CN104262330A - Novel carbamide substituted biphenyl compounds, compositions and applications thereof - Google Patents
Novel carbamide substituted biphenyl compounds, compositions and applications thereof Download PDFInfo
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- CN104262330A CN104262330A CN201410429055.4A CN201410429055A CN104262330A CN 104262330 A CN104262330 A CN 104262330A CN 201410429055 A CN201410429055 A CN 201410429055A CN 104262330 A CN104262330 A CN 104262330A
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- 0 CC(C(C(*)N(*)C(NC1C(C2)C2(C)C(c2cccc(COC3C=C4OCC(CC(O)=O)C4CC3)c2)=C(C)C1)=O)C(C)=C)C=N Chemical compound CC(C(C(*)N(*)C(NC1C(C2)C2(C)C(c2cccc(COC3C=C4OCC(CC(O)=O)C4CC3)c2)=C(C)C1)=O)C(C)=C)C=N 0.000 description 1
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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
Abstract
The invention relates to biphenyl derivatives, a preparation method, pharmaceutical compositions, and medicinal applications thereof. Specifically, the invention relates to novel carbamide substituted biphenyl compounds, pharmaceutical compositions and a preparation method thereof, further relates to an application of the biphenyl derivatives or pharmaceutical compositions containing the biphenyl derivatives as a treating agent, and especially relates to the application of the biphenyl derivatives or pharmaceutical compositions containing the biphenyl derivatives as a GPR40 agonist and in the preparation of drugs for treating diabetes and metabolic diseases. The provided compounds contain a carbamido group, and thus are special and novel in the structure.
Description
Technical field
The present invention relates to the compound and the acceptable composition of pharmacy thereof and the purposes for the preparation of GPR40 relative disease medicine that have and regulate GPR40 activity.Especially, the present invention relates to a kind of New Type Urea substituted biphenyl compounds, pharmaceutical composition containing these compounds and these compounds and be relevant to the purposes in the disease medicament of GPR40 activity for the preparation of some.The compound that 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 superfamilies of G-protein linked receptor (" GPRs ").GPRs is the membranin being characterized as the cross-film district with 7 presumptions, by activating the vital Intracellular signals pipeline of various physiological-function in response to various molecule.First GPR40 is accredited as orphan receptor (that is, not having 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 the G with Intracellular signals transferrin
qthe adjustment of family associates with the induction phase of the calcium level of adjoint rising.Lipid acid is as the part of GPR40, and lipid acid regulates insulin secretion to be known by GPR40.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 compound of many adjustment GPR40 activity is disclosed, the high incidence of type ii diabetes, obesity, hypertension, cardiovascular disorder and hyperlipemia, has pointed out effectively treating or preventing the demand of the new therapy of these diseases urgent.
The futuramic biphenyl compound be substituted of the present invention, it has and regulates the ability of 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 disorder, 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 such as formula the compound shown in the compound shown in (I) or formula (I), geometrical isomer, tautomer, oxynitride, hydrate, solvate, meta-bolites, pharmacy acceptable salt or prodrug
Wherein, B ring is C
2-10heterocyclic radical, C
5-12condense assorted bicyclic group, C
5-12spiral shell is mixed bicyclic group or C
5-12bridge is mixed bicyclic group;
R
1for hydrogen, C
1-6alkyl, C
6-10aryl or C
1-9heteroaryl, wherein said C
1-6alkyl, C
6-10aryl and C
1-9heteroaryl is optionally independently selected from hydrogen, fluorine, chlorine, bromine, hydroxyl, C by 1,2,3 or 4 independently of one another
1-6alkyl, C
1-6haloalkyl, C
1-6alkyl sulphonyl, amino-sulfonyl or C
1-6halogenated alkyl sulfonyl substituting group replaces; With
Each R
2be hydrogen, C independently
1-6alkyl, C
1-6haloalkyl, fluorine, chlorine, bromine, C
1-6alkyl sulphonyl or C
1-6alkyl sulphonyl C
1-6alkyl; Or adjacent two R
2coupled 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
N is 1,2,3 or 4.
In certain embodiments, the present invention relates to a kind of steric isomer such as formula the compound shown in the compound shown in (II) or formula (II), geometrical isomer, tautomer, oxynitride, hydrate, solvate, meta-bolites, pharmacy acceptable salt or prodrug
Wherein, m is 0,1,2 or 3.
In certain embodiments, B ring is
In further embodiments, R
1for hydrogen, C
1-4alkyl, C
6-10aryl or C
1-9heteroaryl, wherein said C
1-4alkyl, C
6-10aryl and C
1-9heteroaryl 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
Each R
2be hydrogen, C independently
1-6alkyl, C
1-6haloalkyl, fluorine, chlorine, bromine, C
1-6alkyl sulphonyl or C
1-6alkyl sulphonyl C
1-6alkyl; Or adjacent two R
2coupled 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.
In further embodiments, R
1for hydrogen, methyl, ethyl, propyl group, butyl, the tertiary butyl or phenyl, wherein said methyl, ethyl, propyl group, butyl, the tertiary butyl and phenyl are optionally independently selected from hydrogen, fluorine, chlorine, bromine, hydroxyl, methyl, ethyl, propyl group, butyl, trifluoromethyl, methyl sulphonyl, amino-sulfonyl or trifluoromethyl sulfonyl substituting group by 1,2,3 or 4 independently of one another and replace; With
Each R
2be hydrogen, methyl, ethyl, propyl group, butyl, the tertiary butyl, trifluoromethyl, fluorine, chlorine, bromine, methyl sulphonyl, sulfonyloxy methyl ylmethyl, methysulfonylethyl or methanesulphonylpropyl independently; Or adjacent two R
2coupled atom forms phenyl together; pyridyl or naphthyl; wherein said phenyl; pyridyl and naphthyl are optionally independently selected from hydrogen, fluorine, chlorine, bromine, hydroxyl, methyl, ethyl by 1,2,3 or 4 independently of one another, and propyl group, butyl, trifluoromethyl, methyl sulphonyl, ethylsulfonyl, amino-sulfonyl or trifluoromethyl sulfonyl substituting group replace.
In further embodiments, the present invention comprises one of them structure following:
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 one compound, comprises pharmaceutically acceptable carrier, vehicle, thinner, assistant agent, vehicle or its combination further.
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 disorder, 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 on the other hand the preparation of compound that formula (I) or formula (II) comprise, the method for abstraction and purification.
Content noted earlier only outlines some aspect of the present invention, but is not limited to these aspects.The content of these aspects and other aspect will do more specifically complete description below.
The detailed description of the invention
Definition and general terms
Present detailed description certain embodiments of the present invention, the example is by the structural formula of enclosing and chemical formula explanation.The invention is intended to contain all to substitute, amendment and equivalent technical solutions, they include in the scope of the invention of such as claim definition.Those skilled in the art will appreciate that many or methods of being equal to similar with described herein and material can be used in putting into practice the present invention.The present invention is never limited to method as herein described and material.Combined document, patent and (include but not limited to defined term, term application, described technology, etc.) in one or more different from the application or conflicting situations of analogous material, be as the criterion with the application.
Should recognize further, some feature of the present invention, for clearly visible, be described in multiple independently embodiment, but also can provide in combination in single embodiment.Otherwise various feature of the present invention, for for purpose of brevity, is described in single embodiment, but also can provide separately or with the sub-portfolio be applicable to arbitrarily.
Unless otherwise indicated, all scientific and technical terminologies used in the present invention have the implication identical with the usual understanding of those skilled in the art of the invention.The all patents that the present invention relates to and public publication by reference entirety are incorporated to the present invention.
Unless otherwise indicated, this paper institute should be applied and use to obtain following definition.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 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, such as, also refer to primate (the such as 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.
Stereochemical definitions Sum fanction used in the present invention generally follows 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 active forms, and namely they have the ability that the plane of plane polarized light is rotated.When describing optically active compound, prefix D and L or R and S is used to represent the absolute configuration of molecule about one or more chiral centre.Prefix d and l or (+) and (-) are the symbols being used to specify plane polarized light rotation caused by compound, and wherein (-) or l represent that compound is left-handed.Prefix is 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 not having stereoselectivity or stereospecificity in chemical reaction or process, can occur this situation.
Come into the open any asymmetric atom (such as, carbon etc.) of compound of the present invention can exist with the form of racemize or enantiomorph enrichment, such as (R)-, (S)-or (R, S)-configuration exist.In certain embodiments, each asymmetric atom has at least 50% enantiomeric excess in (R)-or (S)-configuration, 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 with in possible isomer or their mixture, and the form of such as racemic modification and non-corresponding isomer mixture (this depends on the quantity of unsymmetrical carbon) exists.Optically active (R)-or (S)-isomer can use chiral synthon or chiral reagent preparation, or use routine techniques to split.If compound contains a double bond, substituting group may be E or Z configuration; If containing 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, diastereomer, such as, by chromatography and/or Steppecd crystallization.
By known method, the method that the racemic modification of any gained end product or intermediate is familiar with by those skilled in the art can be split into optical antipode, e.g., by being separated its diastereoisomeric salt obtained.Racemic product also can be separated by chiral chromatography, e.g., uses the high performance liquid chromatography (HPLC) of chiral sorbent.Especially, enantiomer can be prepared by asymmetric synthesis, such as, can 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, S.H.Tables of Resolving Agents and Optical Resolutions p.268 (E.L.Eliel, Ed., Univ.of Notre Dame Press, Notre Dame, IN 1972); Chiral Separation Techniques:A Practical Approach (Subramanian, G.Ed., Wiley-VCH Verlag GmbH & Co.KGaA, Weinheim, Germany, 2007).
Term " tautomer " or " tautomeric form " refer to the constitutional isomer transformed mutually by low energy barrier (low energy barrier) with different-energy.If tautomerism is possible (as in the solution), then can reach the chemical equilibrium of tautomer.Such as, proton tautomer (protontautomer) (comprises the mutual conversion undertaken by proton shifting, as keto-enol isomerization and imine-enamine isomerizations also referred to as Prototropic tautomers (prototropic tautomer).Valence tautomerism body (valence tautomer) comprises the mutual conversion undertaken by the restructuring of some bonding electronss.The specific examples of keto-enol tautomerism is the change of pentane-2,4-diketone and 4-hydroxyl penta-3-alkene-2-keto tautomer.Another example tautomeric 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.
As described in the invention, compound of the present invention can optionally replace by one or more substituting group, as general formula compound above, or special example inside picture embodiment, subclass, and the compounds that the present invention comprises.Should be appreciated that " being optionally substituted " this term and " substituted or non-substituted " this term can exchange use.Generally speaking, term " replacement " represent give the one or more hydrogen atoms in structure replace by concrete substituting group.Unless other aspects show, an optional substituted radical can replace in each commutable position of group.Not only one or more substituting groups that position can be selected from concrete group in given structural formula replaced, and so substituting group can replace in each position identical or differently.
In addition, it should be noted that, unless otherwise explicitly pointed out, adopted in the present invention describing mode " 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 group, did not affect mutually between concrete option expressed between same-sign, also can represent in identical group, not affect mutually between concrete option expressed between same-sign.Such as structure
with
structure, the R in both
2concrete option is unaffected each other, meanwhile, occurs multiple R in same structure
2, multiple R
2between concrete option be independent of each other, i.e. R
2concrete option can be identical, also can be different.
At 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, each the independently sub-combinations thereof that the present invention includes each member of these radical species and scope.Such as, 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, describe connection substituting group.When this structure clearly needs linking group, be interpreted as linking group for the Ma Kushi variable cited by this group.Such as, if this structure needs linking group and Ma Kushi group definition for this variable lists " alkyl " or " aryl ", then should be appreciated that, " alkyl " or " aryl " alkylidene group or the arylene group of connection should be represented respectively.
The term " alkyl " that the present invention uses or " alkyl group ", represent containing 1 to 20 carbon atom, saturated straight or branched univalent hydrocarbyl group, wherein, the substituting group that described alkyl group can optionally be described by one or more the present invention replace.Unless otherwise detailed instructions, alkyl group contains 1-20 carbon atom.In some embodiments, alkyl group contains 1-12 carbon atom; In other embodiments, alkyl group contains 1-6 carbon atom; In other embodiment, 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 " represent alkyl replace by one or more halogen atom, such example comprises, but is not limited to, trifluoromethyl etc.
Term " heterocyclic radical " and " heterocycle " commutative use herein, all refer to and comprise the saturated of 3-12 annular atoms or the undersaturated monocycle of part, 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 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, oxetanylmethoxy, thietanyl, 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, but its core texture does not comprise aromatic nucleus or fragrant heterocycle (but aromatic series can as the substituting group on it).And at least one member ring systems comprises one or more heteroatoms, wherein each member ring systems comprises 3-7 ring, namely comprise 1-6 carbon atom and be selected from 1-3 the heteroatoms of N, O, P, S, at this S or P optionally replace by one or more Sauerstoffatom and obtain such as SO, SO
2, PO, PO
2group.Described annelated heterocycles base can be substituted 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 ring-type carbon special on another ring.Such as, as described above, ring A and ring B shares a carbon atom in two saturated member ring systems, be then called as " volution ".And at least one member ring systems comprises one or more heteroatoms, wherein each member ring systems comprises 3-7 ring, namely comprise 1-6 carbon atom and be selected from 1-3 the heteroatoms of N, O, P, S, at this S or P optionally replace by one or more Sauerstoffatom and obtain such as SO, SO
2, PO, PO
2group.And described spiro heterocyclic radical can be substituted 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, but its core texture does not comprise aromatic nucleus or fragrant heterocycle (but aromatic series can as the substituting group on it).And at least one member ring systems comprises one or more heteroatoms, wherein each member ring systems comprises 3-7 ring, namely comprise 1-6 carbon atom and be selected from 1-3 the heteroatoms of N, O, P, S, at this S or P optionally replace by one or more Sauerstoffatom and obtain such as SO, SO
2, PO, PO
2group, and described assorted bridged ring base can be substituted or unsubstituted, and 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 containing 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 point 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 containing 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 heteroatoms, and has one or more attachment point 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 to alkyl alkylsulfonyl being connected with a present invention and defining, and alkylsulfonyl is connected with the rest part of molecule.
Term " amino-sulfonyl " refers to and alkylsulfonyl is connected with an amino, and alkylsulfonyl is connected with the rest part of molecule.
Term " halogenated alkyl sulfonyl " refers to haloalkyl alkylsulfonyl being connected with a present invention and defining, and alkylsulfonyl is connected with the rest part of molecule.
Term " Alkylsulfonylalkyl " refers to that " alkyl sulphonyl " that the present invention defines is connected on the alkyl that a present invention defines, and alkyl is connected with the rest part of molecule.
Term " two adjacent R
2coupled atom forms aromatic ring or hetero-aromatic ring together " refer to two adjacent atoms and the connection portion R on it
2form aromatic ring or hetero-aromatic ring together.Some of them embodiment is, as two R adjacent on structure H1
2, aromatic ring or hetero-aromatic ring is formed, if structure H2, M ring is aromatic ring or hetero-aromatic ring together with the atom be connected.
Term " leavings group " to refer in chemical reaction from one compared with the atom departed from macromole or functional group.In nucleophilic substitution reaction, be called substrate by the reactant of nucleophilic reagent attack, and the atom ruptured away with pair of electrons from substrate molecule or atomic group are called leavings group.Easily accept electronics, bear the leavings group that the strong group of negative charge ability has been.
Time term " blocking group " or " PG " refer to a substituting group and other reacted with functional groups, be commonly used to block or protect special functional.Such as; " amino blocking group " refer to a substituting group be connected with amino group block or protect in compound amino functional; suitable amido protecting group comprises ethanoyl; trifluoroacetyl group; tertbutyloxycarbonyl (BOC; Boc), carbobenzoxy-(Cbz) (CBZ, Cbz) and the sub-methoxycarbonyl (Fmoc) of 9-fluorenes.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 " refers to that the substituting group of carboxyl is used for blocking or protecting the functional of carboxyl, and general carboxyl-protecting group comprises-CH
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 a compound and is converted into formula (I) or the compound shown in formula (II) in vivo.Such conversion by prodrug be hydrolyzed in blood or blood or tissue in through enzymatic conversion be the impact of precursor structure.Prodrug compounds of the present invention can be ester, and in existing invention, ester can have phenyl ester class, aliphatics (C as prodrug
1-24) ester class, acyloxymethyl ester class, carbonic ether, amino formate and amino acid esters.Such as, a compound in the present invention comprises hydroxyl, namely its acidylate can be obtained the compound of prodrug form.Other prodrug form comprises phosphoric acid ester, if these phosphate compounds are that di on parent obtains.Can with reference to Publication about Document about the complete discussion of prodrug: T.Higuchi and V.Stella, Pro-drugs as Novel Delivery Systems, Vol.14 of the A.C.S.Symposium Series, Edward B.Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, J.Rautio et al., Prodrugs:Design and Clinical Applications, Nature Review Drug Discovery, 2008, 7, 255-270, and S.J.Hecker et al., Prodrugs of Phosphates and Phosphonates, Journal of Medicinal Chemistry, 2008, 51, 2328-2345.
" meta-bolites " refers to concrete compound or its salt in vivo by product that metabolism obtains.The meta-bolites of a compound can be identified by the known technology in affiliated field, and its activity can be characterized by such method of test that adopts as described in the present invention.Such product can be by obtaining through oxidation, reduction, hydrolysis, amidated, desamido-effect, esterification, fat abstraction, enzymatic lysis etc. method to drug compound.Correspondingly, the present invention includes the meta-bolites of compound, comprise and compound of the present invention and Mammals fully contacted the meta-bolites that for some time produces.
" 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 in affiliated field known by us, as document: S.M.Berge et al., describe pharmaceutically acceptable salts in detail in J.Pharmaceutical Sciences, described in 1977,66:1-19..The salt that pharmaceutically acceptable nontoxic acid is formed comprises, but be not limited to, reacting with amino group the inorganic acid salt formed has hydrochloride, hydrobromate, phosphoric acid salt, vitriol, perchlorate and organic acid salt as acetate, oxalate, maleate, tartrate, Citrate trianion, succinate, malonate or obtains these salt by additive method such as ion exchange method described on books document.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 obtained by suitable alkali comprises basic metal, alkaline-earth metal, ammonium and N
+(C
1-4alkyl)
4salt.The quaternary ammonium salt that the compound that the present invention also intends the group contemplating any comprised N is formed.Water-soluble or oil soluble or dispersion product can be obtained by quaternization.Basic metal or alkaline earth salt comprise sodium, lithium, potassium, calcium, magnesium etc.Pharmacy acceptable salt comprises suitable, nontoxic ammonium further, the amine positively charged ion that quaternary ammonium salt and gegenions are formed, as halogenide, and 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 molecule and compound of the present invention are formed.The solvent forming 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 is formed.
Term as used in the present invention " treatment " any disease or illness, some embodiment middle fingers improve disease or illness (namely slow down or stop or palliate a disease or the development of its at least one clinical symptom) wherein.In other embodiments, " treatment " refers to relax or improve at least one body parameter, comprises the body parameter may not discovered for patient.In other embodiments, " treatment " refer to from health (such as stablizing perceptible symptom) or physiology (such as stablizing the parameter of health) or above-mentioned two aspects regulate disease or illnesss.In other embodiments, " treatment " refer to prevent or postpone the outbreak of disease or illness, generation or deterioration.
Pharmaceutically useful acid salt can be formed with mineral acid and organic acid, such as 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.
Such as hydrochloric acid, Hydrogen bromide, sulfuric acid, nitric acid, phosphoric acid etc. can be comprised by its derivative mineral acid obtaining salt.
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. can be comprised by its derivative organic acid obtaining salt.
Pharmaceutically acceptable base addition salt can be formed with mineral alkali and organic bases.
Can be comprised by its derivative mineral alkali obtaining salt, the metal of I race to the XII race of such as ammonium salt and periodictable.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 obtaining salt, the amine of replacement comprises the amine, cyclic amine, deacidite etc. of naturally occurring replacement.Some organic amine comprises, such as, 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 with conventional chemical processes.Generally speaking, such salt can react by making the suitable alkali of the free acid form of these compounds and stoichiometry (oxyhydroxide, carbonate, supercarbonate etc. as Na, Ca, Mg or K), or by making the suitable acid-respons of the free alkali form of these compounds and stoichiometry be prepared.Such reaction is carried out usually in water or organic solvent or the mixture of the two.Usually, when suitable, need to use non-aqueous media as ether, ethyl acetate, ethanol, Virahol or acetonitrile.At such as " 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) other can be found to be suitable for the list of salt in.
In addition, compound disclosed by the invention, comprise their salt, also can obtain, for their crystallization with their hydrate forms or the form comprising its solvent (such as ethanol, methyl-sulphoxide (DMSO), etc.).Compound is come into the open in the present invention can 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 non-solvation.
As described in the present invention, substituting group is drawn a key and is connected to the member ring systems (such as formula (a) Suo Shi) that the ring at center is formed and represents substituent R
5can replace any commutable position on ring.Such as, formula (a) represents any position that may be substituted on W1 ring or W2 ring and all can be substituted.
As described in the present invention, have two tie points to be connected with molecule rest part in member ring systems, such as formula shown in (b), expression both can be E end also can be that E ' end is connected with molecule rest part, and namely 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 that is medicinal, that comprise one or more compounds of the present invention.This pharmaceutical composition can also comprise pharmaceutically acceptable carrier, vehicle, thinner, assistant agent, vehicle or its combination further.Described pharmaceutical composition may 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 disorder, 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 uses 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.Such as, SGLT-2 inhibitor, biguanides, sulfonylureas, alpha-glucosidase inhibitors, PPAR agonist, α P2 inhibitor, PPAR α/γ two activator, 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.
When can be used for treatment, 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 carrier, thinner or vehicle.Term as used herein " treatment significant quantity " refers to the total amount being enough to each active ingredient demonstrating significant patient benefit (such as blood sugar reduction).When using independent activeconstituents individually dosed, this term only refers to this composition.When Combination application, and though this term then refer to combination, successively or simultaneously administration time, all cause 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 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 another aspect of content of the present invention, 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 carrier, 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 that rational medicine judges, to be applicable to patient tissue contacts and without excessive toxicity, pungency, transformation reactions or the other problems symmetrical with rational interests/Hazard ratio and complication, and to be effective to given application.
When the composition of content of the present invention comprises the combination of the compound 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 usually in monotherapy scheme, account for the about 10-150% of bio-occlusion pharmaceutical quantities, more preferably account for the about 10-80% of bio-occlusion pharmaceutical quantities.Pharmaceutical preparation is suitable for by any suitable administration, such as by oral (comprising oral cavity or sublingual), rectum, nose, locally (comprise oral cavity, sublingual or through skin), vagina or parenteral (comprise in subcutaneous, intracutaneous, intramuscular, intraarticular, synovial membrane, in breastbone, in sheath, intralesional, intravenously or intradermal injection or infusion) approach.This kind of preparation can be prepared, such as, by by activeconstituents and carrier or mixed with excipients by any currently known methods of art of pharmacy.Preferred oral administration or drug administration by injection.
Can provide in a unit easily for using the pharmaceutical composition of the compounds of this invention and prepare by any method well-known in the art.All methods comprise the step that activeconstituents is combined with the carrier forming one or more ancillary components.Usually, pharmaceutical composition is prepared by the following method: make activeconstituents and liquid carrier or solid-state carrier in small, broken bits or both equably and combine nearly, then, if needed, makes this product form required preparation.In pharmaceutical composition, the Active Target Compounds comprising enough amounts is with the effect desired by producing the process of disease or situation.
Pharmaceutical composition containing activeconstituents can be suitable for oral form, such as, as tablet, lozenge, sugared agent, aqeous suspension or oil suspension, dispersible pulvis or granule, emulsion, hard capsule or syrup or elixir.Be intended for the composition orally used to prepare according to the manufacture known any method of pharmaceutical composition production field.Such composition can comprise the reagent that one or more are selected from sweeting agent, odorant, tinting material and sanitas, and object is to provide pharmaceutically graceful with good to eat preparation.
Tablet comprises the activeconstituents mixed mutually with other the atoxic pharmaceutically acceptable vehicle being suitable for manufacturing tablet.These vehicle can be, such as, 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 be not coated, or they are coated with by known technology the disintegration that delays in the gastrointestinal tract and absorb and thus provide the continuous action of long period.Such as, the time delay material of such as glyceryl monostearate or distearin can be used.They are also coated with the osmotic therapeutic tablets formed for Co ntrolled release by the technology described in U.S. Patent number 4256108,4160452 and 4265874.
Preparation for orally using also can be used as hard gelatin capsule and provides, wherein activeconstituents and such as calcium carbonate, calcium phosphate or kaolinic inert solid mixing diluents; Or provide as soft gelatin capsule, wherein activeconstituents mixes with the oil medium of water or such as peanut oil, liquid paraffin or sweet oil.
Aqeous suspension comprises and the active substance being suitable for the mixed with excipients manufacturing aqeous suspension.Such vehicle is suspension agent, such as Xylo-Mucine, methylcellulose gum, hydroxyl-propyl methylcellulose gum, sodium alginate, Polyvinyl-pyrrolidone, tragacanth gum and Sudan Gum-arabic; Dispersion agent or wetting agent can be naturally occurring phosphatide, such as 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 hexitol the condensation product of partial ester as octadecanoic acid ester of polyethylene glycol, or oxyethane and derive from lipid acid and hexitan the condensation product of partial ester as polyethylene sorbitan monoleate.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 by activeconstituents is suspended in such as peanut oil, sweet oil, sesame oil or Oleum Cocois vegetables oil in or such as whiteruss mineral oil in and prepare.Oil suspension can comprise thickening material, such as beeswax, paraffinum durum or hexadecanol.Such as those sweeting agents set forth above and odorant can be added to provide good to eat oral preparations.These compositions come anticorrosion by the antioxidant adding such as xitix.
The dispersible pulvis or the granule that are suitable for preparing by adding water aqeous suspension provide the activeconstituents mixed 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 having mentioned above.Also can there is other vehicle, such as 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 the vegetables oil of such as sweet oil or peanut oil or the mineral oil of such as whiteruss or these mixture.Suitable emulsifying agent can be naturally occurring natural gum, as Sudan Gum-arabic or tragacanth gum; Naturally occurring phosphatide, as soybean, Yelkin TTS and the ester or the partial ester that derive from lipid acid and hexitan, such as polyoxyethylene-sorbitan mono-oleate; And the condensation product of described partial ester and oxyethane, as polyethylene sorbitan monoleate.Emulsion also can comprise sweeting agent and odorant.
Syrup can be prepared with elixir together with the sweeting agent of 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 according to known technology, use the above suitable dispersion agent that mention or wetting agent and suspension agent and prepare.The preparation of this sterile injectable can also the solution of sterile injectable in nontoxic, the acceptable thinner of parenteral or solvent or suspension, such as, 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 used as solvent or suspension medium.Therefore, the fixing oil of any gentleness can be used, comprise direactive glyceride or two glyceryl ester of synthesis.In addition, the lipid acid of such as oleic acid finds purposes in the preparation of injectable drug.
Pharmaceutical composition can also be used for suppository form or the enema of the rectal administration of medicine.These compositions by prepared by medicine and suitable non-irritating mixed with excipients, described non-irritating vehicle be solid at normal temperatures but under rectal temperature be liquid and thus will melt in the rectum to discharge medicine.Such material comprises, such as, and theobroma oil and polyoxyethylene glycol.
Local is used, adopts 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 the purposes comprising 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 disorder, 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 disorder, ephrosis, diabetic neuropathy, diabetic retinopathy, sexual dysfunction, tetter, maldigestion, hypoglycemia, cancer is with in oedema or other situations relevant to GPR40 or illness, suitable dosage level is generally about 0.001 to 100mg every kg weight in patients every day, it can single dose or multiple doses be used.Preferably, dosage level was about 0.01 to about 25mg/kg every day; More preferably, about 0.05 to about 10mg/kg every day.Suitable dosage level can be about 0.01 to 25mg/kg every day, about 0.05 to 10mg/kg every day or about 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, the symptom for the dosage to patient to be treated adjusts.Compound can every day the treatment plan of 1 to 4 time use, preferably once a day or twice daily.
But, be to be understood that, can change for the concrete dosage level of any particular patient and administration frequency, and will many factors be depended on, comprise the activity of the particular compound of use, the metabolic stability of this compound and effect duration, age, body weight, general health, sex, diet, mode of administration and time, rate of discharge, drug regimen, the seriousness of particular condition and decent subject host.
The compounds of this invention with other pharmaceutical agent combinations or can combinationally use, other medicaments described 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 disorder, ephrosis, diabetic neuropathy, diabetic retinopathy, sexual dysfunction, tetter, maldigestion, hypoglycemia, cancer and oedema, the disease mediated by GPR40 or situation.Other medicaments like this or medicine are by normally used approach and with normally used amount thus side by side, sequentially or dividually use with the compounds of this invention.When 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 except the compounds of this invention also comprises the pharmaceutical composition of one or more other activeconstituentss or therapeutical agent.
Can combine with the compounds of this invention, separate administration or the example of other treatment agent used in identical pharmaceutical composition comprise, but be not limited to: (a) cholesterol-lowering agent, as HMG-CoA reductase inhibitor (such as, lovastatin, Simvastatin, Pravastatin, fluvastatin, atorvastatin and other statinses), bile acid chelating agent (such as, 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 (such as gemfibrozil, clofibrate, fenofibrate and bezafibrate), probucol, pannonit and cholesterol absorption inhibitor (such as, β-sitosterol and acyl-CoA-cholesterol acyltransferase (ACAT) inhibitor are as AC-233), HMG-CoA synthase inhibitor, squalene epoxidase inhibitor and squalene synthetase inhibitor; (b) antithrombotic, as thrombolytic agent (such as, streptokinase, alteplase, Eminase and reteplase), heparin, r-hirudin and warfarin derivative, beta blocker (such as, atenolol USP 23), beta-adrenergic excitomotor (such as, Racemic isoproterenol), ACE inhibitor and vasodilator (such as, Sodium Nitroprusside, nicardipine hydrochloride, pannonit and enalaprilat); (c) antidiabetic drug, as Regular Insulin and para-insulin drugs with function, sulfourea (such as, Glyburide, meglinatide), biguanides such as N1,N1-Dimethylbiguanide
alpha-glucosidase inhibitor (acarbose), insulin sensitizers is thiazolidone (thiazolidinone) compound, rosiglitazone such as
troglitazone
ciglitazone, pioglitazone
and englitazone, DPP-IV inhibitor is vildagliptin (vildagliptin) such as
its row spit of fland (sitagliptin) (JanuviaTM) and GLP-1 analogue such as Exenatide (exenatide) of west
.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 and any DPP-IV inhibitor proposed in No. 2006/0270701st, U.S. Patent Publication are used, and this U.S. Patent Publication to be incorporated to its entirety and in order to 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 often kind of composition.Usually, often kind of effective dose will be used.The combination of the compounds of this invention and other activeconstituentss also in aforementioned range, but in each case, will should use the effective dose of often kind of activeconstituents usually.
The purposes of the compounds of this invention and pharmaceutical composition
The invention provides compound of the present invention or pharmaceutical composition is preparing the purposes in medicine, described medicine may be used for regulating G-protein linked receptor, and described G-protein linked receptor is preferably GPR40 acceptor.
Comprise the methods for the treatment of of the compounds of this invention or pharmaceutical composition administration, comprise further 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 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 are as single formulation, or the compound separated or pharmaceutical composition are as a part for multi-form.Other treatment diabetes medicament can from the compounds of this invention simultaneously administration or different time administration.The situation of the latter, administration can be staggered and be carried out as 6 hours, 12 hours, 1 day, 2 days, 3 days, 1 week, 2 weeks, 3 weeks, 1 month or 2 months carries out.
" significant quantity " or " effective dose " of compound of the present invention or pharmaceutically acceptable composition refer to process or alleviate one or more the present invention mention the significant quantity of the severity of illness.According to method of the present invention, compound and composition can be any dosage and any route of administration come effectively for the treatment of or the severity that palliates a disease.Situation according to patient changes by required measuring accurately, and this depends on race, the age, the general condition of patient, 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 (in this article, form of presentation " formula (I) or formula (II) compound and steric isomer thereof, 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 "), may be used for producing 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 disorder, 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 may be used for producing the goods regulating GPRs acceptor.Thus, compound of the present invention may be used for producing a kind of pharmaceuticals and is used for alleviating, stop, control or treat the receptor-mediated disease of illness, particularly GPR40 that GPRs acceptor mediates.Thus, compound of the present invention can be used as the activeconstituents of pharmaceutical composition, this pharmaceutical composition can comprise formula (I) or the compound representated by formula (II), can also comprise the pharmaceutically acceptable carrier of at least one, vehicle, thinner, assistant agent and vehicle further.
General building-up process
Usually, compound of the present invention can be prepared by method described in the invention, and unless there are further instruction, wherein substituent definition is such as formula shown in (I) or formula (II).Reaction scheme below and embodiment are used for illustrating content of the present invention further.
Those skilled in the art will realize that: chemical reaction described in the invention can be used for preparing many other compounds of the present invention suitably, and is all contemplated within the scope of the present invention for the preparation of other method of compound of the present invention.Such as; synthesis according to the compound of those non-illustrations of the present invention can successfully be completed by modifying method by those skilled in the art; as suitable protection interference group, by the reagent that utilizes other known except described in the invention, or reaction conditions is made 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, to be 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, all not through being further purified, unless other aspects show during use.General reagent from Xi Long chemical plant, Shantou, Guangdong brilliance chemical reagent factory, Guangzhou Chemical Reagent Factory, Tianjin Hao Yuyu Chemical Company, Qingdao Teng Long chemical reagent company limited, and Haiyang Chemical Plant, Qingdao buy obtain.
Anhydrous tetrahydro furan, dioxane, toluene, ether are through sodium Metal 99.5 backflow drying and obtain.Anhydrous methylene chloride and chloroform are through hydrolith backflow drying and obtain.Ethyl acetate, sherwood oil, normal hexane, N,N-dimethylacetamide and DMF are through the prior Dryly use of anhydrous sodium sulphate.
Below reacting is generally under nitrogen or argon gas positive pressure or on anhydrous solvent, overlap a drying tube (unless showing in other), the soft rubber ball that reaction flask is suitable all beyond the Great Wall, and substrate is squeezed into by syringe.Glassware is all dried.
Chromatographic column uses 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 (reporting in units of ppm), with TMS (0ppm) or chloroform (7.25ppm) as reference standard.In time there is multiplet, abbreviation below will be used: 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 triplet).Coupling constant, represents with hertz (Hz).
Algorithm (MS) data are measured by the spectrograph of the Agilent6320 series LC-MS being equipped with 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 serial LC-MS of Agilent 6120 being equipped with 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 are provided with Agilent Zorbax SB-C18 post, and specification is 2.1 × 30mm, 5 μm.Volume injected is determined by sample concentration; Flow velocity is 0.6mL/min; The peak value of HPLC records reading by the UV-Vis wavelength at 210nm and 254nm place.Moving phase is the formic acid acetonitrile solution (phase A) of 0.1% and the formic acid ultrapure water solution (phase B) of 0.1%.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 chromatography (HPLC), wherein UV detects at 210nm and 254nm place, Zorbax SB-C18 post, specification is 2.1 × 30mm, 4 μm, 10 minutes, flow velocity was 0.6mL/min, (0.1% aqueous formic acid) of (the 0.1% formic acid acetonitrile solution) of 5-95%, 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 schemes 1:
Compound I obtains by synthetic schemes 1.Wherein B, R
1, R
2with the definition of n as described herein; X is halogen; W is alkyl; Q is leavings group.
Compound I ' with Compound II per at metal catalyst (as cuprous iodide etc.) and part (as N, N'-dimethyl-ethylenediamine etc.) effect under, under alkaline condition, (as salt of wormwood, potassiumphosphate etc.) are being that the solvent of inertia is (as 1 to reaction, 4-dioxane, propyl carbinol etc.) in be obtained by reacting compound III; Compound III under the existence of reductive agent (as sodium borohydride etc.) in the solvent to reactionlessness (as methyl alcohol, tetrahydrofuran (THF) and their mixed solvent etc.) obtain compound IV; Compound IV and halogenating agent (as phosphorus trichloride etc.) not to have under solvent or to (as DMF etc.) under the solvent of reactionlessness or be that solvent reaction obtains compound V with excess halogenating agent; Or compounds Ⅳ and sulfonyl agent (as methylsulfonyl chloride, p-methyl benzene sulfonic chloride etc.) are to (as DMF etc.) in the solvent of reactionlessness be obtained by reacting compound V under the existence of alkali (as salt of wormwood etc.); Compound V and compound VI (as salt of wormwood, potassiumphosphate etc.) in the basic conditions to react be inertia solvent (as DMF etc.) in be obtained by reacting compound VI I; Compound VI I under alkaline conditions (as lithium hydroxide, sodium hydroxide etc.) is hydrolyzed and is obtained by reacting Compound I in the solvent (as methyl alcohol, tetrahydrofuran (THF), water and their mixed solvent etc.) to inertia during reaction.
Synthetic schemes 2
Compound I obtains by synthetic schemes 2.Wherein R
1, R
2, R
3definition as described herein; X is halogen; W is alkyl.
Compound VIII and chemical compounds I ' at metal catalyst (as cuprous iodide etc.) and part (as N, N'-dimethyl-ethylenediamine etc.) effect under, under alkaline condition, (as salt of wormwood, potassiumphosphate etc.) are being be obtained by reacting compound VII in the solvent (as DMF etc.) of inertia to reaction; Compound VII under alkaline conditions (as lithium hydroxide, sodium hydroxide etc.) is hydrolyzed and is obtained by reacting Compound I in the solvent (as methyl alcohol, tetrahydrofuran (THF), water and their mixed solvent etc.) to inertia during reaction.
Intermediate
2-(6-((iodo-2', the 6'-dimethyl of 4'--[1,1'-biphenyl]-3-base) methoxyl group)-2,3-Dihydrobenzofuranes-3-bases) methyl acetate
The first step) 4'-amino-2', 6'-dimethyl-[1,1'-biphenyl]-3-methyl-formiate
By bromo-for 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 dichloromethane complex (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 adding water (30mL) dilution after being cooled to room temperature, merge organic phase, with saturated nacl aqueous solution washing (50mL), anhydrous sodium sulfate drying, filter, concentrating under reduced pressure filtrate.Residue, with silica gel chromatography (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) iodo-2', the 6'-dimethyl of 4'--[1,1'-biphenyl]-3-methyl-formiate
By 4'-amino-2', 6'-dimethyl-[1,1'-biphenyl]-3-methyl-formiate (1.5g, 5.9mmol) is dissolved in concentrated hydrochloric acid (6mL), the aqueous solution (5mL) of Sodium Nitrite (0.811g, 11.8mmol) is dripped under ice bath.Drip to stir under reaction solution ice bath after finishing 15 minutes stand-by.Separately get a reaction flask, by water-soluble for potassiumiodide (9.75g, 59mmol) (20mL), under ice bath, drip above-mentioned stand-by solution, drip and finish rear reaction solution stirring at room temperature 2 hours.Be extracted with ethyl acetate (50mL × 2) after reaction solution saturated aqueous sodium thiosulfate (20mL) cancellation, merge organic phase, with saturated nacl aqueous solution washing (50mL), anhydrous sodium sulfate drying, filter, concentrating under reduced pressure filtrate.Residue, with silica gel chromatography (sherwood oil: ethyl acetate=10:1), obtains faint yellow solid shape title compound (1.6g, yield 74%).
3rd step) (iodo-2', the 6'-dimethyl of 4'--[1,1'-biphenyl]-3-base) methyl alcohol
By iodo-for 4'-2', 6'-dimethyl-[1,1'-biphenyl]-3-methyl-formiate (3g, 8.2mmol) is dissolved in toluene (100mL), add diisobutyl aluminium hydride (toluene solution of 33mL, 1M) at-10 DEG C naturally to rise to room temperature reaction afterwards and spend the night.Reaction solution adds aqueous hydrochloric acid cancellation (50mL, 1M), extraction into ethyl acetate (50mL), organic phase saturated nacl aqueous solution washing (30mL), and anhydrous sodium sulfate drying, filters, concentrating under reduced pressure filtrate.Residue, with silica gel chromatography (sherwood oil: ethyl acetate=4:1), obtains faint yellow title compound as oil (2.5g, yield 90%).
1H?NMR(600MHz,CDCl
3)δ7.49(s,2H),7.45(t,J＝7.6Hz,1H),7.38(d,J＝7.7Hz,1H),7.13(s,1H),7.06(d,J＝7.5Hz,1H),4.76(s,2H),1.99(s,6H).
4th step) 2-(6-((iodo-2', the 6'-dimethyl of 4'--[1,1'-biphenyl]-3-base) methoxyl group)-2,3-Dihydrobenzofuranes-3-bases) methyl acetate
By (the iodo-2' of 4'-, 6'-dimethyl-[1,1'-biphenyl]-3-base) methyl alcohol (2.5g, 7.4mmol) with 2-(6-hydroxyl-2,3-Dihydrobenzofuranes-3-base) methyl acetate (1.5g, 7.2mmol) is dissolved in toluene (120mL), adds tri-n-butyl phosphine (3mL successively under room temperature, room temperature reaction 3 hours 12mmol) and after azodicarbonyldipiperidine (3g, 12mmol).Reaction solution thin up (50mL), extraction into ethyl acetate (30mL), organic phase saturated nacl aqueous solution washing (30mL), anhydrous sodium sulfate drying, filters, concentrating under reduced pressure filtrate.Residue, with silica gel chromatography (sherwood oil: ethyl acetate=10:1), obtains white solid title compound (3.2g, yield 82%).
1H?NMR(600MHz,CDCl
3)δ7.49(s,2H),7.45(d,J＝7.5Hz,1H),7.42(s,1H),7.16(s,1H),7.06(dd,J＝20.2,7.8Hz,2H),6.49(m,2H),5.08(s,2H),4.77(t,J＝9.0Hz,1H),4.28(dd,J＝9.2,6.1Hz,1H),3.85-3.80(m,1H),3.74(s,3H),2.77(dd,J＝16.4,5.5Hz,1H),2.58(dd,J＝16.4,9.3Hz,1H),1.98(s,6H).
Embodiment 1
2-(6-((2'; 6'-dimethyl-4'-(3-(4-(methyl sulphonyl) phenyl)-2-imidazolidone-1-base)-[1; 1'-biphenyl]-3-base) methoxyl group)-2,3-Dihydrobenzofuranes-3-bases) acetic acid
The first step) the iodo-4-of 1-(methyl sulphonyl) benzene
4-(methyl sulphonyl) aniline (6g, 35mmol) is dissolved in concentrated hydrochloric acid (35mL), under ice bath, drips the aqueous solution (30mL) of Sodium Nitrite (4.84g, 70mmol).Drip to stir under reaction solution ice bath after finishing 15 minutes stand-by.Separately get a reaction flask, by water-soluble for potassiumiodide (58.2g, 350mmol) (120mL), under ice bath, drip above-mentioned stand-by solution, drip and finish rear reaction solution stirring at room temperature 2 hours.Be extracted with ethyl acetate (200mL × 2) after reaction solution saturated aqueous sodium thiosulfate (200mL) cancellation, merge organic phase, with saturated nacl aqueous solution washing (50mL), anhydrous sodium sulfate drying, filter, concentrating under reduced pressure filtrate.Residue, with silica gel chromatography (sherwood oil: ethyl acetate=4:1), obtains white solid title compound (7.8g, yield 79%).
MS(ESI,pos.ion)m/z:282.9[M+H]
+.
Second step) 1-(4-(methyl sulphonyl) phenyl)-2-imidazolidone
By 2-imidazolidone (2.29g; 26.6mmol); N, N'-dimethyl-ethylenediamine (0.17mL, 1.6mmol); cuprous iodide (0.2g; 1.1mmol), the iodo-4-of 1-(methyl sulphonyl) benzene (1.5g, 5.3mmol) and salt of wormwood (2.2g; 16mmol) in molten propyl carbinol (20mL), stir 2 hours at 100 DEG C.Reaction solution uses dichloromethane extraction (50mL × 2) after adding water (50mL) cancellation after being cooled to room temperature, merges organic phase, with saturated nacl aqueous solution washing (30mL), anhydrous sodium sulfate drying, filters, concentrating under reduced pressure filtrate.Residue, with silica gel chromatography (methylene dichloride: methyl alcohol=60:1), obtains faint yellow solid shape title compound (1.1g, yield 86%).
3rd step) 2', 6'-dimethyl-4'-(3-(4-(methyl sulphonyl) phenyl)-2-imidazolidone-1-base)-[1,1'-biphenyl]-3-methyl-formiate
By 1-(4-(methyl sulphonyl) phenyl)-2-imidazolidone (492mg; 2.0mmol); N; N'-dimethyl-ethylenediamine (0.17mL; 1.6mmol); cuprous iodide (0.2g; 1.1mmol); iodo-2', the 6'-dimethyl of 4'--[1,1'-biphenyl]-3-methyl-formiate (500mg; 1.4mmol) with potassiumphosphate (580mg; 2.8mmol) be dissolved in Isosorbide-5-Nitrae-dioxane (10mL), stir at 110 DEG C and spend the night.Reaction solution uses dichloromethane extraction (50mL × 2) after adding water (50mL) cancellation after being cooled to room temperature, merges organic phase, with saturated nacl aqueous solution washing (30mL), anhydrous sodium sulfate drying, filters, concentrating under reduced pressure filtrate.Residue, with silica gel chromatography (methylene dichloride: methyl alcohol=40:1), obtains faint yellow solid shape title compound (400mg, yield 60%).
4th step) 1-(3'-(methylol)-2,6-dimethyl-[1,1'-biphenyl]-4-base)-3-(4-(methyl sulphonyl) phenyl)-2-imidazolidone
By 2'; 6'-dimethyl-4'-(3-(4-(methyl sulphonyl) phenyl)-2-imidazolidone-1-base)-[1; 1'-biphenyl]-3-methyl-formiate (250mg; 0.5mmol) be dissolved in methylene dichloride (20mL); spend the night 0 DEG C of reaction after adding diisobutyl aluminium hydride (toluene solution of 1mL, 1M) at-20 DEG C.Reaction solution adds aqueous hydrochloric acid (30mL, 1M) cancellation, dichloromethane extraction (30mL), organic phase saturated nacl aqueous solution washing (30mL), and anhydrous sodium sulfate drying, filters, concentrating under reduced pressure filtrate.Residue, with silica gel chromatography (dichloro hexane: methyl alcohol=100:1), obtains white solid title compound (150mg, yield 64%).
5th step) (2', 6'-dimethyl-4'-(3-(4-(methyl sulphonyl) phenyl)-2-imidazolidone-1-base)-[1,1'-biphenyl]-3-base) methylmethanesulfonate ester
By 1-(3'-(methylol)-2; 6-dimethyl-[1; 1'-biphenyl]-4-base)-3-(4-(methyl sulphonyl) phenyl)-2-imidazolidone (150mg; 0.3mmol) with triethylamine (0.04mL; 0.4mmol) be dissolved in methylene dichloride (10mL); react 1 hour at 0 DEG C after adding Methanesulfonyl chloride (0.03mL, 0.4mmol).Reaction solution thin up (30mL), dichloromethane extraction (30mL), organic phase saturated nacl aqueous solution washing (30mL), anhydrous sodium sulfate drying, filters, concentrating under reduced pressure filtrate.Residue, with silica gel chromatography (sherwood oil: ethyl acetate=1:1), obtains white solid title compound (170mg, yield 97%).
6th step) 2-(6-((2'; 6'-dimethyl-4'-(3-(4-(methyl sulphonyl) phenyl)-2-imidazolidone-1-base)-[1; 1'-biphenyl]-3-base) methoxyl group)-2,3-Dihydrobenzofuranes-3-bases) methyl acetate
By (2'; 6'-dimethyl-4'-(3-(4-(methyl sulphonyl) phenyl)-2-imidazolidone-1-base)-[1; 1'-biphenyl]-3-base) methylmethanesulfonate ester (170mg; 0.32mmol); 2-(6-hydroxyl-2; 3-Dihydrobenzofuranes-3-base) methyl acetate (80mg; 0.38mmol) with cesium carbonate (74mg; 0.38mmol) be dissolved in acetonitrile (10mL), be warming up to 75 DEG C of reactions and spend the night.Reaction solution shrend is gone out, extraction into ethyl acetate (20mL × 2), merges organic phase, with saturated nacl aqueous solution washing (10mL), anhydrous sodium sulfate drying, filters, concentrating under reduced pressure filtrate.Residue, with silica gel chromatography (sherwood oil: ethyl acetate=2:1), obtains faint yellow solid shape title compound (178mg, yield 86.4%).
MS(ESI,pos.ion)m/z:641.2[M+H]+.
7th step) 2-(6-((2'; 6'-dimethyl-4'-(3-(4-(methyl sulphonyl) phenyl)-2-imidazolidone-1-base)-[1; 1'-biphenyl]-3-base) methoxyl group)-2,3-Dihydrobenzofuranes-3-bases) acetic acid
By 2-(6-((2'; 6'-dimethyl-4'-(3-(4-(methyl sulphonyl) phenyl)-2-imidazolidone-1-base)-[1; 1'-biphenyl]-3-base) methoxyl group)-2; 3-Dihydrobenzofuranes-3-base) methyl acetate (180mg; 0.28mmol) be dissolved in tetrahydrofuran (THF) (2.8mL); add lithium hydroxide aqueous solution (2.8mL, 1M) stirring at room temperature 2 hours afterwards.Reaction solution adds the rear hydrochloric acid (4mL of 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 titled compound as white solid (165mg, yield 94%).
MS(ESI,neg.ion)m/z:625.6[M-H]
-；
1H?NMR(400MHz,CDCl
3)δ7.95(d,J＝9.0Hz,2H),7.85(d,J＝9.0Hz,2H),7.46–7.42(m,2H),7.34(s,2H),7.19(s,1H),7.09(dd,J＝15.0,7.7Hz,2H),6.50(m,2H),5.10(s,2H),4.77(t,J＝9.0Hz,1H),4.30(dd,J＝9.2,6.1Hz,1H),4.07–4.05(m,4H),3.85–3.81(m,1H),3.07(s,3H),2.82(dd,J＝16.8,5.4Hz,1H),2.63(dd,J＝16.8,9.2Hz,1H),2.06(s,6H).
Embodiment 2
(S)-2-(6-((2'; 6'-dimethyl-4'-(3-(3-(methyl sulphonyl) propyl group)-2-imidazolidone-1 base)-[1; 1'-biphenyl]-3-base) methoxyl group)-2,3-Dihydrobenzofuranes-3-bases) acetic acid
The first step) 3-(methylthio group) methylsulfonic acid propyl ester
By 3-(methylthio group) propyl group-1-alcohol (2mL, 19.4mmol) with triethylamine (3.2mL, 23mmol) be dissolved in methylene dichloride (30mL), under ice bath, drip methylsulfonyl chloride (1.84mL, 23.3mmol).Drip and finish rear reaction solution stirred at ambient temperature 30 minutes.Reaction solution uses dichloromethane extraction (50mL × 2) with after saturated sodium bicarbonate aqueous solution (30mL) cancellation, merge organic phase, with saturated nacl aqueous solution washing (50mL), anhydrous sodium sulfate drying, filter, concentrating under reduced pressure filtrate.Residue, with silica gel chromatography (sherwood oil: ethyl acetate=1:1), obtains faint yellow title compound as oil (7.8g, yield 79%).
Second step) 1-(3-(methylthio group) propyl group) imidazolidin-2-one
By 2-imidazolidone (2.14g, 24.9mmol) be dissolved in N, in dinethylformamide (30mL), add sodium hydride (695mg in batches, 17.4mmol) room temperature reaction 30 minutes afterwards, add 3-(methylthio group) methylsulfonic acid propyl ester (3.05g, 16.5mmol) room temperature reaction afterwards to spend the night.Reaction solution is with saturated aqueous ammonium chloride cancellation (10mL), and extraction into ethyl acetate (20mL × 2), merges organic phase, with saturated nacl aqueous solution washing (10mL), anhydrous sodium sulfate drying, filters, concentrating under reduced pressure filtrate.Residue, with silica gel chromatography (methylene dichloride: methyl alcohol=50:1), obtains faint yellow solid shape title compound (1.5g, yield 52%).
3rd step) 1-(3-(methyl sulphonyl) propyl group) imidazolidin-2-one
Be dissolved in methyl alcohol (50mL) by 1-(3-(methylthio group) propyl group) imidazolidin-2-one (2g, 11.4mmol), room temperature adds potassium hydrogen persulfate (11.2g, 17.3mmol) room temperature for overnight afterwards.Reaction solution uses dichloromethane extraction (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.Residue, with silica gel chromatography (methylene dichloride: methyl alcohol=20:1), obtains faint yellow title compound as oil (0.75g, yield 32%).
MS(ESI,pos.ion)m/z:207.2[M+H]
+.
4th step) (S)-2-(6-((2'; 6'-dimethyl-4'-(3-(3-(methyl sulphonyl) propyl group)-2-imidazolidone-1 base)-[1; 1'-biphenyl]-3-base) methoxyl group)-2,3-Dihydrobenzofuranes-3-bases) methyl acetate
By 1-(3-(methyl sulphonyl) propyl group) imidazolidin-2-one (244mg; 1.2mmol); N; N'-dimethyl-ethylenediamine (0.04mL; 0.4mmol); cuprous iodide (0.045mg; 0.23mmol), (S)-2-(6-((iodo-2', 6'-dimethyl-[1 of 4'-; 1'-biphenyl]-3-base) methoxyl group)-2; 3-Dihydrobenzofuranes-3-base) methyl acetate (500mg, 1.4mmol) and salt of wormwood (490mg, 3.6mmol) is dissolved in N; in dinethylformamide (10mL), stir at 120 DEG C and spend the night.Reaction solution uses dichloromethane extraction (50mL × 2) after adding water (50mL) cancellation after being cooled to room temperature, merges organic phase, with saturated nacl aqueous solution washing (30mL), anhydrous sodium sulfate drying, filters, concentrating under reduced pressure filtrate.Residue, with silica gel chromatography (methylene dichloride: methyl alcohol=50:1), obtains faint yellow solid shape title compound (140mg, yield 19.2%).
MS(ESI,pos.ion)m/z:607.2[M+H]
+.
5th step) (S)-2-(6-((2'; 6'-dimethyl-4'-(3-(3-(methyl sulphonyl) propyl group)-2-imidazolidone-1 base)-[1; 1'-biphenyl]-3-base) methoxyl group)-2,3-Dihydrobenzofuranes-3-bases) acetic acid
By (S)-2-(6-((2'; 6'-dimethyl-4'-(3-(3-(methyl sulphonyl) propyl group)-2-imidazolidone-1 base)-[1; 1'-biphenyl]-3-base) methoxyl group)-2; 3-Dihydrobenzofuranes-3-base) methyl acetate (170mg; 0.28mmol) be dissolved in tetrahydrofuran (THF) (2.8mL); add lithium hydroxide aqueous solution (2.8mL, 1M) stirring at room temperature 2 hours afterwards.Reaction solution adds the rear hydrochloric acid (4mL of 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 titled compound as white solid (140mg, yield 84.3%).
MS(ESI,pos.ion)m/z:593.2[M+H]
+；
1H?NMR(600MHz,CDCl
3)δ7.44(t,J＝7.5Hz,1H),7.39(d,J＝7.5Hz,1H),7.28(s,2H),7.17(s,1H),7.09(d,J＝7.3Hz,1H),7.06(d,J＝8.2Hz,1H),6.50(d,J＝8.2Hz,1H),6.48(s,1H),5.08(s,2H),4.77(t,J＝9.0Hz,1H),4.29(dd,J＝9.0,6.2Hz,1H),3.94–3.84(m,2H),3.81(dd,J＝11.2,5.3Hz,1H),3.55(t,J＝7.9Hz,2H),3.49(t,J＝6.4Hz,2H),3.18–3.09(m,2H),2.97(s,3H),2.80(dd,J＝16.8,5.2Hz,1H),2.61(dd,J＝16.7,9.3Hz,1H),2.21–2.11(m,2H),2.03(s,6H).
Embodiment 3
2-(6-((2'; 6'-dimethyl-4'-(5-(methyl sulphonyl)-2-oxo-2; 3-dihydro-1H-benzo [d] imidazolidone-1-base)-[1; 1'-biphenyl]-3-base) methoxyl group)-2,3-Dihydrobenzofuranes-3-bases) acetic acid
The first step) 2-(6-((4'-(the bromo-2-oxo-2 of 5-, 3-dihydro-1H-benzo [d] imidazolidone-1-base)-2', 6'-dimethyl-[1,1'-biphenyl]-3-base) methoxyl group)-2,3-Dihydrobenzofuranes-3-bases) methyl acetate
By bromo-for 5-1H-benzo [d] imidazolidine-2 (3H)-one (2g, 9.39mmol), N, N'-dimethyl-ethylenediamine (0.05mL, 0.5mmol), cuprous iodide (60mg, 0.32mmol), 2-(6-((iodo-2', the 6'-dimethyl of 4'--[1,1'-biphenyl]-3-base) methoxyl group)-2,3-Dihydrobenzofuranes-3-base) methyl acetate (0.8g, 2mmol) be dissolved in methyl-sulphoxide (20mL) with salt of wormwood (0.6g, 4mmol), stir at 130 DEG C and spend the night.Reaction solution uses dichloromethane extraction (50mL × 2) after adding water (50mL) cancellation after being cooled to room temperature, merges organic phase, with saturated nacl aqueous solution washing (30mL), anhydrous sodium sulfate drying, filters, concentrating under reduced pressure filtrate.Residue, with silica gel chromatography (sherwood oil: ethyl acetate=2:1), obtains faint yellow solid shape title compound (195mg, yield 20%).
Second step) 2-(6-((2'; 6'-dimethyl-4'-(5-(methyl sulphonyl)-2-oxo-2; 3-dihydro-1H-benzo [d] imidazolidone-1-base)-[1; 1'-biphenyl]-3-base) methoxyl group)-2,3-Dihydrobenzofuranes-3-bases) methyl acetate
By 2-(6-((4'-(the bromo-2-oxo-2 of 5-, 3-dihydro-1H-benzo [d] imidazolidone-1-base)-2', 6'-dimethyl-[1,1'-biphenyl]-3-base) methoxyl group)-2,3-Dihydrobenzofuranes-3-base) methyl acetate (50mg, 0.082mmol), cuprous iodide (3mg, 0.016mmol), L-PROLINE sodium salt (2mg, 0.015mmol) be dissolved in methyl-sulphoxide (1mL) with methyl-sulfinic acid sodium (24mg, 0.23mmol), reaction solution was 95 DEG C of reactions 24 hours.Reaction solution adds water after being cooled to room temperature cancellation (30mL), extraction into ethyl acetate (30mL), organic phase saturated nacl aqueous solution washing (30mL), and anhydrous sodium sulfate drying, filters, concentrating under reduced pressure filtrate.Residue, with silica gel chromatography (sherwood oil: ethyl acetate=1:1), obtains faint yellow solid shape title compound (40mg, yield 80%).
MS(ESI,pos.ion)m/z:613.2[M+H]
+.
3rd step) 2-(6-((2'; 6'-dimethyl-4'-(5-(methyl sulphonyl)-2-oxo-2; 3-dihydro-1H-benzo [d] imidazolidone-1-base)-[1; 1'-biphenyl]-3-base) methoxyl group)-2,3-Dihydrobenzofuranes-3-bases) acetic acid
By 2-(6-((2'; 6'-dimethyl-4'-(5-(methyl sulphonyl)-2-oxo-2; 3-dihydro-1H-benzo [d] imidazolidone-1-base)-[1; 1'-biphenyl]-3-base) methoxyl group)-2; 3-Dihydrobenzofuranes-3-base) methyl acetate (40mg; 0.065mmol) be dissolved in tetrahydrofuran (THF) (0.6mL); add lithium hydroxide aqueous solution (0.6mL, 1M) stirring at room temperature 2 hours afterwards.Reaction solution adds the rear hydrochloric acid (1mL of 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 titled compound as white solid (30mg, yield 76.8%).
MS(ESI,neg.ion)m/z:597.0[M-H]
-；
1H?NMR(600MHz,DMSO-d
6)δ12.32(s,1H),11.65(s,1H),7.61(d,J＝7.7Hz,1H),7.58–7.49(m,2H),7.46(d,J＝6.6Hz,1H),7.31(s,2H),7.26(s,1H),7.20(dd,J＝28.3,7.3Hz,2H),7.11(d,J＝7.6Hz,1H),6.58–6.40(m,2H),5.14(s,2H),4.68(t,J＝8.6Hz,1H),4.31–4.11(m,1H),3.68(s,1H),3.20(s,3H),2.70(dd,J＝16.3,4.5Hz,1H),2.47(s,1H),2.03(s,6H).
Embodiment 4
(S)-2-(6-((4'-(3-(tertiary butyl)-2-imidazolidone-1-base)-2', 6'-dimethyl-[1,1'-biphenyl]-3-base) methoxyl group)-2,3-Dihydrobenzofuranes-3-bases) acetic acid
Synthesis step is with embodiment 2.
MS(ESI,pos.ion)m/z:529.0[M+H]
+；
1H?NMR(600MHz,CDCl
3)δ7.44(t,J＝7.5Hz,1H),7.39(d,J＝7.6Hz,1H),7.29(s,2H),7.18(s,1H),7.10(d,J＝7.3Hz,1H),7.06(d,J＝8.2Hz,1H),6.51(dd,J＝8.2,1.9Hz,1H),6.49(d,J＝1.7Hz,1H),5.08(s,2H),4.77(t,J＝9.0Hz,1H),4.30(dd,J＝9.1,6.2Hz,1H),3.82–3.79(m,1H),3.78–3.70(m,2H),3.52(t,J＝7.8Hz,2H),2.81(dd,J＝16.8,5.2Hz,1H),2.62(dd,J＝16.8,9.4Hz,1H),2.03(s,6H),1.46(s,9H).
Embodiment 5
2-(6-((4'-(the bromo-2-oxo-2 of 6-, 3-dihydro-1H-benzo [d] imidazolidone-1-base)-2', 6'-dimethyl-[1,1'-biphenyl]-3-base) methoxyl group)-2,3-Dihydrobenzofuranes-3-bases) acetic acid
Synthesis step is with embodiment 3.
MS(ESI,pos.ion)m/z:598.8[M+H]
+；
1H?NMR(600MHz,DMSO-d
6)δ11.34(s,1H),7.52(t,J＝7.3Hz,1H),7.45(d,J＝7.2Hz,1H),7.27(d,J＝6.8Hz,3H),7.24(d,J＝8.2Hz,1H),7.18(d,J＝6.9Hz,1H),7.11(d,J＝7.4Hz,2H),7.04(d,J＝8.1Hz,1H),6.53–6.44(m,2H),5.13(s,2H),4.68(t,J＝8.9Hz,1H),4.23–4.15(m,1H),3.68(s,1H),2.70(dd,J＝16.5,5.2Hz,1H),2.47(s,1H),2.02(s,6H).
Embodiment 6
2-(6-((4'-(the bromo-2-oxo-2 of 5-, 3-dihydro-1H-benzo [d] imidazolidone-1-base)-2', 6'-dimethyl-[1,1'-biphenyl]-3-base) methoxyl group)-2,3-Dihydrobenzofuranes-3-bases) acetic acid
Synthesis step is with embodiment 3.
MS(ESI,pos.ion)m/z:599.1[M+H]
+；
1H?NMR(600MHz,DMSO-d
6)δ11.34(s,1H),7.92–6.63(m,10H),6.47(s,2H),5.13(s,2H),4.68(s,1H),4.18(s,1H),3.66(s,1H),2.68(s,1H),2.47–2.38(m,1H),2.01(s,6H).
Embodiment 7
2-(6-((2', 6'-dimethyl-4'-(2-oxo-2,3-dihydro-1H-benzo [d] imidazolidone-1-base)-[1,1'-biphenyl]-3-base) methoxyl group)-2,3-Dihydrobenzofuranes-3-bases) acetic acid
Synthesis step is with embodiment 3.
MS(ESI,pos.ion)m/z:521.2[M+H]
+；
1H?NMR(600MHz,DMSO-d
6)δ12.36(s,1H),11.15(s,1H),7.51(t,J＝7.4Hz,1H),7.44(d,J＝7.4Hz,1H),7.28(s,2H),7.25(s,1H),7.16(d,J＝7.1Hz,1H),7.12–6.98(m,5H),6.52–6.44(m,2H),5.13(s,2H),4.68(t,J＝8.9Hz,1H),4.24–4.13(m,1H),3.73–3.64(m,1H),2.70(dd,J＝16.5,5.0Hz,1H),2.50–2.45(m,1H),2.02(s,6H).
Embodiment 8
(S)-2-(6-((2', 6'-dimethyl-4'-(3-(methyl)-2-imidazolidone-1-base)-[1,1'-biphenyl]-3-base) methoxyl group)-2,3-Dihydrobenzofuranes-3-bases) acetic acid
Synthesis step is with embodiment 2.
MS(ESI,pos.ion)m/z:487.2[M+H]
+；
1H?NMR(600MHz,CDCl
3)δ7.44(t,J＝7.5Hz,1H),7.40(d,J＝7.6Hz,1H),7.30(s,2H),7.18(s,1H),7.10(d,J＝7.3Hz,1H),7.06(d,J＝8.1Hz,1H),6.51(dd,J＝8.2,1.9Hz,1H),6.48(s,1H),5.08(s,2H),4.80–4.74(m,1H),4.33–4.23(m,1H),3.85–3.80(m,3H),3.55–3.46(m,2H),2.93(s,3H),2.81(dd,J＝16.8,5.2Hz,1H),2.61(dd,J＝16.7,9.4Hz,1H),2.03(s,6H).
Embodiment 9
2-(6-((2'; 6'-dimethyl-4'-(3-(4-(methyl sulphonyl) phenyl)-2-tetrahydropyrimidine alkane ketone-1 (2H)-Ji)-[1; 1'-biphenyl]-3-base) methoxyl group)-2,3-Dihydrobenzofuranes-3-bases) acetic acid
Synthesis step is with embodiment 1.
MS(ESI,pos.ion)m/z:641.2[M+H]
+；
1H?NMR(600MHz,CDCl
3)δ7.91(d,J＝8.4Hz,2H),7.62(d,J＝8.4Hz,2H),7.47–7.36(m,2H),7.18(s,1H),7.13–7.02(m,4H),6.55–6.42(m,2H),5.08(s,2H),4.76(t,J＝8.7Hz,1H),4.35–4.20(m,1H),3.93–3.88(m,4H),3.83–3.77(m,1H),3.05(s,3H),2.79(d,J＝13.8Hz,1H),2.60(d,J＝8.3Hz,1H),2.36(d,J＝5.2Hz,2H),2.01(s,6H).
Embodiment 10
2-(6-((2'; 6'-dimethyl-4'-(3-(4-(methyl sulphonyl) phenyl)-2-oxo-2; 3-dihydro-1H-benzo [d] imidazolidone-1-base)-[1; 1'-biphenyl]-3-base) methoxyl group)-2,3-Dihydrobenzofuranes-3-bases) acetic acid
Synthesis step is with embodiment 1.
1H?NMR(600MHz,CDCl
3)δ8.17(d,J＝8.5Hz,2H),7.94(d,J＝8.5Hz,2H),7.51(t,J＝7.5Hz,1H),7.45(d,J＝7.6Hz,1H),7.32(s,2H),7.28–7.15(m,6H),7.08(d,J＝8.2Hz,1H),6.53(dd,J＝8.2,1.9Hz,1H),6.50(s,1H),5.12(s,2H),4.78(t,J＝9.0Hz,1H),4.31(dd,J＝9.1,6.1Hz,1H),3.86–3.79(m,1H),3.15(s,3H),2.82(dd,J＝16.8,5.3Hz,1H),2.63(dd,J＝16.8,9.3Hz,1H),2.09(d,J＝22.5Hz,6H).
Biological assessment
Test case the compounds of this invention is to the Activation Activity of 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 at 37 DEG C, 5%CO
2cultivate 24 hours under condition.During experiment, 384 orifice plates being covered with cell are taken out from incubator, discard substratum, add (the preparation of calcium dyestuff: 20mL HBSS (20mM HEPES)+2tube dye+200 μ L10%BSA of calcium dyestuff, Calcium4assay kit, Molecular Device), 40 μ L/ holes.384 orifice plates are put back in incubator, hatch 1 hour.Setting 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, Ca in the cell using FLIPR instrument to carry out increasing
2+the detection of concentration.Raw data XLfit carries out matching, 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 | 111 | Embodiment 2 | 56 | Embodiment 3 | 57 |
| Embodiment 4 | 26 | Embodiment 5 | 111 | Embodiment 6 | 131 |
| Embodiment 7 | 81 | Embodiment 8 | 27 | Embodiment 9 | 120 |
| Embodiment 10 | 173 | ? | ? | ? | ? |
Conclusion: the compounds of this invention has obvious agonist activity to GPR40.
Claims (10)
1. a compound, it is for such as formula the compound shown in (I), or the steric isomer of the compound shown in formula (I), geometrical isomer, tautomer, oxynitride, hydrate, solvate, meta-bolites, pharmacy acceptable salt or prodrug
Wherein, B ring is C
2-10heterocyclic radical, C
5-12condense assorted bicyclic group, C
5-12spiral shell is mixed bicyclic group or C
5-12bridge is mixed bicyclic group;
R
1for hydrogen, C
1-6alkyl, C
6-10aryl or C
1-9heteroaryl, wherein said C
1-6alkyl, C
6-10aryl and C
1-9heteroaryl is optionally independently selected from hydrogen, fluorine, chlorine, bromine, hydroxyl, C by 1,2,3 or 4 independently of one another
1-6alkyl, C
1-6haloalkyl, C
1-6alkyl sulphonyl, amino-sulfonyl or C
1-6halogenated alkyl sulfonyl substituting group replaces; With
Each R
2be hydrogen, C independently
1-6alkyl, C
1-6haloalkyl, fluorine, chlorine, bromine, C
1-6alkyl sulphonyl or C
1-6alkyl sulphonyl C
1-6alkyl; Or adjacent two R
2coupled 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
N is 1,2,3 or 4.
2. compound according to claim 1, it has such as formula the structure shown in (II), or the steric isomer of the compound shown in formula (II), geometrical isomer, tautomer, oxynitride, hydrate, solvate, meta-bolites, pharmacy acceptable salt or prodrug
Wherein, m is 0,1,2 or 3.
3. compound according to claim 1, wherein
B ring is
4. according to the arbitrary described compound of claim 1-3, wherein
R
1for hydrogen, C
1-4alkyl, C
6-10aryl or C
1-9heteroaryl, wherein said C
1-4alkyl, C
6-10aryl and C
1-9heteroaryl 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
Each R
2be hydrogen, C independently
1-4alkyl, C
1-4haloalkyl, fluorine, chlorine, bromine, C
1-4alkyl sulphonyl or C
1-4alkyl sulphonyl C
1-4alkyl; Or adjacent two R
2coupled 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.
5. according to the arbitrary described compound of claim 1-3, wherein
R
1for hydrogen, methyl, ethyl, propyl group, butyl, the tertiary butyl or phenyl, wherein said methyl, ethyl, propyl group, butyl, the tertiary butyl and phenyl are optionally independently selected from hydrogen, fluorine, chlorine, bromine, hydroxyl, methyl, ethyl, propyl group, butyl, trifluoromethyl, methyl sulphonyl, amino-sulfonyl or trifluoromethyl sulfonyl substituting group by 1,2,3 or 4 independently of one another and replace; With
Each R
2be hydrogen, methyl, ethyl, propyl group, butyl, the tertiary butyl, trifluoromethyl, fluorine, chlorine, bromine, methyl sulphonyl, sulfonyloxy methyl ylmethyl, methysulfonylethyl or methanesulphonylpropyl independently; Or adjacent two R
2coupled atom forms phenyl together; pyridyl or naphthyl; wherein said phenyl; pyridyl and naphthyl are optionally independently selected from hydrogen, fluorine, chlorine, bromine, hydroxyl, methyl, ethyl by 1,2,3 or 4 independently of one another, and propyl group, butyl, trifluoromethyl, methyl sulphonyl, ethylsulfonyl, amino-sulfonyl or trifluoromethyl sulfonyl substituting group replace.
6., according to the arbitrary described compound of claim 1-3, comprise one of them structure following:
Or its steric isomer, geometrical isomer, tautomer, oxynitride, hydrate, solvate, meta-bolites, pharmacy acceptable salt or prodrug.
7. a pharmaceutical composition, said composition comprises the compound according to any one of claim 1-6, comprises pharmaceutically acceptable carrier, vehicle, thinner, assistant agent, vehicle or its combination further.
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. the pharmaceutical composition according to any one of claim 7-8, it further comprises at least one GPR40 receptor stimulant.
10. the compound according to any one of a claim 1-6 or the pharmaceutical composition described in any one in claim 7-9 are 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 disorder, 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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