CN104193731A - Novel urea-substituted biphenyl compounds as well as composition and application thereof - Google Patents

Novel urea-substituted biphenyl compounds as well as composition and application thereof Download PDF

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CN104193731A
CN104193731A CN201410428191.1A CN201410428191A CN104193731A CN 104193731 A CN104193731 A CN 104193731A CN 201410428191 A CN201410428191 A CN 201410428191A CN 104193731 A CN104193731 A CN 104193731A
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methyl
compound
alkyl
pharmaceutical composition
sulphonyl
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CN104193731B (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 invention relates to biphenyl derivatives as well as a preparation method and a pharmaceutical composition and application thereof on medicines. And particularly, the invention relates to novel urea-substituted biphenyl derivatives as well as a pharmaceutical composition and a preparation method thereof, and further relates to application to using the biphenyl derivatives and (or) the pharmaceutical composition containing the derivatives as a therapeutic agent, especially as a GPR40 agonist and preparing a drug for treating diseases such as diabetes and metabolic diseases. The novel urea-substituted biphenyl compounds contain urea radicals which have peculiarity and novelty on structure modification of the compounds.

Description

New Type Urea substituted biphenyl compounds and composition thereof and purposes
Technical field
The present invention relates to have and regulate the compound of GPR40 activity and the acceptable composition of pharmacy thereof and the purposes for the preparation of GPR40 relative disease medicine.Especially, the present invention relates to a kind of New Type Urea substituted biphenyl compounds, the pharmaceutical composition that contains these compounds and the purposes of these compounds in the disease medicament that is relevant to GPR40 activity for the preparation of some.The compound the present invention relates to contains urea groups, and this group has uniqueness and novelty on this compounds structure of modification.
Background of invention
GPR40 is the member of the gene superfamily of G-protein linked receptor (" GPRs ").GPRs is characterized as the membranin with 7 cross-film districts of inferring, by activating to signaling pathways in the vital cell of various physiological-function and in response to various molecules.First GPR40 is accredited as orphan receptor (, there is no the acceptor of known ligand) from human genome DNA's fragment.The people such as Sawzdargo (1997) Biochem.Biophys.Res.Commun.239:543-547.GPR40 is high expression level in beta Cell of islet and insulin secretory cell system.GPR40 activates associated with the induction phase of the calcium level of the adjusting of the Gq family of intracellular signal transferrin carefully and the rising followed.Lipid acid is as the part of GPR40, and lipid acid to regulate insulin secretion by GPR40 be known.The people such as Itoh (2003) Nature 422:173-176; The people such as Briscor (2003) J.Biol.Chem.278:11303-11311; The people such as Kotarsky (2003) Biochem.Biophys.Res.Commun.301:406-410.
Although the compounds of many adjustings GPR40 activity are disclosed, the high incidence of type ii diabetes, obesity, hypertension, cardiovascular disorder and hyperlipemia, has pointed out effective treatment or has prevented the demand of new therapy of these diseases urgent.
The futuramic biphenyl compound being substituted of the present invention, it has the ability that regulates GPR40, and therefore described compound is used for the treatment of or prevent diabetes and associated conditions potentially.
Abstract of invention
The invention provides and can be used for treating diabetes, diabetic retinopathy, diabetic neuropathy, diabetic nephropathy, insulin resistance, hyperglycemia, hyperinsulinemia, the elevated levels of lipid acid or glycerine, hyperlipidaemia, obesity, hypertriglyceridemia, X syndromes, ketoacidosis, glucose intolerance, hypercholesterolemia, hyperlipemia, metabolic syndrome, cardiovascular disorder, kidney disease, thrombotic illness, ephrosis, sexual dysfunction, tetter, maldigestion, hypoglycemia, cancer, oedema, diabetic complication, atherosclerosis or hypertensive compound, pharmaceutical composition and method.The compounds of this invention or pharmaceutical composition have good regulating effect to GPR40 acceptor.
On the one hand, the present invention relates to a kind of steric isomer, geometrical isomer, tautomer, oxynitride, hydrate, solvate, meta-bolites, pharmacy acceptable salt or prodrug suc as formula the compound shown in the compound shown in (I) or formula (I)
Wherein, ring A is C 2-10heterocyclic radical, C 5-12condense assorted bicyclic group, C 5-12the assorted bicyclic group of spiral shell or C 5-12the bridge bicyclic group of mixing;
Each R 1be hydrogen, C independently 1-6alkyl, C 1-6haloalkyl, halogen, C 1-6alkyl sulphonyl or C 1-6alkyl sulphonyl C 1-6alkyl; Or two adjacent R 1coupled atom forms C together 6-10aromatic ring or C 1-9hetero-aromatic ring, wherein said C 6-10aromatic ring and C 1-9hetero-aromatic ring is optionally independently selected from hydrogen, fluorine, chlorine, bromine, hydroxyl, C by 1,2,3 or 4 independently of one another 1-4alkyl, C 1-4haloalkyl, C 1-4alkyl sulphonyl, amino-sulfonyl or C 1-4halogenated alkyl sulfonyl substituting group replaces;
R 2for hydrogen or C 1-6alkyl; With
N is 1,2,3 or 4.
In certain embodiments, the present invention relates to a kind of steric isomer, geometrical isomer, tautomer, oxynitride, hydrate, solvate, meta-bolites, pharmacy acceptable salt or prodrug suc as formula the compound shown in the compound shown in (II) or formula (II)
Wherein, k and m are 0,1,2,3 or 4 independently of one another.
In certain embodiments, A ring is
In further embodiments, each R 1be hydrogen, C independently 1-4alkyl, C 1-4haloalkyl, fluorine, chlorine, bromine, C 1-4alkyl sulphonyl or C 1-4alkyl sulphonyl C 1-4alkyl; Or two adjacent R 1coupled atom forms C together 6-10aromatic ring or C 1-9hetero-aromatic ring, wherein said C 6-10aromatic ring and C 1-9hetero-aromatic ring is optionally independently selected from hydrogen, fluorine, chlorine, bromine, hydroxyl, C by 1,2,3 or 4 independently of one another 1-4alkyl, C 1-4haloalkyl, C 1-4alkyl sulphonyl, amino-sulfonyl or C 1-4halogenated alkyl sulfonyl substituting group replaces; With
R 2for hydrogen or C 1-4alkyl.
In further embodiments, each R 1be hydrogen, methyl, ethyl, propyl group, butyl, the tertiary butyl, trifluoromethyl, fluorine, chlorine, bromine, methyl sulphonyl, sulfonyloxy methyl ylmethyl, methyl sulphonyl ethyl or methyl sulphonyl propyl group independently; With
R 2for hydrogen, methyl, ethyl, propyl group or butyl.
In further embodiments, the present invention comprises following one of them structure:
Or its steric isomer, geometrical isomer, tautomer, oxynitride, hydrate, solvate, meta-bolites, pharmacy acceptable salt or prodrug.
On the other hand, the invention provides a kind of pharmaceutical composition, described pharmaceutical composition comprises above-mentioned any compound, further comprises pharmaceutically acceptable carrier, vehicle, thinner, assistant agent, vehicle or its combination.
In other embodiment schemes, described pharmaceutical composition further comprises antidiabetic medicine, hyperglycemia medicine, anti-obesity medicine, antihypertensive drug, antiplatelet drug, Antiatherosclerosis medicine, fat-reducing medicament, anti-inflammation drugs or its combination.
In other embodiment schemes, described pharmaceutical composition, it further comprises at least one GPR40 receptor stimulant.
On the other hand, the invention provides a kind of described compound and described pharmaceutical composition for the preparation of prevention, treatment, alleviate or delay diabetes, diabetic retinopathy, diabetic neuropathy, diabetic nephropathy, insulin resistance, hyperglycemia, hyperinsulinemia, the elevated levels of lipid acid or glycerine, hyperlipidaemia, obesity, hypertriglyceridemia, X syndromes, ketoacidosis, glucose intolerance, hypercholesterolemia, hyperlipemia, metabolic syndrome, cardiovascular disorder, kidney disease, thrombotic illness, ephrosis, sexual dysfunction, tetter, maldigestion, hypoglycemia, cancer, oedema, diabetic complication, atherosclerosis or hypertension or for increasing the purposes in hdl level medicine.
The present invention relates to the method for preparation, separation and the purifying of the compound that formula (I) or formula (II) comprise on the other hand.
Content noted earlier has only been summarized some aspect of the present invention, but is not limited to these aspects.The content of these aspects and other aspect will be done more concrete complete description below.
The detailed description of the invention
Definition and general terms
Describe now certain embodiments of the present invention in detail, the example is illustrated by the structural formula of enclosing and chemical formula.The invention is intended to contain all substitute, amendment and equivalent technical solutions, they include as the scope of the invention that defines of claim in.Those skilled in the art will appreciate that the similar or method that is equal to many and described herein and material can be used in puts into practice the present invention.The present invention is never limited to method as herein described and material.In one or more different from the application or conflicting situations of document, patent and the analogous material of institute's combination (include but not limited to defined term, term application, described technology, etc.), be as the criterion with the application.
Should further recognize that some feature of the present invention for clearly visible, is described, but also can in single embodiment, provides with array configuration in multiple independently embodiments.Otherwise various features of the present invention for for purpose of brevity, are described in single embodiment, but also can provide separately or with applicable arbitrarily sub-portfolio.
Unless otherwise indicated, all scientific and technical terminologies used in the present invention have the implication identical with those skilled in the art of the invention's common understanding.The all patents that the present invention relates to and public publication by reference entirety are incorporated to the present invention.
Unless otherwise indicated, should apply the following definition that uses to obtain herein.For purposes of the present invention, chemical element and periodic table of elements CAS version, and " chemistry and physics handbook ", the 75th edition, 1994 is consistent.In addition, organic chemistry General Principle can be with reference to " Organic Chemistry ", Thomas Sorrell, University Science Books, Sausalito:1999, and " March's Advanced Organic Chemistry " by Michael B.Smith and Jerry March, John Wiley & Sons, description in New York:2007, its full content is incorporated to herein by reference.
Term used in the present invention " study subject " refers to animal.Typically described animal is Mammals.Study subject, for example, also refer to primate (for example mankind, sex), ox, sheep, goat, horse, dog, cat, rabbit, rat, mouse, fish, bird etc.In certain embodiments, described study subject is primate.In other embodiments, described study subject is people.
Term used in the present invention " patient " refers to people's (comprising adult and children) or other animals.In some embodiments, " patient " refers to people.
Stereochemistry definition used in the present invention and rule are generally followed 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 compound exist with optical activity form, and they have the ability that the plane of plane polarized light is rotated.Describing when optically active compound, represent the absolute configuration of molecule or mulitiple chiral centers individual about one with prefix D and L or R and S.Prefix d and l or (+) and (-) are the symbols that is used to specify plane polarized light rotation due to compound, and wherein (-) or l represent that compound is left-handed.Prefix is that the compound of (+) or d is dextrorotation.Concrete steric isomer is an enantiomer, and the mixture of this isomer is called enantiomeric mixture.The 50:50 mixture of enantiomer is called racemic mixture or racemic modification, when there is no stereoselectivity or stereospecificity in chemical reaction or process time, can occur this situation.
Come into the open any asymmetric atom (for example, carbon etc.) of compound of the present invention can exist with the form of racemize or enantiomorph enrichment, for example (R)-, (S)-or (R, S)-configuration form exist.In certain embodiments, each asymmetric atom (R)-or (S)-configuration aspect there is at least 50% enantiomeric excess, at least 60% enantiomeric excess, at least 70% enantiomeric excess, at least 80% enantiomeric excess, at least 90% enantiomeric excess, at least 95% enantiomeric excess, or at least 99% enantiomeric excess.
According to the selection of starting material and method, the compounds of this invention can be with one in possible isomer or their mixture, and the form of for example racemic modification and non-corresponding isomer mixture (this depends on the quantity of unsymmetrical carbon) exists.Optically active (R)-or (S)-isomer can use the preparation of chiral synthon or chiral reagent, or use routine techniques to split.If compound contains a two key, substituting group may be E or Z configuration; If contain dibasic cycloalkyl in compound, the substituting group of cycloalkyl may have cis or transconfiguration.
The mixture of any steric isomer of gained can be separated into pure or substantially pure geometrical isomer according to the difference in component physicochemical property, enantiomer, and diastereomer, for example, by chromatography and/or Steppecd crystallization.
Can the racemic modification of any gained end product or intermediate be split into optical antipode by the familiar method of those skilled in the art by known method, as, by its diastereoisomeric salt obtaining is separated.Racemic product also can separate by chiral chromatography, as, the high performance liquid chromatography (HPLC) of use chiral sorbent.Especially, enantiomer can be prepared by asymmetric synthesis, for example, can be with reference to Jacques, et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Principles of Asymmetric Synthesis (2 nded.Robert E.Gawley, Jeffrey Aub é, Elsevier, Oxford, UK, 2012); Eliel, E.L.Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); Wilen, p.268 (E.L.Eliel, Ed., Univ.of Notre Dame Press, Notre Dame, IN 1972) of S.H.Tables of Resolving Agents and Optical Resolutions; Chiral Separation Techniques:A Practical Approach (Subramanian, G.Ed., Wiley-VCH Verlag GmbH & Co.KGaA, Weinheim, Germany, 2007).
Term " tautomer " or " tautomeric form " refer to the constitutional isomer that low energy barrier (low energy barrier) transforms mutually that passes through with different-energy.If tautomerism is possible (as in solution), can reach the chemical equilibrium of tautomer.For example, proton tautomerism body (protontautomer) comprises also referred to as prototropy tautomer (prototropic tautomer) the mutual conversion of being undertaken by proton shifting, as keto-enol isomerization and the isomerization of imines-enamine.Valence tautomerism body (valence tautomer) comprises the mutual conversion of being undertaken by the restructuring of some bonding electronss.The specific examples of keto-enol tautomerism is pentane-2, the change of 4-diketone and 4-hydroxyl penta-3-alkene-2-keto tautomer.Tautomeric another example is phenol-keto tautomerism.A specific examples of phenol-keto tautomerism is the change of pyridine-4-alcohol and pyridine-4 (1H)-one tautomer.Unless otherwise noted, all tautomeric forms of the compounds of this invention all within the scope of the present invention.
Picture is described in the invention, and compound of the present invention can optionally be replaced by one or more substituting group, as general formula compound above, or the special example in picture embodiment the inside, and subclass, and the compounds that comprises of the present invention.Should be appreciated that " optionally substituted " this term and " substituted or non-substituted " this term can exchange use.Generally speaking, term " replacement " represents that one or more hydrogen atoms of give in structure are substituted by concrete substituting group.Unless other aspects show, an optional substituted radical can replace in each commutable position of group.When one or more substituting group that in given structural formula, not only position can be selected from concrete group replaces, substituting group can replace in each position identical or differently so.
In addition, it should be noted that, unless otherwise explicitly pointed out, the describing mode that adopted in the present invention " each ... be independently " and " ... be independently of one another " and " ... be independently " can exchange, all should be interpreted broadly, it both can refer in different groups, between same-sign, between expressed concrete option, did not affect mutually, also can be illustrated in identical group, between same-sign, between expressed concrete option, not affect mutually.For example structure and structure r in both 1concrete option is unaffected each other, meanwhile, occurs multiple R in same structure 1, multiple R 1between concrete option be independent of each other, i.e. R 1concrete option can be identical, also can be different.
At the each several part of this specification sheets, the come into the open substituting group of compound of the present invention is open according to radical species or scope.Particularly point out, the present invention includes each sub-combinations thereof independently of each member of these radical species and scope.For example, term " C 1-6alkyl " refer in particular to independent disclosed methyl, ethyl, C 3alkyl, C 4alkyl, C 5alkyl and C 6alkyl.
At each several part of the present invention, connection substituting group is described.In the time that this structure clearly needs linking group, the Ma Kushi variable cited for this group is interpreted as linking group.For example, if this structure needs linking group and enumerated " alkyl " or " aryl " for the Ma Kushi group definition of this variable, should be appreciated that, should " alkyl " or " aryl " represent respectively the alkylidene group or the arylene group that connect.
Term " alkyl " or " alkyl group " that the present invention uses, represent to contain 1 to 20 carbon atom, saturated straight or branched univalent hydrocarbyl group, and wherein, the substituting group that described alkyl group can optionally be described by one or more the present invention replaces.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, alkyl group contains 1-4 carbon atom; Also in some embodiments, alkyl group contains 1-3 carbon atom.The example of alkyl group comprises, but is not limited to, methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, sec-butyl, the tertiary butyl, n-pentyl, 3-methyl isophthalic acid-butyl, 3-hexyl, n-heptyl, n-octyl etc.
Term " haloalkyl " represents that alkyl is replaced by one or more halogen atom, and such example comprises, but is not limited to, trifluoromethyl etc.
Term " heterocyclic radical " and " heterocycle " commutative use herein, all refers to the undersaturated monocycle of saturated or part that comprises 3-12 annular atoms, and wherein at least one annular atoms is selected from nitrogen, sulphur and Sauerstoffatom.Unless otherwise indicated, heterocyclic radical can be carbon back or nitrogen base, and-CH 2-group can be optionally by-C (=O)-substitute.The sulphur atom of ring can optionally be oxidized to S-oxide compound.The nitrogen-atoms of ring can optionally be oxidized to N-oxygen compound.The example of heterocyclic radical includes, but are not limited to: Oxyranyle, azelidinyl, oxa-cyclobutyl, thia cyclobutyl, pyrrolidyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrazolinyl, pyrazolidyl, imidazolinyl, hexahydropyrimidine base etc.
Term " thick assorted bicyclic group " represents saturated or undersaturated and bicyclic system, relates to the also member ring systems of non-aromatic.Such system can comprise independently or the undersaturated condition of conjugation.And at least one member ring systems comprises one or more heteroatomss, wherein each member ring systems comprises 3-7 ring, comprise 1-6 carbon atom and 1-3 the heteroatoms that is selected from N, O, P, S, optionally replaced and obtain for example SO, SO by one or more Sauerstoffatom at this S or P 2, PO, PO 2group.Described annelated heterocycles base can be replacement or unsubstituted, wherein substituting group can be, but be not limited to deuterium, oxo (=O), hydroxyl, amino, halogen, cyano group, aryl, heteroaryl, alkoxyl group, alkylamino, alkyl, thiazolinyl, alkynyl, heterocyclic radical, sulfydryl, nitro.
Term " spiro heterocyclic radical " represents that a ring originates from the upper special ring-type carbon of another ring, relates to the bridged-ring system of non-aromatic.Such system can comprise independently or the undersaturated condition of conjugation.And at least one member ring systems comprises one or more heteroatomss, wherein each member ring systems comprises 3-7 ring, comprise 1-6 carbon atom and 1-3 the heteroatoms that is selected from N, O, P, S, optionally replaced and obtain for example SO, SO by one or more Sauerstoffatom at this S or P 2, PO, PO 2group.And described spiro heterocyclic radical can be replacement or unsubstituted, and wherein substituting group can be, but is not limited to, deuterium, oxo (=O), hydroxyl, amino, halogen, cyano group etc.
Term " bridge heterocyclic radical " represents saturated or undersaturated bridged-ring system, relates to the bridged-ring system of non-aromatic.Such system can comprise independently or the undersaturated condition of conjugation.And at least one member ring systems comprises one or more heteroatomss, wherein each member ring systems comprises 3-7 ring, comprise 1-6 carbon atom and 1-3 the heteroatoms that is selected from N, O, P, S, optionally replaced and obtain for example SO, SO by one or more Sauerstoffatom at this S or P 2, PO, PO 2group, and described assorted bridged ring base can be replace or unsubstituted, wherein substituting group can be, but is 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 " represent to contain 6-14 annular atoms, or 6-12 annular atoms, or the carbocyclic ring system with aromaticity of the monocycle of 6-10 annular atoms, dicyclo and three rings, and have one or more attachment points to be connected with the rest part of molecule.The example of aromatic yl group can include, but are not limited to phenyl, naphthyl and anthracene etc.
Term " heteroaryl " or " hetero-aromatic ring " represent to contain 5-12 annular atoms, or 5-10 annular atoms, or the monocycle of 5-6 annular atoms, dicyclo and three rings have the system of aromaticity, at least one member ring systems comprises one or more heteroatomss, and has one or more attachment points to be connected with molecule rest part.The example of heteroaryl groups comprises, but be not limited to, 2-furyl, TMSIM N imidazole base, 3-isoxazolyl, 2-oxazolyl, 2-pyrryl, 2-pyridyl, 4-pyrimidyl, 5-pyrimidyl, pyridazinyl, 4-thiazolyl, tetrazyl, triazolyl, 2-thienyl, pyrazolyl benzimidazolyl-, benzofuryl, benzothienyl, indyl, purine radicals, quinolyl, imidazo [1,2-a] pyridyl etc.
Term " alkyl sulphonyl " refers on alkylsulfonyl and is connected with a defined alkyl of the present invention, and alkylsulfonyl is connected with the rest part of molecule.
Term " alkyl sulphonyl alkyl " refers to that the present invention's defined " alkyl sulphonyl " is connected on a defined alkyl of the present invention, and alkyl is connected with the rest part of molecule.
Term " two adjacent R 1coupled atom forms aromatic ring or hetero-aromatic ring together " refer to two adjacent atoms and the connection portion R on it 1form together aromatic ring or hetero-aromatic ring.Some of them embodiment is, as upper two R 1adjacent, form aromatic ring or hetero-aromatic ring with together with connected atom, as m ring is aromatic ring or hetero-aromatic ring.
Term " leavings group " refers in chemical reaction from one compared with the atom departing from macromole or functional group.In nucleophilic substitution reaction, be called substrate by the reactant of nucleophilic reagent attack, and the atom rupturing away with pair of electrons are or atomic group are called leavings group from substrate molecule.Easily accept electronics, bear the leavings group that group that negative charge ability is strong has been.
When term " blocking group " or " PG " refer to a substituting group and other reacted with functional groups, be commonly used to blocking-up or protect special functional.For example; " amino blocking group " refers to that a substituting group is connected to block or protect in compound amino functional with amino group; suitable amido protecting group comprises ethanoyl; trifluoroacetyl group; tertbutyloxycarbonyl (BOC; Boc), the sub-methoxycarbonyl of carbobenzoxy-(Cbz) (CBZ, Cbz) and 9-fluorenes (Fmoc).Similarly, " hydroxy-protective group " refers to that the substituting group of hydroxyl is used for blocking or protecting the functional of hydroxyl, and suitable blocking group comprises ethanoyl and silyl." carboxy protective group " refer to the substituting group of carboxyl be used for blocking-up or protection carboxyl functional, comprise-CH of general carboxyl-protecting group 2cH 2sO 2ph; cyano ethyl; 2-(TMS) ethyl; 2-(TMS) ethoxyl methyl; 2-(p-toluenesulfonyl) ethyl, 2-(p-nitrophenyl alkylsulfonyl) ethyl, 2-(diphenylphosphino) ethyl; nitro-ethyl, etc.Can reference for the general description of blocking group: T W.Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, New York, 1991; And P.J.Kocienski, Protecting Groups, Thieme, Stuttgart, 2005.
Term used in the present invention " prodrug ", represents that a compound is converted into the compound shown in formula (I) or formula (II) in vivo.Such conversion is hydrolyzed by prodrug or the impact that is precursor structure through enzymatic conversion in blood or tissue in blood.Prodrug compounds of the present invention can be ester, and what in existing invention, ester can be used as prodrug has phenyl ester class, an aliphatics (C 1-24) ester class, acyloxy methyl ester class, carbonic ether, amino formate and amino acid esters.For example a compound in the present invention comprises hydroxyl, its acidylate can be obtained to the compound of prodrug form.Other prodrug form comprises phosphoric acid ester, if these phosphate compounds are that hydroxyl phosphorylation on parent obtains.Can be with reference to Publication about Document about the complete discussion of prodrug: T.Higuchi and V.Stella, Pro-drugs as Novel Delivery Systems, Vol.14of 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.
" meta-bolites " refers to the product that concrete compound or its salt obtains by metabolism in vivo.The meta-bolites of a compound can identify by the known technology in affiliated field, and its activity can characterize by the method that adopts test as described in the invention.Such product can be by the oxidation of drug compound process, reduces, and hydrolysis, amidated, desamido-effect, esterification, fat abstraction, enzymatic lysis etc. method obtains.Correspondingly, the present invention includes the meta-bolites of compound, comprise compound of the present invention is fully contacted to the meta-bolites that for some time produces with Mammals.
" pharmacy acceptable salt " used in the present invention refers to organic salt and the inorganic salt of compound of the present invention.Pharmacy acceptable salt is for we are known in affiliated field, as document: S.M.Berge et al., describe pharmaceutically acceptable salts in detail in J.Pharmaceutical Sciences, 1977,66:1-19. records.The salt that pharmaceutically acceptable nontoxic acid forms comprises, but is not limited to, and the inorganic acid salt that react formation with amino group has hydrochloride, hydrobromate, phosphoric acid salt, vitriol, perchlorate, and organic acid salt is as acetate, oxalate, maleate, tartrate, Citrate trianion, succinate, malonate, or obtain these salt by the additive method recorded on books document as ion exchange method.Other pharmacy acceptable salts comprise adipate, alginate, ascorbate salt, aspartate, benzene sulfonate, benzoate, bisulfate, borate, butyrates, camphorate, camsilate, cyclopentyl propionate, digluconate, dodecyl sulfate, esilate, formate, fumarate, gluceptate, glycerophosphate, gluconate, Hemisulphate, enanthate, hexanoate, hydriodate, 2-hydroxy-ethanesulfonate salt, lactobionate, lactic acid salt, lauroleate, lauryl sulfate, malate, malonate, mesylate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, palmitate, pamoate, pectate, persulphate, 3-phenylpropionic acid salt, picrate, pivalate, propionic salt, stearate, thiocyanate-, tosilate, undecylate, valerate, etc..The salt obtaining by suitable alkali comprises basic metal, alkaline-earth metal, ammonium and N +(C 1-4alkyl) 4salt.The present invention also intends the quaternary ammonium salt that the compound of the group of having conceived any comprised N forms.Water-soluble or oil soluble or disperse product to obtain by quaternization.Basic metal or alkaline earth salt comprise sodium, lithium, and potassium, calcium, magnesium, etc.Pharmacy acceptable salt further comprises suitable, nontoxic ammonium, the amine positively charged ion that quaternary ammonium salt and gegenions form, and as halogenide, oxyhydroxide, carboxylate, hydrosulfate, phosphoric acid compound, nitric acid compound, C 1-8azochlorosulfonate acid compound and aromatic sulphonic acid compound.
" solvate " of the present invention refers to the associated complex that one or more solvent molecules and compound of the present invention form.The solvent that forms solvate comprises, but is not limited to water, Virahol, ethanol, methyl alcohol, methyl-sulphoxide, ethyl acetate, acetic acid and monoethanolamine.Term " hydrate " refers to that solvent molecule is the associated complex that water forms.
Any disease of term " treatment " or illness as used in the present invention, some embodiment middle fingers improve disease or illness (slow down or stop or palliate a disease or the development of its at least one clinical symptom) therein.In other embodiments, " treatment " refers to relax or improve at least one body parameter, comprises the body parameter that may not discover for patient.In other embodiments, " treatment " refer to (for example to stablize perceptible symptom) from health or physiology on (for example stablizing the parameter of health) or above-mentioned two aspects regulate disease or illnesss.In other embodiments, " treatment " refer to prevention or postpone outbreak, generation or the deterioration of disease or illness.
Pharmaceutically useful acid salt can form with mineral acid and organic acid, for example acetate, aspartate, benzoate, benzene sulfonate, bromide/hydrobromate, bicarbonate/carbonate, hydrosulfate/vitriol, camsilate, muriate/hydrochloride, chloro theophylline salt, Citrate trianion, ethanedisulphonate, fumarate, gluceptate, gluconate, glucuronate, hippurate, hydriodate/iodide, isethionate, lactic acid salt, lactobionate, lauryl sulfate, malate, maleate, malonate, mandelate, mesylate, Methylsulfate, naphthoate, naphthalenesulfonate, nicotinate, nitrate, octadecanoate, oleate, oxalate, palmitate, pamoate, phosphate/phosphor acid hydrogen salt/dihydrogen phosphate, poly-semi-lactosi hydrochlorate, propionic salt, stearate, succinate, sulfosalicylate, tartrate, tosylate and trifluoroacetate.
Can comprise such as hydrochloric acid, Hydrogen bromide, sulfuric acid, nitric acid, phosphoric acid etc. by its derivative mineral acid that obtains salt.
Can comprise such as acetic acid, propionic acid, oxyacetic acid, oxalic acid, toxilic acid, propanedioic acid, succsinic acid, fumaric acid, tartrate, citric acid, phenylformic acid, amygdalic acid, methylsulfonic acid, ethyl sulfonic acid, tosic acid, sulphosalicylic acid etc. by its derivative organic acid that obtains salt.
Pharmaceutically acceptable base addition salt can form with mineral alkali and organic bases.
Can be comprised by its derivative mineral alkali that obtains salt the metal of the I family of for example ammonium salt and periodictable to XII family.In certain embodiments, this salt is derived from sodium, potassium, ammonium, calcium, magnesium, iron, silver, zinc and copper; Particularly suitable salt comprises ammonium, potassium, sodium, calcium and magnesium salts.
Can comprise primary amine, secondary amine and tertiary amine by its derivative organic bases that obtains salt, the amine of replacement comprises the amine of naturally occurring replacement, cyclic amine, deacidite etc.Some organic amine comprises, for example, and Isopropylamine, dibenzylethylenediamine dipenicillin G (benzathine), choline salt (cholinate), diethanolamine, diethylamine, Methionin, meglumine (meglumine), piperazine and Trometamol.
Pharmacologically acceptable salt of the present invention can be synthesized by parent compound, alkalescence or acidic moiety by conventional chemical method.Generally speaking, such salt can be by the free acid form of these compounds is reacted with the suitable alkali of stoichiometry (as the oxyhydroxide of Na, Ca, Mg or K, carbonate, supercarbonate etc.), or by the free alkali form of these compounds and the suitable acid-respons of stoichiometry are prepared.Such reaction is carried out conventionally in water or organic solvent or the mixture of the two.Usually, in suitable situation, need to use non-aqueous media as ether, ethyl acetate, ethanol, Virahol or acetonitrile.In for example " Remington ' s Pharmaceutical Sciences ", the 20th edition, Mack Publishing Company, Easton, Pa., (1985); " pharmaceutical salts handbook: character, choice 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, comprise their salt, also can for example, obtain with their hydrate forms or the form that comprises its solvent (ethanol, methyl-sulphoxide (DMSO), etc.), for their crystallization.Compound is come into the open in the present invention can be with pharmaceutically acceptable solvent (comprising water) inherently or by design forming solvate; Therefore, the present invention be intended to comprise solvation and the form of solvation not.
As described in the invention, a key of substituting group picture is connected to the member ring systems (shown in (a)) forming on the ring at center and represents substituent R 5can on ring, replace any commutable position.For example, formula (a) represents any may all can being substituted substituted position on W1 ring or W2 ring.
As described in the invention, in member ring systems, there are two tie points to be connected with molecule rest part, shown in (b), represent it can had been both that E end can be also that E ' end is connected with molecule rest part, the mode of connection at two ends can be exchanged.
The composition of the compounds of this invention, preparation and administration
The invention provides and be suitable for pharmaceutical composition medicinal, that comprise one or more compounds of the present invention.This pharmaceutical composition can also further comprise pharmaceutically acceptable carrier, vehicle, thinner, assistant agent, vehicle or its combination.Described pharmaceutical composition can be used for the treatment of diabetes, diabetic retinopathy, diabetic neuropathy, diabetic nephropathy, insulin resistance, hyperglycemia, hyperinsulinemia, the elevated levels of lipid acid or glycerine, hyperlipidaemia, obesity, hypertriglyceridemia, X syndromes, ketoacidosis, glucose intolerance, hypercholesterolemia, hyperlipemia, metabolic syndrome, cardiovascular disorder, kidney disease, thrombotic illness, ephrosis, sexual dysfunction, tetter, maldigestion, hypoglycemia, cancer, oedema, diabetic complication, atherosclerosis or hypertension or for increasing hdl level disease, especially, it has good regulating effect to GPR40 acceptor.
The compounds of this invention can be used separately or use with one or more combination with other therapeutic agents.Pharmaceutical composition further comprises other antidiabetic medicines, hyperglycemia medicine, anti-obesity medicine, antihypertensive drug, antiplatelet drug, Antiatherosclerosis medicine, fat-reducing medicament, anti-inflammation drugs or its combination.Described antidiabetic medicine can for any known be different from the compounds of this invention other for antidiabetic medicine.For example, SGLT-2 inhibitor, biguanides, sulfonylureas, alpha-glucosidase inhibitors, PPAR agonist, α P2 inhibitor, the two activator of PPAR α/γ, dipeptide amido peptidase TV (DPP-IV) inhibitor, glinides, Regular Insulin, glucagon-like-peptide-1 (GLP-1) inhibitor, PTP1B inhibitor, glycogen phosphorylase inhibitors or Robison ester enzyme inhibitors.
In the time can be used for treating, the compounds of this invention for the treatment of significant quantity, especially formula (I) or formula (II) compound and pharmacy acceptable salt thereof can be used as unprocessed pharmaceutical chemicals and give, and the activeconstituents that also can be used as pharmaceutical composition provides.Therefore, the pharmaceutical composition that content of the present invention provides comprises the compounds of this invention for the treatment of significant quantity, especially formula (I) or formula (II) compound or its pharmacy acceptable salt and one or more pharmaceutically acceptable carriers, thinner or vehicle.Term as used herein " treatment significant quantity " refers to the total amount that is enough to the each active ingredient that demonstrates significant patient's benefit (for example blood sugar reduction).In the time using independent activeconstituents individually dosed, this term only refers to this composition.In the time of applied in any combination, no matter this term refers to combination, successively or when simultaneously administration, all causes the combined amount of the activeconstituents of result for the treatment of.The compounds of this invention, especially formula (I) or formula (II) compound and pharmacy acceptable salt thereof are described above.From compatible with other compositions of preparation and harmless to its recipient meaning, carrier, thinner or vehicle must be acceptable.According to the present invention, content on the other hand, also be provided for the method for useful in preparing drug formulations, the method comprises the compounds of this invention, and especially formula (I) or formula (II) compound or its pharmacy acceptable salt and one or more pharmaceutically acceptable carriers, thinner or vehicle mix.Term used in the present invention " pharmaceutically acceptable " refers to such compound, raw material, composition and/or formulation, they are in the scope of rational medicine judgement, be applicable to contact with patient tissue and without excessive toxicity, pungency, transformation reactions or with rational interests/risk than symmetrical other problems and complication, and be effective to set purposes.
When the combination of the compound that comprises content of the present invention when the composition of content of the present invention and one or more other treatment medicines or prophylactic agent, the dosage level of compound and other medicine is conventionally in monotherapy scheme, account for the approximately 10-150% of bio-occlusion pharmaceutical quantities, more preferably account for the approximately 10-80% of bio-occlusion pharmaceutical quantities.Pharmaceutical preparation is suitable for by any suitable administration, for example, by oral (comprising oral cavity or hypogloeeis), rectum, nose, part (comprise oral cavity, hypogloeeis or through skin), vagina or parenteral (comprise in subcutaneous, intracutaneous, intramuscular, intraarticular, synovial membrane, in breastbone, in sheath, intralesional, intravenously or corium hemostasis or infusion) approach.Can prepare this class preparation by any currently known methods in pharmaceutics field, for example, pass through activeconstituents and carrier or mixed with excipients.Preferred oral administration or drug administration by injection.
For using the pharmaceutical composition of the compounds of this invention to provide with unit dosage form easily and can preparing by any method well-known in the art.All methods comprise the step that activeconstituents is combined with the carrier that forms one or more ancillary components.Conventionally, pharmaceutical composition is prepared by the following method: activeconstituents and liquid carrier or solid-state carrier in small, broken bits or both are combined equably and nearly, then, if needed, make this product form needed preparation.In pharmaceutical composition, the active target compound that comprises enough amounts produces desired effect with the process to disease or situation.
The pharmaceutical composition that contains activeconstituents can be to be suitable for oral form, for example, and as tablet, lozenge, sugared agent, aqeous suspension or oil suspension, dispersible pulvis or granule, emulsion, hard capsule or syrup or elixir.Being intended for the composition orally using can prepare according to manufacturing the known any method of pharmaceutical composition production field.Such composition can comprise one or more and be selected from the reagent of sweeting agent, odorant, tinting material and sanitas, and object is to provide pharmaceutically graceful and good to eat preparation.
Tablet comprises the activeconstituents mixing mutually with other atoxic pharmaceutically acceptable vehicle that are suitable for manufacturing tablet.These vehicle can be that for example, inert diluent, as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; Granule and disintegrating agent, as W-Gum or Lalgine; Tackiness agent, as starch, gelatin or gum arabic; And lubricant, as Magnesium Stearate, stearic acid or talcum.Tablet can not be coated, thereby or they can be coated with and delay the disintegration in gi tract and absorb and the continuous action of long period is provided by known technology.For example, can use the time delay material such as glyceryl monostearate or distearin.They also can be coated with and be formed for controlling the osmotic therapeutic tablets discharging by the technology of describing in U.S. Patent number 4256108,4160452 and 4265874.
Also can be used as hard gelatin capsule and provide for the preparation that orally uses, wherein activeconstituents with such as calcium carbonate, calcium phosphate or kaolinic inert solid mixing diluents; Or provide as soft gelatin capsule, wherein activeconstituents mixes with water or such as the oil medium of peanut oil, liquid paraffin or sweet oil.
Aqeous suspension comprises and the active substance that is suitable for the mixed with excipients of manufacturing aqeous suspension.Such vehicle is suspension agent, for example Xylo-Mucine, methylcellulose gum, hydroxyl-propyl methylcellulose gum, sodium alginate, polyethylene-pyrrolidone, tragacanth gum and Sudan Gum-arabic; Dispersion agent or wetting agent can be naturally occurring phosphatide, for example Yelkin TTS, or the condensation product of alkylene oxide and lipid acid is as polyoxyethylene stearic acid ester, or oxyethane and long chain aliphatic alcohol are as the condensation product of 17 vinyloxy group hexadecanols, or oxyethane and derive from lipid acid and the condensation product of the partial ester of hexitol as octadecanoic acid ester of polyethylene glycol, or oxyethane and derive from lipid acid and the condensation product of the partial ester of hexitan as polyethylene polyoxyethylene-sorbitan mono-oleate.Described aqeous suspension also can comprise one or more sanitass (as ethyl p-hydroxybenzoate or P-hydroxybenzoic acid n-propyl), one or more tinting materials, one or more odorants and one or more sweeting agents (as sucrose or asccharin).
Oil suspension can be by being suspended in activeconstituents such as preparing in the mineral oil in the vegetables oil of peanut oil, sweet oil, sesame oil or Oleum Cocois or such as whiteruss.Oil suspension can comprise thickening material, for example beeswax, paraffinum durum or hexadecanol.Can add such as those sweeting agents set forth above and odorant so that good to eat oral preparations to be provided.These compositions can come anticorrosion such as the antioxidant of xitix by adding.
The dispersible pulvis or the granule that are suitable for preparing by adding water aqeous suspension provide the activeconstituents mixing with dispersion agent or wetting agent, suspension agent and one or more sanitass.Suitable dispersion agent or wetting agent and suspension agent carry out exemplary illustration by those that mentioned above.Also can there is other vehicle, for example sweeting agent, odorant and tinting material.
The form of all right oil-in-water emulsion of pharmaceutical composition of the present invention.Oil phase can be such as the vegetables oil of sweet oil or peanut oil or such as the mineral oil of whiteruss or these mixture.Suitable emulsifying agent can be naturally occurring natural gum, as Sudan Gum-arabic or tragacanth gum; Naturally occurring phosphatide, for example, as soybean, Yelkin TTS with derive from lipid acid and the ester of hexitan or partial ester, polyoxyethylene-sorbitan mono-oleate; And the condensation product of described partial ester and oxyethane, as polyethylene polyoxyethylene-sorbitan mono-oleate.Emulsion also can comprise sweeting agent and odorant.
Syrup and elixir can be prepared with together with sweeting agent such as glycerine, propylene glycol, sorbyl alcohol or sucrose.Such preparation also can comprise negative catalyst, sanitas and odorant and tinting material.
Pharmaceutical composition can the aqeous suspension of sterile injectable or the form of oil suspension.This suspension can be prepared according to known technology, the above suitable dispersion agent of having mentioned of use or wetting agent and suspension agent.The preparation of this sterile injectable can also be in nontoxic, the acceptable thinner of parenteral or solvent solution or the suspension of sterile injectable, for example, as the solution in 1,3 butylene glycol.Spendable acceptable vehicle and solvent are water, Ringer's solution and isotonic sodium chlorrde solution.In addition, aseptic fixing oil is traditionally as solvent or suspension medium.Therefore, the fixing oil of any gentleness be can use, synthetic direactive glyceride or two glyceryl ester comprised.In addition, in the preparation of injectable drug, find purposes such as the lipid acid of oleic acid.
Pharmaceutical composition can also be used for suppository form or the enema of the rectal administration of medicine.These compositions can be by prepared by medicine and suitable non-irritating mixed with excipients, thereby described non-irritating vehicle is solid at normal temperatures but under rectal temperature, is liquid and will in rectum, melt with release medicine.Such material comprises, for example, and theobroma oil and polyoxyethylene glycol.
Use for part, adopt the ointment, ointment, suspensoid, lotion, powder, solution, paste, gelifying agent, sprays, aerosol, oil formulation or the transdermal patch that comprise the compounds of this invention.As used herein topical application is also intended to comprise the purposes of collutory and mouth-washes.
Pharmaceutical composition of the present invention and method also can comprise, bright as referred to herein, can be used for the compound of the other treatment activity for the treatment of following disease: type ii diabetes, fat, hyperglycemia, glucose intolerance, insulin resistant, hyperinsulinemia, hypercholesterolemia, hypertension, hyperlipoproteinemia, hyperlipidaemia, HTC, hyperlipemia, metabolism syndrome, X syndrome, cardiovascular disorder, atherosclerosis, kidney disease, ketoacidosis, thrombotic illness, ephrosis, diabetic neuropathy, diabetic retinopathy, sexual dysfunction, tetter, maldigestion, hypoglycemia, cancer and oedema.
At treatment or prevention type ii diabetes, fat, hyperglycemia, glucose intolerance, insulin resistant, hyperinsulinemia, hypercholesterolemia, hypertension, hyperlipoproteinemia, hyperlipidaemia, HTC, hyperlipemia, metabolism syndrome, X syndrome, cardiovascular disorder, atherosclerosis, kidney disease, ketoacidosis, thrombotic illness, ephrosis, diabetic neuropathy, diabetic retinopathy, sexual dysfunction, tetter, maldigestion, hypoglycemia, in cancer and oedema or other situations or illness relevant to GPR40, suitable dosage level was generally for approximately 0.001 to 100mg every kg weight in patients every day, its can single dose or multiple doses use.Preferably, dosage level was approximately 0.01 to about 25mg/kg every day; More preferably, approximately 0.05 to about 10mg/kg every day.Suitable dosage level can be approximately 0.01 to 25mg/kg every day, approximately 0.05 to 10mg/kg every day or approximately 0.1 to 5mg/kg every day.Within the scope of this, dosage can be 0.005 to 0.05,0.05 to 0.5 or 0.5 to 5.0mg/kg every day.For Orally administered, composition preferably provides with tablet form, described tablet comprises 1.0 to 1000 milligrams of activeconstituentss, particularly 1.0,3.0,5.0,10.0,15.0,20.0,25.0,50.0,75.0,100.0,150.0,200.0,250.0,300.0,400.0,500.0,600.0,750.0,800.0,900.0 and 1000.0 milligrams of activeconstituentss, for the symptom adjustment of the dosage to patient to be treated.Compound can every day the treatment plan of 1 to 4 time use, preferably once a day or twice of every day.
But, be to be understood that, concrete dosage level and administration frequency for any particular patient can change, and will depend on many factors, comprise seriousness and the decent subject host of the metabolic stability of activity, this compound of the particular compound of use and effect duration, age, body weight, general health, sex, diet, mode of administration and time, rate of discharge, drug regimen, particular condition.
The compounds of this invention can or be used in combination with other medicament combinations, described other medicaments can be used for treatment, prevention, suppress or improve the compounds of this invention to its useful disease or situation, comprise type ii diabetes, fat, hyperglycemia, glucose intolerance, insulin resistant, hyperinsulinemia, hypercholesterolemia, hypertension, hyperlipoproteinemia, hyperlipidaemia, HTC, hyperlipemia, metabolism syndrome, X syndrome, cardiovascular disorder, atherosclerosis, kidney disease, ketoacidosis, thrombotic illness, ephrosis, diabetic neuropathy, diabetic retinopathy, sexual dysfunction, tetter, maldigestion, hypoglycemia, cancer and oedema, the disease being mediated by GPR40 or situation.Thereby other medicaments like this or medicine can be by normally used approach and with normally used amount and the compounds of this invention side by side, sequentially or dividually use.In the time that the compounds of this invention and one or more other drugs use the same period, except the compounds of this invention, preferably comprise the pharmaceutical composition of such other drug.Therefore, pharmaceutical composition of the present invention comprises the pharmaceutical composition that also comprises one or more other activeconstituentss or therapeutical agent except the compounds of this invention.
Can comprise with the example of the compounds of this invention combination, separate administration or the other treatment agent of using in identical pharmaceutical composition, but be not limited to: (a) cholesterol-lowering agent, as HMG-CoA reductase inhibitor (for example, lovastatin, Simvastatin, Pravastatin, fluvastatin, atorvastatin and other statinses), bile acid chelating agent (for example, Colestyramine and colestipol), vitamins B 3(being also called nicotinic acid or nicotinic acid), vitamins B 6(VB6), vitamins B 12(cyanocobalamin), fiber acid derivative (for example gemfibrozil, clofibrate, fenofibrate and bezafibrate), probucol, pannonit and cholesterol absorption inhibitor (for example, β-sitosterol and acyl-CoA-cholesterol acyltransferase (ACAT) inhibitor is as AC-233), HMG-CoA synthase inhibitor, squalene epoxidase inhibitor and squalene synthetase inhibitor; (b) antithrombotic, as thrombolytic agent (for example, streptokinase, alteplase, Eminase and reteplase), heparin, r-hirudin and warfarin derivative, beta blocker (for example, atenolol USP 23), beta-adrenergic excitomotor (for example, Racemic isoproterenol), ACE inhibitor and vasodilator (for example, Sodium Nitroprusside, nicardipine hydrochloride, pannonit and enalaprilat); (c) antidiabetic drug, as Regular Insulin and para-insulin drugs with function, sulfourea (for example, Glyburide, meglinatide), for example N1,N1-Dimethylbiguanide of biguanides ( ), alpha-glucosidase inhibitor (acarbose), for example thiazolidone of insulin sensitizers (thiazolidinone) compound, rosiglitazone ( ), troglitazone ( ), ciglitazone, pioglitazone ( ) and englitazone, for example vildagliptin of DPP-IV inhibitor (vildagliptin) ( ), west its row spits of fland (sitagliptin) (JanuviaTM) and for example Exenatide of GLP-1 analogue (exenatide) ( ).In certain embodiments, the compounds of this invention can be used together with DPP-IV inhibitor or GLP-1 analogue.In certain embodiments, the compounds of this invention is used with any DPP-IV inhibitor proposing in No. 2006/0270701st, U.S. Patent Publication, and this U.S. Patent Publication is incorporated to its entirety and for all objects are as special proposition herein by reference at this.
The weight ratio of the compounds of this invention and the second activeconstituents can change and will depend on the effective dose of every kind of composition.Conventionally, will use every kind of effective dose.The combination of the compounds of this invention and other activeconstituentss conventionally also will be in aforementioned range, but in each case, should use the effective dose of every kind of activeconstituents.
The purposes of the compounds of this invention and pharmaceutical composition
Preparing the purposes in medicine the invention provides compound of the present invention or pharmaceutical composition, described medicine can be for regulating G-protein linked receptor, and described G-protein linked receptor is preferably GPR40 acceptor.
The methods for the treatment of that comprises the compounds of this invention or pharmaceutical composition administration, further comprises patient to other GPR40 conditioning agents, SGLT-2 inhibitor, biguanides, sulfonylureas, alpha-glucosidase inhibitors, PPAR agonist, α P2 inhibitor, the two activator of PPAR α/γ, dipeptide amido peptidase TV (DPP-IV) inhibitor, glinides, Regular Insulin, glucagon-like-peptide-1 (GLP-1) inhibitor, PTP1B inhibitor, glycogen phosphorylase inhibitors or Robison ester enzyme inhibitors, thus can be by compound of the present invention and other GPR40 conditioning agents, SGLT-2 inhibitor, biguanides, sulfonylureas, alpha-glucosidase inhibitors, PPAR agonist, α P2 inhibitor, the two activator of PPAR α/γ, dipeptide amido peptidase TV (DPP-IV) inhibitor, glinides, Regular Insulin, glucagon-like-peptide-1 (GLP-1) inhibitor, PTP1B inhibitor, glycogen phosphorylase inhibitors or Robison ester enzyme inhibitors Combined Preparation.The compounds of this invention or pharmaceutical composition be as single formulation, or the compound separating or pharmaceutical composition are as a part for multi-form.Other treatment diabetes medicament can from simultaneously administration of the compounds of this invention or administration when different.The latter's situation, administration can be staggered and be carried out carrying out as 6 hours, 12 hours, 1 day, 2 days, 3 days, 1 week, 2 weeks, 3 weeks, 1 month or 2 months.
" significant quantity " of compound of the present invention or pharmaceutically acceptable composition or " effective dose " refer to the significant quantity of processing or alleviating the severity of illness that one or more the present invention mentions.The method according to this invention, compound and composition can be the severity that any dosage and any route of administration are come effectively for the treatment of or palliated a disease.Essential measuring accurately changes the situation according to patient, and this depends on race, the age, and patient's general condition, the severity of infection, special factor, administering mode, etc.Compound or composition can with one or more other treatment agent Combined Preparation, as discussed in the present invention.
Compound of the present invention (form of presentation " formula (I) or formula (II) compound and steric isomer thereof in this article, geometrical isomer, tautomer, mesomeride, racemic modification, enantiomer, diastereomer, oxynitride, hydrate, solvate, meta-bolites and pharmacy acceptable salt and prodrug " can be referred to as " compound of the present invention "), can be for the production of pharmaceutical prod for prevention, treatment, alleviate or delay diabetes, diabetic retinopathy, diabetic neuropathy, diabetic nephropathy, insulin resistance, hyperglycemia, hyperinsulinemia, the elevated levels of lipid acid or glycerine, hyperlipidaemia, obesity, hypertriglyceridemia, X syndromes, ketoacidosis, glucose intolerance, hypercholesterolemia, hyperlipemia, metabolic syndrome, cardiovascular disorder, kidney disease, thrombotic illness, ephrosis, sexual dysfunction, tetter, maldigestion, hypoglycemia, cancer, oedema, diabetic complication, atherosclerosis or hypertension or for increasing hdl level, comprise that those are described in the invention.Further, compound of the present invention can be for the production of the goods that regulate GPRs acceptor.Thus, compound of the present invention can be used for alleviating, stop, control or treating the receptor-mediated disease of the illness that GPRs acceptor mediates, particularly GPR40 for the production of a kind of pharmaceuticals.Thus, compound of the present invention can be as the activeconstituents of pharmaceutical composition, this pharmaceutical composition can comprise the compound of formula (I) or formula (II) representative, can also further comprise at least one pharmaceutically acceptable carrier, vehicle, thinner, assistant agent and vehicle.
General building-up process
Usually, compound of the present invention can prepare by method described in the invention, unless there is further instruction, wherein substituent definition is suc as formula shown in (I) or formula (II).Reaction scheme below and embodiment are for further illustrating content of the present invention.
Those skilled in the art will realize that: chemical reaction described in the invention can be used for preparing suitably many other compounds of the present invention, and be all contemplated within the scope of the present invention for the preparation of other method of compound of the present invention.For example; according to the present invention, the synthetic of the compound of those non-illustrations can successfully be completed by modifying method by those skilled in the art; disturb group as suitable protection, by utilizing other known reagent except described in the invention, or reaction conditions is made to the amendment of some routines.In addition, reaction disclosed in this invention or known reaction conditions are also applicable to the preparation of other compounds of the present invention admittedly.
The embodiments described below, are decided to be degree Celsius unless other aspects show all temperature.Reagent is bought in goods providers as Aldrich Chemical Company, Inc., Arco Chemical Company and Alfa Chemical Company, when use all not through being further purified, unless other aspects show.General reagent is from Xi Long chemical plant, Shantou, Guangdong brilliance chemical reagent factory, and Guangzhou Chemical Reagent Factory, Tianjin Hao Yuyu chemical company limited, Qingdao Teng Long chemical reagent company limited, and Haiyang Chemical Plant, Qingdao buys and obtains.
Anhydrous tetrahydro furan, dioxane, toluene, ether are to reflux to be dried through sodium Metal 99.5 to obtain.Anhydrous methylene chloride and chloroform are to reflux to be dried through hydrolith to obtain.Ethyl acetate, sherwood oil, normal hexane, N,N-dimethylacetamide and DMF are through the prior Dryly use of anhydrous sodium sulphate.
Below reaction is generally at nitrogen or argon gas direct draught or on anhydrous solvent, overlaps a drying tube (unless showing aspect other), all suitable soft rubber balls beyond the Great Wall of reaction flask, and substrate is squeezed into by syringe.Glassware was all dried.
Chromatographic column is to use silicagel column.Silica gel (300-400 order) is purchased from Haiyang Chemical Plant, Qingdao.NMR (Nuclear Magnetic Resonance) spectrum is with CDC1 3, DMSO-d 6, CD 3oD or acetone-d 6for solvent (report is taking ppm as unit), use TMS (0ppm) or chloroform (7.25ppm) as reference standard.In the time there is multiplet, the abbreviation by using below: s (singlet, unimodal), d (doublet, bimodal), t (triplet, triplet), q (quartet, quartet), m (multiplet, multiplet), br (broadened, broad peak), dd (doublet of doublets, two are bimodal), dt (doublet of triplets, two triplets).Coupling constant, represents with hertz (Hz).
Algorithm (MS) data are measured by the spectrograph of the Agilent6320 series LC-MS of outfit G1312A binary pump and a G1316A TCC (column temperature remains on 30 DEG C), G1329A automatic sampler and G1315B DAD detector applies are in analysis, and ESI source is applied to LC-MS spectrograph.
Algorithm (MS) data are measured by the spectrograph of the Agilent 6120 serial LC-MS of outfit G1311A quaternary pump and G1316A TCC (column temperature remains on 30 DEG C), G1329A automatic sampler and G1315D DAD detector applies are in analysis, and ESI source is applied to LC-MS spectrograph.
Above two kinds of spectrographs have all been equipped with Agilent Zorbax SB-C18 post, and specification is 2.1 × 30mm, 5 μ m.Volume injected is to determine by sample concentration; Flow velocity is 0.6mL/min; The peak value of HPLC is by recording and read at the UV-Vis wavelength at 210nm and 254nm place.Moving phase is 0.1% formic acid acetonitrile solution (phase A) and 0.1% formic acid ultrapure water solution (phase B).Condition of gradient elution is as shown in table 1:
Table 1
Time (min) A(CH 3CN,0.1％HCOOH) B(H 2O,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 Agilent 1100 series of high efficiency liquid chromatographies (HPLC), wherein UV detects at 210nm and 254nm place, Zorbax SB-C18 post, specification is 2.1 × 30mm, 4 μ m, 10 minutes, flow velocity was 0.6mL/min, (0.1% aqueous formic acid) of 5-95% (0.1% formic acid acetonitrile solution), column temperature remains on 40 DEG C.
The use of brief word below runs through the present invention:
G gram
Mg milligram
Mmol mmole
Ml, mL milliliter
L liter
DEG C degree Celsius
1h NMR hydrogen 1 NMR (Nuclear Magnetic Resonance) spectrum
13c NMR carbon-13 magnetic resonance wave spectrum
MS mass spectrum
MHz megahertz
Hz hertz
DMSO-d 6deuterated dimethyl sulfoxide
CDCl 3deuterochloroform
Pos.ion positive ion
Neg.ion negative ion
ESI electron spray ionisation
M/z mass-charge ratio
Synthetic method
Compound I can obtain by synthetic method.Wherein A, R 1, R 2with the definition of n as described herein; W is alkyl; Q is leavings group.
Compound I ' in to the solvent of reactionlessness, (as methyl-sulphoxide etc.) obtains compound III with the compound ii with cyclic amino; Compound III under the existence of reductive agent (as sodium borohydride etc.) in to the solvent of reactionlessness (as methyl alcohol, tetrahydrofuran (THF) and their mixed solvent etc.) obtain compound IV; Compounds Ⅳ and halogenating agent (as phosphorus trichloride etc.) are not having under solvent or under to the solvent of reactionlessness (as DMF etc.) or obtaining compound V taking excess of halide agent as solvent reaction; Or compounds Ⅳ and sulfonyl agent (as methylsulfonyl chloride p-methyl benzene sulfonic chloride etc.) in to the solvent of reactionlessness (as DMF etc.) and react and obtain compound V under the existence of alkali (as salt of wormwood etc.); Compound V and compound VI under alkaline condition (as salt of wormwood, potassiumphosphate etc.) being that in the solvent (as DMF etc.) of inertia, reaction obtains compound VI I to reacting; Compound VII (as lithium hydroxide, sodium hydroxide etc.) under the alkali condition reaction that is hydrolyzed in to the solvent (as methyl alcohol, tetrahydrofuran (THF), water and their mixed solvent etc.) of when reaction inertia obtains Compound I
Synthesizing of intermediate
2', 6'-dimethyl-4'-((carbobenzoxy) amino)-[1,1'-biphenyl]-3-methyl-formiate
The first step) 4'-amino-2', 6'-dimethyl-[1,1'-biphenyl]-3-methyl-formiate
By bromo-4-3,5-xylidine (1g, 10mmol), (3-(methoxycarbonyl) phenyl) boric acid (2.7g, 15mmol), salt of wormwood (4.14g, 30mmol), [1, two (diphenylphosphine) ferrocene of 1'-] palladium chloride methylene dichloride complex compound (0.37g, 0.5mmol) be dissolved in DMF (30mL) and water (10mL) stirring reaction 1 hour at 90 DEG C.Reaction solution is extracted with ethyl acetate (200mL × 2) after being cooled to and adding water (30mL) dilution after room temperature, merge organic phase, with saturated nacl aqueous solution washing (50mL), anhydrous sodium sulfate drying, filter concentrating under reduced pressure filtrate.Silica gel chromatography for residue (sherwood oil: ethyl acetate=4:1), obtains faint yellow solid shape title compound (2.1g, yield 82%).
MS(ESI,pos.ion)m/z:256.1[M+H] +。
Second step) 2', 6'-dimethyl-4'-((carbobenzoxy) amino)-[1,1'-biphenyl]-3-methyl-formiate
By 4'-amino-2', 6'-dimethyl-[1,1'-biphenyl]-3-methyl-formiate (5g, 19.6mmol) and pyridine (3.2mL, 40mmol) be dissolved in methylene dichloride (50mL), after adding phenyl chloroformate (3.7mL, 29mmol) under ice bath, naturally rise to room temperature reaction 7 hours.Reaction solution adds aqueous hydrochloric acid cancellation (10mL, 1M), dichloromethane extraction (50mL), saturated nacl aqueous solution washing (30mL) for organic phase, anhydrous sodium sulfate drying, filter, concentrating under reduced pressure filtrate obtains faint yellow solid shape title compound (7.35g, yield 100%).
MS(ESI,pos.ion)m/z:376.2[M+H] +。
Embodiment 1
2-(6-((2', 6'-dimethyl-4'-(5-(methyl sulphonyl) indoline-1-formamido-)-[1,1'-biphenyl]-3-yl) methoxyl group)-2,3-Dihydrobenzofuranes-3-yl) 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) be dissolved in methyl-sulphoxide (10mL) with methyl-sulfinic acid sodium (618mg, 6.05mmol), at 95 DEG C, stir 24 hours.Reaction solution is cooled to and adds after room temperature after water (50mL) cancellation with dichloromethane extraction (50mL × 2), merge organic phase, with saturated nacl aqueous solution washing (30mL), anhydrous sodium sulfate drying, filter, concentrating under reduced pressure filtrate obtains yellow solid shape title compound (0.99g, yield 99.4%).
Second step) 2', 6'-dimethyl-4'-(5-(methyl sulphonyl) indoline-1-formamido-)-[1,1'-biphenyl]-3-methyl-formiate
By 5-(methyl sulphonyl) indoline (410mg; 2.1mmol) and 2'; 6'-dimethyl-4'-((benzene oxygen formyl radical) amino)-[1; 1'-biphenyl]-3-methyl-formiate (0.94g; 2.5mmol), in molten methyl-sulphoxide (10mL), at 85 DEG C, stir and spend the night.Reaction solution is extracted with ethyl acetate (50mL × 2) after adding water (50mL) cancellation, merges organic phase, with saturated nacl aqueous solution washing (30mL), anhydrous sodium sulfate drying, filters concentrating under reduced pressure filtrate.Silica gel chromatography for residue (sherwood oil: ethyl acetate=2:1), obtains yellow solid shape title compound (0.87g, yield 87%).
MS(ESI,pos.ion)m/z:479.2[M+H] +。
The 3rd step) N-(3'-(methylol)-2,6-dimethyl-[1,1'-biphenyl]-4-yl)-5-(methyl sulphonyl) indoline-1-methane amide
By 2'; 6'-dimethyl-4'-(5-(methyl sulphonyl) indoline-1-formamido-)-[1; 1'-biphenyl]-3-methyl-formiate (460mg; 0.96mmol) be dissolved in ethanol (10mL) and water (10mL); under ice bath, add sodium borohydride (344mg; 9.6mmol), finish rear reaction solution room temperature reaction and spend the night after back flow reaction 1 hour.Dichloromethane extraction (100mL × 2) after reaction solution washing (50mL), merges organic phase, with saturated nacl aqueous solution washing (30mL), anhydrous sodium sulfate drying, filters concentrating under reduced pressure filtrate.Silica gel chromatography for residue (methylene dichloride: methyl alcohol=50:1), obtains yellowish solid state title compound (100mg, yield 20%).
The 4th step) N-(3'-(chloromethyl)-2,6-dimethyl-[1,1'-biphenyl]-4-yl)-5-(methyl sulphonyl) indoline-1-methane amide
By N-(3'-(methylol)-2; 6-dimethyl-[1; 1'-biphenyl]-4-yl)-5-(methyl sulphonyl) indoline-1-methane amide (100mg; 0.22mmol) and triethylamine (0.06mL; 0.4mmol) be dissolved in methylene dichloride (3mL); after adding Methanesulfonyl chloride (0.02mL, 0.3mmol), spend the night 0 DEG C of reaction.Reaction solution thin up (30mL), dichloromethane extraction (30mL), saturated nacl aqueous solution washing (30mL) for organic phase, anhydrous sodium sulfate drying, filters concentrating under reduced pressure filtrate.Silica gel chromatography for residue (sherwood oil: ethyl acetate=2:1), obtains white solid title compound (45mg, yield 43%).
MS(ESI,pos.ion)m/z:469.1[M+H] +。
The 5th step) 2-(6-((2'; 6'-dimethyl-4'-(5-(methyl sulphonyl) indoline-1-formamido-)-[1; 1'-xenyl]-3-yl) methoxyl group)-2,3-Dihydrobenzofuranes-3-yl) methyl acetate
By N-(3'-(methylol)-2; 6-dimethyl-[1; 1'-biphenyl]-4-yl)-5-(methyl sulphonyl) indoline-1-methane amide (45mg; 0.1mmol), 2-(6-hydroxyl-2,3-Dihydrobenzofuranes-3-yl) methyl acetate (24mg; 0.12mmol) and potassiumphosphate (30mg; 0.1mmol) be dissolved in DMF (4mL), be warming up to 70 DEG C of reactions and spend the night.The cancellation of reaction solution water, ethyl acetate extraction (20mL × 2), merges organic phase, with saturated nacl aqueous solution washing (10mL), anhydrous sodium sulfate drying, filters concentrating under reduced pressure filtrate.Silica gel chromatography for residue (sherwood oil: ethyl acetate=1:1), obtains yellow oily title compound (58mg, yield 94%).
MS(ESI,pos.ion)m/z:641.2[M+H] +。
The 6th step) 2-(6-((2'; 6'-dimethyl-4'-(5-(methyl sulphonyl) indoline-1-formamido-)-[1; 1'-biphenyl]-3-yl) methoxyl group)-2,3-Dihydrobenzofuranes-3-yl) acetic acid
By 2-(6-((2'; 6'-dimethyl-4'-(5-(methyl sulphonyl) indoline-1-formamido-)-[1; 1'-xenyl]-3-yl) methoxyl group)-2; 3-Dihydrobenzofuranes-3-yl) methyl acetate (58mg; 0.09mmol) be dissolved in tetrahydrofuran (THF) (1mL); add the rear stirring at room temperature of lithium hydroxide aqueous solution (1mL, 1M) 2 hours.Reaction solution is used hydrochloric acid (2mL after adding water (5mL) dilution, 1M) acidifying, and extract by ethyl acetate (10mL × 2), merge organic phase, with saturated nacl aqueous solution washing (10mL), anhydrous sodium sulfate drying, filter, concentrating under reduced pressure filtrate obtains white solid title compound (20mg, yield 40%).
MS(ESI,neg.ion)m/z:625.2[M-H] -；
1H?NMR(400MHz,CDCl 3)δ8.19(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) tetramethyleneimine-1-formamido-)-[1; 1'-biphenyl]-3-yl) methoxyl group)-2,3-Dihydrobenzofuranes-3-yl) acetic acid
The first step) (R)-3-(methylol) tetramethyleneimine-1-benzyl formate
By (R)-pyrrolidin-3-yl methyl alcohol (2g, 19.77mmol) and sodium bicarbonate (3.3g, 39mmol) be dissolved in ethyl acetate (20mL) and water (20mL) and add chloroformic acid benzyl ester (4.24mL) under room temperature.Reaction solution was room temperature reaction 5 hours.After reaction solution water dilution (20mL), be extracted with ethyl acetate (40mL × 2), merge organic phase, with saturated nacl aqueous solution washing (50mL), anhydrous sodium sulfate drying, filter concentrating under reduced pressure filtrate.Silica gel chromatography for residue (sherwood oil: ethyl acetate=2:1), obtains colorless oil title compound (1.64g, yield 35.2%).
Second step) (R)-3-(((methyl sulphonyl) oxo) methyl) tetramethyleneimine-1-benzyl formate
By (R)-3-(methylol) tetramethyleneimine-1-benzyl formate (1.64g, 6.97mmol) and triethylamine (1.2mL, 8.5mmol) be dissolved in methylene dichloride (20mL), add after Methanesulfonyl chloride (0.66mL, 8.4mmol) room temperature reaction 1 hour.Reaction solution thin up (30mL), dichloromethane extraction (30mL), saturated nacl aqueous solution washing (30mL) for organic phase, anhydrous sodium sulfate drying, filters concentrating under reduced pressure filtrate.Silica gel chromatography for residue (sherwood oil: ethyl acetate=4:1), obtains colorless oil title compound (2.1g, yield 96%).
The 3rd step) (R)-3-((methylthio group) methyl) tetramethyleneimine-1-benzyl formate
By (R)-3-(((methyl sulphonyl) oxo) methyl) tetramethyleneimine-1-benzyl formate (2.1g; 6.7mmol) be dissolved in methyl alcohol (4mL); add and be warming up to 60 DEG C of reactions after sodium methyl mercaptide (2.8g, 40mmol) and spend the night.The cancellation of reaction solution water, ethyl acetate extraction (20mL × 2), merges organic phase, with saturated nacl aqueous solution washing (10mL), anhydrous sodium sulfate drying, filters concentrating under reduced pressure filtrate.Silica gel chromatography for residue (sherwood oil: ethyl acetate=20:1), obtains faint yellow oily title compound (1.68g, yield 94%).
The 4th step) (R)-3-((methyl sulphonyl) methyl) tetramethyleneimine-1-benzyl formate
By (R)-3-((methylthio group) methyl) tetramethyleneimine-1-benzyl formate (1.68g, 6.33mmol) be dissolved in methyl alcohol (50mL), after room temperature adds potassium hydrogen persulfate (6g, 9.5mmol), room temperature reaction spends the night.Reacting liquid filtering, filtrate washing (50mL), ethyl acetate extraction (100mL × 2), merges organic phase, with saturated nacl aqueous solution washing (20mL), anhydrous sodium sulfate drying, filters concentrating under reduced pressure filtrate.Silica gel chromatography for residue (methylene dichloride: methyl alcohol=50:1), obtains white solid title compound (1.5g, yield 80%).
The 5th step) (R)-3-((methyl sulphonyl) methyl) pyrroles
By (R)-3-((methyl sulphonyl) methyl) tetramethyleneimine-1-benzyl formate (1.5g; 5mmol) be dissolved in ethanol (25mL), room temperature adds room temperature reaction in the rear atmosphere of hydrogen of 10% palladium carbon (0.3g) to spend the night.Reacting liquid filtering, concentrating under reduced pressure filtrate.Residue is directly used in next step reaction.
The 6th step) (R)-2', 6'-dimethyl-4'-(3-((methyl sulphonyl) methyl) tetramethyleneimine-1-formamido-)-[1,1'-biphenyl]-3-methyl-formiate
By (R)-3-((methyl sulphonyl) methyl) pyrroles (365mg; 2.24mmol) and 2'; 6'-dimethyl-4'-((carbobenzoxy) amino)-[1; 1'-biphenyl]-3-methyl-formiate (700mg; 1.86mmol) be dissolved in methyl-sulphoxide (10mL), at 80 DEG C, stir and spend the night.Reaction solution is extracted with ethyl acetate (50mL × 2) after adding water (50mL) cancellation, merges organic phase, with saturated nacl aqueous solution washing (30mL), anhydrous sodium sulfate drying, filters concentrating under reduced pressure filtrate.Silica gel chromatography for residue (sherwood oil: ethyl acetate=1:1), obtains yellow solid shape title compound (566mg, yield 68%).
The 7th step) (R)-N-(3'-(methylol)-2,6-dimethyl-[1,1'-biphenyl]-4-yl)-3-((methyl sulphonyl) methyl) tetramethyleneimine-1-methane amide
By (R)-2'; 6'-dimethyl-4'-(3-((methyl sulphonyl) methyl) tetramethyleneimine-1-formamido-)-[1; 1'-biphenyl]-3-methyl-formiate (1g; 2.25mmol) be dissolved in ethanol (30mL) and water (15mL); under ice bath, add sodium borohydride (860mg; 22.6mmol), after finishing rear reaction solution room temperature reaction and spending the night, back flow reaction 1 hour.Dichloromethane extraction (100mL × 2) after reaction solution washing (50mL), merges organic phase, with saturated nacl aqueous solution washing (30mL), anhydrous sodium sulfate drying, filters concentrating under reduced pressure filtrate.Silica gel chromatography for residue (methylene dichloride: methyl alcohol=50:1), obtains white solid title compound (376mg, yield 59.6%).
The 8th step) (R)-(2', 6'-dimethyl-4'-(3-((methyl sulphonyl) methyl) tetramethyleneimine-1-formamido-)-[1,1'-biphenyl]-3-yl) methyl mesylate
By (R)-N-(3'-(methylol)-2; 6-dimethyl-[1; 1'-biphenyl]-4-yl)-3-((methyl sulphonyl) methyl) tetramethyleneimine-1-methane amide (0.55g; 1.32mmol) and triethylamine (0.22mL; 1.6mmol) be dissolved in methylene dichloride (30mL); under ice bath, drip the rear room temperature reaction of methylsulfonyl chloride (0.125mL, 1.58mmol) 1 hour.The reaction solution cancellation (30mL) that adds water, dichloromethane extraction (30mL), saturated nacl aqueous solution washing (30mL) for organic phase, anhydrous sodium sulfate drying, filters concentrating under reduced pressure filtrate.Silica gel chromatography for residue (methylene dichloride: methyl alcohol=50:1), obtains white solid title compound (400mg, yield 61.3%).
The 9th step) 2-((S)-6-((2'; 6'-dimethyl-4'-((R)-3-((methyl sulphonyl) methyl) tetramethyleneimine-1-formamido-)-[1; 1'-xenyl]-3-yl) methoxyl group)-2,3-Dihydrobenzofuranes-3-yl) methyl acetate
By (R)-(2'; 6'-dimethyl-4'-(3-((methyl sulphonyl) methyl) tetramethyleneimine-1-formamido-)-[1; 1'-biphenyl]-3-yl) methyl mesylate (0.4g; 0.81mmol); (S)-2-(6-hydroxyl-2; 3-Dihydrobenzofuranes-3-yl) methyl acetate (120mg; 0.58mmol) and salt of wormwood (250mg; 1.81mmol) be dissolved in N; in dinethylformamide (10mL), be warming up to 80 DEG C of reactions and spend the night.The cancellation of reaction solution water, ethyl acetate extraction (20mL × 2), merges organic phase, with saturated nacl aqueous solution washing (10mL), anhydrous sodium sulfate drying, filters concentrating under reduced pressure filtrate.Silica gel chromatography for residue (sherwood oil: ethyl acetate=1:1), obtains faint yellow oily title compound (260mg, yield 74.4%).
MS(ESI,pos.ion)m/z:607.3[M+H] +。
The tenth step) 2-((S)-6-((2'; 6'-dimethyl-4'-((R)-3-((methyl sulphonyl) methyl) tetramethyleneimine-1-formamido-)-[1; 1'-biphenyl]-3-yl) methoxyl group)-2,3-Dihydrobenzofuranes-3-yl) acetic acid
By 2-((S)-6-((2'; 6'-dimethyl-4'-((R)-3-((methyl sulphonyl) methyl) tetramethyleneimine-1-formamido-)-[1; 1'-xenyl]-3-yl) methoxyl group)-2; 3-Dihydrobenzofuranes-3-yl) methyl acetate (260mg; 0.43mmol) be dissolved in tetrahydrofuran (THF) (4.5mL); add the rear stirring at room temperature of lithium hydroxide aqueous solution (4.5mL, 1M) 2 hours.Reaction solution is used hydrochloric acid (8mL after adding water (5mL) dilution, 1M) acidifying, and extract by ethyl acetate (10mL × 2), merge organic phase, with saturated nacl aqueous solution washing (10mL), anhydrous sodium sulfate drying, filter, concentrating under reduced pressure filtrate obtains white solid title compound (160mg, yield 63%).
MS(ESI,pos.ion)m/z:593.2[M+H] +；
1H?NMR(400MHz,CDCl 3)δ7.40(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) tetramethyleneimine-1-formamido-)-[1; 1'-biphenyl]-3-yl) methoxyl group)-2,3-Dihydrobenzofuranes-3-yl) acetic acid
The first step) (R)-3-(methylol) tetramethyleneimine-1-benzyl formate
By (R)-pyrrolidin-3-yl methyl alcohol (2g, 19.77mmol) and sodium bicarbonate (3.3g, 39mmol) be dissolved in ethyl acetate (20mL) and water (20mL) and add chloroformic acid benzyl ester (4.24mL) under room temperature.Reaction solution was room temperature reaction 5 hours.After reaction solution water dilution (20mL), be extracted with ethyl acetate (40mL × 2), merge organic phase, with saturated nacl aqueous solution washing (50mL), anhydrous sodium sulfate drying, filter concentrating under reduced pressure filtrate.Silica gel chromatography for residue (sherwood oil: ethyl acetate=2:1), obtains colorless oil title compound (1.64g, yield 35.2%).
Second step) (R)-3-(((methyl sulphonyl) oxo) methyl) tetramethyleneimine-1-benzyl formate
By (R)-3-(methylol) tetramethyleneimine-1-benzyl formate (1.64g, 6.97mmol) and triethylamine (1.2mL, 8.5mmol) be dissolved in methylene dichloride (20mL), add after Methanesulfonyl chloride (0.66mL, 8.4mmol) room temperature reaction 1 hour.Reaction solution thin up (30mL), dichloromethane extraction (30mL), saturated nacl aqueous solution washing (30mL) for organic phase, anhydrous sodium sulfate drying, filters concentrating under reduced pressure filtrate.Silica gel chromatography for residue (sherwood oil: ethyl acetate=4:1), obtains colorless oil title compound (2.1g, yield 96%).
The 3rd step) (R)-3-((methylthio group) methyl) tetramethyleneimine-1-benzyl formate
By (R)-3-(((methyl sulphonyl) oxo) methyl) tetramethyleneimine-1-benzyl formate (2.1g; 6.7mmol) be dissolved in methyl alcohol (4mL); add and be warming up to 60 DEG C of reactions after sodium methyl mercaptide (2.8g, 40mmol) and spend the night.The cancellation of reaction solution water, ethyl acetate extraction (20mL × 2), merges organic phase, with saturated nacl aqueous solution washing (10mL), anhydrous sodium sulfate drying, filters concentrating under reduced pressure filtrate.Silica gel chromatography for residue (sherwood oil: ethyl acetate=20:1), obtains faint yellow oily title compound (1.68g, yield 94%).
The 4th step) (R)-3-((methyl sulphonyl) methyl) tetramethyleneimine-1-benzyl formate
By (R)-3-((methylthio group) methyl) tetramethyleneimine-1-benzyl formate (1.68g, 6.33mmol) be dissolved in methyl alcohol (50mL), after room temperature adds potassium hydrogen persulfate (6g, 9.5mmol), room temperature reaction spends the night.Reacting liquid filtering, filtrate washing (50mL), ethyl acetate extraction (100mL × 2), merges organic phase, with saturated nacl aqueous solution washing (20mL), anhydrous sodium sulfate drying, filters concentrating under reduced pressure filtrate.Silica gel chromatography for residue (methylene dichloride: methyl alcohol=50:1), obtains white solid title compound (1.5g, yield 80%).
The 5th step) (R)-3-((methyl sulphonyl) methyl) pyrroles
By (R)-3-((methyl sulphonyl) methyl) tetramethyleneimine-1-benzyl formate (1.5g; 5mmol) be dissolved in ethanol (25mL), room temperature adds room temperature reaction in the rear atmosphere of hydrogen of 10% palladium carbon (0.3g) to spend the night.Reacting liquid filtering, concentrating under reduced pressure filtrate.Residue is directly used in next step reaction.
The 6th step) (R)-2', 6'-dimethyl-4'-(3-((methyl sulphonyl) methyl) tetramethyleneimine-1-formamido-)-[1,1'-biphenyl]-3-methyl-formiate
By (R)-3-((methyl sulphonyl) methyl) pyrroles (365mg; 2.24mmol) and 2'; 6'-dimethyl-4'-((carbobenzoxy) amino)-[1; 1'-biphenyl]-3-methyl-formiate (700mg; 1.86mmol), in molten methyl-sulphoxide (10mL), at 80 DEG C, stir and spend the night.Reaction solution is extracted with ethyl acetate (50mL × 2) after adding water (50mL) cancellation, merges organic phase, with saturated nacl aqueous solution washing (30mL), anhydrous sodium sulfate drying, filters concentrating under reduced pressure filtrate.Silica gel chromatography for residue (sherwood oil: ethyl acetate=1:1), obtains yellow solid shape title compound (566mg, yield 68%).
The 7th step) (R)-2', 6'-dimethyl-4'-(N-methyl-3-((methylsulfonyl) methyl) tetramethyleneimine-1-formamido-)-[1,1'-biphenyl]-3-methyl-formiate
By (R)-2'; 6'-dimethyl-4'-(3-((methyl sulphonyl) methyl) tetramethyleneimine-1-formamido-)-[1; 1'-biphenyl]-3-methyl-formiate (710mg; 1.6mmol) be dissolved in anhydrous N; in dinethylformamide (10mL); room temperature adds the rear room temperature reaction of sodium hydride (77mg, 1.9mmol) 15 minutes.After adding methyl iodide (0.12mL, 1.9mmol) toward reaction solution, room temperature reaction spends the night.Reaction solution saturated aqueous ammonium chloride cancellation (20mL), ethyl acetate extraction (20mL × 2), merges organic phase, with saturated nacl aqueous solution washing (20mL), anhydrous sodium sulfate drying, filters concentrating under reduced pressure filtrate.Silica gel chromatography for residue (sherwood oil: ethyl acetate=1:1), obtains yellow solid shape title compound (650mg, yield 80.7%).
MS(ESI,pos.ion)m/z:459.2[M+H] +。
The 8th step) (R)-N-(3'-(methylol)-2,6-dimethyl-[1,1'-biphenyl]-4-yl)-N-methyl-3-((methyl sulphonyl) methyl) tetramethyleneimine-1-methane amide
By (R)-2'; 6'-dimethyl-4'-(N-methyl-3-((methylsulfonyl) methyl) tetramethyleneimine-1-formamido-)-[1; 1'-biphenyl]-3-methyl-formiate (800mg; 1.74mmol) be dissolved in ethanol (15mL) and water (8mL); under ice bath, add sodium borohydride (670mg; 17.6mmol), finish rear reaction solution room temperature reaction and spend the night after back flow reaction 1 hour.Dichloromethane extraction (100mL × 2) after reaction solution washing (50mL), merges organic phase, with saturated nacl aqueous solution washing (30mL), anhydrous sodium sulfate drying, filters concentrating under reduced pressure filtrate.Silica gel chromatography for residue (methylene dichloride: methyl alcohol=40:1), obtains white solid title compound (340mg, yield 45.3%).
The 9th step) (R)-N-(3'-(chloromethyl)-2,6-dimethyl-[1,1'-biphenyl]-4-yl)-N-methyl-3-((methyl sulphonyl) methyl) tetramethyleneimine-1-methane amide
By (R)-N-(3'-(methylol)-2; 6-dimethyl-[1; 1'-biphenyl]-4-yl)-N-methyl-3-((methyl sulphonyl) methyl) tetramethyleneimine-1-methane amide (340mg; 0.79mmol) be dissolved in N; in dinethylformamide (10mL); under room temperature, drip the rear room temperature reaction of phosphorus oxychloride (0.086mL, 0.94mmol) 3 hours.The reaction solution cancellation (30mL) that adds water, ethyl acetate extraction (30mL), saturated nacl aqueous solution washing (30mL) for organic phase, anhydrous sodium sulfate drying, filter, concentrating under reduced pressure filtrate obtains yellow oily shape title compound (340mg, yield 96%).
MS(ESI,pos.ion)m/z:449.2[M+H] +。
The tenth step) 2-(6-((2'; 6'-dimethyl-4'-((R)-N-methyl-3-((methyl sulphonyl) methyl) tetramethyleneimine-1-formamido-)-[1; 1'-xenyl]-3-yl) methoxyl group)-2,3-Dihydrobenzofuranes-3-yl) methyl acetate
By (R)-N-(3'-(chloromethyl)-2; 6-dimethyl-[1; 1'-biphenyl]-4-yl)-N-methyl-3-((methyl sulphonyl) methyl) tetramethyleneimine-1-methane amide (130mg; 0.62mmol); 2-(6-hydroxyl-2; 3-Dihydrobenzofuranes-3-yl) methyl acetate (125mg; 0.62mmol) and potassiumphosphate (212mg; 0.99mmol) be dissolved in N; in dinethylformamide (5mL), be warming up to 60 DEG C of reactions 3 hours.The cancellation of reaction solution water, ethyl acetate extraction (20mL × 2), merges organic phase, with saturated nacl aqueous solution washing (10mL), anhydrous sodium sulfate drying, filters concentrating under reduced pressure filtrate.Silica gel chromatography for residue (sherwood oil: ethyl acetate=2:1), obtains faint yellow oily title compound (250mg, yield 60.3%).
MS(ESI,pos.ion)m/z:621.2[M+H] +。
The 11 step) 2-(6-((2'; 6'-dimethyl-4'-((R)-N-methyl-3-((methyl sulphonyl) methyl) tetramethyleneimine-1-formamido-)-[1; 1'-biphenyl]-3-yl) methoxyl group)-2,3-Dihydrobenzofuranes-3-yl) acetic acid
By 2-(6-((2'; 6'-dimethyl-4'-((R)-N-methyl-3-((methyl sulphonyl) methyl) tetramethyleneimine-1-formamido-)-[1; 1'-xenyl]-3-yl) methoxyl group)-2; 3-Dihydrobenzofuranes-3-yl) methyl acetate (250mg; 0.40mmol) be dissolved in tetrahydrofuran (THF) (4mL); add the rear stirring at room temperature of lithium hydroxide aqueous solution (4mL, 1M) 2 hours.Reaction solution is used hydrochloric acid (7mL after adding water (5mL) dilution, 1M) acidifying, and extract by ethyl acetate (10mL × 2), merge organic phase, with saturated nacl aqueous solution washing (10mL), anhydrous sodium sulfate drying, filter, concentrating under reduced pressure filtrate obtains white solid title compound (200mg, yield 82%).
MS(ESI,neg.ion)m/z:605.3[M-H] -；
1H?NMR(400MHz,CDCl 3)δ7.44(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-formamido-)-[1,1'-biphenyl]-3-yl) methoxyl group)-2,3-Dihydrobenzofuranes-3-yl) acetic acid
Synthesis step is with embodiment 2.
MS(ESI,pos.ion)m/z:515.0[M+H] +；
1H?NMR(600MHz,CDCl 3)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) tetramethyleneimine-1-formamido-)-[1; 1'-biphenyl]-3-yl) methoxyl group)-2,3-Dihydrobenzofuranes-3-yl) acetic acid
Synthesis step is with embodiment 2.
MS(ESI,pos.ion)m/z:593.2[M+H] +；
1H?NMR(600MHz,CDCl 3)δ7.50–7.33(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'-(tetramethyleneimine-1-formamido-)-[1,1'-biphenyl]-3-yl) methoxyl group)-2,3-Dihydrobenzofuranes-3-yl) acetic acid
Synthesis step is with embodiment 2.
MS(ESI,pos.ion)m/z:501.1[M+H] +；
1H?NMR(600MHz,CDCl 3)δ7.49–7.33(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-formamido-)-[1,1'-biphenyl]-3-yl) methoxyl group)-2,3-Dihydrobenzofuranes-3-yl) acetic acid
Synthesis step is with embodiment 2.
MS(ESI,pos.ion)m/z:592.9[M+H] +；
1H?NMR(600MHz,CDCl 3)δ7.42(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-((2', 6'-dimethyl-4'-(3-(methyl sulphonyl) azetidine-1-formamido-)-[1,1'-biphenyl]-3-yl) methoxyl group)-2,3-Dihydrobenzofuranes-3-yl) acetic acid
Synthesis step is with embodiment 2.
MS(ESI,pos.ion)m/z:565.2[M+H] +；
1H?NMR(400MHz,DMSO-d 6)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
The Activation Activity of test case the compounds of this invention to GPR40 cell
In 384 orifice plates, inoculate hGPR40 high expressing cell (the HEK293 clone of stably express hGPR40 is protected promise science and technology (Beijing) company limited and built), inoculum density is 8000/hole.Cell is at 37 DEG C, 5%CO 2under condition, cultivate 24 hours.When experiment, 384 orifice plates that are covered with cell are taken out from incubator, discard substratum, add (the preparation of calcium dyestuff: 20mL HBSS (20mM HEPES)+2tube dye+200 μ L 10%BSA of calcium dyestuff, Calcium 4assay kit, Molecular Device), 40 μ L/ holes.384 orifice plates are put back in incubator, hatch 1 hour.Set FLIPR experimental arrangement, every hole adds the compounds of this invention and the positive control of 3 times of gradient dilutions, 10 μ L/ holes, the interior Ca of cell that uses FLIPR instrument to increase 2+the detection of concentration.Raw data is carried out matching with XLfit, obtains the EC of each compound 50value.Experimental result sees the following form.
Compound number EC 50(nM) Compound number EC 50(nM) Compound number EC 50(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 (10)

1. a compound, it is suc as formula the compound shown in (I), or steric isomer, geometrical isomer, tautomer, oxynitride, hydrate, solvate, meta-bolites, pharmacy acceptable salt or the prodrug of the compound shown in formula (I)
Wherein, ring A is C 2-10heterocyclic radical, C 5-12condense assorted bicyclic group, C 5-12the assorted bicyclic group of spiral shell or C 5-12the bridge bicyclic group of mixing;
Each R 1be hydrogen, C independently 1-6alkyl, C 1-6haloalkyl, halogen, C 1-6alkyl sulphonyl or C 1-6alkyl sulphonyl C 1-6alkyl; Or two adjacent R 1coupled atom forms C together 6-10aromatic ring or C 1-9hetero-aromatic ring, wherein said C 6-10aromatic ring and C 1-9hetero-aromatic ring is optionally independently selected from hydrogen, fluorine, chlorine, bromine, hydroxyl, C by 1,2,3 or 4 independently of one another 1-4alkyl, C 1-4haloalkyl, C 1-4alkyl sulphonyl, amino-sulfonyl or C 1-4halogenated alkyl sulfonyl substituting group replaces;
R 2for hydrogen or C 1-6alkyl; With
N is 1,2,3 or 4.
2. compound according to claim 1, it has suc as formula the structure shown in (II), or steric isomer, geometrical isomer, tautomer, oxynitride, hydrate, solvate, meta-bolites, pharmacy acceptable salt or the prodrug of the compound shown in formula (II)
Wherein, k and m are 0,1,2,3 or 4 independently of one another.
3. compound according to claim 1, wherein
A ring is
4. according to the arbitrary described compound of claim 1-3, wherein
Each R 1be hydrogen, C independently 1-4alkyl, C 1-4haloalkyl, fluorine, chlorine, bromine, C 1-4alkyl sulphonyl or C 1-4alkyl sulphonyl C 1-4alkyl;
Or two adjacent R 1coupled atom forms C together 6-10aromatic ring or C 1-9hetero-aromatic ring, wherein said C 6-10aromatic ring and C 1-9hetero-aromatic ring is optionally independently selected from hydrogen, fluorine, chlorine, bromine, hydroxyl, C by 1,2,3 or 4 independently of one another 1-4alkyl, C 1-4haloalkyl, C 1-4alkyl sulphonyl, amino-sulfonyl or C 1-4halogenated alkyl sulfonyl substituting group replaces; With
R 2for hydrogen or C 1-4alkyl.
5. according to the arbitrary described compound of claim 1-3, wherein
Each R 1be hydrogen, methyl, ethyl, propyl group, butyl, the tertiary butyl, trifluoromethyl, fluorine, chlorine, bromine, methyl sulphonyl, ethylsulfonyl, sulfonyloxy methyl ylmethyl, methyl sulphonyl ethyl or methyl sulphonyl propyl group independently; With
R 2for hydrogen, methyl, ethyl, propyl group or butyl.
6. according to the arbitrary described compound of claim 1-3, comprise following one of them structure:
or its steric isomer, geometrical isomer, tautomer, oxynitride, hydrate, solvate, meta-bolites, pharmacy acceptable salt or prodrug.
7. a pharmaceutical composition, described pharmaceutical composition comprises the compound described in any one in claim 1-6, further comprises pharmaceutically acceptable carrier, vehicle, thinner, assistant agent, vehicle or its combination.
8. pharmaceutical composition according to claim 7, it further comprises antidiabetic medicine, hyperglycemia medicine, anti-obesity medicine, antihypertensive drug, antiplatelet drug, Antiatherosclerosis medicine, fat-reducing medicament, anti-inflammation drugs or its combination.
9. according to the pharmaceutical composition described in any one in claim 7-8, it further comprises at least one GPR40 receptor stimulant.
In a claim 1-6 pharmaceutical composition described in the compound described in any one or any one in claim 7-9 for the preparation of prevention, treatment, alleviate or delay diabetes, diabetic retinopathy, diabetic neuropathy, diabetic nephropathy, insulin resistance, hyperglycemia, hyperinsulinemia, the elevated levels of lipid acid or glycerine, hyperlipidaemia, obesity, hypertriglyceridemia, X syndromes, ketoacidosis, glucose intolerance, hypercholesterolemia, hyperlipemia, metabolic syndrome, cardiovascular disorder, kidney disease, thrombotic illness, ephrosis, sexual dysfunction, tetter, maldigestion, hypoglycemia, cancer, oedema, diabetic complication, atherosclerosis or hypertension or for increasing the purposes in hdl level medicine.
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