance liquid chromatography (HPLC) of chiral sorbent.Especially, mapping Isomers can be prepared by asymmetric syntheses, for example, refer to Jacques, et al., Enantiomers, Racemates and Resolutions(Wiley Interscience,New York,1981)；Principles of Asymmetric Synthesis(2ndEd.Robert E.Gawley,Jeffrey Aubé,Elsevier,Oxford,UK,2012)；Eliel, E.L.Stereochemistry of Carbon Compounds(McGraw-Hill,NY,1962)；Wilen,S.H.Tables of Resolving Agents and Optical Resolutions p.268(E.L.Eliel,Ed.,Univ.of Notre Dame Press,Notre Dame,IN 1972)；Chiral Separation Techniques:A Practical Approach(Subramanian,G.Ed.,Wiley-VCH Verlag GmbH&Co.KGaA,Weinheim,Germany, 2007).
Term " dynamic isomer " or " tautomeric form " refer to that Tong Guo the low energy with different-energy builds (low Energy barrier) mutual inversion of phases constitutional isomer.If tautomerism is possible (as in the solution), can reach The chemical balance of dynamic isomer.For example, proton tautomer (protontautomer) also referred to as proton translocation mutually makes a variation Structure body (prototropic tautomer) includes migrating the mutual inversion of phases to carry out by proton, such as keto-enol isomerization and Imine-enamine isomerizations.Valence tautomerism body (valence tautomer) include by the restructuring of some bonding electrons come The mutual inversion of phases for carrying out.The instantiation of ketoenol tautomerization is that pentane -2,4- diketone and the amyl- 3- alkene -2- ketone of 4- hydroxyls are mutual The change of tautomeric.Another example tautomeric is phenol-keto tautomerism.One of phenol-keto tautomerism is concrete real Example is the change of pyridine -4- alcohol and pyridine -4 (1H) -one dynamic isomer.Unless otherwise noted, the compounds of this invention is all Tautomeric forms are within the scope of the present invention.
As described in the invention, the compound of the present invention optionally can be replaced by one or more substituents, such as General formula compound above, or as special example inside embodiment, subclass, and the class compound included by the present invention. Should be appreciated that " being optionally substituted " this term can exchange use with " substituted or non-substituted " this term.General and Speech, term " substituted " represent to structure in one or more hydrogen atoms substituted by concrete substituent.Unless its other party Face shows that an optional substituted radical can be replaced each commutable position in group.When given structural formula Middle more than one position can be selected from one or more substituents of concrete group and be replaced, then substituent can be with identical or not Replace in each position with ground.
In addition, it is necessary to illustrate, unless otherwise explicitly point out, the describing mode for being adopted in the present invention " each ... independently be " and " ... be each independently " and " ... independently be " can be exchanged, and all should be interpreted broadly, and which both may be used To refer in different groups, do not affected between expressed concrete option mutually between same-sign, it is also possible to represent in phase In same group, do not affected between expressed concrete option mutually between same-sign.Such as structureAnd structureR in both1Concrete option is unaffected each other, meanwhile, occur multiple R in same structure1, multiple R1Between concrete option be independent of each other, i.e. R1Concrete option can be with identical, it is also possible to different.
In each several part of this specification, the present invention discloses the substituent of compound and discloses according to radical species or scope.Special Do not point out, the present invention includes each independent sub-combinations thereof of each member of these radical species and scope.For example, term “C1-6Alkyl " refers in particular to individually disclosed methyl, ethyl, C3Alkyl, C4Alkyl, C5Alkyl and C6Alkyl.
In each several part of the present invention, connect substituent is described.When the structure clearly needs linking group, for this Markush variable cited by group is interpreted as linking group.For example, if the structure needs linking group and be directed to be somebody's turn to do The Markush group definition of variable lists " alkyl " or " aryl ", then represented it should be understood that being somebody's turn to do " alkyl " or " aryl " respectively The alkylidene group of connection or arylene group.
Terminology used in the present invention " alkyl " or " alkyl group ", represent contain 1 to 20 carbon atom, the straight chain of saturation or Side chain univalent hydrocarbyl group, wherein, the alkyl group can optionally by the substituent institute of one or more present invention descriptions Replace.Unless otherwise detailed instructions, alkyl group contains 1-20 carbon atom.In some embodiments, alkyl group contains 1-12 carbon atom；In other embodiments, alkyl group contains 1-6 carbon atom；In other embodiment, alkane Base group contains 1-4 carbon atom；Also in some embodiments, alkyl group contains 1-3 carbon atom.The reality of alkyl group Example includes, but is not limited to, methyl, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl group, sec-butyl, the tert-butyl group, n-pentyl, 3- methyl isophthalic acids-butyl, 3- hexyls, n-heptyl, n-octyl etc..
Term " haloalkyl " represents that alkyl is replaced by one or more halogen atoms, and such example includes, but simultaneously It is not limited to, trifluoromethyl etc..
Term " heterocyclic radical " and " heterocycle " are used interchangeably herein, all referring to the saturation comprising 3-12 annular atom or portion Point undersaturated monocyclic, wherein at least one annular atom is selected from nitrogen, sulphur and oxygen atom.Unless otherwise indicated, heterocyclic radical can be Carbon-based or nitrogen base, and-CH2- group can optionally by-C (=O)-replacement.The sulphur atom of ring can optionally be oxidized to S- Oxide.The nitrogen-atoms of ring can optionally be oxidized to N- oxygen compounds.The example of heterocyclic radical includes, but are not limited to：Epoxy Ethyl group, azelidinyl, oxetanylmethoxy, thietanyl, pyrrolidinyl, 2- pyrrolinyls, 3- pyrrolinyls, pyrazoline Base, pyrazolidinyl, imidazolinyl, hexahydropyrimidine base etc..
Term " thick miscellaneous bicyclic group " represents saturation or undersaturated and bicyclic system, is related to the simultaneously member ring systems of non-aromatic. Such system can include the undersaturated condition of independent or conjugation.And at least one member ring systems include one or more miscellaneous originals Son, each of which member ring systems include 3-7 yuan of rings, i.e., comprising 1-6 carbon atom and the 1-3 hetero atom selected from N, O, P, S, This S or P are optionally replaced by one or more oxygen atoms and obtain such as SO, SO2、PO、PO2Group.The annelated heterocycles base Can be substituted or unsubstituted, wherein substituent can be, but be not limited to, deuterium, oxo (=O), hydroxyl, amino, halogen, Cyano group, aryl, heteroaryl, alkoxyl, alkylamino, alkyl, thiazolinyl, alkynyl, heterocyclic radical, sulfydryl, nitro.
Term " spiro heterocyclic radical " represents that a ring originates from particularly ring-shaped carbon on another ring, is related to the bridge of non-aromatic Member ring systems.Such system can include the undersaturated condition of independent or conjugation.And at least one member ring systems comprising one or Multiple hetero atoms, each of which member ring systems include 3-7 yuan of rings, i.e. 1-3 comprising 1-6 carbon atom and selected from N, O, P, S Hetero atom, is optionally replaced by one or more oxygen atoms in this S or P and obtains such as SO, SO2、PO、PO2Group.And The spiro heterocyclic radical can be substituted or unsubstituted, and wherein substituent can be, but be not limited to, deuterium, oxo (=O), hydroxyl Base, amino, halogen, cyano group etc..
Term " bridge heterocyclic radical " represents saturation or undersaturated bridged-ring system, is related to the bridged-ring system of non-aromatic.So System can include independent or conjugation undersaturated condition.And at least one member ring systems include one or more hetero atoms, Each of which member ring systems include 3-7 yuan of rings, i.e., comprising 1-6 carbon atom and the 1-3 hetero atom selected from N, O, P, S, in this S Or P is optionally replaced by one or more oxygen atoms and obtains such as SO, SO2、PO、PO2Group, and the miscellaneous bridged ring base Can be substituted or unsubstituted, wherein substituent can be, but be not limited to, deuterium, oxo (=O), hydroxyl, amino, halogen, Cyano group etc..
Term " halogen " refers to fluorine (F), chlorine (Cl), bromine (Br) or iodine (I).
Term " aryl " or " aromatic ring " are represented and contain 6-14 annular atom, or 6-12 annular atom, or 6-10 annular atom Monocyclic, bicyclic and three rings the carbocyclic ring system with armaticity, and have the remainder of one or more attachment points and molecule It is connected.The example of aromatic yl group can include, but are not limited to phenyl, naphthyl and anthracene etc..
Term " heteroaryl " or " hetero-aromatic ring " are represented and contain 5-12 annular atom, or 5-10 annular atom, or 5-6 ring is former Monocyclic, bicyclic and three rings of son have the system of armaticity, and at least one member ring systems include one or more hetero atoms, and have one Individual or multiple attachment points are connected with molecule remainder.The example of heteroaryl groups is included, but is not limited to, 2- furyls, N- Imidazole radicals, 3- isoxazolyls, 2- oxazolyls, 2- pyrrole radicals, 2- pyridine radicals, 4- pyrimidine radicals, 5- pyrimidine radicals, pyridazinyl, 4- thiazoles Base, tetrazole radical, triazolyl, 2- thienyls, pyrazolyl benzimidazolyl, benzofuranyl, benzothienyl, indyl, purine Base, quinolyl, imidazo [1,2-a] pyridine radicals etc..
Term " alkyl sulphonyl " refers to, sulfonyl and molecule Remainder is connected.
It is determined that term " Alkylsulfonylalkyl " refers to that " alkyl sulphonyl " defined in the present invention is connected in a present invention On the alkyl of justice, alkyl is connected with the remainder of molecule.
Term " two adjacent R1Coupled atom constitutes aromatic ring or hetero-aromatic ring together " refer to two adjacent originals Son and coupling part R thereon1Aromatic ring or hetero-aromatic ring are constituted together.Some of them embodiment is, such asUpper two R1Phase Neighbour, constitutes aromatic ring or hetero-aromatic ring, such as together with the atom being connectedM rings are aromatic ring or hetero-aromatic ring.
Term " leaving group " refers to the atom or functional group departed from from a bigger molecule in chemical reaction.In nucleophilic In substitution reaction, substrate is referred to as by the reactant of nucleopilic reagent attack, and is ruptured away with pair of electrons from substrate molecule Atom or atomic group be referred to as leaving group.It is easily accepted by electronics, bears the leaving group that the strong group of negative electrical charge ability has been.
When term " blocking group " or " PG " refer to a substituent with other reacted with functional groups, it is commonly used to hinder Break or protect special feature.For example, " blocking group of amino " refers to that a substituent is connected to block with amino group Or in protection compound amino feature, suitable amido protecting group includes acetyl group, trifluoroacetyl group, tertbutyloxycarbonyl (BOC, Boc), benzyloxycarbonyl group (CBZ, Cbz) and 9- fluorenes methylene oxygen carbonyl (Fmoc).Similarly, " hydroxy-protective group " refers to hydroxyl The substituent of base is used for the feature for blocking or protecting hydroxyl, and suitable blocking group includes acetyl group and silicyl." carboxyl Blocking group " refers to the substituent of carboxyl for blocking or protecting the feature of carboxyl, general carboxyl-protecting group includes- CH2CH2SO2Ph, cyano ethyl, 2- (TMS) ethyl, 2- (TMS) ethoxyl methyl, 2- is (to toluene Sulfonyl) ethyl, 2- (p-nitrophenyl sulfonyl) ethyl, 2- (diphenylphosphino) ethyl, nitro-ethyl, etc..For protection The general description of group refers to document：T W.Greene,Protective Groups in Organic Synthesis, John Wiley&Sons,New York,1991；and P.J.Kocienski,Protecting Groups,Thieme, Stuttgart,2005.
Term " prodrug " used in the present invention, represents a compound and is converted into shown in formula (I) or formula (II) in vivo Compound.Such conversion by pro-drug hydrolyze in blood or in blood or tissue through enzymatic conversion for precursor structure Affect.Pro-drug compounds of the present invention can be ester, and in existing invention, ester can have phenyl ester as pro-drug Class, aliphatic (C1-24) esters, pivaloyloxymethyl esters, carbonic ester, carbamates and amino acid esters.The such as present invention In a compound include hydroxyl, you can be acylated the compound for obtaining prodrug form.Other pro-drugs Form includes phosphate, and such as these phosphate compounds are obtained through the di on parent.With regard to pro-drug Complete discussion may be referred to documents below：T.Higuchi and V.Stella,Pro-drugs as Novel Delivery Systems,Vol.14 of the A.C.S.Symposium Series,Edward B.Roche,ed.,Bioreversible Carriers in Drug Design,American Pharmaceutical Association and Pergamon Press,1987,J.Rautio et al.,Prodrugs:Design and Clinical Applications,Nature Review Drug Discovery,2008,7,255-270,and S.J.Hecker et al.,Prodrugs of Phosphates and Phosphonates,Journal of Medicinal Chemistry,2008,51,2328-2345.
" metabolite " refers to specific compound or its salt in vivo by the product obtained by metabolism.One change The metabolite of compound can be identified by technology known to art that its activity can pass through the present invention such as and retouch Adopt as stating and experimentally characterized.Such product can be by compound being administered through peroxidating, reducing, water Solution, amidated, desamido- are acted on, esterification, degreasing, and enzymatic lysis etc. method is obtained.Correspondingly, the present invention includes compound Metabolite, including compound and the mammal of the present invention are fully contacted the metabolite produced by a period of time.
" pharmaceutically acceptable salt " used in the present invention refers to the organic salt and inorganic salts of the compound of the present invention.Medicine On, acceptable salt is known to us in art, such as document：S.M.Berge et al.,describe pharmaceutically acceptable salts in detail in J.Pharmaceutical Sciences, 1977,66:1-19. it is described.The salt that pharmaceutically acceptable nontoxic acid is formed is included, but is not limited to, with amino base The inorganic acid salt that group's reaction is formed has hydrochloride, hydrobromate, phosphate, sulfate, perchlorate, and acylate such as acetic acid Salt, oxalates, maleate, tartrate, citrate, succinate, malonate, or by described on books document Additive method such as ion-exchange obtaining these salt.Other pharmaceutically acceptable salts include that adipate, alginates resist Bad hematic acid salt, aspartate, benzene sulfonate, benzoate, bisulphate, borate, butyrate, camphor hydrochlorate, camphor sulphur Hydrochlorate, cyclopentyl propionate, digluconate, lauryl sulfate, esilate, formates, fumarate, Portugal Heptose hydrochlorate, glycerophosphate, gluconate, Hemisulphate, enanthate, caproate, hydriodate, 2- hydroxy-ethanesulfonic acids Salt, lactobionate, lactate, laruate, lauryl sulfate, malate, malonate, mesylate, 2- naphthalene sulphurs Hydrochlorate, nicotinate, nitrate, oleate, palmitate, pamoate, pectate, persulfate, 3- phenylpropionic acid salt, bitter taste Hydrochlorate, pivalate, propionate, stearate, rhodanate, tosilate, undecylate, valerate, etc..Pass through The salt that appropriate alkali is obtained includes alkali metal, alkaline-earth metal, ammonium and N+(C1-4Alkyl)4Salt.The present invention is also intended to contemplate any The quaternary ammonium salt formed by the compound of the group of included N.Water-soluble or oil-soluble or dispersion product can be turned into by quaternary ammonium With obtaining.Alkali metal or alkali salt include sodium, lithium, potassium, calcium, magnesium, etc..Pharmaceutically acceptable salt further includes to fit When, nontoxic ammonium, the amine cation that quaternary ammonium salt and gegenions are formed, such as halide, hydroxide, carboxylate, sulfuric acid Compound, phosphoric acid compound, nitric acid compound, C1-8Azochlorosulfonate acid compound and aromatic sulphonic acid compound.
" solvate " of the present invention refers to the association formed by one or more solvent molecules with compound of the invention Thing.The solvent for forming solvate is included, but is not limited to, water, isopropanol, ethanol, methyl alcohol, dimethyl sulfoxide, ethyl acetate, second Acid and ethylaminoethanol.Term " hydrate " refers to that solvent molecule is the associated matter formed by water.
The as used in the present invention any disease of term " treatment " or illness, wherein some embodiment middle fingers improve disease Disease or illness (slowing down or prevent or mitigate the development of disease or its at least one clinical symptoms).In other embodiments In, " treatment " refers to mitigation or improves at least one body parameter, including the body parameter that may not be discovered by patient.Another In a little embodiments, " treatment " refers to and (for example stablizes perceptible symptom) from body or physiologically (for example stablize body Parameter) or above-mentioned two in terms of adjust disease or illness.In other embodiments, " treat " and refer to prevention or postpone disease or disease The outbreak of disease, generation or deterioration.
Pharmaceutically useful acid-addition salts can be formed with inorganic acid and organic acid, for example acetate, aspartate, benzoic acid Salt, benzene sulfonate, bromide/hydrobromate, bicarbonate/carbonate, disulfate/sulfate, camsilate, chlorination Thing/hydrochloride, chloro theophylline salt, citrate, ethanedisulphonate, fumarate, gluceptate, gluconate, glucuronic acid Salt, hippurate, hydriodate/iodide, isethionate, lactate, lactobionate, lauryl sulfate, apple Hydrochlorate, maleate, malonate, mandelate, mesylate, Methylsulfate, naphthoate, naphthalene sulfonate, nicotinate, Nitrate, octadecanoate, oleate, oxalates, palmitate, pamoate, phosphate/phosphor acid hydrogen salt/dihydric phosphate, poly- half Lactobionate, propionate, stearate, succinate, sulfosalicylate, tartrate, toluene fulfonate and trifluoroacetic acid Salt.
Such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid etc. can be included by its derivative inorganic acid for obtaining salt.
Can by its derivative organic acid for obtaining salt include for example acetic acid, propionic acid, hydroxyacetic acid, oxalic acid, maleic acid, the third two Acid, butanedioic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, mandelic acid, methanesulfonic acid, ethyl sulfonic acid, p-methyl benzenesulfonic acid, sulfo group water Poplar acid etc..
Pharmaceutically acceptable base addition salts can be formed with inorganic base and organic base.
Can be included by its derivative inorganic base for obtaining salt, the metal of the I races to XII races of such as ammonium salt and periodic table.? In some embodiments, the salt is derived from sodium, potassium, ammonium, calcium, magnesium, iron, silver, zinc and copper；Particularly suitable salt include ammonium, potassium, Sodium, calcium and magnesium salts.
Can include that primary amine, secondary amine and tertiary amine, substituted amine include naturally occurring by its derivative organic base for obtaining salt Substituted amine, cyclic amine, deacidite etc..Some organic amines include, for example, isopropylamine, tardocillin (benzathine), choline salt (cholinate), diethanol amine, diethylamine, lysine, meglumine (meglumine), piperazine And tromethamine.
The officinal salt of the present invention can be synthesized by parent compound, alkalescence or acidic moiety with conventional chemical processes. In general, such salt can by make the free acid form of these compounds and stoichiometry suitable alkali (as Na, Ca, The hydroxide of Mg or K, carbonate, bicarbonate etc.) reaction, or by making the free alkali form and chemistry of these compounds The suitable acid reaction of metered amount is being prepared.Such reaction is generally carried out in water or organic solvent or the mixture of the two. Usually, in the case of appropriate, need using non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile.? Such as " Remington ' s Pharmaceutical Sciences ", the 20th edition, Mack Publishing Company, Easton,Pa.,(1985)；" pharmaceutical salts handbook：Property, selection and application (Handbook of Pharmaceutical Salts:Properties, Selection, and Use) ", Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002) in can find the list of the suitable salt of other.
In addition, compound disclosed by the invention, include their salt, it is also possible to their hydrate forms or include its The form of solvent (such as ethanol, dimethyl sulfoxide (DMSO), etc.) is obtained, for their crystallization.The present invention discloses compound Inherently or design forming solvate can be passed through with pharmaceutically acceptable solvent (including water)；Therefore, it is contemplated that Including solvation and unsolvated form.
As described in the present invention, substituent draws the member ring systems formed on a ring for being bonded the center of being connected to (such as formula (a) institute Show) represent substituent R5Can be replaced any commutable position on ring.For example, formula (a) is represented on W1 rings or W2 rings Any position that may be substituted can be substituted.
As described in the present invention, two tie points are connected with molecule remainder in member ring systems, as shown in formula (b), It can also be that E ' ends are connected with molecule remainder that expression can both be E ends, i.e., the connected mode at two ends can be exchanged.
The composition of the compounds of this invention, preparation and administration
The invention provides being suitable to the pharmaceutical composition of the medicinal, compound comprising one or more present invention.The medicine Compositions can also further include pharmaceutically acceptable carrier, excipient, diluent, assistant agent, medium or its combination. Described pharmaceutical composition can be used for treating diabetes, diabetic retinopathy, diabetic neuropathy, diabetic keratopathy kidney The elevated levels of disease, insulin resistance, hyperglycaemia, hyperinsulinemia, aliphatic acid or glycerine, hyperlipidemia, obesity, height are sweet Oily three ester mass formed by blood stasis, X syndromes, DKA, GI, hypercholesterolemia, dyslipidemia, Metabolic syndrome Disease, angiocardiopathy, kidney trouble, thrombotic disorder, ephrosis, sex dysfunction, skin disease, indigestion, hypoglycemia, cancer Disease, oedema, diabetic complication, atherosclerotic or hypertension are used for increasing hdl level disease, special Not, which has good adjustment effect to GPR40 acceptors.
The compounds of this invention can be administered alone or apply with one or more combination with other therapeutic agents.Pharmaceutical composition more enters One step ground includes other antidiabetic medicines, antihyperglycemic medicine, anti-obesity medicine, drug for hypertension, antiplatelet drug Thing, Antiatherosclerosis medicine, fat-reducing medicament, anti-inflammation drugs or its combination.The antidiabetic medicine can be any Know different from the compounds of this invention other be used for antidiabetic medicine.For example, SGLT-2 inhibitor, biguanides, sulphur Sulfonylurea, alpha-glucosidase inhibitors, PPAR activators, α P2 inhibitor, PPAR α/γ double activator, dipeptide amido peptidase TVs (DPP-IV) inhibitor, glinides, insulin, glucagon-like-peptide-1 (GLP-1) inhibitor, PTP1B inhibitor, Glycogen phosphorylase inhibitors or Robison ester enzyme inhibitor.
When can be used to treat, the compounds of this invention of therapeutically effective amount, especially formula (I) or formula (II) compound and its Pharmaceutically acceptable salt can be given as unprocessed chemicals, and the active component for being alternatively arranged as pharmaceutical composition is provided. Therefore, the pharmaceutical composition that present invention is provided includes the compounds of this invention of therapeutically effective amount, especially formula (I) or formula (II) compound or its pharmaceutically acceptable salt and one or more pharmaceutically acceptable carrier, diluent or excipient. Term as used herein " therapeutically effective amount " refers to and be enough to show that significant patient benefit's (such as blood sugar reduction) is each The total amount of active component.When being administered alone using single active component, the term only refers to the composition.When combination application, No matter the term then refers to combination, is sequentially or simultaneously administered, all cause the combined amount of the active component of therapeutic effect.The present invention Compound, especially formula (I) or formula (II) compound and its pharmaceutically acceptable salt are as described above.From with preparation other compositions For in the sense that compatible and harmless to its recipient, carrier, diluent or excipient must be acceptable.According to this The another aspect of bright content, also provides the method for preparing pharmaceutical preparation, and the method is included the compounds of this invention, especially Formula (I) or formula (II) compound or its pharmaceutically acceptable salt and one or more pharmaceutically acceptable carrier, diluent Or excipient is mixed.Term " pharmaceutically acceptable " used in the present invention refers to such compound, raw material, composition And/or formulation, they rational medicine judge in the range of, it is adaptable to patient tissue contacts and without excessive toxicity, excitant, Allergy or the other problemses symmetrical with rational interests/Hazard ratio and complication, and effective for given application.
When present invention composition comprising present invention compound and one or more other treatment medicine or During the combination of prophylactic agent, the dosage level of compound and other medicine accounts for normal administration generally in monotherapy scheme The about 10-150% of dosage, more preferably accounts for the about 10-80% of normal dosage.Pharmaceutical preparation is suitable to by any suitable way Footpath is administered, for example by oral (including oral cavity or sublingual), rectum, nose, locally (including oral cavity, sublingual or percutaneous), vagina or Parenteral (including in subcutaneous, intracutaneous, intramuscular, joint, in intrasynovial, breastbone, in intrathecal, focus, the bet of intravenous or corium Penetrate or be transfused) approach.This kind of preparation can be prepared by any known method of art of pharmacy, for example, be passed through active component and load Body or excipient mixing.It is preferred that being administered orally or drug administration by injection.
For easily being provided in a unit using the pharmaceutical composition of the compounds of this invention and being led to Cross any method well-known in the art to prepare.All methods include making active component and constitute one or more auxiliary element Carrier the step of combine.Generally, pharmaceutical composition is prepared by the following method：Active component is made with liquid carrier or in small, broken bits Solid-state carrier or both combine equably and nearly, then, if it is desired, the preparation required for being formed the product. In pharmaceutical composition, the Active Target Compounds comprising enough amounts produce desired effect with the process to disease or situation Really.
Pharmaceutical composition containing active component can be adapted for oral form, for example, as tablet, lozenge, sugared agent, Water slurry or oil suspension, dispersible pulvis or granule, emulsion, hard capsule or syrup or elixir.It is intended for mouth The composition that uses of clothes can according to known to pharmaceutical composition production field any method and prepare.Such composition can Comprising one or more reagent selected from sweetener, flavoring agent, colouring agent and preservative, it is therefore an objective to provide pharmaceutically graceful sum Good to eat preparation.
Tablet includes the activity mixed with other the atoxic pharmaceutically acceptable excipient for being suitable to manufacture tablet Composition.These excipient can be, for example, inert diluent, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate；? Granula and disintegrant, such as cornstarch or alginic acid；Adhesive, such as starch, gelatin or Arabic gum；And lubricant, such as stearic Sour magnesium, stearic acid or talcum.Tablet can be uncoated, or they can be coated with by known technology and be delayed in the gastrointestinal tract Disintegration and absorption and thereby provide the long period continuous action.For example, can be hard using such as glycerin monostearate or two The time delay material of glycerol.They can also pass through the skill described in U.S. Patent number 4256108,4160452 and 4265874 Art and be coated with the osmotic therapeutic tablets to be formed for control release.
Formulations for oral use is alternatively arranged as hard gelatin capsule and provides, wherein active component and such as calcium carbonate, Calcium phosphate or the mixing of kaolinic inert solid diluent；Or provide as Perle, wherein active component and water or The oil medium mixing of such as peanut oil, liquid paraffin or olive oil.
Water slurry includes the active material mixed with the excipient for being suitable to manufacture water slurry.Such excipient is outstanding Floating agent, such as sodium carboxymethylcellulose, methylcellulose, hydroxyl-propyl methylcellulose, sodium alginate, polyethylene-pyrrolidines Ketone, bassora gum and gum arabic；Dispersant or wetting agent can be naturally occurring phosphatide, such as lecithin, or alkylene oxide With the condensation product such as polyoxyethylene stearic acid ester of aliphatic acid, or oxirane and long-chain fatty alcohol such as 17 ethyleneoxies 16 The condensation product of alcohol, or the condensation product such as polyoxyethylene sorbitol list of oxirane and the partial ester for deriving from aliphatic acid and hexitol Oleate, or oxirane is oily with the condensation product such as polyethylene sorbitan list of the partial ester for deriving from aliphatic acid and hexitan Acid esters.The water slurry can also include one or more preservative (such as ethyl-para-hydroxybenzoate or P-hydroxybenzoic acid just Propyl ester), one or more colouring agent, one or more flavoring agent and one or more sweetener (such as sucrose or saccharin).
Oil suspension can be by active component to be suspended in the plant of such as peanut oil, olive oil, sesame oil or coconut oil Prepare in oil or in the mineral oil of such as atoleine.Oil suspension can include thickener, such as beeswax, hard paraffin or spermaceti Alcohol.Those sweeteners such as set forth above and flavoring agent can be added to provide good to eat oral formulations.These compositions can By adding the antioxidant of such as ascorbic acid come anti-corrosion.
The dispersible pulvis or granule for being suitable to prepare water slurry by adding water is provided and dispersant or moistening The active component of agent, suspending agent and one or more preservative mixing.Suitable dispersant or wetting agent and suspending agent pass through Those already mentioned above carry out exemplary illustration.Also there may be other excipient, such as sweetener, flavoring agent and colouring agent.
The pharmaceutical composition of the present invention can be in the form of oil in water emulsion.Oil phase can be such as olive oil or peanut oil Vegetable oil or such as atoleine mineral oil or these mixture.Suitable emulsifying agent can be naturally occurring tree Glue, such as gum arabic or bassora gum；Naturally occurring phosphatide, such as soybean, lecithin and derives from aliphatic acid and hexitan Ester or partial ester, such as Arlacel-80；And the condensation product of the partial ester and oxirane, such as polyethylene dehydration Sorbitol monooleate.Emulsion may also include sweetener and flavoring agent.
Syrup and elixir can be prepared together with the sweetener of such as glycerine, propane diols, sorbierite or sucrose.Such preparation Moderator, preservative and flavoring agent and colouring agent can also be included.
Pharmaceutical composition can be in the form of the water slurry of sterile injectable or oil suspension.The suspension can be according to known Technology, prepared using suitable dispersant already mentioned above or wetting agent and suspending agent.The system of the sterile injectable Agent can also be the solution or suspension of the sterile injectable in nontoxic, the acceptable diluent of parenteral or solvent, example As the solution in 1,3 butylene glycol.Spendable acceptable medium and solvent are water, Ringer's mixture and isotonic Sodium chloride solution.Additionally, aseptic fixing oil is traditionally used as solvent or suspension media.Therefore, can use any gentle Fixing oil, including the monoglyceride or two glyceride of synthesis.Additionally, the aliphatic acid of such as oleic acid is in the preparation of injectable drug Find purposes.
Pharmaceutical composition can be also used for the suppository form of the rectal administration of medicine or enema.These compositions can pass through Medicine is mixed with suitably nonirritant excipient and is prepared, the nonirritant excipient be at normal temperatures solid but It is liquid under rectal temperature and thereby will melts in the rectum to discharge medicine.Such material includes, for example, cupu oil and Polyethylene glycol.
For local uses, using comprising the ointment of the compounds of this invention, cream, supensoid agent, lotion, powder, molten Liquor, paste, gel, spray, aerosol, oil formulation or transdermal patch.As used herein topical application is alsoed attempt to Including mouthwash and the purposes of mouth-wash.
The pharmaceutical composition and method of the present invention may also include, bright as referred to herein, can be used to treat following disease The compound of other treatment activity：Type ii diabetes, obesity, hyperglycemia, GI, insulin resistance, high pancreas Island element mass formed by blood stasis, hypercholesterolemia, hypertension, hyperlipoprotememia, hyperlipidemia, HTC, dyslipidemia, Metabolic syndrome, X syndrome, angiocardiopathy, atherosclerotic, kidney trouble, DKA, thrombotic disorder, kidney Disease, diabetic neuropathy, diabetic retinopathy, sex dysfunction, skin disease, indigestion, hypoglycemia, cancer and Oedema.
Treating or preventing type ii diabetes, obesity, hyperglycemia, GI, insulin resistance, high pancreas islet Plain mass formed by blood stasis, hypercholesterolemia, hypertension, hyperlipoprotememia, hyperlipidemia, HTC, dyslipidemia, generation Thank syndrome, X syndrome, angiocardiopathy, atherosclerotic, kidney trouble, DKA, thrombotic disorder, ephrosis, Diabetic neuropathy, diabetic retinopathy, sex dysfunction, skin disease, indigestion, hypoglycemia, cancer and water In swollen or other situations related to GPR40 or illness, suitable dosage level is typically about 0.001 to 100mg per kg patient Daily, which can be applied body weight with single dose or multiple dose.Preferably, dosage level for about 0.01 is daily to about 25mg/kg；More excellent Selection of land, about 0.05 is daily to about 10mg/kg.Suitable dosage level can be about 0.01 to 25mg/kg daily, about 0.05 to 0.1 to 5mg/kg is daily daily or about for 10mg/kg.Within the range, dosage can be 0.005 to 0.05,0.05 to 0.5 or 0.5 to 5.0mg/kg is daily.For Orally administered, composition is preferably provided in form of tablets, the tablet comprising 1.0 to 1000 milligrams of active components, particularly 1.0,3.0,5.0,10.0,15.0,20.0,25.0,50.0,75.0,100.0,150.0, 200.0th, 250.0,300.0,400.0,500.0,600.0,750.0,800.0,900.0 and 1000.0 milligrams of active components, use Adjust in the symptom of the dosage to patient to be treated.Compound can daily 1 to 4 time therapeutic scheme apply, preferably daily Once or twice daily.
It will be appreciated, however, that can change for the concrete dosage level and administration frequency of any particular patient, and will take Certainly in many factors, the activity of the particular compound including using, the metabolic stability of the compound and effect duration, the age, Body weight, general health, sex, diet, mode of administration and time, rate of discharge, drug regimen, the seriousness of particular condition and just Through treated host.
The compounds of this invention can with other pharmaceutical agent combinations or be applied in combination, other medicaments described can be used to treat, prevent, press down System improves the compounds of this invention to its useful disease or situation, including type ii diabetes, obesity, hyperglycemia, glucose Intolerance, insulin resistance, hyperinsulinemia, hypercholesterolemia, hypertension, hyperlipoprotememia, hyperlipidemia, height Triglyceride mass formed by blood stasis, dyslipidemia, metabolic syndrome, X syndrome, angiocardiopathy, atherosclerotic, kidney trouble, DKA, thrombotic disorder, ephrosis, diabetic neuropathy, diabetic retinopathy, sex dysfunction, skin disease, Indigestion, hypoglycemia, cancer and oedema, the disease mediated by GPR40 or situation.Other medicaments such or medicine can lead to Cross the approach that is usually used and with the amount that is usually used so as to simultaneously, sequentially or dividually applying with the compounds of this invention. When using the compounds of this invention and one or more other drugs same period, except the compounds of this invention, preferably comprise such The pharmaceutical composition of other drugs.Therefore, pharmaceutical composition of the invention include except the compounds of this invention also comprising a kind of or Multiple other active components or the pharmaceutical composition of therapeutic agent.
Can combine with the compounds of this invention, separate administration or the other therapeutic agents that applies in the identical pharmaceutical composition Example includes, but are not limited to：(a) cholesterol-lowering agent, such as HMG-CoA reductase inhibitor (for example, Lovastatin, Simvastatin, Pravastatin, Fluvastatin, Atorvastatin and other statinses), bile acid sequestrant (for example, Cholestyramine and examines Come for pool), Cobastab3(also known as niacin or nicotinic acid), Cobastab6(VB6), Cobastab12(cyanocobalamin), fine Dimension acid derivative (such as Gemfibrozil, Clofibrate, fenofibrate and Bezafibrate), probucol, monobel and courage are solid Alcohol absorption inhibitor (for example, cupreol and acyl-CoA-cholesterol acyltransferase (ACAT) inhibitor such as first Asia oleoyl Amine), HMG-CoA synthase inhibitors, squalene epoxidase inhibitor and squalene synthetase inhibitor；B () antithrombotic, such as thrombus are molten Solution agent (for example, streptokinase, Alteplase, Anistreplase and Reteplase), heparin, hirudin and warfarin derivative, β-resistance Disconnected agent (for example, atenolol), beta-adrenergic excitomotor (for example, isoprel), Vel-Tyr-Pro-Trp-Thr-Gln-Arg-Phe and blood vessel dilatation Agent (for example, sodium nitroprussiate, Licardipine Hydrochloride, monobel and enalaprilat)；(c) antidiabetic, such as insulin and Para-insulin drugs with function, sulfonylureas (for example, glibenclamide, meglinatide), biguanides such as melbineAlpha-glucosidase inhibitor (acarbose), insulin sensitizers such as thiazolidone (thiazolidinone) compound, RosiglitazoneTroglitazoneCiglitazone, PioglitazoneAnd Englitazone, DPP-IV inhibitor such as vildagliptin (vildagliptin)Its row spit of fland of west (sitagliptin) (JanuviaTM) and GLP-1 analogs such as Exenatide (exenatide)In some realities Apply in scheme, the compounds of this invention can be applied together with DPP-IV inhibitor or GLP-1 analogs.In certain embodiments, The compounds of this invention is applied with any DPP-IV inhibitor proposed in U.S. Patent Publication the 2006/0270701st, the U.S. State patent disclosure here is integrally incorporated with which and for all purposes as especially set out in this paper by quoting.
The weight ratio of the compounds of this invention and the second active component can change and will depend on the effective dose of every kind of composition. Generally, will be using every kind of effective dose.The compounds of this invention and other active components combine generally will also in aforementioned range, But the effective dose of every kind of active component in each case, should be used.
The compounds of this invention and the purposes of pharmaceutical composition
The invention provides the purposes in medicine is prepared of compound or pharmaceutical composition of the present invention, the medicine can For adjusting G- G-protein linked receptors, the G- G-protein linked receptors are preferably GPR40 acceptors.
Comprising the treatment method that the compounds of this invention or pharmaceutical composition are administered, further include to patient to other GPR40 conditioning agents, SGLT-2 inhibitor, biguanides, sulfonylureas, alpha-glucosidase inhibitors, PPAR activators, α The double activator of P2 inhibitor, PPAR α/γ, dipeptide amido peptidase TV (DPP-IV) inhibitor, glinides, insulin, pancreas are high Blood sugar element sample peptide -1 (GLP-1) inhibitor, PTP1B inhibitor, glycogen phosphorylase inhibitors or Robison ester enzyme level Agent, it is possible thereby to the compound and other GPR40 conditioning agents, SGLT-2 inhibitor, biguanides, sulfonylurea by the present invention Medicine, alpha-glucosidase inhibitors, PPAR activators, α P2 inhibitor, PPAR α/γ double activator, dipeptide amido peptidase TV (DPP- IV) inhibitor, glinides, insulin, glucagon-like-peptide-1 (GLP-1) inhibitor, PTP1B inhibitor, glycogen Phosphorglase inhibitor or Robison ester enzyme inhibitor administering drug combinations.The compounds of this invention or pharmaceutical composition are used as single Formulation, or separate compound or pharmaceutical composition are used as a part for multi-form.Other treatment diabetes medicament can be with this Invention compound is administered simultaneously or is not administered simultaneously.The situation of the latter, administration can stagger carry out as 6 hours, 12 hours, 1 day, Carry out within 2 days, 3 days, 1 week, 2 weeks, 3 weeks, 1 month or 2 months.
The present invention compound or pharmaceutically acceptable composition " effective dose " or " effective dose " refer to process or Mitigate the effective dose that one or more present invention are previously mentioned the severity of illness.The method according to the invention, compound and combination Thing can be any dosage and any method of administration being efficiently used for the order of severity for processing or mitigating disease.Required standard Situation according to patient is changed by true amount, this depend on race, the age, the general condition of patient, the order of severity of infection, Special factor, administering mode, etc..Compound or composition can with one or more other therapeutic agents administering drug combinations, such as The present invention is discussed.
(herein, form of presentation is " formula (I) or formula (II) compound and its stereoisomer, several for the compound of the present invention What isomers, dynamic isomer, mesomer, racemic modification, enantiomter, diastereoisomer, nitrogen oxides, hydration Thing, solvate, metabolite and pharmaceutically acceptable salt and prodrug " may be collectively referred to as the compound of the present invention " "), can be with It is used for preventing, treat, mitigate or delaying diabetes, diabetic retinopathy, diabetic nerve for producing medical product The elevated levels of disease, nephrosis, insulin resistance, hyperglycaemia, hyperinsulinemia, aliphatic acid or glycerine, hyperlipemia Disease, obesity, hypertriglyceridemia, X syndromes, DKA, GI, hypercholesterolemia, blood fat Exception, metabolic syndrome, angiocardiopathy, kidney trouble, thrombotic disorder, ephrosis, sex dysfunction, skin disease, digestion are not Good, hypoglycemia, cancer, oedema, diabetic complication, atherosclerotic or hypertension are used for increasing high density lipoprotein level White level, described in the invention including those.Further, compound of the invention can be used for production regulation GPRs acceptors Product.Thus, compound of the invention can be used for producing a kind of pharmaceuticals for mitigating, prevent, control or treat GPRs The receptor-mediated disease of the illness mediated by acceptor, particularly GPR40.Thus, compound of the invention can serve as medicine group The active component of compound, the pharmaceutical composition can further can also be wrapped including the compound representated by formula (I) or formula (II) Containing at least one pharmaceutically acceptable carrier, excipient, diluent, assistant agent and medium.
General building-up process
Usually, compound of the invention can be prepared by method described in the invention, unless there are further Explanation, wherein shown in the definition of substituent such as formula (I) or formula (II).Following reaction scheme and embodiment are used for further lifting Example explanation present disclosure.
Those skilled in the art will realize that：Chemical reaction described in the invention can be used to suitably prepare perhaps Other compounds of many present invention, and the model in the present invention is considered as preparing other methods of the compound of the present invention Within enclosing.For example, can successfully by those skilled in the art according to the synthesis of the compound of those non-illustrations of the invention Completed by method of modifying, group is disturbed in such as appropriate protection, by using reagent known to other except described in the invention , or reaction condition is made some conventional modifications.In addition, reaction disclosed in this invention or known reaction condition are also generally acknowledged Ground is applied to the preparation of other compounds of the invention.
The embodiments described below, unless shown in terms of other that all of temperature is set to degree Celsius.Reagent is bought in business Product supplier such as Aldrich Chemical Company, Inc., Arco Chemical Company and Alfa Chemical Company, not through being further purified during use, unless shown in terms of other.General reagent is from the western Gansu Province chemical industry in Shantou Imperial chemistry examination is risen by factory, Guangdong brilliance chemical reagent factory, Guangzhou Chemical Reagent Factory, Tianjin Hao Yuyu Chemical Companies, Qingdao Agent Co., Ltd, and Haiyang Chemical Plant, Qingdao is commercially available.
Anhydrous tetrahydro furan, dioxane, toluene, ether are dried to obtain through metallic sodium backflow.Anhydrous methylene chloride It is to be dried to obtain through calcium hydride backflow with chloroform.Ethyl acetate, petroleum ether, n-hexane, DMAC N,N' dimethyl acetamide and N, N- Dimethylformamide is to dry in advance to use through anhydrous sodium sulfate.
Hereinafter reaction is usually to cover a drying tube under nitrogen or argon gas positive pressure or on anhydrous solvent (unless in terms of other Show), reaction bulb all suitable rubber stoppers beyond the Great Wall, substrate are squeezed into by syringe.Glassware is all dried.
Chromatographic column is to use silicagel column.Silica gel (300-400 mesh) is purchased from Haiyang Chemical Plant, Qingdao.NMR spectrum with CDC13、DMSO-d6、CD3OD or acetone-d6(report in units of ppm) for solvent, with TMS (0ppm) or chloroform (7.25ppm) As reference standard.When there is multiplet, following abbreviation will be used：S (singlet, unimodal), d (doublet, double Peak), and t (triplet, triplet), q (quartet, quartet), m (multiplet, multiplet), br (broadened, wide Peak), dd (doublet of doublets, two are bimodal), dt (doublet of triplets, double triplets).Coupling is often Number, is represented with hertz (Hz).
By outfit G1312A binary pumps and a G1316A TCC, (column temperature is maintained at 30 to Algorithm (MS) data DEG C) Agilent6320 series LC-MS spectrometer determining, G1329A automatic samplers and G1315B DAD detectors It is applied to analyze, ESI sources are applied to LC-MS spectrometers.
Algorithm (MS) data are by being equipped with G1311A quaternary pumps and G1316A TCC (column temperature is maintained at 30 DEG C) Agilent 6120 series LC-MS spectrometer determining, G1329A automatic samplers and G1315D DAD detectors should For analyzing, ESI sources are applied to LC-MS spectrometers.
Both the above spectrometer is provided with Agilent Zorbax SB-C18 posts, and specification is 2.1 × 30mm, 5 μm.Note Beam product is determined by sample concentration；Flow velocity is 0.6mL/min；The peak value of HPLC is by 210nm and 254nm UV-Vis wavelength is recording reading.Mobile phase be 0.1% formic acid acetonitrile solution (phase A) and 0.1% formic acid ultrapure water-soluble Liquid (phase B).Condition of gradient elution is as shown in table 1：
Table 1
Time (min) A(CH3CN, 0.1%HCOOH) B(H2O, 0.1%HCOOH)
0-3 5-100 95-0
3-6 100 0
6-6.1 100-5 0-95
6.1-8 5 95
Compound purifying is evaluated by 1100 series of high efficiency liquid chromatograies (HPLC) of Agilent, and wherein UV is detected At 210nm and 254nm, Zorbax SB-C18 posts, specification are 2.1 × 30mm, and 4 μm, 10 minutes, flow velocity was 0.6mL/min, (0.1% aqueous formic acid) of (0.1% formic acid acetonitrile solution) of 5-95%, column temperature is maintained at 40 DEG C.
The use of brief word below is through the present invention：
G gram
Mg milligrams
Mmol mM
Ml, mL milliliter
L liters
DEG C degree Celsius
11 NMR spectrum of H NMR hydrogen
13C NMR carbon-13 magnetic resonance wave spectrums
MS mass spectrums
MHz megahertz
Hz hertz
DMSO-d6Deuterated dimethyl sulfoxide
CDCl3Deuterochloroform
Pos.ion cations
Neg.ion anions
ESI electron spray ionisations
M/z mass-charge ratios
Synthetic method
Compound I can be obtained by synthetic method.Wherein A, R1、R2Definition with n is as described herein；W is alkyl；Q is Leaving group.
In the solvent to reactionlessness (such as dimethyl sulfoxide etc.) is obtained compound I' with the compound ii with cyclic amino Arrive compound III；Compound III is in the presence of reducing agent (such as sodium borohydride etc.) (such as first in the solvent to reactionlessness Alcohol, tetrahydrofuran and their mixed solvent etc.) obtain compound IV；Compounds Ⅳ is not being had with halogenating agent (such as phosphorus trichloride etc.) Have under solvent or under the solvent to reactionlessness (such as N,N-dimethylformamide etc.) or anti-as solvent with excess halogenating agent Compound V should be obtained；Or compounds Ⅳ and sulfonyl agent (such as mesyl chloride p-methyl benzene sulfonic chloride etc.) are to reactionlessness In solvent (such as N,N-dimethylformamide etc.) and in the presence of alkali (such as potassium carbonate etc.) reaction obtain compound V；Compound V It is being inert solvent (such as N, N- dimethyl at (such as potassium carbonate, potassium phosphate etc.) in the basic conditions to reaction with compound VI Formamide etc.) in reaction obtain compound VII；Compound VII under alkaline conditions (such as lithium hydroxide, NaOH etc.) to anti- At once the reaction that is hydrolyzed in inert solvent (such as methyl alcohol, tetrahydrofuran, water and their mixed solvent etc.) obtains compound I
The synthesis of intermediate
2', 6'- dimethyl -4'- ((carbobenzoxy) amino)-[1,1'- biphenyl] -3- methyl formates
The first step) 4'- amino -2', 6'- dimethyl-[1,1'- biphenyl] -3- methyl formates
By bromo- for 4- 3,5- dimethylanilines (1g, 10mmol), (3- (methoxycarbonyl group) phenyl) boric acid (2.7g, 15mmol), Potassium carbonate (4.14g, 30mmol), [1,1'- double (diphenylphosphine) ferrocene] palladium chloride dichloromethane complex (0.37g, 0.5mmol) it is dissolved in DMF (30mL) and water (10mL), stirring reaction 1 hour at 90 DEG C.Reactant liquor is cold But be extracted with ethyl acetate (200mL × 2) after water (30mL) dilution being added to room temperature, merge organic phase, use saturated sodium-chloride Solution washs (50mL), anhydrous sodium sulfate drying, filters, reduced pressure concentration filtrate.Residue silica gel chromatography (oil Ether:Ethyl acetate=4:1) (2.1g, yield is 82%), to obtain faint yellow solid shape title compound.
MS(ESI,pos.ion)m/z:256.1[M+H]+.
Second step) 2', 6'- dimethyl -4'- ((carbobenzoxy) amino)-[1,1'- biphenyl] -3- methyl formates
By 4'- amino -2', 6'- dimethyl-[1,1'- biphenyl] -3- methyl formates (5g, 19.6mmol) and pyridine (3.2mL, 40mmol) is dissolved in dichloromethane (50mL), adds phenyl chloroformate (3.7mL, 29mmol) to rise naturally under ice bath afterwards To room temperature reaction 7 hours.Reactant liquor salt adding aqueous acid is quenched (10mL, 1M), and dichloromethane extracts (50mL), and organic phase is used full (30mL) is washed with sodium chloride solution, anhydrous sodium sulfate drying is filtered, and it is titled that reduced pressure concentration filtrate obtains faint yellow solid shape (7.35g, yield is 100%) for compound.
MS(ESI,pos.ion)m/z:376.2[M+H]+.
Embodiment 1
(((2', 6'- dimethyl -4'- (5- (methyl sulphonyl) indoline -1- formamidos)-[1,1'- joins 6- 2- Benzene] -3- bases) methoxyl group) -2,3- Dihydrobenzofuranes -3- bases) acetic acid
The first step) 5- (methyl sulphonyl) indoline
By 5- bromine indoline (1g, 5.05mmol), L-PROLINE sodium salt (139mg, 1.0mmol), cuprous iodide (96mg, 0.50mmol) and methyl sulfinic acid sodium (618mg, 6.05mmol) are dissolved in dimethyl sulfoxide (10mL), are stirred at 95 DEG C Mix 24 hours.Reactant liquor extracts (50mL × 2) with dichloromethane after adding water (50mL) to be quenched after being cooled to room temperature, merges organic Phase, is washed with saturated nacl aqueous solution (30mL), anhydrous sodium sulfate drying, is filtered, and reduced pressure concentration filtrate obtains yellow solid (0.99g, yield is 99.4%) for title compound.
Second step) 2', 6'- dimethyl -4'- (5- (methyl sulphonyl) indoline -1- formamidos)-[1,1'- joins Benzene] -3- methyl formates
By 5- (methyl sulphonyl) indoline (410mg, 2.1mmol) and 2', 6'- dimethyl -4'- ((benzene oxygen formyls Base) amino)-[1,1'- biphenyl] -3- methyl formates (0.94g, 2.5mmol) molten dimethyl sulfoxide (10mL) in, at 85 DEG C stir Overnight.Reactant liquor adds water (50mL) to be extracted with ethyl acetate (50mL × 2) after being quenched, and merges organic phase, uses saturated sodium-chloride Solution washs (30mL), anhydrous sodium sulfate drying, filters, reduced pressure concentration filtrate.Residue silica gel chromatography (oil Ether:Ethyl acetate=2:1) (0.87g, yield is 87%), to obtain yellow solid title compound.
MS(ESI,pos.ion)m/z:479.2[M+H]+.
3rd step) N- (3'- (methylol) -2,6- dimethyl-[1,1'- biphenyl] -4- bases) -5- (methyl sulphonyl) dihydro Indoles -1- formamides
By 2', 6'- dimethyl -4'- (5- (methyl sulphonyl) indoline -1- formamidos)-[1,1'- biphenyl] -3- Methyl formate (460mg, 0.96mmol) is dissolved in ethanol (10mL) and water (10mL), under ice bath add sodium borohydride (344mg, 9.6mmol), back flow reaction 1 hour after finishing rear reactant liquor room temperature reaction overnight.Dichloromethane extracts reactant liquor washing (50mL) afterwards Take (100mL × 2), merge organic phase, washed with saturated nacl aqueous solution (30mL), anhydrous sodium sulfate drying, filter, reduce pressure dense Contracting filtrate.Residue silica gel chromatography (dichloromethane:Methyl alcohol=50:1), yellowish solid-like title compound is obtained (100mg, yield is 20%).
4th step) N- (3'- (chloromethyl) -2,6- dimethyl-[1,1'- biphenyl] -4- bases) -5- (methyl sulphonyl) dihydro Indoles -1- formamides
By N- (3'- (methylol) -2,6- dimethyl-[1,1'- biphenyl] -4- bases) -5- (methyl sulphonyl) indoline - 1- formamides (100mg, 0.22mmol) and triethylamine (0.06mL, 0.4mmol) are dissolved in dichloromethane (3mL), add methyl After sulfonic acid chloride (0.02mL, 0.3mmol) in 0 DEG C of reaction overnight.Reactant liquor is diluted with water (30mL), and dichloromethane is extracted (30mL), organic phase saturated nacl aqueous solution is washed (30mL), anhydrous sodium sulfate drying, is filtered, reduced pressure concentration filtrate.Residual Thing silica gel chromatography (petroleum ether:Ethyl acetate=2:1), white solid title compound (45mg, yield are obtained 43%).
MS(ESI,pos.ion)m/z:469.1[M+H]+.
5th step) and 2- (6- ((2', 6'- dimethyl -4'- (5- (methyl sulphonyl) indoline -1- formamidos)-[1, 1'- xenyls] -3- bases) methoxyl group) -2,3- Dihydrobenzofuranes -3- bases) methyl acetate
By N- (3'- (methylol) -2,6- dimethyl-[1,1'- biphenyl] -4- bases) -5- (methyl sulphonyl) indoline - 1- formamides (45mg, 0.1mmol), 2- (6- hydroxyl -2,3- Dihydrobenzofuranes -3- bases) methyl acetate (24mg, 0.12mmol) it is dissolved in DMF (4mL) with potassium phosphate (30mg, 0.1mmol), is warming up to 70 DEG C and reacted Night.Reactant liquor is quenched with water, and ethyl acetate extracts (20mL × 2), merges organic phase, is washed with saturated nacl aqueous solution (10mL), anhydrous sodium sulfate drying, filters, reduced pressure concentration filtrate.Residue silica gel chromatography (petroleum ether:Acetic acid second Ester=1:1) (58mg, yield is 94%), to obtain title compound as yellow oil.
MS(ESI,pos.ion)m/z:641.2[M+H]+.
6th step) and 2- (6- ((2', 6'- dimethyl -4'- (5- (methyl sulphonyl) indoline -1- formamidos)-[1, 1'- biphenyl] -3- bases) methoxyl group) -2,3- Dihydrobenzofuranes -3- bases) acetic acid
By 2-, (((2', 6'- dimethyl -4'- (5- (methyl sulphonyl) indoline -1- formamidos)-[1,1'- joins 6- Phenyl] -3- bases) methoxyl group) -2,3- Dihydrobenzofuranes -3- bases) methyl acetate (58mg, 0.09mmol) is dissolved in tetrahydrofuran (1mL), in, 2 hours are stirred at room temperature after adding lithium hydroxide aqueous solution (1mL, 1M).Reactant liquor uses salt after adding water (5mL) dilution Sour (2mL, 1M) acidifying, and extracted with ethyl acetate (10mL × 2), merge organic phase, washed with saturated nacl aqueous solution (10mL), anhydrous sodium sulfate drying, filters, and reduced pressure concentration filtrate obtains titled compound as white solid, and (20mg, yield is 40%).
MS(ESI,neg.ion)m/z:625.2[M-H]-；
1H NMR(400MHz,CDCl3) δ 8.19 (d, J=8.6Hz, 1H), 7.85 7.71 (m, 2H), 7.50 7.37 (m, 2H), 7.20 (d, J=14.0Hz, 3H), 7.09 (dd, J=11.6,7.7Hz, 2H), 6.57 6.44 (m, 3H), 5.09 (s, 2H), 4.78 (t, J=9.1Hz, 1H), 4.31 (dd, J=9.2,6.1Hz, 1H), 4.21 (t, J=8.6Hz, 2H), 3.86 3.80 (m, 1H), 3.37 (dd, J=16.7,8.3Hz, 2H), 3.06 (s, 3H), 2.82 (dd, J=16.9,5.3Hz, 1H), 2.63 (dd, J=16.7,9.2Hz, 1H), 2.03 (s, 6H).
Embodiment 2
2- ((S) -6- ((2', 6'- dimethyl -4'- ((R) 3- ((methyl sulphonyl) methyl) pyrrolidines -1- formamides Base)-[1,1'- biphenyl] -3- bases) methoxyl group) -2,3- Dihydrobenzofuranes -3- bases) acetic acid
The first step) (R) -3- (methylol) pyrrolidines -1- benzyl formates
(R)-pyrrolidin-3-yl methyl alcohol (2g, 19.77mmol) and sodium acid carbonate (3.3g, 39mmol) are dissolved in acetic acid second Benzyl chloroformate (4.24mL) is added in ester (20mL) and water (20mL) under room temperature.Reactant liquor was in room temperature reaction 5 hours.Reactant liquor Be extracted with ethyl acetate (40mL × 2) after water dilution (20mL), merge organic phase, (50mL) is washed with saturated nacl aqueous solution, Anhydrous sodium sulfate drying, filters, reduced pressure concentration filtrate.Residue silica gel chromatography (petroleum ether:Ethyl acetate=2: 1) (1.64g, yield is 35.2%), to obtain colorless oil title compound.
Second step) (R) -3- (((methyl sulphonyl) oxo) methyl) pyrrolidines -1- benzyl formates
By (R) -3- (methylol) pyrrolidines -1- benzyl formates (1.64g, 6.97mmol) and triethylamine (1.2mL, 8.5mmol) it is dissolved in dichloromethane (20mL), adds after methylsufonyl chloride (0.66mL, 8.4mmol) in room temperature reaction 1 hour. Reactant liquor is diluted with water (30mL), and dichloromethane extracts (30mL), and organic phase saturated nacl aqueous solution is washed (30mL), anhydrous Sodium sulphate is dried, and is filtered, reduced pressure concentration filtrate.Residue silica gel chromatography (petroleum ether:Ethyl acetate=4:1), obtain To colorless oil title compound, (2.1g, yield is 96%).
3rd step) (R) -3- ((methyl mercapto) methyl) pyrrolidines -1- benzyl formates
(R) -3- (((methyl sulphonyl) oxo) methyl) pyrrolidines -1- benzyl formates (2.1g, 6.7mmol) are dissolved in first In alcohol (4mL), 60 DEG C of reactions are warming up to after adding sodium methyl mercaptide (2.8g, 40mmol) overnight.Reactant liquor is quenched with water, acetic acid second Ester extracts (20mL × 2), merges organic phase, is washed with saturated nacl aqueous solution (10mL), anhydrous sodium sulfate drying, filters, subtracts Pressure concentration filtrate.Residue silica gel chromatography (petroleum ether:Ethyl acetate=20:1) it is titled that, faint yellow oily is obtained (1.68g, yield is 94%) for compound.
4th step) (R) -3- ((methyl sulphonyl) methyl) pyrrolidines -1- benzyl formates
(R) -3- ((methyl mercapto) methyl) pyrrolidines -1- benzyl formates (1.68g, 6.33mmol) are dissolved in methyl alcohol (50mL) In, room temperature adds potassium hydrogen persulfate (6g, 9.5mmol), and room temperature reaction is overnight afterwards.Reacting liquid filtering, filtrate wash (50mL), second Acetoacetic ester extracts (100mL × 2), merges organic phase, washs (20mL), anhydrous sodium sulfate drying, mistake with saturated nacl aqueous solution Filter, reduced pressure concentration filtrate.Residue silica gel chromatography (dichloromethane:Methyl alcohol=50:1), white solid mark is obtained (1.5g, yield is 80%) for topic compound.
5th step) (R) -3- ((methyl sulphonyl) methyl) pyrroles
(R) -3- ((methyl sulphonyl) methyl) pyrrolidines -1- benzyl formates (1.5g, 5mmol) are dissolved in ethanol (25mL) In, room temperature adds 10% palladium carbon (0.3g), and room temperature reaction is overnight in atmosphere of hydrogen afterwards.Reacting liquid filtering, reduced pressure concentration filtrate.Residual Thing is stayed to be directly used in next step reaction.
6th step) (R) -2', 6'- dimethyl -4'- (3- ((methyl sulphonyl) methyl) pyrrolidines -1- formamidos) - [1,1'- biphenyl] -3- methyl formates
By (R) -3- ((methyl sulphonyl) methyl) pyrroles (365mg, 2.24mmol) and 2', 6'- dimethyl -4'- ((benzene Oxygen carbonyl) amino)-[1,1'- biphenyl] -3- methyl formates (700mg, 1.86mmol) is dissolved in dimethyl sulfoxide (10mL), 80 It is stirred overnight at DEG C.Reactant liquor adds water (50mL) to be extracted with ethyl acetate (50mL × 2) after being quenched, and merges organic phase, with full (30mL) is washed with sodium chloride solution, anhydrous sodium sulfate drying is filtered, reduced pressure concentration filtrate.Residue is pure with silica gel column chromatography Change (petroleum ether:Ethyl acetate=1:1) (566mg, yield is 68%), to obtain yellow solid title compound.
7th step) (R)-N- (3'- (methylol) -2,6- dimethyl-[1,1'- biphenyl] -4- bases) -3- ((sulfonyloxy methyls Base) methyl) pyrrolidines -1- formamides
By (R) -2', 6'- dimethyl -4'- (3- ((methyl sulphonyl) methyl) pyrrolidines -1- formamidos)-[1,1'- Biphenyl] -3- methyl formates (1g, 2.25mmol) are dissolved in ethanol (30mL) and water (15mL), add sodium borohydride under ice bath (860mg, 22.6mmol), after finishing rear reactant liquor room temperature reaction overnight, back flow reaction 1 hour.After reactant liquor washing (50mL) Dichloromethane extracts (100mL × 2), merges organic phase, is washed with saturated nacl aqueous solution (30mL), anhydrous sodium sulfate drying, Filter, reduced pressure concentration filtrate.Residue silica gel chromatography (dichloromethane:Methyl alcohol=50:1), white solid is obtained (376mg, yield is 59.6%) for title compound.
8th step) (R)-(2', 6'- dimethyl -4'- (3- ((methyl sulphonyl) methyl) pyrrolidines -1- formamidos) - [1,1'- biphenyl] -3- bases) methyl mesylate
By (R)-N- (3'- (methylol) -2,6- dimethyl-[1,1'- biphenyl] -4- bases) -3- ((methyl sulphonyl) first Base) pyrrolidines -1- formamides (0.55g, 1.32mmol) and triethylamine (0.22mL, 1.6mmol) be dissolved in dichloromethane (30mL) In, mesyl chloride (0.125mL, 1.58mmol) room temperature reaction 1 hour afterwards is added dropwise under ice bath.Reactant liquor adds water and (30mL) is quenched, Dichloromethane extracts (30mL), and organic phase saturated nacl aqueous solution is washed (30mL), anhydrous sodium sulfate drying, filters, decompression Concentration filtrate.Residue silica gel chromatography (dichloromethane:Methyl alcohol=50:1), white solid title compound is obtained (400mg, yield is 61.3%).
9th step) 2- ((S) -6- ((2', 6'- dimethyl -4'- ((R) -3- ((methyl sulphonyl) methyl) pyrrolidines -1- Formamido)-[1,1'- xenyls] -3- bases) methoxyl group) -2,3- Dihydrobenzofuranes -3- bases) methyl acetate
By (R)-(2', 6'- dimethyl -4'- (3- ((methyl sulphonyl) methyl) pyrrolidines -1- formamidos)-[1,1'- Biphenyl] -3- bases) methyl mesylate (0.4g, 0.81mmol), (S) -2- (6- hydroxyl -2,3- Dihydrobenzofuranes -3- bases) acetic acid Methyl esters (120mg, 0.58mmol) and potassium carbonate (250mg, 1.81mmol) are dissolved in DMF (10mL), are heated up To 80 DEG C of reactions overnight.Reactant liquor is quenched with water, and ethyl acetate extracts (20mL × 2), merges organic phase, molten with saturated sodium-chloride Liquid washs (10mL), anhydrous sodium sulfate drying, filters, reduced pressure concentration filtrate.Residue silica gel chromatography (petroleum ether: Ethyl acetate=1:1) (260mg, yield is 74.4%), to obtain faint yellow title compound as oil.
MS(ESI,pos.ion)m/z:607.3[M+H]+.
Tenth step) 2- ((S) -6- ((2', 6'- dimethyl -4'- ((R) -3- ((methyl sulphonyl) methyl) pyrrolidines -1- Formamido)-[1,1'- biphenyl] -3- bases) methoxyl group) -2,3- Dihydrobenzofuranes -3- bases) acetic acid
By 2- ((S) -6- ((2', 6'- dimethyl -4'- ((R) -3- ((methyl sulphonyl) methyl) pyrrolidines -1- formamides Base)-[1,1'- xenyls] -3- bases) methoxyl group) -2,3- Dihydrobenzofuranes -3- bases) methyl acetate (260mg, 0.43mmol) It is dissolved in tetrahydrofuran (4.5mL), after adding lithium hydroxide aqueous solution (4.5mL, 1M), is stirred at room temperature 2 hours.Reactant liquor is added It is acidified with hydrochloric acid (8mL, 1M) after water (5mL) dilution, and is extracted with ethyl acetate (10mL × 2), is merged organic phase, use saturation chlorine Change sodium solution washing (10mL), anhydrous sodium sulfate drying is filtered, and reduced pressure concentration filtrate obtains titled compound as white solid (160mg, yield is 63%).
MS(ESI,pos.ion)m/z:593.2[M+H]+；
1H NMR(400MHz,CDCl3) δ 7.40 (dt, J=15.2,7.6Hz, 2H), 7.18 7.13 (m, 3H), 7.06 (dd, J=11.7,7.7Hz, 2H), 6.52 6.44 (m, 2H), 6.38 (s, 1H), 5.07 (s, 2H), 4.74 (t, J=9.0Hz, 1H), 4.28 (dd, J=9.2,6.1Hz, 1H), 3.90 (t, J=8.3Hz, 1H), 3.84 3.75 (m, 1H), 3.67 (s, 1H), 3.49 (d, J=7.8Hz, 1H), 3.32 (t, J=8.4Hz, 1H), 3.20 (s, 2H), 2.96 (d, J=29.2Hz, 4H), 2.78 (dd, J=16.7,5.4Hz, 1H), 2.59 (dd, J=16.7,9.2Hz, 1H), 2.35 (s, 1H), 1.99 (d, J=8.0Hz, 6H),1.91–1.87(m,1H).
Embodiment 3
2- (6- ((2', 6'- dimethyl -4'- ((R)-N- methyl -3- ((methyl sulphonyl) methyl) pyrrolidines -1- formyls Amido)-[1,1'- biphenyl] -3- bases) methoxyl group) -2,3- Dihydrobenzofuranes -3- bases) acetic acid
The first step) (R) -3- (methylol) pyrrolidines -1- benzyl formates
(R)-pyrrolidin-3-yl methyl alcohol (2g, 19.77mmol) and sodium acid carbonate (3.3g, 39mmol) are dissolved in acetic acid second Benzyl chloroformate (4.24mL) is added in ester (20mL) and water (20mL) under room temperature.Reactant liquor was in room temperature reaction 5 hours.Reactant liquor Be extracted with ethyl acetate (40mL × 2) after water dilution (20mL), merge organic phase, (50mL) is washed with saturated nacl aqueous solution, Anhydrous sodium sulfate drying, filters, reduced pressure concentration filtrate.Residue silica gel chromatography (petroleum ether:Ethyl acetate=2: 1) (1.64g, yield is 35.2%), to obtain colorless oil title compound.
Second step) (R) -3- (((methyl sulphonyl) oxo) methyl) pyrrolidines -1- benzyl formates
By (R) -3- (methylol) pyrrolidines -1- benzyl formates (1.64g, 6.97mmol) and triethylamine (1.2mL, 8.5mmol) it is dissolved in dichloromethane (20mL), adds after methylsufonyl chloride (0.66mL, 8.4mmol) in room temperature reaction 1 hour. Reactant liquor is diluted with water (30mL), and dichloromethane extracts (30mL), and organic phase saturated nacl aqueous solution is washed (30mL), anhydrous Sodium sulphate is dried, and is filtered, reduced pressure concentration filtrate.Residue silica gel chromatography (petroleum ether:Ethyl acetate=4:1), obtain To colorless oil title compound, (2.1g, yield is 96%).
3rd step) (R) -3- ((methyl mercapto) methyl) pyrrolidines -1- benzyl formates
(R) -3- (((methyl sulphonyl) oxo) methyl) pyrrolidines -1- benzyl formates (2.1g, 6.7mmol) are dissolved in first In alcohol (4mL), 60 DEG C of reactions are warming up to after adding sodium methyl mercaptide (2.8g, 40mmol) overnight.Reactant liquor is quenched with water, acetic acid second Ester extracts (20mL × 2), merges organic phase, is washed with saturated nacl aqueous solution (10mL), anhydrous sodium sulfate drying, filters, subtracts Pressure concentration filtrate.Residue silica gel chromatography (petroleum ether:Ethyl acetate=20:1) it is titled that, faint yellow oily is obtained (1.68g, yield is 94%) for compound.
4th step) (R) -3- ((methyl sulphonyl) methyl) pyrrolidines -1- benzyl formates
(R) -3- ((methyl mercapto) methyl) pyrrolidines -1- benzyl formates (1.68g, 6.33mmol) are dissolved in methyl alcohol (50mL) In, room temperature adds potassium hydrogen persulfate (6g, 9.5mmol), and room temperature reaction is overnight afterwards.Reacting liquid filtering, filtrate wash (50mL), second Acetoacetic ester extracts (100mL × 2), merges organic phase, washs (20mL), anhydrous sodium sulfate drying, mistake with saturated nacl aqueous solution Filter, reduced pressure concentration filtrate.Residue silica gel chromatography (dichloromethane:Methyl alcohol=50:1), white solid mark is obtained (1.5g, yield is 80%) for topic compound.
5th step) (R) -3- ((methyl sulphonyl) methyl) pyrroles
(R) -3- ((methyl sulphonyl) methyl) pyrrolidines -1- benzyl formates (1.5g, 5mmol) are dissolved in ethanol (25mL) In, room temperature adds 10% palladium carbon (0.3g), and room temperature reaction is overnight in atmosphere of hydrogen afterwards.Reacting liquid filtering, reduced pressure concentration filtrate.Residual Thing is stayed to be directly used in next step reaction.
6th step) (R) -2', 6'- dimethyl -4'- (3- ((methyl sulphonyl) methyl) pyrrolidines -1- formamidos) - [1,1'- biphenyl] -3- methyl formates
By (R) -3- ((methyl sulphonyl) methyl) pyrroles (365mg, 2.24mmol) and 2', 6'- dimethyl -4'- ((benzene Oxygen carbonyl) amino)-[1,1'- biphenyl] -3- methyl formates (700mg, 1.86mmol) molten dimethyl sulfoxide (10mL) in, at 80 DEG C Under be stirred overnight.Reactant liquor adds water (50mL) to be extracted with ethyl acetate (50mL × 2) after being quenched, and merges organic phase, uses saturation Sodium chloride solution washs (30mL), anhydrous sodium sulfate drying, filters, reduced pressure concentration filtrate.Residue silica gel chromatography (petroleum ether:Ethyl acetate=1:1) (566mg, yield is 68%), to obtain yellow solid title compound.
7th step) (R) -2', 6'- dimethyl -4'- (N- methyl -3- ((mesyl) methyl) pyrrolidines -1- formamides Base)-[1,1'- biphenyl] -3- methyl formates
By (R) -2', 6'- dimethyl -4'- (3- ((methyl sulphonyl) methyl) pyrrolidines -1- formamidos)-[1,1'- Biphenyl] -3- methyl formates (710mg, 1.6mmol) are dissolved in anhydrous DMF (10mL), and room temperature adds hydrogenation Sodium (77mg, 1.9mmol) room temperature reaction 15 minutes afterwards.Iodomethane (0.12mL, 1.9mmol) room temperature reaction afterwards is added toward reactant liquor Overnight.Reactant liquor saturated aqueous ammonium chloride is quenched (20mL), and ethyl acetate extracts (20mL × 2), merges organic phase, uses saturation Sodium chloride solution washs (20mL), anhydrous sodium sulfate drying, filters, reduced pressure concentration filtrate.Residue silica gel chromatography (petroleum ether:Ethyl acetate=1:1) (650mg, yield is 80.7%), to obtain yellow solid title compound.
MS(ESI,pos.ion)m/z:459.2[M+H]+.
8th step) (R)-N- (3'- (methylol) -2,6- dimethyl-[1,1'- biphenyl] -4- bases)-N- methyl -3- ((first Base sulfonyl) methyl) pyrrolidines -1- formamides
By (R) -2', 6'- dimethyl -4'- (N- methyl -3- ((mesyl) methyl) pyrrolidines -1- formamidos) - [1,1'- biphenyl] -3- methyl formates (800mg, 1.74mmol) is dissolved in ethanol (15mL) and water (8mL), adds boron under ice bath Sodium hydride (670mg, 17.6mmol), back flow reaction 1 hour after finishing rear reactant liquor room temperature reaction overnight.Reactant liquor is washed (50mL) dichloromethane extracts (100mL × 2) afterwards, merges organic phase, washs (30mL), anhydrous slufuric acid with saturated nacl aqueous solution Sodium is dried, and is filtered, reduced pressure concentration filtrate.Residue silica gel chromatography (dichloromethane:Methyl alcohol=40:1), white is obtained (340mg, yield is 45.3%) for solid-like title compound.
9th step) (R)-N- (3'- (chloromethyl) -2,6- dimethyl-[1,1'- biphenyl] -4- bases)-N- methyl -3- ((first Base sulfonyl) methyl) pyrrolidines -1- formamides
By (R)-N- (3'- (methylol) -2,6- dimethyl-[1,1'- biphenyl] -4- bases)-N- methyl -3- ((sulfonyloxy methyls Base) methyl) pyrrolidines -1- formamides (340mg, 0.79mmol) is dissolved in DMF (10mL), drips under room temperature Plus POCl3 (0.086mL, 0.94mmol) room temperature reaction 3 hours afterwards.Reactant liquor adds water and is quenched (30mL), and ethyl acetate is extracted (30mL), organic phase saturated nacl aqueous solution is washed (30mL), anhydrous sodium sulfate drying, is filtered, and reduced pressure concentration filtrate obtains (340mg, yield is 96%) for yellow oily shape title compound.
MS(ESI,pos.ion)m/z:449.2[M+H]+.
Tenth step) 2- (6- ((2', 6'- dimethyl -4'- ((R)-N- methyl -3- ((methyl sulphonyl) methyl) pyrrolidines - 1- formamidos)-[1,1'- xenyls] -3- bases) methoxyl group) -2,3- Dihydrobenzofuranes -3- bases) methyl acetate
By (R)-N- (3'- (chloromethyl) -2,6- dimethyl-[1,1'- biphenyl] -4- bases)-N- methyl -3- ((sulfonyloxy methyls Base) methyl) pyrrolidines -1- formamides (130mg, 0.62mmol), 2- (6- hydroxyl -2,3- Dihydrobenzofuranes -3- bases) acetic acid Methyl esters (125mg, 0.62mmol) and potassium phosphate (212mg, 0.99mmol) are dissolved in DMF (5mL), are heated up React 3 hours to 60 DEG C.Reactant liquor is quenched with water, and ethyl acetate extracts (20mL × 2), merges organic phase, uses saturated sodium-chloride Solution washs (10mL), anhydrous sodium sulfate drying, filters, reduced pressure concentration filtrate.Residue silica gel chromatography (oil Ether:Ethyl acetate=2:1) (250mg, yield is 60.3%), to obtain faint yellow title compound as oil.
MS(ESI,pos.ion)m/z:621.2[M+H]+.
11st step) 2- (6- ((2', 6'- dimethyl -4'- ((R)-N- methyl -3- ((methyl sulphonyl) methyl) pyrroles Alkane -1- formamidos)-[1,1'- biphenyl] -3- bases) methoxyl group) -2,3- Dihydrobenzofuranes -3- bases) acetic acid
By 2- (6- ((2', 6'- dimethyl -4'- ((R)-N- methyl -3- ((methyl sulphonyl) methyl) pyrrolidines -1- first Amide groups)-[1,1'- xenyls] -3- bases) methoxyl group) -2,3- Dihydrobenzofuranes -3- bases) methyl acetate (250mg, 0.40mmol) it is dissolved in tetrahydrofuran (4mL), after adding lithium hydroxide aqueous solution (4mL, 1M), is stirred at room temperature 2 hours.Reactant liquor Add water (5mL) dilution after with hydrochloric acid (7mL, 1M) be acidified, and with ethyl acetate (10mL × 2) extract, merging organic phase, with satisfy (10mL) is washed with sodium chloride solution, anhydrous sodium sulfate drying is filtered, and reduced pressure concentration filtrate obtains titled compound as white solid (200mg, yield is 82%).
MS(ESI,neg.ion)m/z:605.3[M-H]-；
1H NMR(400MHz,CDCl3) δ 7.44 (dt, J=15.2,7.6Hz, 2H), 7.19 (s, 1H), 7.16 6.99 (m, 2H), 6.87 (s, 2H), 6.64 6.36 (m, 2H), 5.09 (s, 2H), 4.78 (t, J=9.0Hz, 1H), 4.31 (dd, J=9.2, 6.2Hz, 1H), 3.85 3.80 (m, 1H), 3.55 (dd, J=10.9,7.1Hz, 1H), 3.39 3.15 (m, 4H), 3.12 2.98 (m, 4H), 2.92 (s, 3H), 2.80 (dd, J=16.7,5.4Hz, 1H), 2.68 2.63 (m, 2H), 2.16 (dd, J=9.7, 5.9Hz,1H),2.00(s,6H),1.70–1.65(m,1H).
Embodiment 4
2- (6- ((2', 6'- dimethyl -4'- (piperidines -1- formamidos)-[1,1'- biphenyl] -3- bases) methoxyl group) -2, 3- Dihydrobenzofuranes -3- bases) acetic acid
Synthesis step is with embodiment 2.
MS(ESI,pos.ion)m/z:515.0[M+H]+；
1H NMR(600MHz,CDCl3)δ7.47–7.35(m,2H),7.16(s,1H),7.13–7.02(m,4H),6.58 (s, 1H), 6.53 6.41 (m, 2H), 5.07 (s, 2H), 4.76 (t, J=9.0Hz, 1H), 4.28 (dd, J=9.1,6.2Hz, 1H), 3.83 3.78 (m, 1H), 3.56 3.37 (m, 4H), 2.79 (dd, J=16.8,5.3Hz, 1H), 2.60 (dd, J= 16.7,9.4Hz,1H),1.99(s,6H),1.66-1.64(m,6H).
Embodiment 5
2- ((S) -6- ((2', 6'- dimethyl -4'- ((S) -2- ((methyl sulphonyl) methyl) pyrrolidines -1- formamides Base)-[1,1'- biphenyl] -3- bases) methoxyl group) -2,3- Dihydrobenzofuranes -3- bases) acetic acid
Synthesis step is with embodiment 2.
MS(ESI,pos.ion)m/z:593.2[M+H]+；
1H NMR(600MHz,CDCl3) δ 7.50 7.33 (m, 2H), 7.14 (d, J=11.3Hz, 3H), 7.07 (dd, J= 11.4,8.0Hz, 2H), 6.48 (dd, J=22.7,11.3Hz, 3H), 5.07 (s, 2H), 4.76 (t, J=9.0Hz, 1H), 4.48 (s, 1H), 4.29 (dd, J=9.0,6.2Hz, 1H), 3.86 3.76 (m, 1H), 3.72 (d, J=14.1Hz, 1H), 3.55 3.41 (m, 2H), 3.07 (d, J=19.8Hz, 3H), 3.03 (dd, J=14.0,9.7Hz, 1H), 2.80 (dd, J=16.8, 5.2Hz, 1H), 2.61 (dd, J=16.8,9.3Hz, 1H), 2.24 (t, J=10.7Hz, 2H), 2.15 2.08 (m, 2H), 2.00 (s,6H).
Embodiment 6
2- (6- ((2', 6'- dimethyl -4'- (pyrrolidines -1- formamidos)-[1,1'- biphenyl] -3- bases) methoxyl group) - 2,3- Dihydrobenzofuranes -3- bases) acetic acid
Synthesis step is with embodiment 2.
MS(ESI,pos.ion)m/z:501.1[M+H]+；
1H NMR(600MHz,CDCl3) δ 7.49 7.33 (m, 2H), 7.18 7.15 (m, 3H), 7.07 (dd, J=21.1, 7.7Hz, 2H), 6.48 (dd, J=13.6,4.7Hz, 2H), 6.22 (s, 1H), 5.07 (s, 2H), 4.76 (t, J=9.0Hz, 1H), 4.28 (dd, J=8.8,6.4Hz, 1H), 4.14 (dd, J=14.2,7.1Hz, 1H), 3.92 3.74 (m, 1H), 3.49 (s, 4H), 2.79 (dd, J=16.7,5.2Hz, 1H), 2.60 (dd, J=16.7,9.4Hz, 1H), 2.03 1.94 (m, 9H).
Embodiment 7
2- (6- ((2', 6'- dimethyl -4'- (4- (methyl sulphonyl) piperidines -1- formamidos)-[1,1'- biphenyl] -3- Base) methoxyl group) -2,3- Dihydrobenzofuranes -3- bases) acetic acid
Synthesis step is with embodiment 2.
MS(ESI,pos.ion)m/z:592.9[M+H]+；
1H NMR(600MHz,CDCl3) δ 7.42 (t, J=7.5Hz, 1H), 7.38 (d, J=7.7Hz, 1H), 7.14 (s, 1H), 7.10 7.00 (m, 4H), 6.76 (s, 1H), 6.50 6.44 (m, 2H), 5.06 (s, 2H), 4.74 (t, J=9.0Hz, 1H), 4.32 4.24 (m, 2H), 3.84 3.74 (m, 1H), 3.10 3.05 (m, 1H), 2.95 (dd, J=18.6,7.1Hz, 2H), 2.88 (s, 3H), 2.77 (dd, J=16.7,5.4Hz, 1H), 2.59 (dd, J=16.7,9.2Hz, 1H), 2.21 (d, J= 11.2Hz,2H),2.07(s,1H),1.97(s,6H),1.90–1.80(m,2H).
Embodiment 8
(((2', 6'- dimethyl -4'- (3- (methyl sulphonyl) azetidine -1- formamidos)-[1,1'- joins 6- 2- Benzene] -3- bases) methoxyl group) -2,3- Dihydrobenzofuranes -3- bases) acetic acid
Synthesis step is with embodiment 2.
MS(ESI,pos.ion)m/z:565.2[M+H]+；
1H NMR(400MHz,DMSO-d6)δ8.57(s,1H),7.48–7.35(m,2H),7.25(s,2H),7.18–7.03 (m, 3H), 6.48 (dd, J=10.7,2.5Hz, 2H), 5.10 (s, 2H), 4.68 (t, J=9.0Hz, 1H), 4.34 4.10 (m, 6H), 3.75 3.62 (m, 1H), 3.04 (s, 3H), 2.69 (dd, J=16.6,5.6Hz, 1H), 2.47 (d, J=9.0Hz, 1H), 1.91(s,6H).
Biological assessment
Activation Activity of the test case the compounds of this invention to GPR40 cells
In 384 orifice plates, inoculation hGPR40 high expressing cells (are stably expressed the HEK293 clones of hGPR40, protect promise science and technology (Beijing) Co., Ltd builds), inoculum density is 8000/hole.Cell at 37 DEG C, 5%CO2Under the conditions of cultivate 24 hours.Real When testing, 384 orifice plates for being covered with cell are taken out from incubator, discard culture medium, add (the preparation of calcium dyestuff of calcium dyestuff： 20mL HBSS (20mM HEPES)+2tube dye+200 μ L 10%BSA, Calcium 4assay kit, Molecular Device), 40 μ L/ holes.384 orifice plates are put back in incubator, are incubated 1 hour.FLIPR experimental arrangements are set, and 3 are added per hole The compounds of this invention and positive control of times gradient dilution, 10 μ L/ holes, the intracellular Ca increased using FLIPR instruments2+ The detection of concentration.Initial data is fitted with XLfit, obtains the EC of each compound50Value.Experimental result see the table below.
Compound number EC50(nM) Compound number EC50(nM) Compound number EC50(nM)
Embodiment 1 51 Embodiment 2 37 Embodiment 3 256
Embodiment 4 100 Embodiment 5 40 Embodiment 6 70
Embodiment 7 92 Embodiment 8 52
Conclusion：The compounds of this invention has obvious agonist activity to GPR40.

Claims (8)

1. a kind of compound, which has the structure as shown in formula (II), or stereoisomer, the medicine of the compound shown in formula (II) Acceptable salt on,
Wherein, k and m are each independently 0,1,2,3 or 4；
Each R1It independently is hydrogen, C1-6Alkyl sulphonyl or C1-6Alkyl sulphonyl C1-6Alkyl；Or two adjacent R1Coupled Atom constituted in phenyl or Formula II structure togetherForWherein described phenyl orOn pyridine radicals be optionally independently selected from hydrogen, fluorine, chlorine, bromine, hydroxyl, C by 1 independently of one another1-4Alkyl Sulfonyl, amino-sulfonyl or C1-4Halogenated alkyl sulfonyl substituent replaces；With
R2For hydrogen or C1-6Alkyl.
2. compound according to claim 1, wherein
Each R1It independently is hydrogen, C1-4Alkyl sulphonyl or C1-4Alkyl sulphonyl C1-4Alkyl；
Or two adjacent R1Coupled atom is constituted in phenyl or Formula II structure togetherForWherein described phenyl orOn pyridine radicals independently of one another optionally by 1 independence It is selected from hydrogen, C1-4Alkylsulfonyl substituents replace；With
R2For hydrogen or C1-4Alkyl.
3. compound according to claim 1, wherein
Each R1It independently is hydrogen, methyl sulphonyl, ethylsulfonyl, sulfonyloxy methyl ylmethyl, methysulfonylethyl or methyl sulphur Acyl propyl；With
R2For hydrogen, methyl, ethyl, propyl group or butyl.
4. compound according to claim 1, selected from one of following structure：
Or its stereoisomer, pharmaceutically acceptable salt.
5. a kind of pharmaceutical composition, described pharmaceutical composition include the compound any one of claim 1-4, further Comprising pharmaceutically acceptable carrier, excipient, diluent, assistant agent, medium or its combination.
6. pharmaceutical composition according to claim 5, its further include antidiabetic medicine, antihyperglycemic Thing, anti-obesity medicine, drug for hypertension, antiplatelet drug, Antiatherosclerosis medicine, fat-reducing medicament, antiphlogistic Thing or its combination.
7. the pharmaceutical composition according to any one of claim 5-6, which is further received comprising at least one GPR40 Body activator.
8. the medicine group described in any one of a kind of compound any one of claim 1-4 or claim 5-7 Compound is used for preventing, treat, mitigate or delaying by the receptor-mediated diabetes of GPR40, diabetic retinopathy, sugar in preparation The rising water of urine characteristic of disease neuropathy, nephrosis, insulin resistance, hyperglycaemia, hyperinsulinemia, aliphatic acid or glycerine Flat, hyperlipidemia, obesity, hypertriglyceridemia, X syndromes, DKA, GI, high cholesterol Mass formed by blood stasis, metabolic syndrome, angiocardiopathy, thrombotic disorder, ephrosis, sex dysfunction, skin disease, indigestion, hypoglycemia Disease, cancer, oedema, atherosclerotic or hypertension or for increasing the purposes in hdl level medicine.
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