CN106748922B - A kind of novel sulfone acid derivative, preparation method and its purposes as drug - Google Patents

A kind of novel sulfone acid derivative, preparation method and its purposes as drug Download PDF

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CN106748922B
CN106748922B CN201710029918.2A CN201710029918A CN106748922B CN 106748922 B CN106748922 B CN 106748922B CN 201710029918 A CN201710029918 A CN 201710029918A CN 106748922 B CN106748922 B CN 106748922B
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phenyl
base
sulfonyl
dmso
nmr
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CN106748922A (en
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黄文龙
钱海
刘春霞
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China Pharmaceutical University
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China Pharmaceutical University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C317/00—Sulfones; Sulfoxides
    • C07C317/44—Sulfones; Sulfoxides having sulfone or sulfoxide groups and carboxyl groups bound to the same carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D207/32—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D207/325—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms with substituted hydrocarbon radicals directly attached to the ring nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
    • C07D261/02—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings
    • C07D261/06—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members
    • C07D261/08—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/22—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D277/24—Radicals substituted by oxygen atoms

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  • Organic Chemistry (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

The present invention relates to novel sulfone acid derivative, preparation method shown in a kind of logical formula (I) and contain medicinal usage of the pharmaceutical composition of the derivative as preparation treatment diabetes and metabolic syndrome.The sulfone acid derivative has excellent internal hypoglycemic activity, can be used for preventing or treating diabetes.

Description

A kind of novel sulfone acid derivative, preparation method and its purposes as drug
Technical field
The present invention relates to field of pharmacology relevant to diabetes, and in particular to the novel sulfone acid derivative of one kind, its system Preparation Method and the pharmaceutical composition for containing the derivative treat the application in diabetes and Metabolic syndrome disease drug as preparation.This Upper unique and novelty is transformed in this class compound structure in sulfone acid derivative structure involved in invention, and shows excellent Different administration safety.
Background technique
Diabetes are one group of metabolic diseases characterized by hyperglycemia, are divided into type 1 diabetes (insulin-dependent glycosuria Disease) and diabetes B (non-insulin-dependent diabetes mellitus).There are about 4.15 hundred million people to suffer from diabetes in the whole world at present, separately there is 3.18 Hundred million people are hiding very high diabetes risk.Diabetes mellitus in China patient is 1.096 hundred million, occupy global the first, wherein 2 types are sugared Urine patient accounts for about the 90~95% of diabetic's sum.
Diabetes can pass through dietary adjustments and exercise treatment.When these cannot alleviate symptom, needs to carry out drug and control It treats.The therapeutic agent of diabetes includes: biguanides such as melbine at present, can reduce the formation of glucose in liver；Sulphonyl Ureas such as glibenclamide and benzoic acid derivative such as Repaglinide, being capable of the more insulin of stimulating pancreas β cell secretion；Thiophene Oxazolidinedione class such as pioglitazone enhances insulin by activation peroxisome proliferator activated receptor γ (PPAR- γ) Purificatiou；Alpha-glucosidase restrainer such as acarbose, is able to suppress the generation of glucose in enteron aisle；Glucagon Peptide -1 (GLP-1) analog such as Liraglutide, can promote the β cells secrete insulin of pancreas；DPP IV (DPP- IV) inhibitor such as Xi Gelieting is able to suppress the degradation of internal GLP-1.But the method for existing treatment diabetes is all at present There is certain defect.Such as injection of insulin agent and sulfonylurea, it may cause hypoglycemia and weight gain side effect；Diformazan is double Guanidine, alpha-glucosidase restrainer and GLP-1 analog may cause gastrointestinal side effect；PPAR- gamma agonist may draw Play weight gain and oedema side effect；DPP-IV inhibitor may cause epipharyngitis, headache and infection side effect.For multiple The research in field is carrying out, to bring safer and more effective novel blood sugar lowing drug for diabetic.
Free-fat acid acceptor (FFAR) is the g protein coupled receptor (GPCRs) for going orphanization in recent years.It has determined that at present Free fatty acids receptor have g protein coupled receptor 40 (GPR40) family, including GPR40 (also referred to as free-fat acid acceptor 1, FFA1), GPR41 (also referred to as free-fat acid acceptor 3, FFA3), GPR43 (also referred to as free-fat acid acceptor 2, FFA2) And GPR84, GPR120 of other families.GPR40 is to find new galanin-galanin receptors (GALR) The orphan type GPCR found when hypotype, is highly expressed in the cell line of pancreatic beta cell and excreting insulin.GPR40 can be combined Such as palmitic acid, stearic acid, oleic acid, the fatty acid in the blood plasma such as linoleic acid plus linolenic acid realizes various physiological-function.Such as long-chain Free fatty acid in conjunction with GPR40 after activate, calcium ion level increases in inducing cell, the insulin of enhancing glucose stimulation It secretes (GSIS).GPR40 regulator plays incretin and acts on to promote GISI, furthermore can also be with a variety for the treatment of Rezulins Object is used in combination.Based on the above, GPR40 agonist can treat diabetes and related indication, especially diabetes B, fertilizer Fat insulin resistance, poor glucose tolerance and other metabolic syndrome illnesss.With GPR40 for potential therapy target, hair Now there is important researching value and application prospect with compound of the transformation with GPR40 agonist activity.
A series of patent application of GPR40 agonists has been disclosed at present, including WO2004041266, WO2005087710, WO2005051890, WO2006083781, WO2007013689, WO2008066097, WO2009054390, WO2010085525, WO2015024448, WO2015088868 etc..
The present invention relates to the sulfone acid derivatives of structure novel, living with excellent GPR40 agonist activity and internal hypoglycemic Property, and it was unexpectedly found that the compound with this class formation shows the lower liver kidney of more existing clinical medicine TAK-875 Risk of toxicity.Therefore the sulfone acid derivative and pharmaceutically acceptable ester or its officinal salt can potentially be used to treat or Person prevents diabetes and related disease, has wide development prospect.
Summary of the invention
The purpose of the present invention is to provide a kind of logical formula (I) compound represented and pharmaceutically acceptable ester or its can medicine Salt:
Wherein:
Ring A is selected from aryl or heteroaryl；
Ring B is selected from aryl or heteroaryl；
R1, R2And R3It is each independently selected from hydrogen, halogen, cyano, alkyl, alkoxy, naphthenic base, wherein the alkyl, cycloalkanes Base, alkoxy optionally further by it is one or more selected from halogen, cyano, alkyl, alkoxy, naphthenic base group replaced；
R4Selected from hydrogen, alkyl, halogen；
R5And R6Selected from hydrogen, alkyl, naphthenic base；
R7Selected from hydrogen, alkyl.
Preferred embodiment of the invention, preferably self-drifting (I) compound represented and pharmaceutically acceptable ester or its can medicine Salt:
Wherein:
Ring A preferably is selected from phenyl ring, pyrrole ring or isozole ring；
Ring B preferably is selected from phenyl ring, thiphene ring；
R1, R2And R3It is each independently selected from hydrogen, halogen, cyano, alkyl, alkoxy, naphthenic base, wherein the alkyl, cycloalkanes Base, alkoxy optionally further by it is one or more selected from halogen, cyano, alkyl, alkoxy, naphthenic base group replaced；
R4Selected from hydrogen, alkyl, halogen；
R5And R6Selected from hydrogen, alkyl, naphthenic base；
R7Selected from hydrogen, alkyl.
It is preferred that self-drifting (I) compound represented and pharmaceutically acceptable ester or its pharmaceutical salt:
Wherein:
Ring A preferably is selected from phenyl ring, pyrrole ring or isozole ring；
Ring B preferably is selected from phenyl ring, thiphene ring；
R1, R2And R3It is each independently selected from hydrogen, halogen, cyano, C1-C4Alkyl, C1-C4Alkoxy, naphthenic base, wherein described Alkyl, naphthenic base, alkoxy optionally further by it is one or more selected from halogen, cyano, alkyl, alkoxy, naphthenic base base Replaced group；
R4Selected from hydrogen, methyl, halogen；
R5And R6Selected from hydrogen, C1-C2Alkyl, cyclopropyl；
R7Selected from hydrogen, alkyl.
It is preferred that self-drifting (I) compound represented and pharmaceutically acceptable ester or its pharmaceutical salt:
Wherein:
Ring A preferably be selected from phenyl ring or:
Ring B preferably be selected from phenyl ring or:
R1, R2And R3It is each independently selected from hydrogen, F, Cl, cyano, C1-C4Alkyl, C1-C4Alkoxy, naphthenic base, wherein described Alkyl, naphthenic base, alkoxy are optionally further selected from F, cyano, C by one or more1-C4Alkyl, C1-C4Alkoxy, cycloalkanes Replaced the group of base；
R4Selected from hydrogen, methyl, Cl；
R5And R6Selected from hydrogen, C1-C2Alkyl, cyclopropyl；
R7Selected from hydrogen, alkyl.
More preferably logical formula (I) compound and pharmaceutically acceptable ester or its pharmaceutical salt:
Wherein:
Ring A preferably be selected from phenyl ring or:
Ring B preferably be selected from phenyl ring or:
R1, R2And R3It is each independently selected from hydrogen, F, Cl, cyano, trifluoromethyl, propyl, isopropyl, methoxyl group, cyclopropyl methoxy Base, ethyoxyl, propoxyl group, isobutoxy, 3- methyl sulphonyl propoxyl group, 2- methoxy ethoxy；
R4Selected from hydrogen, methyl, Cl；
R5And R6Selected from hydrogen, methyl, ethyl, cyclopropyl；
R7Selected from hydrogen, methyl.
The preferred present invention has the compound or pharmaceutically acceptable salt thereof of logical formula (I), and the compound is selected from:
2- ((4- ((2 '-chloro- [1,1 '-biphenyl] -3- base) methoxyl group) phenyl) sulfonyl) methyl acetate (I-1)；
2- ((4- ([1,1 '-biphenyl] -3- methoxyl group) phenyl) sulfonyl) acetic acid (I-2)；
2- ((4- ((2 '-chloro- [1,1 '-biphenyl] -3- base) methoxyl group) phenyl) sulfonyl) acetic acid (I-3)；
2- ((4- ((2 ', 6 '-dimethyl-[1,1 '-biphenyl] -3- base) methoxyl group) phenyl) sulfonyl) acetic acid (I-4)；
2- ((4- ((2 '-methyl-[1,1 '-biphenyl] -3- base) methoxyl group) phenyl) sulfonyl) acetic acid (I-5)；
2- ((4- (2 '-methoxyl groups-(1,1 '-biphenyl -3- base) methoxyl group) phenyl) sulfonyl) acetic acid (I-6)；
2- ((4- ((4 '-(cyclopropyl methoxyl group) 2 ', 6 '-dimethyl-[1,1 '-biphenyl] -3- base) methoxyl group) phenyl) sulphonyl Base) acetic acid (I-7)；
2- ((4- ((2 '-fluoro- [1,1 '-biphenyl] -3- base) methoxyl group) phenyl) sulfonyl) acetic acid (I-8)；
2- ((4- ((2 '-(trifluoromethyls)-[1,1 '-biphenyl] -3- base) methoxyl group) phenyl) sulfonyl) acetic acid (I-9)；
2- ((4- ((4 '-methoxyl groups -2 ', 6 '-dimethyl-[1,1 '-biphenyl] -3- base) methoxyl group) phenyl) sulfonyl) second Sour (I-10)；
2- ((4- ((2 '-cyano-[1,1 '-biphenyl] -3- base) methoxyl group) phenyl) sulfonyl) acetic acid (I-11)；
2- ((4- ((4- methyl -2- phenyl thiazole -5- base) methoxyl group) phenyl) sulfonyl) acetic acid (I-12)；
2- ((4- ((4- methyl -2- (3- aminomethyl phenyl) thiazole -5- base) methoxyl group) phenyl) sulfonyl) acetic acid (I-13)；
2- ((4- ((2- (2- fluorophenyl) -4- methylthiazol -5- base) methoxyl group) phenyl) sulfonyl) acetic acid (I-14)；
2- ((4- ((2 '-isopropyls-[1,1 '-biphenyl] -3- base) methoxyl group) phenyl) sulfonyl) acetic acid (I-15)；
2- ((4- ((2- (3- chlorphenyl) -4- methylthiazol -5- base) methoxyl group) phenyl) sulfonyl) acetic acid (I-16)；
2- ((4- ((2 ', 6 '-dimethyl -4- propoxyl group-[1,1 '-biphenyl] -3- base) methoxyl group) phenyl) sulfonyl) second Sour (I-17)；
2- ((4- ((4 '-ethyoxyls -2 ', 6 '-dimethyl-[1,1 '-biphenyl] -3- base) methoxyl group) phenyl) sulfonyl) second Sour (I-18)；
2- (4- (2,6- dimethyl -4- (3- (methyl sulphonyl) propoxyl group)-[1,1 '-xenyl] -3- base) methoxyl group) Phenyl) sulfonyl) acetic acid (I-19)；
2- ((4- ((4 '-isobutyl groups -2 ', 6 '-dimethyl-[1,1 '-biphenyl] -3- base) methoxyl group) phenyl) sulfonyl) second Sour (I-20)；
2- ((4- (4 '-(2- methoxy ethoxy) -2 ', 6 '-dimethyl-[1,1 '-biphenyl -3- base] methoxyl group) phenyl) Sulfonyl) acetic acid (I-21)；
2- (4- (5- (3,5- dimethyl oxazoline -4- base) -2- methyl) oxygroup) phenyl) sulfonyl) acetic acid (I-22)；
2- (4- (3- (3,5- dimethyl oxazoline -4- base) -2- methyl) oxygroup) phenyl) sulfonyl) acetic acid (I-23)；
2- ((4- ((the chloro- 3- of 4- (3,5- dimethyl oxazoline -4- base) benzyl) oxygroup) phenyl) sulfonyl) acetic acid (I-24)；
2- (4- (3- (2- methyl-1 H- pyrroles -1- base) phenoxy group) phenyl) sulfonyl) acetic acid (I-25)；
2- (4- (3- (3,5- dimethyl oxazoline -4- base) phenoxy group) phenyl) sulfonyl) acetic acid (I-26)；
2- ((4- ((2- (4- fluorophenyl) -4- methylthiazol -5- base) methoxyl group) phenyl) sulfonyl) acetic acid (I-27)；
2- ((4- ((4 '-methoxyl groups -2 ', 6 '-dimethyl-[1,1 '-biphenyl] -3- base) methoxyl group) phenyl) sulfonyl) third Sour (I-28)；
2- ((4- ((the chloro- 5- of 2- (3,5- dimethyl oxazoline -4- base) benzyl) oxygroup) phenyl) sulfonyl) acetic acid (I-29)；
2- ((3- ([1,1 '-biphenyl] -4- methoxyl group) phenyl) sulfonyl) acetic acid (I-30)；
2- ((3- ((2 '-methyl-[1,1 '-biphenyl -4- methoxyl group])) phenyl) sulfonyl) acetic acid (I-31)；
2- ((4- ((3- phenoxy group) oxygroup) phenyl) sulfonyl) acetic acid (I-32)；
1- ((4- ((4 '-methoxyl groups -2 ', 6 '-dimethyl-[1,1 '-biphenyl] -3- base) methoxyl group) phenyl) sulphonyl)-ring Propane-acetic acid (I-33)；
2- ((4- ((4 '-methoxyl groups -2 ', 6 '-dimethyl-[1,1 '-biphenyl] -3- base) methoxyl group) phenyl) sulfonyl) - 2 Methylpropionic acid (I-34)；
2- ((4- ((4 '-methoxyl groups -2 ', 6 '-dimethyl-[1,1 '-biphenyl] -3- base) methoxyl group) phenyl) sulfonyl) fourth Sour (I-35)；
Another aspect of the present invention relates to a kind of pharmaceutical compositions, change described in the logical formula (I) containing treatment effective dose Close object and pharmaceutically acceptable ester or its pharmaceutical salt and carrier appropriate, diluent or excipient.
Present invention simultaneously relates to the compound and pharmaceutically acceptable ester or its pharmaceutical salt or its medicine groups Close application of the object in preparation treatment diabetes and Metabolic syndrome disease drug.
Detailed description of the invention
Unless otherwise stated, following have following meanings with term in the specification and in the claims.
" alkyl " refers to the aliphatic hydrocarbon group of saturation, straight chain and branched group including 1 to 20 carbon atom.Preferably comprise 1 To the alkyl of 10 carbon atoms, the more preferably alkyl containing 1 to 6 carbon atom, the alkyl of further preferably 1 to 3 carbon atom, Most preferably methyl.Non-limiting embodiment includes methyl, ethyl, propyl, isopropyl, butyl, isobutyl group, sec-butyl, tertiary fourth Base, amyl, isopentyl, neopentyl, hexyl etc. and its various branched isomers etc..Alkyl can be substituted or unsubstituted, When substituted, substituent group can be substituted on any workable tie point, preferably one or more following groups, solely Group on the spot selected from halogen, hydroxyl, cyano, nitro, alkyl, alkoxy, naphthenic base, heterocycle, aryl, heteroaryl is taken Generation.
" naphthenic base " refers to the unsaturated monocycle of saturation or part or polycyclic cyclic hydrocarbon substituent comprising 3 to 20 carbon atoms, 3 to 12 carbon atoms are preferably included, more preferable cycloalkyl ring includes 3 to 10 carbon atoms.The non-limiting reality of monocyclic cycloalkyl Applying example includes cyclopropyl, cyclobutyl, cyclopenta, cyclopentenyl, cyclohexyl, cyclohexenyl group, cyclohexadienyl, suberyl, cycloheptyl Trialkenyl, cyclooctyl etc.
" aryl " refers to that 6 to 14 yuan of full carbon monocycles of the pi-electron system with conjugation or fused polycycle are (namely shared to adjoin The ring of carbon atom pair) group, preferably 6 to 10 yuan, such as phenyl and naphthalene.The aryl rings can be condensed in heteroaryl, miscellaneous In ring group or cycloalkyl ring, wherein being aryl rings with the ring that precursor structure links together.
Aryl can be substituted or unsubstituted, and when substituted, substituent group is preferably one or more following groups, Independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio group, alkyl amino, halogen, mercaptan, hydroxyl, nitro, cyano, cycloalkanes Base, Heterocyclylalkyl, aryl, heteroaryl, cycloalkyloxy, heterocyclylalkoxy groups, cycloalkylthio, heterocycle alkylthio group group replaced.
" heteroaryl " refers to comprising 1 to 4 hetero atom, the heteroaromatic system of 5 to 14 annular atoms, and wherein hetero atom includes Oxygen, sulphur and nitrogen.Preferably 5 to 10 yuan.Heteroaryl is preferably 5- or 6-membered, such as furyl, thienyl, pyridyl group, pyrroles Base, N- alkyl pyrrole radicals, pyrimidine radicals, pyrazinyl, imidazole radicals, tetrazole radical etc..The heteroaryl ring can be condensed in aryl, heterocycle On base or cycloalkyl ring, wherein being heteroaryl ring with the ring that precursor structure links together.
Heteroaryl can be it is optionally substituted or unsubstituted, when substituted, substituent group be preferably it is one or more with Lower group, independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio group, alkyl amino, halogen, mercaptan, hydroxyl, nitro, cyanogen Base, naphthenic base, Heterocyclylalkyl, aryl, heteroaryl, cycloalkyloxy, heterocyclylalkoxy groups, cycloalkylthio, heterocycle alkylthio group group It is replaced.
" alkoxy " refers to-O- (alkyl) and-O- (unsubstituted naphthenic base), and wherein alkyl is as defined above.Non- limit Property embodiment processed includes methoxyl group, ethyoxyl, propoxyl group, butoxy, cyclopropyl oxygroup, cyclobutoxy group, cyclopentyloxy, cyclohexyloxy Deng.Alkoxy can be optionally substituted or unsubstituted, and when substituted, substituent group is preferably one or more following bases Group, independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio group, alkyl amino, halogen, mercaptan, hydroxyl, nitro, cyano, Naphthenic base, Heterocyclylalkyl, aryl, heteroaryl, cycloalkyloxy, heterocyclylalkoxy groups, cycloalkylthio, heterocycle alkylthio group group taken Generation.
" optional " or " optionally " mean ground described later event or environment can with but need not occur, which includes The event or environment generation or not spot occasion.For example, meaning that alkyl can be with " optionally by alkyl-substituted heterocyclic group " But necessarily exist, the explanation include heterocyclic group by alkyl-substituted situation and heterocyclic group not by alkyl-substituted situation.
" substituted " refers to one or more hydrogen atoms in group, preferably at most 5, more preferably 1~3 hydrogen atom Replaced independently of one another by the substituent group of respective number.Self-evident, substituent group is only in their possible chemical position, this Field technical staff, which can determine in the case where not paying excessive make great efforts and (pass through experiment or theoretical), may or impossible take Generation.It may be unstable when for example, amino or hydroxyl with free hydrogen are in conjunction with the carbon atom with unsaturated (such as olefinic) key Fixed.
" pharmaceutical composition " is indicated containing one or more compounds of the present invention or its pharmaceutical salt or its prodrug With the mixture of other chemical constituents, for example pharmaceutical carrier of other chemical constituents and excipient.The purpose of pharmaceutical composition It is the absorption for promoting organism to active constituent, plays bioactivity in vivo conducive to active constituent.
Logical formula (I) compound of the present invention can be synthesized by following steps:
The compound that logical formula (II) indicates and the compound that logical formula (III) indicates are obtained into general formula under the reaction of alkali (IV), lead to the compound that formula (IV) indicates and general formula compound (I) is prepared by hydrolysis.
Wherein W is leaving group, R1-R7Definition as described in logical formula (I).
W indicates leaving group, it can be mentioned that such as Cl, Br, I, optionally halogenated C1-C6Alkyl sulphonyl oxygroup (for example, Mesyl oxygroup, ethylsulfonyl oxygroup, three chloromethanesulfonyls), optionally with substituent group C6-C10Aryl sulfonyl oxygroup (for example, phenyl sulfonyl oxygroup, p-toluenesulfonyl oxygroup, m- nitrobenzenesulfonyl oxygroup etc.) etc..
It include inorganic base and organic base as the alkali, the inorganic base can be mentioned that for example, alkali carbonate Class such as sodium carbonate, potassium carbonate, cesium carbonate etc.；Alkali metal hydrogencarbonate class such as saleratus etc.；Alkali metal hydroxide is for example Lithium hydroxide, sodium hydroxide, potassium hydroxide etc.；The organic base can be mentioned that for example triethylamine, pyridine, lutidines, N-BuLi, potassium tert-butoxide etc..
The GPR40 agonist activity of compound and internal hypoglycemic activity can be by using measurements as described below in the present invention System measurement.
The present invention is explained in following biology testing example description.
The experimental method of actual conditions usually routinely condition or is built according to commodity manufacturer in test case of the present invention The condition of view.The reagent in specific source is not specified, for the common agents of market purchase.
1 the compounds of this invention of test case surely turns the agonist activity of cell to hGPR40-CHO
The present invention measures the GPR40 agonist activity of the compounds of this invention using following methods:
HGPR40-CHO turns cell surely with 3 × 104The density in/hole is seeded to 96 orifice plates, is placed in 37 DEG C, 5%CO2Cell Incubator is incubated overnight；Culture medium is discarded, after 100ul HBSS cleaning is added in every hole, 100ul is added containing Probenecid's 37 DEG C of incubation 90min of Fluo-4 dye solution；After incubation, Fluo-4 dye solution is sucked out, adds 100 μ l HBSS buffers, Wash away dyestuff；HBSS of the 100 μ l containing Probenecid, 37 DEG C of incubation 10min is added in every hole；Every hole is added different dense in 96 orifice plates The drug of degree is read according to parameter setting table with FLIPR (Molecular Devices).Analyze experimental result.Agonist activity= (compound well fluorescent value-blank control wells fluorescent value)/(linoleic acid hole fluorescent value-blank control wells fluorescent value) × 100%, knot Fruit is shown in Table 1.
Table 1:hGPR40 receptor agonist activity
Conclusion: all compounds of the present invention have apparent agonist activity to GPR40, wherein I-3, I-4, I-5, I-7, I- 9, I-10 and I-15 has stronger GPR40 agonist activity.
The internal hypoglycemic activity of compound can be surveyed by using measurement system as described below in 2 present invention of test case It is fixed:
Normal mouse oral glucose tolerance tests (OGTT): 10 week old Kunming kind cleaning grade mouse, 18~22g of weight, male, It is randomly divided into 7 groups, blank control group (blank solvent: 0.5% carboxymethylcellulose sodium solution), positive drug control group (TAK- 875:20mg/kg), test-compound group (20mg/kg), every group 8, mouse is deprived of food but not water 12 hours before testing, and each group is equal Oral administration gavage administration, docking take blood, measure blood glucose value (being denoted as -30min).Then blank solvent, TAK-875 are given in stomach-filling respectively And test-compound, measurement blood glucose value is denoted as 0min after 30min, and giving concentration by 10ml/kg stomach-filling immediately later is 2g/10ml Glucose solution, and in 15,30,60,120min measure blood glucose values.It the results are shown in Table 2.
Table 2: influence of the preferred compound to normal mouse oral glucose tolerance
Note:*P≤0.05 is Student ' the s t inspection result relative to blank control group.
Normal mouse oral glucose tolerance experiments have shown that: ester prodrugs I-1, I-3, I-4, I-5 and I-10 in vivo also can be bright The aobvious oral glucose tolerance for improving normal mouse, shows preferable hypoglycemic effect.
The liver nephrotoxic risks assessment of compound can pass through the assessment side described in following examples in 3 present invention of test case Method:
10 week old ICR kind cleaning grade mouse, 18~22g of weight, male are randomly divided into 4 groups, (blank is molten for blank control group Matchmaker: 0.5% cmc soln), positive drug control group (TAK-875:20mg/kg), test-compound I-3 group (30mg/kg), test-compound I-5 group (30mg/kg), after every group 8, successive administration 30 days, it is small that mouse is deprived of food but not water 12 When, it plucks eyeball and takes whole blood into centrifuge tube, centrifuging and taking upper serum after standing measured third turn of ammonia of paddy with biochemical instruments within 24 hours Enzyme (ALT), glutamic-oxalacetic transaminease (AST), the total bilirubin (TBIL) in serum, urea nitrogen (BUN) and serum creatinine (Scr) index, Investigate influence of the test-compound long term administration to liver function.
Table 3: influence of the test-compound to hepatic and renal function
Note:#P≤0.05 is Student ' the s t inspection result relative to blank control group.
The result shows that ALT the and AST index of positive drug TAK-875 group is higher compared with blank after successive administration 30 days, exist Cause hepatotoxic risk, and the index of compound I-3 and I-5 group is suitable with blank, illustrates that it causes the wind of liver renal toxicity Danger is lower.I.e. test-compound group dosage is that 30mg/kg still shows the administration safety for being better than TAK-875 (20mg/kg), is Further clinical development provides safeguard.
Specific embodiment
Below with reference to embodiment, the invention will be further described.It should be noted that following embodiments are only for It is bright, and it is not intended to limit the present invention.The various change that those skilled in the art's training centre according to the present invention is made should all be Within protection scope required by the claim of this application.
Embodiment 1
Methyl 2 ((4- hydroxy phenyl) sulfonyl) acetic acid
Step 1: 4- methoxybenzenethiol (0.88ml, 7.13mmol) is dissolved in 15ml acetonitrile, potassium carbonate is added (2.96g, 21.4mmol), gained mixed liquor are placed in ice bath cooling, the second of dropwise addition bromoacetate (1.03ml, 9.27mmol) Nitrile solution (5ml) controls interior temperature and is lower than 0 DEG C during being added dropwise, drop finishes, and 3h is stirred at room temperature in gained brown reaction solution, and TLC is detected After fully reacting, water 30ml is added to dilute, ethyl acetate (30ml × 4) extraction, merge it is organic it is interdependent time with 1N NaOH (20ml × 1), (20ml × 1) 1N HCl, saturation NaCl solution (20ml × 2) washing, gained organic phase is dry with anhydrous sodium sulfate, filters, Filtrate decompression is evaporated off solvent and obtains yellowish-brown oily liquids 1.8g, crude yield 112%.
Step 2: above-mentioned crude product (1g, 6.63mmol) is taken to be dissolved in 30ml methanol, ice bath is cooled to -5 DEG C hereinafter, being added dropwise The 30ml aqueous solution of oxone (8.15g, 13.26mmol) controls interior temperature and is lower than 0 DEG C during being added dropwise, drop finishes, and reacts at room temperature For 24 hours, water 50ml is added to dilute, ethyl acetate (40ml × 4) extraction merges organic phase and is washed with being saturated NaCl solution (20ml × 2), Gained organic phase is dry with anhydrous sodium sulfate, filters, and filtrate decompression is evaporated off solvent and obtains yellow oily liquid 0.8g, crude yield 72%.
Step 3: above-mentioned crude material (0.5g, 1.94mmol) is taken to be dissolved in 48% hydrogen bromide solution of 20ml, it is added 0.05g TBAB catalysis, gained reaction solution react 8h after TLC detects fully reacting in 100 DEG C of heating and reaction solution are cooled to room Temperature adds water 50ml to dilute, and ethyl acetate (40ml × 5) extraction merges organic phase and washed with being saturated NaCl solution (25ml × 2), Gained organic phase is dry with anhydrous sodium sulfate, filters, and filtrate decompression is evaporated off solvent and obtains yellowish-brown crystal 0.3g.Gained crystal is molten In 15ml methanol, the 1.5ml concentrated sulfuric acid is added dropwise, drop finishes, and is heated to reflux 4h, and TLC detects fully reacting, reaction solution is cooled to room Temperature adds water 30ml to dilute, and ethyl acetate (40ml × 4) extraction merges organic phase and washed with being saturated NaCl solution (20ml × 2), Gained organic phase is dry with anhydrous sodium sulfate, filters, and solvent is evaporated off in filtrate decompression, and residue chromatographs (petroleum ether/acetic acid second through column Ester, 75:25, v/v) purifying obtain white solid 0.31g, yield 70%.
1H NMR (300MHz, DMSO-d6) δ: 10.67 (s, 1H), 7.72 (d, J=8.7Hz, 2H), 6.97 (d, J= 8.7Hz, 2H), 4.47 (s, 2H), 3.59 (s, 3H)
Embodiment 2
Methyl 1- ((4- ((4 '-methoxyl groups -2 ', 6 '-dimethyl-[1,1 '-biphenyl] -3- base) methoxyl group) phenyl) sulphonyl Base) cyclopropyl -1- methyl acetate
Raw material (0.2g, 0.44mmol) is dissolved in 10ml DMF, and potassium carbonate (0.15g, 1.1mmol) and catalytic amount is added TEBA after 15min is stirred at room temperature, is added dropwise 1,2- Bromofume (0.10g, 0.55mmol), and gained reaction solution is anti-in 60 DEG C of heating After answering 3h, TLC to detect fully reacting, reaction solution is cooled to room temperature, water 30ml is added to dilute, ethyl acetate (30ml × 4) extraction is closed And organic phase, to be saturated NaCl solution (20ml × 2) washing, gained organic phase is dry with anhydrous sodium sulfate, filters, filtrate decompression Solvent is evaporated off, residue obtains white solid 0.2g, yield through column chromatography (petrol ether/ethyl acetate, 85: 25, v/v) purifying 97%.
Embodiment 3
2 '-chloro- [1,1 '-biphenyl] -4- formaldehyde
Raw material II I-1 (0.5g, 2.6mmol) is dissolved in 42ml in the mixed solvent (toluene/ethanol/water, 3: 1: 3, v/v/v), It is added raw material II I-2 (0.3g, 2.6mmol), triphenyl phosphorus palladium (0.15g, 0.13mmol), natrium carbonicum calcinatum (0.69g, 6.5mmol), under nitrogen protection, 60 DEG C of heating reactions are for 24 hours.It is cooled to room temperature after reaction, adds water 20ml to dilute, with diatom Soil is laid the groundwork suction filtration, and ethyl acetate (15ml × 3) washs filter cake, and filtrate merges organic phase with ethyl acetate (30ml × 4) extraction To be saturated NaCl solution (20ml × 2) washing, gained organic phase is dry with anhydrous sodium sulfate, filters, and solvent is evaporated off in filtrate decompression, Residue obtains pale solid 0.47g, yield 84% through column chromatography (petrol ether/ethyl acetate, 70: 30, v/v) purifying.
Embodiment 4
2- ((4- ((2 '-chloro- [1,1 '-biphenyl] -3- base) methoxyl group) phenyl) sulfonyl) acetic acid (I-3)
Raw material II I-3 (0.2g, 0.92mmol) is dissolved in the solution of 20ml in the mixed solvent (THF/MeOH, 1: 1, v/v), It is slowly added under ice bath sodium borohydride (0.05g, 1.2mmol), under ice bath after reaction, adds 20ml water quenching reaction, acetic acid Ethyl ester extraction (30ml × 3) merges organic phase to be saturated NaCl solution (20ml × 2) washing, and gained organic phase is with anhydrous sodium sulfate It is dry, it filters, solvent is evaporated off in filtrate decompression, not purified to be directly used in the next step.The compound that upper step obtains is dissolved in 20ml In methylene chloride, it is slowly dropped into 0.5ml thionyl chloride, 1 drop DMF is added, 25 DEG C of heating reactions remove under reduced pressure molten after reaction Agent obtains light yellow oil III-4.III-4 (0.2g, 0.90mmol) is dissolved in 20ml acetonitrile, and raw material II -3 is added (0.25g, 1.08mmol), Anhydrous potassium carbonate (0.5g, 3.62mmol), catalytic amount KI are heated to 60 DEG C of reaction 8h, and filtering subtracts Solvent is evaporated off in pressure, and residue is dissolved in 30ml water, and ethyl acetate (20ml × 3) extraction merges organic phase, with saturated salt solution (15ml × 2) washing, anhydrous sodium sulfate dry, filter, and solvent is evaporated off in filtrate decompression, and residue chromatographs (petroleum ether/acetic acid through column Ethyl ester, 4: 1, v/v) 0.26g white solid III-5 is purified to obtain, it is dissolved in 14ml in the mixed solvent (THF/MeOH/H2O, 3: 3: 1, V/v/v), LiOH (0.07g, 2.79mmol) is added, reacts at room temperature 8h, removes tetrahydrofuran and methanol under reduced pressure, dripped under ice-water bath Add 1N dilute hydrochloric acid to adjust PH2-3, white solid is precipitated, filters, dry white powdery solids I-3 0.25g, fusing point 103- 105 DEG C, yield 66%.
1H NMR (300MHz, DMSO-d6) δ: 13.03 (s, 1H), 7.85 (d, J=8.8Hz, 2H), 7.54,7.49 (dd, J =13.2,9.2Hz, 4H), 7.45-7.40 (m, 4H), 7.27 (d, J=8.8Hz, 2H), 5.30 (s, 2H), 4.40 (s, 2H)13C NMR (75MHz, DMSO-d6) δ: 164.60,162.86,139.89,139.35,136.71,131.96,131.51,130.88, 130.32,129.79,129.45,129.12,128.95,128.02,127.71,115.57,70.01,60.81.ESI-MS m/ Z:371.0 [M-45]-.Anal.calcd.For C21H17ClO5S:C, 60.51；H, 4.11；Cl, 8.50；Found:C, 60.46； H, 4.12；Cl, 8.51.
Embodiment 5
2- ((4- ((2 '-chloro- [1,1 '-biphenyl] -3- base) methoxyl group) phenyl) sulfonyl) methyl acetate (I-1)
The same I-3 of synthetic method, obtains white solid 0.26g, and 82-84 DEG C of fusing point, yield 70%.
1H NMR (300MHz, DMSO-d6) δ: 13.03 (s, 1H), 7.85 (d, J=8.8Hz, 2H), 7.54,7.49 (dd, J =13.2,9.2Hz, 4H), 7.45-7.40 (m, 4H), 7.27 (d, J=8.8Hz, 2H), 5.16 (s, 2H), 4.46 (s, 2H), 3.73 (s, 3H)
13C NMR (75MHz, DMSO-d6) δ: 164.0,160.4,141.7,139.4,136.71,132.6,132.0, 132.0,131.2,129.4,129.3,129.3,129.0,128.9,127.3,126.8,126.0,115.3,115.3,71.1, 63.7,51.6.ESI-MS m/z:430.0 [M-1]-.Anal.calcd.For C22H19ClO5S:C, 61.32；H, 4.44； Found:C, 60.29；H, 4.32.
Embodiment 6
2- ((4- ([1,1 '-biphenyl] -3- methoxyl group) phenyl) sulfonyl) acetic acid (I-2)
The same I-3 of synthetic method, obtains white solid 0.36g, and 110-112 DEG C of fusing point, yield 73%.
1H NMR (300MHz, DMSO-d6) δ: 7.90-7.75 (m, 3H), 7.71-7.66 (m, 3H), 7.50-7.46 (m, 4H), 7.42-7.23 (m, 3H), 5.30 (s, 2H), 4.37 (s, 2H)13C NMR (75MHz, DMSO-d6) δ: 178.88, 164.54,137.43,137.38,130.94,130.87,129.71,129.48,128.12,127.43,127.18,126.92, 126.72,115.60,70.18,61.17.ESI-MS m/z:337.1 [M-45]-.Anal.calcd.For C21H18O5S:C, 65.95；H, 4.74；Found:C, 65.92；H, 4.73.
Embodiment 7
2- ((4- ((2 ', 6 '-dimethyl-[1,1 '-biphenyl] -3- base) methoxyl group) phenyl) sulfonyl) acetic acid (I-4)
The same I-3 of synthetic method, obtains white solid 0.56g, and 165-167 DEG C of fusing point, yield 85%.
1H NMR (300MHz, DMSO-d6) δ: 7.83 (d, J=8.4Hz, 2H), 7.55-7.40 (m, 2H), 7.24-7.07 (m, 7H), 5.25 (s, 2H), 4.14 (s, 2H), 1.93 (s, 6H)13C NMR (75MHz, DMSO-d6) δ: 164.95,162.44, 141.43,140.99,137.03,135.60,132.43,130.78,129.26,128.95,128.61,127.76,127.55, 126.68,115.36,70.04,62.56,20.97.ESI-MS m/z:365.1 [M-45]-.Anal.calcd.For C23H22O5S:C, 67.30；H, 5.40；Found:C, 67.34；H, 5.41.
Embodiment 8
2- ((4- ((2 '-methyl-[1,1 '-biphenyl] -3- base) methoxyl group) phenyl) sulfonyl) acetic acid (I-5)
The same I-3 of synthetic method, obtains white solid 0.24g, and 113-114 DEG C of fusing point, yield 68%.
1H NMR (300MHz, DMSO-d6) δ: 7.84 (d, J=8.5Hz, 2H), 7.55-7.42 (m, 3H), 7.39-7.16 (m, 7H), 5.29 (s, 2H), 4.34 (s, 2H), 2.21 (s, 3H)13C NMR (75MHz, DMSO-d6) δ: 164.50,162.78, 141.41,140.92,136.68,130.86,129.95,129.15,128.94,127.89,126.90,126.44,115.49, 70.08,61.20,20.59.ESI-MS m/z:351.1 [M-45]-.Anal.calcd.For C22H20O5S:C, 66.65；H, 5.09；Found:C, 66.61；H, 5.08.
Embodiment 9
2- ((4- (2 '-methoxyl groups-(1,1 '-biphenyl -3- base) methoxyl group) phenyl) sulfonyl) acetic acid (I-6)
The same I-3 of synthetic method, obtains white solid 0.35g, and 101-102 DEG C of fusing point, yield 73%.
1H NMR (300MHz, DMSO-d6) δ: 7.85 (d, J=8.8Hz, 2H), 7.57 (s, 1H), 7.50-7.38 (m, 3H), 7.38-7.19 (m, 4H), 7.15-6.97 (m, 2H), 5.27 (s, 2H), 4.38 (s, 2H), 3.74 (s, 3H)13C NMR (75MHz, DMSO-d6) δ: 164.53,162.71,157.72,141.45,140.91,136.64,132.82,131.67, 129.91,129.12,128.96,127.83,126.92,126.43,116.70,115.49,70.08,61.20, 56.13.ESI-MS m/z:367.1 [M-45]-.Anal.calcd.For C22H20O6S:C, 64.07；H, 4.89；Found:C, 64.01；H, 4.88.
Embodiment 10
2- ((4- ((4 '-(cyclopropyl methoxyl group) 2 ', 6 '-dimethyl-[1,1 '-biphenyl] -3- base) methoxyl group) phenyl) sulphonyl Base) acetic acid (I-7)
The same I-3 of synthetic method, obtains white solid 0.43g, and 104-106 DEG C of fusing point, yield 76%.
1H NMR (300MHz, DMSO-d6) δ: 7.82 (d, J=7.7Hz, 2H), 7.56-7.35 (m, 2H), 7.17-7.06 (m, 4H), 6.68 (s, 2H), 5.25 (s, 2H), 4.11 (s, 2H), 3.79 (d, J=5.9Hz, 2H), 1.91 (s, 6H), 1.39 (d, J=5.9Hz, 1H), 0.56 (d, J=5.8Hz, 2H), 0.30 (d, J=5.8Hz, 2H)13C NMR (75MHz, DMSO-d6) δ: 164.59,162.75,156.12,141.44,140.93,136.93,132.76,131.07,130.76,128.95, 127.84,126.91,126.34,118.41,115.30,113.63,72.22,70.08,61.20,21.23,10.69, 3.57.ESI-MS m/z:435.1 [M-45]-.Anal.calcd.For C27H28O6S:C, 67.48；H, 5.87；Found:C, 67.43；H, 5.86.
Embodiment 11
2- ((4- ((2 '-fluoro- [1,1 '-biphenyl] -3- base) methoxyl group) phenyl) sulfonyl) acetic acid (I-8)
The same I-3 of synthetic method, obtains white solid 0.22g, and 115-117 DEG C of fusing point, yield 67%.
1H NMR (300MHz, DMSO-d6) δ: 7.85 (d, J=7.7Hz, 2H), 7.65 (s, 1H), 7.60-7.39 (m, 5H), 7.30 (d, J=7.6Hz, 2H), 7.21 (d, J=7.7Hz, 2H), 5.28 (s, 2H), 4.06 (s, 2H)13C NMR (75MHz, DMSO-d6) δ: 164.51,162.03,136.67,135.27,132.76,130.77,129.67,129.18, 128.85,128.50,128.13,127.24,124.94,116.25,115.94,115.31,69.50,43.89.ESI-MS m/ Z:355.1 [M-45]-.Anal.calcd.For C21H17FO5S:C, 62.99；H, 4.28；Found:C, 62.93；H, 4.27.
Embodiment 12
2- ((4- ((2 '-(trifluoromethyls)-[1,1 '-biphenyl] -3- base) methoxyl group) phenyl) sulfonyl) acetic acid (I-9)
The same I-3 of synthetic method, obtains white solid 0.36g, and 179-180 DEG C of fusing point, yield 84%.
1H NMR (300MHz, DMSO-d6) δ: 7.89-7.78 (m, 3H), 7.68 (dd, J=25.1,7.1Hz, 2H), 7.57-7.39 (m, 4H), 7.31 (s, 1H), 7.17 (d, J=8.3Hz, 2H), 5.25 (s, 2H), 3.80 (s, 2H)13C NMR (75MHz, DMSO-d6) δ: 173.79,164.41,161.53,139.45,136.01,132.30,132.13,131.78, 130.20,129.14,128.37,128.15,127.96,127.18,126.07,115.33,114.48,69.45,64.08, 43.90.ESI-MS m/z:405.1 [M-45]-.Anal.calcd.For C22H17F3O5S:C, 58.66；H, 3.80；Found: C, 58.61；H, 3.81.
Embodiment 13
2- ((4- ((4 '-methoxyl groups -2 ', 6 '-dimethyl-[1,1 '-biphenyl] -3- base) methoxyl group) phenyl) sulfonyl) second Sour (I-10)
The same I-3 of synthetic method, obtains white solid 0.16g, and 97-98 DEG C of fusing point, yield 72%.
1H NMR (300MHz, DMSO-d6) δ: 7.81 (d, J=8.4Hz, 2H), 7.46 (d, J=7.8Hz, 2H), 7.25- 7.04 (m, 4H), 6.70 (s, 2H), 5.25 (s, 2H), 3.88 (s, 2H), 3.75 (s, 3H), 1.93 (s, 6H)13C NMR (75MHz, DMSO-d6) δ: 162.49,158.41,140.89,136.99,136.88,134.00,133.19,129.58, 129.18,126.46,115.91,113.13,70.07,55.36,44.40,21.19.ESI-MS m/z:395.1 [M-45]- .Anal.calcd.For C24H24O6S:C, 65.44；H, 5.49；Found:C, 65.41；H, 5.48.
Embodiment 14
2- ((4- ((2 '-cyano-[1,1 '-biphenyl] -3- base) methoxyl group) phenyl) sulfonyl) acetic acid (I-11)
The same I-3 of synthetic method, obtains white solid 0.25g, and 187-190 DEG C of fusing point, yield 79%.
1H NMR (300MHz, DMSO-d6) δ: 7.96 (d, J=6.8Hz, 1H), 7.88-7.76 (m, 3H), 7.72-7.52 (m, 6H), 7.24 (d, J=7.6Hz, 2H), 5.31 (s, 2H), 4.16 (s, 2H)13C NMR (75MHz, DMSO-d6) δ: 164.31,162.39,142.35,138.50,137.45,134.32,134.05,130.85,130.61,129.69,129.45, 128.81,128.63,115.80,114.98,110.65,69.85,61.23.ESI-MS m/z:362.1 [M-45]- .Anal.calcd.For C22H17NO5S:C, 64.85；H, 4.21；N, 3.44；Found:C, 64.81；H, 4.21；N, 3.43.
Embodiment 15
4- methyl -2- phenyl thiazole -5- Ethyl formate
Thiobenzamide (1.0g, 7.3mmol), 2- chloroacetyl acetacetic ester (1.4g, 8.6mmol) are dissolved in 20ml ethyl alcohol In, catalytic amount sodium carbonate is added, is heated to reflux 6h, has reacted, be cooled to room temperature, filters out insoluble matter, filtrate decompression concentration is added full With sodium bicarbonate solution to alkalescent, ethyl acetate (20ml × 3) extraction merges organic phase, with saturated salt solution (15ml × 2) Washing, anhydrous sodium sulfate dries, filters, and filtrate decompression is evaporated off solvent, residue chromatograph through column (petrol ether/ethyl acetate, 5: 1, V/v 1.2g white solid) is purified to obtain, 74-76 DEG C of fusing point, yield 72.8%.
1H NMR (300MHz, DMSO-d6) δ: 7.93,7.91 (dd, J=1.26,7.57Hz, 2H, ArH), 7.45-7.40 (m, 3H, ArH), 4.30 (q, J=7.07Hz, 2H ,-OCH2), 2.68 (s, 3H, ArCH3), 1.31 (t, J=7.07Hz, 3H ,- CH3).
Embodiment 16
2- ((4- ((4- methyl -2- phenyl thiazole -5- base) methoxyl group) phenyl) sulfonyl) acetic acid (I-12)
Raw material II I-1 (0.80g, 3.23mmol) is dissolved in 15ml THF, and NaBH is added portionwise4(0.31g, 8.0mmol), It finishes, is heated to reflux lower dropwise addition 0.5ml methanol, drop Bi Jixu reflux about 30min stops stirring, is cooled to room temperature, by reaction solution It is poured into 20ml ice water, ethyl acetate (20ml × 3) extraction merges organic phase, with saturated salt solution (15ml × 2) washing, nothing Aqueous sodium persulfate dries, filters, and solvent is evaporated off in filtrate decompression, obtains beige solid 0.54g, and not purified to be directly used in lower step anti- It answers, is added portionwise under ice bath into the thionyl chloride 5ml pre-cooled, be heated to 60 DEG C of reaction 1h after mixing evenly, react Liquid removes extra thionyl chloride under reduced pressure, and gained brown oil III-2 is dissolved in 20ml THF, and raw material II -3 is added (0.64g, 2.79mmol), Anhydrous potassium carbonate (1.15g, 8.34mmol), catalytic amount KI are heated to 60 DEG C of reaction 8h, and filtering subtracts Solvent is evaporated off in pressure, and residue is dissolved in 30ml water, and ethyl acetate (20ml × 3) extraction merges organic phase, with saturated salt solution (15ml × 2) washing, anhydrous sodium sulfate dry, filter, and solvent is evaporated off in filtrate decompression, and residue chromatographs (petroleum ether/acetic acid through column Ethyl ester, 4: 1, v/v) 0.76g white solid III-3 is purified to obtain, it is dissolved in 14mL mixed solvent (THF/MeOH/H2O, 3: 3: 1, v/ V/v), LiOH (0.1g, 3.99mmol) is added, reacts at room temperature 8h, removes tetrahydrofuran and methanol under reduced pressure, 1N is added dropwise under ice-water bath Dilute hydrochloric acid adjusts PH 2-3, and white solid is precipitated, and filters, dry white powdery solids I-120.61g, fusing point 155-157 DEG C, yield 80.3%.
1H NMR (300MHz, DMSO-d6) δ: 8.02-7.82 (m, 4H), 7.57-7.44 (m, 3H), 7.28 (d, J= 8.8Hz, 2H), 5.46 (s, 2H), 4.43 (s, 2H), 2.47 (s, 3H)13C NMR (75MHz, DMSO-d6) δ: 165.77, 163.98,161.83,151.83,132.61,131.42,130.40,129.22,125.98,115.20,62.02,60.29, 15.00.ESI-MS m/z:358.1 [M-45]-.Anal.calcd.For C19H17NO5S2: C, 56.56；H, 4.25；N, 3.47； Found:C, 56.50；H, 4.26；N, 3.46.
Embodiment 17
2- ((4- ((4- methyl -2- (3- aminomethyl phenyl) thiazole -5- base) methoxyl group) phenyl) sulfonyl) acetic acid (I-13)
The same I-12 of synthetic method, obtains white solid 0.25g, and 122-124 DEG C of fusing point, yield 69%.
1H NMR (300MHz, DMSO-d6) δ: 13.22 (s, 1H), 7.87 (d, J=8.9Hz, 2H), 7.78-7.66 (m, 2H), 7.41-7.24 (m, 4H), 5.45 (s, 2H), 4.44 (s, 2H), 2.46 (s, 3H), 2.37 (s, 3H)13C NMR (75MHz, DMSO-d6) δ: 164.56,162.34,152.45,139.08,133.25,131.49,130.89,129.60,126.78, 123.66,115.66,114.99,69.76,62.51,21.32,15.57.ESI-MS m/z:372.1 [M-45]- .Anal.calcd.For C20H19NO5S2: C, 57.54；H, 4.59；N, 3.36；Found:C, 57.57；H, 4.58；N, 3.36.
Embodiment 18
2- ((4- ((2- (2- fluorophenyl) -4- methylthiazol -5- base) methoxyl group) phenyl) sulfonyl) acetic acid (I-14)
The same I-12 of synthetic method, obtains white solid 0.18g, and 195-196 DEG C of fusing point, yield 60%.
1H NMR (300MHz, DMSO-d6) δ: 13.18 (s, 1H), 7.88 (d, J=8.6Hz, 2H), 7.81-7.64 (m, 2H), 7.56,7.51 (dd, J=13.8,7.6Hz, 1H), 7.41-7.22 (m, 3H), 5.47 (s, 2H), 4.42 (s, 2H), 2.47 (s, 3H)13C NMR (75MHz, DMSO-d6) δ: 164.07,161.84,160.78,152.15,131.43,130.41, 127.06,122.21,117.16,115.17,112.44,112.12,61.98,60.31,15.00.ESI-MS m/z:376.0 [M-45]-.Anal.calcd.For C19H16FNO5S2: C, 54.15；H, 3.83；N, 3.32；Found:C, 54.12；H, 3.83； N, 3.32.
Embodiment 19
2- ((4- ((2 '-isopropyls-[1,1 '-biphenyl] -3- base) methoxyl group) phenyl) sulfonyl) acetic acid (I-15)
The same I-3 of synthetic method, obtains white solid 0.26g, and 68-70 DEG C of fusing point, yield 74%.
1H NMR (300MHz, DMSO-d6) δ: 7.85 (d, J=8.9Hz, 2H), 7.48 (d, J=4.4Hz, 2H), 7.40- 7.33 (m, 3H), 7.30-7.11 (m, 5H), 5.30 (s, 2H), 4.42 (s, 2H), 2.98-2.85 (m, 1H), 1.08 (d, J= 6.8Hz, 6H)13C NMR (75MHz, DMSO-d6) δ: 164.59,162.37,147.35,141.23,136.78,132.05, 131.49,130.89,129.60,128.67,126.78,126.43,125.66,115.36,69.73,62.54,28.92, 23.57.ESI-MS m/z:379.1 [M-45]-.Anal.calcd.For C24H24O5S:C, 67.90；H, 5.70；Found:C, 67.95；H, 5.71.
Embodiment 20
2- ((4- ((2- (3- chlorphenyl) -4- methylthiazol -5- base) methoxyl group) phenyl) sulfonyl) acetic acid (I-16)
The same I-12 of synthetic method, obtains white solid 0.36g, and 190-192 DEG C of fusing point, yield 64%.
1H NMR (300MHz, DMSO-d6) δ: 13.26 (s, 1H), 8.03-7.80 (m, 4H), 7.65-7.42 (m, 2H), 7.28 (d, J=7.7Hz, 2H), 5.48 (s, 2H), 4.44 (s, 2H)13C NMR (75MHz, DMSO-d6) δ: 164.09, 161.83,152.22,134.69,133.95,131.50,131.19,130.42,129.99,125.19,124.75,115.19, 62.00,60.29,15.06.ESI-MS m/z:392.1 [M-45]-.Anal.calcd.For C19H16ClNO5S2: C, 52.11； H, 3.68；N, 3.20；Found:C, 52.15；H, 3.67；N, 3.21.
Embodiment 21
2- ((4- ((2 ', 6 '-dimethyl -4- propoxyl group-[1,1 '-biphenyl] -3- base) methoxyl group) phenyl) sulfonyl) second Sour (I-17)
The same I-3 of synthetic method, obtains white solid 0.31g, and 103-105 DEG C of fusing point, yield 64%.
1H NMR (300MHz, DMSO-d6) δ: 7.82 (d, J=8.5Hz, 2H), 7.56-7.37 (m, 2H), 7.26-7.04 (m, 4H), 6.68 (s, 2H), 5.27 (s, 2H), 4.19 (s, 2H), 3.93 (t, J=6.4Hz, 2H), 1.92 (s, 6H), 1.73 (dd, J=13.8,6.8Hz, 2H), 0.99 (t, J=7.3Hz, 3H)13C NMR (75MHz, DMSO-d6) δ: 164.57, 162.01,157.36,140.44,136.48,133.41,130.28,129.11,128.65,126.02,114.89,113.18, 69.57,68.68,62.54,22.08,20.72,10.41.ESI-MS m/z:423.1 [M-45]-.Anal.calcd.For C26H28O6S:C, 66.65；H, 6.02；Found:C, 66.68；H, 6.02.
Embodiment 22
2- ((4- ((4 '-ethyoxyls -2 ', 6 '-dimethyl-[1,1 '-biphenyl] -3- base) methoxyl group) phenyl) sulfonyl) second Sour (I-18)
The same I-3 of synthetic method, obtains white solid 0.47g, and 128-130 DEG C of fusing point, yield 78%.
1H NMR (300MHz, DMSO-d6) δ: 7.82 (d, J=8.6Hz, 2H), 7.56-7.37 (m, 2H), 7.34-7.02 (m, 4H), 6.68 (s, 2H), 5.27 (s, 2H), 4.20 (s, 2H), 4.02 (q, J=6.7Hz, 2H), 1.92 (s, 6H), 1.31 (t, J=6.7Hz, 3H)13C NMR (75MHz, DMSO-d6) δ: 163.90,162.08,157.18,140.43,136.48, 136.38,133.40,131.63,130.27,129.10,128.78,128.66,126.03,115.43,114.95,113.14, 69.57,62.71,61.55,20.72,14.71.ESI-MS m/z:409.1 [M-45]-.Anal.calcd.For C25H26O6S: C, 66.06；H, 5.77；Found:C, 66.09；H, 5.76.
Embodiment 23
2- (4- (2,6- dimethyl -4- (3- (methyl sulphonyl) propoxyl group)-[1,1 '-xenyl] -3- base) methoxyl group) Phenyl) sulfonyl) acetic acid (I-19)
The same I-3 of synthetic method, obtains white solid 0.38g, and 117-119 DEG C of fusing point, yield 73%.
1H NMR (300MHz, DMSO-d6) δ: 7.82 (d, J=8.1Hz, 2H), 7.56-7.40 (m, 2H), 7.36-7.03 (m, 5H), 6.71 (s, 2H), 5.26 (s, 2H), 4.18 (s, 2H), 4.09 (t, J=5.9Hz, 2H), 3.37-3.20 (m, 2H), 3.03 (s, 3H), 2.27-2.09 (m, 2H), 1.92 (s, 6H)13C NMR (75MHz, DMSO-d6) δ: 164.20,162.53, 156.78,140.81,137.08,134.26,132.17,130.78,129.16,126.59,115.40,113.75,70.04, 65.84,62.06,51.00,40.67,22.51,21.22.ESI-MS m/z:501.1 [M-45]-.Anal.calcd.For C27H30O8S2: C, 59.32；H, 5.53；Found:C, 59.36；H, 5.52.
Embodiment 24
2- ((4- ((4 '-isobutyl groups -2 ', 6 '-dimethyl-[1,1 '-biphenyl] -3- base) methoxyl group) phenyl) sulfonyl) second Sour (I-20)
The same I-3 of synthetic method, obtains white solid 0.32g, and 113-115 DEG C of fusing point, yield 67%.
1H NMR (300MHz, DMSO-d6) δ: 7.82 (d, J=8.0Hz, 2H), 7.46 (d, J=7.7Hz, 2H), 7.30- 7.00 (m, 4H), 6.69 (s, 2H), 5.27 (s, 2H), 4.08 (s, 2H), 3.74 (d, J=6.2Hz, 2H), 1.92 (s, 6H), 1.39-1.16 (m, 1H), 0.99 (d, J=6.4Hz, 6H)13C NMR (75MHz, DMSO-d6) δ: 162.01,157.47, 140.44,136.47,136.38,133.40,132.69,129.10,128.69,125.96,115.42,113.20,73.52, 69.57,43.90,27.71,20.66,19.03.ESI-MS m/z:437.1 [M-45]-.Anal.calcd.For C27H30O6S: C, 67.20；H, 6.27；Found:C, 67.25；H, 6.28.
Embodiment 25
2- ((4- (4 '-(2- methoxy ethoxy) -2 ', 6 '-dimethyl-[1,1 '-biphenyl -3- base] methoxyl group) phenyl) Sulfonyl) acetic acid (I-21)
The same I-3 of synthetic method, obtains white solid 0.23g, and 107-109 DEG C of fusing point, yield 60%.
1H NMR (300MHz, DMSO-d6) δ: 7.82 (d, J=8.0Hz, 2H), 7.43 (d, J=7.7Hz, 2H), 7.31- 7.00 (m, 4H), 6.70 (s, 2H), 5.24 (s, 2H), 4.05 (d, J=14.0Hz, 7H), 3.64 (s, 2H), 1.91 (s, 6H) .13C NMR (75MHz, DMSO-d6) δ: 164.25,162.33,157.61,140.87,137.02,130.73,129.13, 126.51,115.27,114.99,113.66,70.89,67.13,58.61,21.22.ESI-MS m/z:439.1 [M-45]- .Anal.calcd.For C26H28O7S:C, 64.45；H, 5.82；Found:C, 64.41；H, 5.81.
Embodiment 26
3- (3,5- dimethyl isoxazole -4- base) benzaldehyde
By 3,5- dimethyl isoxazole -4- pinacol borate (0.4g, 2.67mmol), 3- bromobenzaldehyde (0.54g, 2.67mmol) be dissolved in 21ml in the mixed solvent (water/ethanol/toluene, 3: 1: 3, v/v), sequentially add sodium carbonate (0.71g, 6.67mmol), Pd (PPh3) 4 (0.09g, 0.08mmol), gained mixed liquor heats 80 DEG C of reactions for 24 hours under nitrogen protection, cold But to room temperature, water 20ml is added to dilute, is laid the groundwork suctions filtration with diatomite, ethyl acetate (15ml × 3) washing filter cake, filtrate is with acetic acid Ethyl ester (30ml × 4) extraction merges organic phase to be saturated NaCl solution (20ml × 2) washing, and gained organic phase is with anhydrous slufuric acid Sodium is dry, filters, and solvent is evaporated off in filtrate decompression, and residue is purified through column chromatography (petrol ether/ethyl acetate, 70: 30, v/v) To pale solid 0.38g, yield 71%.
1H NMR (300MHz, DMSO-d6) δ: 10.08 (s, 1H), 7.99-7.85 (m, 2H), 7.81-7.63 (m, 2H), 2.43 (s, 3H), 2.25 (s, 3H)
Embodiment 27
2- (4- (3- (3,5- dimethyl oxazoline -4- base) phenoxy group) phenyl) sulfonyl) acetic acid (I-26)
Raw material II -1 (0.2g, 0.99mmol) is dissolved in the solution of 20ml in the mixed solvent (THF/MeOH, 1: 1, v/v), It is added portionwise under ice bath sodium borohydride (0.05g, 1.2mmol), under ice bath after reaction, adds 20ml water quenching reaction, acetic acid Ethyl ester extraction (30ml × 3) merges organic phase to be saturated NaCl solution (20ml × 2) washing, and gained organic phase is with anhydrous sodium sulfate It is dry, it filters, solvent is evaporated off in filtrate decompression, not purified to be directly used in the next step.The compound that upper step obtains is dissolved in 20ml In methylene chloride, it is slowly dropped into 0.5ml thionyl chloride, 1 drop DMF is added, 25 DEG C of heating reactions remove under reduced pressure molten after reaction Agent obtains light yellow oil II-2.II-2 (0.2g, 0.90mmol) is dissolved in 20ml acetonitrile, addition raw material II -3 (0.25g, 1.08mmol), Anhydrous potassium carbonate (0.5g, 3.62mmol), catalytic amount KI are heated to 60 DEG C of reaction 8h, and filtering removes under reduced pressure molten Agent, residue are dissolved in 30ml water, and ethyl acetate (20ml × 3) extraction merges organic phase, with saturated salt solution (15ml × 2) Washing, anhydrous sodium sulfate dries, filters, and filtrate decompression is evaporated off solvent, residue chromatograph through column (petrol ether/ethyl acetate, 4: 1, V/v 0.26g white solid II-4) is purified to obtain, 14mL in the mixed solvent (THF/MeOH/H is dissolved in2O, 3: 3: 1, v/v/v), it is added LiOH (0.07g, 2.79mmol) reacts at room temperature 8h, removes tetrahydrofuran and methanol under reduced pressure, 1N dilute hydrochloric acid tune is added dropwise under ice-water bath PH 2-3 is saved, white solid is precipitated, is filtered, dry white powdery solids I-26 0.2g, 125-126 DEG C of fusing point, yield 56%.
1H NMR (300MHz, DMSO-d6) δ: 7.53-7.30 (m, 4H), 7.10 (d, J=7.9Hz, 1H), 6.55-6.42 (m, 2H), 5.10 (s, 2H), 4.66 (t, J=9.0Hz, 1H), 4.21-4.12 (m, 1H), 3.68-3.64 (m, 1H), 2.71, 2.66 (dd, J=16.6,5.5Hz, 1H), 2.49-2.40 (m, 1H), 2.36 (s, 3H), 2.19 (s, 3H)13C NMR (75MHz, DMSO-d6) δ: 173.00,165.13,160.65,158.99,158.04,137.81,129.87,128.94,128.65, 128.13,127.92,126.64,124.59,121.99,117.74,115.68,106.84,96.80,77.08,68.98, 40.19,37.04,11.22,10.36.ESI-MS m/z:378.1 [M-H]-Anal.calcd.For C22H21NO5: C, 69.65； H, 5.58；N, 3.69；Found:C, 69.61；H, 5.57；N, 3.68.
Embodiment 28
2- (4- (5- (3,5- dimethyl oxazoline -4- base) -2- methyl) oxygroup) phenyl) sulfonyl) acetic acid (I-22)
The same I-26 of synthetic method, obtains white solid 0.48g, and 88-90 DEG C of fusing point, yield 67%.
1H NMR (300MHz, DMSO-d6) δ: 13.29 (s, 1H), 7.86 (d, J=7.9Hz, 2H), 7.55-7.22 (m, 5H), 5.28 (s, 2H), 4.43 (s, 2H), 2.37 (s, 3H), 2.35 (s, 3H), 2.18 (s, 3H)13C NMR (75MHz, DMSO- d6) δ: 164.59,162.89,137.90,135.17,133.00,131.26,131.21,130.88,130.38,129.52, 128.08,115.58,68.67,60.79,18.67,11.71,10.88.ESI-MS m/z:370.1 [M-45]- .Anal.calcd.For C21H21NO6S:C, 60.71；H, 5.10；N, 3.37；Found:C, 60.75；H, 5.11；N, 3.37.
Embodiment 29
2- (4- (3- (3,5- dimethyl oxazoline -4- base) -2- methyl) oxygroup) phenyl) sulfonyl) acetic acid (I-23)
The same I-26 of synthetic method, obtains white solid 0.36g, and 86-88 DEG C of fusing point, yield 78%.
1H NMR (300MHz, DMSO-d6) δ: 7.87 (d, J=8.9Hz, 2H), 7.53 (d, J=7.4Hz, 1H), 7.36- 7.15 (m, 4H), 5.28 (s, 2H), 4.42 (s, 2H), 2.21 (s, 3H), 2.13 (s, 3H), 2.03 (s, 3H)13C NMR (75MHz, DMSO-d6) δ: 165.72,164.53,162.96,159.22,136.65,135.62,131.29,130.90, 130.10,129.27,126.37,115.53,113.25,69.24,60.88,15.78,11.60,10.62.ESI-MS m/z: 370.1[M-45]-.Anal.calcd.For C21H21NO6S:C, 60.71；H, 5.10；N, 3.37；Found:C, 60.78；H, 5.11；N, 3.37.
Embodiment 30
2- ((4- ((the chloro- 3- of 4- (3,5- dimethyl oxazoline -4- base) benzyl) oxygroup) phenyl) sulfonyl) acetic acid (I-24)
The same I-26 of synthetic method, obtains white solid 0.34g, and 111-113 DEG C of fusing point, yield 53%.
1H NMR (300MHz, DMSO-d6) δ: 7.84 (d, J=8.8Hz, 2H), 7.65 (d, J=8.2Hz, 1H), 7.60- 7.48 (m, 2H), 7.23 (d, J=8.9Hz, 2H), 5.27 (s, 2H), 4.31 (s, 2H), 2.25 (s, 3H), 2.07 (s, 3H)13C NMR (75MHz, DMSO-d6) δ: 166.20,163.98,162.01,158.55,135.89,132.91,131.67,131.51, 130.38,129.90,129.54,128.46,115.02,113.82,68.57,60.93,11.29,10.13.ESI-MS m/z: 390.1[M-45]-.Anal.calcd.For C20H18ClNO6S:C, 55.11；H, 4.16；Cl, 8.13；N, 3.21；Found:C, 55.15；H, 4.15；Cl, 8.12；N, 3.21.
Embodiment 31
2- (4- (3- (2- methyl-1 H- pyrroles -1- base) phenoxy group) phenyl) sulfonyl) acetic acid (I-25)
The same I-3 of synthetic method, obtains white solid 0.17g, and 110-112 DEG C of fusing point, yield 56%.
1H NMR (300MHz, DMSO-d6) δ: 7.90-7.80 (m, 3H), 7.57-7.52 (m, 2H), 7.28-7.22 (m, 3H), 5.80 (s, 2H), 5.31 (s, 2H), 4.33 (s, 2H), 1.94 (s, 6H)13C NMR (75MHz, DMSO-d6) δ: 164.01,162.13,138.39,137.59,131.39,130.35,129.46,127.48,127.10,126.91,115.07, 106.00,69.02,60.80,12.81.ESI-MS m/z:354.1 [M-45]-.Anal.calcd.For C21H21NO5S:C, 63.14；H, 5.30；N, 3.51；Found:C, 63.11；H, 5.31；N, 3.51.
Embodiment 32
2- ((4- ((2- (4- fluorophenyl) -4- methylthiazol -5- base) methoxyl group) phenyl) sulfonyl) acetic acid (I-27)
The same I-12 of synthetic method, obtains white solid 0.27g, and 175-177 DEG C of fusing point, yield 76%.
1H NMR (300MHz, DMSO-d6) δ: 8.02-7.84 (m, 4H), 7.38-7.24 (m, 4H), 5.45 (s, 2H), 4.43 (s, 2H), 2.46 (s, 3H)13CNMR (75MHz, DMSO-d6) δ: 164.09,161.85,152.04,131.42, 130.41,129.46,128.31,128.19,126.29,116.37,116.08,115.17,61.98,60.27, 15.03.ESI-MS m/z:376.0 [M-45]-.Anal.calcd.For C19H16FNO5S2: C, 54.15；H, 3.83；F, 4.51；N, 3.32；Found:C, 54.11；H, 3.83；F, 4.51；N, 3.32.
Embodiment 33
2- ((4- ((4 '-methoxyl groups -2 ', 6 '-dimethyl-[1,1 '-biphenyl] -3- base) methoxyl group) phenyl) sulfonyl) third Sour (I-28)
The same I-3 of synthetic method, obtains white solid 0.31g, and 106-108 DEG C of fusing point, yield 59%.
1H NMR (300MHz, DMSO-d6) δ: 7.76 (d, J=8.1Hz, 2H), 7.55-7.37 (m, 2H), 7.29-7.02 (m, 4H), 6.69 (s, 2H), 5.26 (s, 2H), 4.11-3.97 (m, 1H), 3.74 (s, 3H), 1.92 (s, 6H), 1.30 (d, J= 6.4Hz, 3H)13C NMR (75MHz, DMSO-d6) δ: 167.22,162.17,157.92,140.41,136.52,136.38, 133.52,131.09,129.58,129.11,128.79,128.66,126.09,114.90,112.63,69.57,65.70, 54.86,20.73,12.32.ESI-MS m/z:409.1 [M-45]-.Anal.calcd.For C25H26O6S:C, 66.06；H, 5.77；Found:C, 66.02；H, 5.76.
Embodiment 34
2- ((4- ((the chloro- 5- of 2- (3,5- dimethyl oxazoline -4- base) benzyl) oxygroup) phenyl) sulfonyl) acetic acid (I-29)
The same I-26 of synthetic method, obtains white solid 0.26g, and 73-74 DEG C of fusing point, yield 60%.
1H NMR (300MHz, DMSO-d6) δ: 7.96-7.82 (m, 2H), 7.68-7.54 (m, 2H), 7.51-7.27 (m, 3H), 5.34 (s, 2H), 4.40 (s, 2H), 2.36 (s, 3H), 2.19 (s, 3H)13C NMR (75MHz, DMSO-d6) δ: 165.56,164.07,162.09,157.99,133.99,132.12,131.42,130.74,130.46,129.98,129.13, 115.03,114.68,67.21,60.44,11.24,10.31.ESI-MSm/z:390.0 [M-45]-.Anal.calcd.For C20H18ClNO6S:C, 55.11；H, 4.16；C1,8.13；N, 3.21；Found:C, 55.14；H, 4.16；Cl, 8.12；N, 3.21.
Embodiment 35
2- ((3- ([1,1 '-biphenyl] -4- methoxyl group) phenyl) sulfonyl) acetic acid (I-30)
The same I-3 of synthetic method, obtains white solid 0.19g, and 63-65 DEG C of fusing point, yield 57%.
1H NMR (300MHz, DMSO-d6) δ: 7.73-7.66 (m, 4H), 7.61-7.37 (m, 9H), 5.25 (s, 2H), 4.56 (s, 2H)13C NMR (75MHz, DMSO-d6) δ: 163.90,158.43,140.56,139.89,139.70,135.48, 130.45,128.94,128.46,128.12,127.53,126.79,126.66,120.59,120.18,113.72,69.48, 59.78.ESI-MS m/z:337.1 [M-45]-.Anal.calcd.For C21H18O5S:C, 65.95；H, 4.74；Found:C, 65.91；H, 4.73.
Embodiment 36
2- ((3- ((2 '-methyl-[1,1 '-biphenyl -4- methoxyl group])) phenyl) sulfonyl) acetic acid (I-31)
The same I-3 of synthetic method, obtains white solid 0.23g, and 113-115 DEG C of fusing point, yield 69%.
1H NMR (300MHz, DMSO-d6) δ: 7.72-7.50 (m, 5H), 7.47-7.35 (m, 3H), 7.33-7.13 (m, 4H), 5.25 (s, 2H), 4.53 (s, 2H), 2.24 (s, 3H)13C NMR (75MHz, DMSO-d6) δ: 163.94,158.52, 141.05,140.84,140.59,134.89,134.68,130.45,130.33,129.47,129.08,127.79,127.36, 125.94,120.58,120.20,113.64,69.63,59.87,20.13.ESI-MS m/z:351.1 [M-45]- .Anal.calcd.For C22H20O5S:C, 66.65；H, 5.09；Found:C, 66.60；H, 5.08.
Embodiment 37
2- ((4- ((3- phenoxy group) oxygroup) phenyl) sulfonyl) acetic acid (I-32)
The same I-1 of synthetic method, obtains white solid 0.20g, and 73-75 DEG C of fusing point, yield 67%.
1H NMR (300MHz, DMSO-d6) δ: 7.85 (d, J=8.8Hz, 2H), 7.43,7.38 (dd, J=14.7, 7.4Hz, 3H), 7.30-7.10 (m, 5H), 7.04-6.92 (m, 3H), 5.22 (s, 2H), 4.40 (s, 2H)13C NMR (75MHz, DMSO-d6) δ: 164.09,162.23,156.84,156.33,138.45,131.16,130.38,130.21,130.06, 123.61,122.61,118.75,118.01,117.62,115.06,69.18,60.46.ESI-MS m/z:353.1 [M- 45]-.Anal.calcd.For C21H18O6S:C, 63.31；H, 4.55；Found:C, 63.34；H, 4.56.
Embodiment 38
1- ((4- ((4 '-methoxyl groups -2 ', 6 '-dimethyl-[1,1 '-biphenyl] -3- base) methoxyl group) phenyl) sulphonyl)-ring Propane-acetic acid (I-33)
The same I-3 of synthetic method, obtains white solid 0.12g, and 106-108 DEG C of fusing point, yield 73%.
1H NMR (300MHz, DMSO-d6) δ: 7.88 (d, J=8.5Hz, 2H), 7.46 (d, J=6.8Hz, 2H), 7.30- 7.04 (m, 4H), 6.69 (s, 2H), 5.28 (s, 2H), 3.74 (s, 3H), 1.91 (s, 6H), 1.82-1.71 (m, 2H), 1.64- 1.50 (m, 2H)13C NMR (75MHz, DMSO-d6) δ: 167.75,162.14,157.93,140.40,136.51,136.39, 133.52,131.20,129.09,128.76,128.66,126.06,114.88,112.64,69.56,54.86,43.70, 20.69,15.51.ESI-MS m/z:421.1 [M-45]-.Anal.calcd.For C26H26O6S:C, 66.94；H, 5.62； Found:C, 66.96；H, 5.61.
Embodiment 39
2- ((4- ((4 '-methoxyl groups -2 ', 6 '-dimethyl-[1,1 '-biphenyl] -3- base) methoxyl group) phenyl) sulfonyl) - 2 Methylpropionic acid (I-34)
The same I-3 of synthetic method, obtains white solid 0.18g, and 143-145 DEG C of fusing point, yield 62%.
1H NMR (300MHz, DMSO-d6) δ: 7.73 (d, J=8.5Hz, 2H), 7.45 (d, J=6.8Hz, 2H), 7.37- 7.00 (m, 4H), 6.69 (s, 2H), 5.28 (s, 2H), 3.74 (s, 3H), 1.91 (s, 6H), 1.43 (s, 6H)13C NMR (75MHz, DMSO-d6) δ: 169.72,162.57,157.93,140.43,136.51,132.30,129.16,128.83, 126.16,114.90,112.65,69.62,54.87,43.70,20.71,19.99.ESI-MS m/z:423.1 [M-45]- .Anal.calcd.For C26H28O6S:C, 66.65；H, 6.02；Found:C, 66.68；H, 6.03.
Embodiment 40
2- ((4- ((4 '-methoxyl groups -2 ', 6 '-dimethyl-[1,1 '-biphenyl] -3- base) methoxyl group) phenyl) sulfonyl) fourth Sour (I-35)
The same I-3 of synthetic method, obtains white solid 0.43g, and 100-102 DEG C of fusing point, yield 53%.
1H NMR (300MHz, DMSO-d6) δ: 7.76 (d, J=8.4Hz, 2H), 7.46 (d, J=6.5Hz, 2H), 7.35- 7.05 (m, 4H), 6.69 (s, 2H), 5.28 (s, 2H), 4.09 (t, J=6.9Hz, 1H), 3.73 (s, 3H), 1.91 (s, 6H), 1.83-1.67 (m, 2H), 0.88 (t, J=6.8Hz, 3H)13C NMR (75MHz, DMSO-d6) δ: 166.72,162.57, 157.93,140.43,136.52,136.29,133.52,131.11,129.14,128.93,128.79,128.69,126.13, 115.22,114.50,112.65,71.15,69.66,54.88,20.71,20.34,10.97.ESI-MS m/z:423.1 [M- 45]-.Anal.calcd.For C26H28O6S:C, 66.65；H, 6.02；Found:C, 66.63；H, 6.01.
Embodiment 41
The tablet of the I-3 containing activating agent:
Active constituent, pregelatinized starch and microcrystalline cellulose are sieved, are sufficiently mixed, it is molten that polyvinylpyrrolidone is added Liquid, mixing, softwood processed, sieving, wet granular processed, in 50-60 DEG C of drying, by Sodium carboxymethyl starch, magnesium stearate and talcum powder The compression molding into above-mentioned particle is added in sieving.
Verified, above-mentioned composition also has excellent internal hypoglycemic activity.

Claims (3)

1. following compound or its pharmaceutical salt:
2- ((4- ((2 '-chloro- [1,1 '-biphenyl] -3- base) methoxyl group) phenyl) sulfonyl) methyl acetate；
2- ((4- ((2 '-chloro- [1,1 '-biphenyl] -3- base) methoxyl group) phenyl) sulfonyl) acetic acid；
2- ((4- ((2 ', 6 '-dimethyl-[1,1 '-biphenyl] -3- base) methoxyl group) phenyl) sulfonyl) acetic acid；
2- ((4- ((2 '-methyl-[1,1 '-biphenyl] -3- base) methoxyl group) phenyl) sulfonyl) acetic acid；
2- ((4- ((4 '-methoxyl groups -2 ', 6 '-dimethyl-[1,1 '-biphenyl] -3- base) methoxyl group) phenyl) sulfonyl) acetic acid.
2. a kind of pharmaceutical composition contains compound or pharmaceutically acceptable salt thereof described in claim 1 and carrier appropriate or figuration Agent.
3. compound defined in claim 1 or its pharmaceutical salt or its pharmaceutical composition are in preparation prevention or treatment glycosuria Purposes in terms of medicine.
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