CN104059039A - Fused ring compound with GPR40 receptor function adjusting effect - Google Patents

Fused ring compound with GPR40 receptor function adjusting effect Download PDF

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Publication number
CN104059039A
CN104059039A CN201310096531.0A CN201310096531A CN104059039A CN 104059039 A CN104059039 A CN 104059039A CN 201310096531 A CN201310096531 A CN 201310096531A CN 104059039 A CN104059039 A CN 104059039A
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alkyl
cycloalkyl
compound
heteroaryl
aryl
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CN104059039B (en
Inventor
刘希杰
校登明
胡远东
王树龙
刘志华
沈宇
彭勇
王欢
罗鸿
孔凡胜
韩永信
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Chia Tai Tianqing Pharmaceutical Group Co Ltd
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Centaurus Biopharma Co Ltd
Chia Tai Tianqing Pharmaceutical Group Co Ltd
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Priority to CN201310096531.0A priority Critical patent/CN104059039B/en
Priority to PCT/CN2014/073852 priority patent/WO2014146604A1/en
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
    • C07D307/79—Benzo [b] furans; Hydrogenated benzo [b] furans with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/655—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having oxygen atoms, with or without sulfur, selenium, or tellurium atoms, as the only ring hetero atoms
    • C07F9/65515—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having oxygen atoms, with or without sulfur, selenium, or tellurium atoms, as the only ring hetero atoms the oxygen atom being part of a five-membered ring
    • C07F9/65517—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having oxygen atoms, with or without sulfur, selenium, or tellurium atoms, as the only ring hetero atoms the oxygen atom being part of a five-membered ring condensed with carbocyclic rings or carbocyclic ring systems

Abstract

The invention relates to a fused ring compound with GPR40 receptor function adjusting effect as shown in formula I, a preparation method thereof, a pharmaceutical composition thereof, and an application of the compound in medicaments for treating and/or preventing GPR40-related diseases, especially diabetes. The compound of the invention has very good GPR40 activation activity, and excellent in-vivo blood sugar-reducing effect.

Description

There is the fused ring compound of GPR40 function of receptors regulating effect
Technical field
The present invention relates to a kind of new fused ring compound with GPR40 function of receptors regulating effect, its preparation method, its pharmaceutical composition, and as the purposes of medicine.
Background technology
Diabetes have become the Chronic Non-Communicable Diseases of the third-largest serious threat human health after tumour, cardiovascular disorder, are day by day serious public health problems.The AUTHORITATIVE DATA of the up-to-date announcement of the World Health Organization (WHO) shows, global onset diabetes rate rapid development in recent years.Number of patients has exceeded 1.77 hundred million, expects 2025 and will reach 3.7 hundred million.And diabetes set people thingking especially at Chinese severe situation, China has become diabetes the second big country, has 23,800,000 diabetic subjects, is only second to India.Expect the year two thousand thirty, diabetic subject's number will break through 4,320 ten thousand.According to the up-to-date report of the Ministry of Health, such rising tendency, by causing China to increase by 3000 new diabetic subjects every day, increases by 1,200,000 diabetic subjects every year.In view of the situation of current sternness, development of new Remedies for diabetes is necessary.The curative effect of the traditional orally-taken blood sugar reducing medicine such as sulfourea and biguanides is not good enough, and exists the side effects such as hypoglycemia such as, liver injury and serious stomach reaction.Though some other traditional clinical application thing has certain curative effect, cannot stop the necrosis of beta Cell of islet, no longer applicable to patients with terminal.Therefore a kind of active drug that can repair and can stimulate the continuous excreting insulin of islet cells of necessary research and development.
G protein coupled receptor 40 (G protein coupled receptor40, GPR40) is a member of g protein coupled receptor superfamily, is seven transmembrane receptors of recent findings, in, long-chain free fatty acids is its ligands specific.Existing result of study demonstration, this new transmembrane receptor may be relevant with neural class disease with some cancer, especially diabetes.In the situation that high concentration glucose exists, free fatty acid (free fatty acid, FFA) can be by stimulating the GPR40 on beta Cell of islet film to amplify the insulin secretion that glucose stimulates.That is to say, FFA except serving as nutritive substance, can also play the effect of a signaling molecule in human body.But, if long-term exposure in the FFA of high density, islet cells, due to long-time a large amount of excreting insulins, finally will weaken the secreting function of Regular Insulin.Therefore,, for some obesity patient, in body, FFA level is too high, may cause the relative diseases such as diabetes.Studies have shown that, activate GPR40 acceptor, can reduce blood sugar, and cause hardly hypoglycemic reaction.The mechanism of action of GPR40 agonist treatment diabetes B and sulfonylurea drugs (as ) difference, stimulate insulin secretion in the mode that depends on blood sugar, greatly reduce risk of hypoglycemia.
Therefore, the target using GPR40 as treatment diabetes, design function is in the medicine of GPR40, and for the insulin secretion function that regulates pancreas, treatment diabetes, have very important researching value and application prospect.
Summary of the invention
One aspect of the present invention relates to formula I compound or its salt:
Formula I
Wherein,
R 1, R 2, R 3, R 4, R 5, R 6, R 7, R 8be selected from independently of one another hydrogen, halogen, cyano group, hydroxyl, nitro, amino, alkyl, alkoxyl group, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl ,-NHCO-alkyl ,-NHCO-cycloalkyl ,-SO 2-alkyl ,-SO 2-cycloalkyl ,-SO-alkyl ,-SO-cycloalkyl ,-N (alkyl)-SO 2-alkyl ,-N (alkyl)-SO 2-cycloalkyl ,-N (alkyl)-SO 2-aryl ,-N (alkyl)-SO 2-heteroaryl ,-NHSO 2-alkyl ,-NHSO 2-cycloalkyl ,-NHSO 2-aryl ,-NHSO 2-heteroaryl ,-SO 2-NH 2,-SO 2-NH-alkyl ,-SO 2n-(alkyl) 2,-CO-alkyl ,-COO-alkyl ,-CONH-alkyl ,-CON-(alkyl) 2,-CONH 2;
L 1for-CH 2o-,-CH 2nH-or
L 2for key, O or-NR 12-;
R 9, R 10be selected from independently of one another hydrogen, halogen, alkyl, hydroxyl, alkoxyl group, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl, cyano group;
N is 0,1,2,3,4 or 5;
L 3for key or-NR 13-;
R 12, R 13be selected from independently of one another hydrogen, alkyl, cycloalkyl, aryl, heteroaryl ,-SO 2-alkyl ,-SO 2-cycloalkyl ,-SO-alkyl ,-SO-cycloalkyl ,-CO-alkyl ,-CO-cycloalkyl ,-CO-aryl ,-CO-heteroaryl, or R 12with R 13and connected N atom forms the Heterocyclylalkyl that at least contains two N atoms together;
L 4for-P (O) (R 14)-or-SO 2-;
R 11for-NR 15r 16, halogen, hydroxyl, cyano group, nitro, alkyl, alkoxyl group, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl, or R 11with R 13connect at least Heterocyclylalkyl containing a nitrogen-atoms;
Z 1be selected from hydrogen, halogen, hydroxyl, cyano group, nitro, amino, alkyl, alkoxyl group, thiazolinyl, alkynyl;
Z 2be selected from-(CR 17r 18) mcOL 5r 19;
R 14, R 15, R 16, R 17, R 18be selected from independently of one another hydrogen, halogen, hydroxyl, alkyl, alkoxyl group, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl;
L 5for-NH-,-N (alkyl)-,-N (cycloalkyl)-or-O-;
M is 0,1,2,3,4 or 5;
R 19be selected from hydrogen, alkyl, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl, amino ,-SO 2-alkyl ,-SO 2-cycloalkyl ,-SO 2-aryl ,-SO 2-heteroaryl ,-SO-alkyl ,-SO-cycloalkyl ,-SO-aryl ,-SO-heteroaryl;
Condition is: work as L 1for-CH 2o-or-CH 2nH-, and L 2for O, R 9=R 10=hydrogen, n=2 or 3, L 3for key, L 4for-SO 2-and R 11for methyl or ethyl, Z 2for CH 2cOOR 19time, R 19be selected from cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl, amino ,-SO 2-alkyl ,-SO 2-cycloalkyl ,-SO 2-aryl ,-SO 2-heteroaryl ,-SO-alkyl ,-SO-cycloalkyl ,-SO-aryl ,-SO-heteroaryl.
In some embodiments, R 1, R 2, R 3, R 4, R 5, R 6, R 7, R 8be selected from independently of one another hydrogen, halogen, cyano group, hydroxyl, alkyl, alkoxyl group, amino; In some preferred embodiments, R 1, R 4, R 5, R 6, R 7and R 8for hydrogen, R 2and R 3for methyl.
In some embodiments, R 9and R 10be selected from hydrogen.
In some embodiments, work as L 2for O, n is 1,2,3 or 4, L 3for key, L 4for-SO 2-time, R 11for-NR 15r 16, alkyl, alkoxyl group, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl; In some preferred embodiments, work as L 2for O, n is 2 or 3, L 3for key, L 4for-SO 2-time, R 11for-NR 15r 16, alkyl, cycloalkyl; More preferably in embodiment, work as L at some 2for O, n is 3, L 3for key, L 4for-SO 2-time, R 11for-NR 15r 16, alkyl; In some preferred embodiments, work as L 2for O, n is 3, L 3for key, L 4for-SO 2-time, R 11for-N (alkyl) 2,-NH (alkyl), alkyl; In some the most preferred embodiment, work as L 2for O, n is 3, L 3for key, L 4for-SO 2-time, R 11for-N (CH 3) 2,-NHCH 3,-CH 3.
In some embodiments, work as L 2for O, n is 1,2,3 or 4, L 3for-NR 13-, L 4for-SO 2-time, R 11for-NR 15r 16, alkyl, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl, or R 11with R 13connect at least Heterocyclylalkyl containing a nitrogen-atoms; In some preferred embodiments, work as L 2for O, n is 2 or 3, L 3for-NR 13-, L 4for-SO 2-time, R 11for-NR 15r 16, alkyl, cycloalkyl, Heterocyclylalkyl, or R 11with R 13connect at least 3-12 unit Heterocyclylalkyl containing a nitrogen-atoms; In some preferred embodiments, work as L 2for O, n is 2 or 3, L 3for-NR 13-, L 4for-SO 2-time, R 11with R 13connect at least 3,4,5 or 6 yuan of Heterocyclylalkyls containing a nitrogen-atoms, or R 11for alkyl, cycloalkyl, Heterocyclylalkyl; In some the most preferred embodiment, work as L 2for O, n is 2, L 3for-NR 13-, L 4for-SO 2-time, R 11with R 13connect at least Heterocyclylalkyl containing a nitrogen-atoms; Or work as L 2for O, n is 2, L 3for-NH-, L 4for-SO 2-time, R 11for alkyl, cycloalkyl.
In some embodiments, work as L 2and L 3for key, n is 0 o'clock, L 4for-P (O) (R 14)-, R 11for alkyl, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl; In some preferred embodiments, work as L 2and L 3for key, n is 0 o'clock, L 4for-P (O) (alkyl)-, R 11for alkyl, cycloalkyl, Heterocyclylalkyl; In some preferred embodiments, work as L 2and L 3for key, n is 0 o'clock, L 4for-P (O) (CH 3)-, R 11for methyl, ethyl, sec.-propyl ,-CH 2-cyclopropyl, cyclopropyl.
In some embodiments, work as L 2for O, n is 1,2,3 or 4, L 3during for key, L 4for-P (O) (R 14)-, R 11for alkyl, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl; In some preferred embodiments, work as L 2for O, n is 3, L 3during for key, L 4for-P (O) (alkyl)-, R 11for alkyl, cycloalkyl, Heterocyclylalkyl; In some preferred embodiments, work as L 2for O, n is 3, L 3during for key, L 4for-P (O) (CH 3)-, R 11for methyl, ethyl, sec.-propyl ,-CH 2-cyclopropyl, cyclopropyl, cyclopropyl.
In some embodiments, work as L 2for-NR 12-, L 3for-NR 13-and L 4for-SO 2-time, R 12with R 13and connected N atom forms the Heterocyclylalkyl that at least contains two N atoms together; In some preferred embodiments, L 2for-NR 12-, L 3for-NR 13-and L 4for-SO 2-time, R 12with R 13and connected N atom forms piperazinyl together.
In some embodiments, L 1for-CH 2o-.
In some embodiments, L 1for-CH 2nH-.
In some embodiments, L 1for
In some embodiments, Z 1for hydrogen, Z 2for-CH 2cOL 5r 19.
In some embodiments, work as L 5during for-NH-, R 19be selected from alkyl, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl ,-SO 2-alkyl ,-SO 2-cycloalkyl ,-SO 2-aryl ,-SO 2-heteroaryl ,-SO-alkyl ,-SO-cycloalkyl ,-SO-aryl ,-SO-heteroaryl; Preferably, R 19be selected from-SO 2-alkyl ,-SO 2-cycloalkyl ,-SO 2-aryl ,-SO 2-heteroaryl ,-SO-alkyl ,-SO-cycloalkyl ,-SO-aryl ,-SO-heteroaryl; More preferably, R 19be selected from-SO 2-alkyl ,-SO 2-cycloalkyl; Most preferably, R 19be selected from-SO 2-methyl ,-SO 2-ethyl ,-SO 2-cyclopropyl ,-SO 2-CH 2-cyclopropyl.
In some embodiments, work as L 5during for-O-, R 19be selected from hydrogen, alkyl, cycloalkyl; Preferably, R 19be selected from hydrogen, methyl, ethyl, propyl group, sec.-propyl, cyclopropyl, cyclobutyl, cyclohexyl.
Another aspect of the present invention, relates to the compound or its salt of following formula:
Another aspect of the present invention also relates to the preparation method of formula I compound or its salt, wherein, and L 1, L 2, L 3, L 4, R 1, R 2, R 3, R 4, R 5, R 6, R 7, R 8, R 9, R 10, R 11, Z 1, Z 2identical with the definition of Chinese style I compound above, comprise definition and all preferred definition that scope is the widest.
formula I
Work as L 1for-CH 2when O-, the preparation that formula I compound or its salt can be by the following method:
In the time that X is hydroxyl, Compound I can the compound of through type 1 and the compound of formula 2 carry out Mitsunobu and react to prepare.In Mitsunobu reaction, compound 1 and compound 2 for example, at azo dicarbonyl compound (diethyl azodiformate, diisopropyl azodiformate, 1,1 '-(azo dicarbapentaborane) two piperidines) and the existence of organic phosphine compound (for example triphenylphosphine, tributylphosphine) under react;
In the time that X is leavings group, Compound I can the compound of through type 1 and the reaction and preparing under alkali exists of the compound of formula 2.Described leavings group can be the alkyl sulphonyl oxygen base of halogen atom, optional chloro.The alkali adopting can be alkali metal hydroxide, alkaline carbonate class or organic bases.
Work as L 1for-CH 2when NH-, the preparation that formula I compound or its salt can be by the following method:
Or
X is leavings group, the compound that the compound that Compound I can through type 1 represents and formula 3 represent reaction and preparing under alkali exists.Also can through type 4 compounds and formula 3 compounds reactions generate Schiff alkali, and then reduce and prepares Compound I by reductive agent.
Work as L 1for time, the preparation that formula I compound or its salt can be by the following method:
X is leavings group, and the compound that the compound that Compound I can through type 5 represents and formula 6 represent, under palladium metal catalyst exists, is prepared by coupled reaction.
The compound that formula 1,4 and 5 represents can be prepared by the following method:
In the time that X is leavings group, the compound that the compound that the compound that formula 1,4 and 5 represents can through type 7 represents and formula 8 represent reaction and preparing under alkali exists.
Segment bounds I compound or its salt of the present invention also can prepare by following method:
Or
Above-mentioned synthetic method has just been enumerated the preparation method of part of compounds in the present invention, and according to the known technology of this area, technician, on the basis of above-mentioned synthetic schemes, adopts similar method also can synthesize compound of the present invention.
The compounds of this invention can be asymmetric, for example, has one or more steric isomers.Except as otherwise noted, all steric isomers all comprise, as enantiomer and diastereomer.The compound that contains unsymmetrical carbon of the present invention can be separated with the pure form of optical activity or racemic form.The pure form of optical activity can be from racemic mixture, or by using chiral raw material or chiral reagent synthetic.
The compounds of this invention also comprises tautomeric forms.Tautomeric forms derive from a singly-bound and adjacent two keys exchanges and together with follow the migration of a proton.
As the salt of compound (I), for example, the salt that can mention metal-salt, ammonium salt, form with organic bases, the salt forming with mineral acid, the salt forming with organic acid, the salt that forms with alkalescence or acidic amino acid etc.The non-limiting example of metal-salt includes but not limited to that an alkali metal salt is such as sodium salt, sylvite etc.; Alkaline earth salt is such as calcium salt, magnesium salts, barium salt etc.; Aluminium salt etc.The non-limiting example of salt forming with organic bases includes but not limited to and Trimethylamine 99, triethylamine, pyridine, picoline, 2, the salt that 6-lutidine, thanomin, diethanolamine, trolamine, hexahydroaniline, dicyclohexylamine etc. form.The non-limiting example of salt forming with mineral acid includes but not limited to the salt forming with hydrochloric acid, Hydrogen bromide, nitric acid, sulfuric acid, phosphoric acid etc.The non-limiting example of salt forming with organic acid includes but not limited to the salt forming with formic acid, acetic acid, trifluoroacetic acid, fumaric acid, oxalic acid, oxysuccinic acid, toxilic acid, tartrate, citric acid, succsinic acid, methylsulfonic acid, Phenylsulfonic acid, p-methyl benzenesulfonic acid etc.The non-limiting example of salt forming with basic aminoacids includes but not limited to the salt forming with arginine, Methionin, ornithine etc.The non-limiting example of salt forming with acidic amino acid includes but not limited to the salt forming with aspartic acid, L-glutamic acid etc.
Another aspect of the present invention also relates to pharmaceutical composition, and it comprises the defined formula I compound or its salt of the present invention and the pharmaceutically acceptable carrier for the treatment of significant quantity.
Pharmaceutical composition of the present invention can be by preparing compound of the present invention and suitable pharmaceutically acceptable carrier combinations, for example can be mixed with solid-state, semi-solid state, liquid state or gaseous state preparation, as tablet, pill, capsule, pulvis, granule, paste, emulsion, suspension agent, solution, suppository, injection, inhalation, gelifying agent, microballoon and aerosol etc.
That the typical approach that gives the compounds of this invention or the acceptable salt of its medicine or its pharmaceutical composition includes but not limited to is oral, rectum, thoroughly mucous membrane, through enteral administration, or local, in skin, suction, parenteral, hypogloeeis, intravaginal, nose, intraocular, intraperitoneal, intramuscular, subcutaneous, intravenous administration.Preferred route of administration is oral administration.
Pharmaceutical composition of the present invention can adopt method manufacture well-known in the art, as conventional hybrid system, dissolution method, granulation, dragee method processed, levigate method, emulsion process, freeze-drying etc.
In preferred embodiments, pharmaceutical composition is oral form.For oral administration, can, by active compound is mixed with pharmaceutically acceptable carrier well known in the art, prepare this pharmaceutical composition.These carriers can make compound of the present invention be formulated into tablet, pill, lozenge, sugar-coat agent, capsule, liquid, gelifying agent, slurry agent, suspension agent etc., for the oral administration to patient.
Can prepare solid oral composition by conventional mixing, filling or tabletting method.For example, can obtain by following method: described active compound is mixed with solid excipient, the mixture of the gained of optionally milling, if need to, add other suitable assistant agent, then this mixture is processed into particle, has obtained the core of tablet or sugar-coat agent.Applicable auxiliary material includes but not limited to: tackiness agent, thinner, disintegrating agent, lubricant, glidant, sweeting agent or correctives etc.As Microcrystalline Cellulose, glucose solution, mucialga of arabic gummy, gelatin solution, sucrose and starch paste; Talcum, starch, Magnesium Stearate, calcium stearate or stearic acid; Lactose, sucrose, starch, mannitol, Sorbitol Powder or Si Liaodengji dicalcium phosphate feed grade; Silicon-dioxide; Croscarmellose sodium, pre-paying starch, primojel, alginic acid, W-Gum, yam starch, methylcellulose gum, agar, carboxymethyl cellulose, cross-linked polyvinylpyrrolidone etc.Can optionally carry out dressing to the core of sugar-coat agent according to known method in common medicinal practice, especially use enteric coating.
Pharmaceutical composition is also applicable to administered parenterally, as sterile solution agent, suspensoid or the freeze-drying prods of suitable unit dosage.Can use suitable vehicle, for example weighting agent, buffer reagent or tensio-active agent.
Another aspect of the present invention also relates to formula I compound or its salt of the present invention or its pharmaceutical composition in the purposes for the preparation for the treatment of and/or preventing in the medicine of the disease relevant to GPR40.
Another aspect of the present invention also relates to formula I compound or its salt of the present invention or its pharmaceutical composition in the purposes for the preparation for the treatment of and/or preventing in the medicine of diabetes.
In all application processes of generalformulaⅰcompound as herein described, the dosage of administration every day is preferably 0.01 to 200mg/Kg body weight.
The GPR40 agonist activity of compound of the present invention, preferably EC 50be less than 10000nM, further preferred EC 50be less than 2000nM, more preferably EC 50be less than 1000nM, more preferably EC 50be less than 100nM, most preferably EC 50be less than 10nM.
Except as otherwise noted, term used herein has following implication:
Term " halogen " refers to fluorine, chlorine, bromine or iodine, preferably fluorine or chlorine.
Refer to-OH of term " hydroxyl " group, hydrogen atom wherein can be substituted base and replace.
Refer to-CN of term " cyano group " group.
Refer to-NO of term " nitro " 2group.
Term " alkyl " refers to the saturated aliphatic hydrocarbon group of the straight or branched being made up of carbon atom and hydrogen atom, and it is connected with the rest part of molecule by singly-bound.For example described alkyl can have 1-20 carbon atom, preferably has 1-8 carbon atom, more preferably has 1-4 carbon atom.Described alkyl can be do not replace or be substituted base replacement.The limiting examples of alkyl includes but not limited to methyl, ethyl, propyl group, 2-propyl group, normal-butyl, isobutyl-, tert-butyl, n-amyl group, 2-methyl butyl, neo-pentyl, n-hexyl, 2-methyl hexyl ,-CH 2-cyclopropyl etc.
Refer to-O-of term " alkoxyl group " alkyl, wherein alkyl is with defined above identical.Preferably contain the alkoxyl group of 1-4 carbon atom.Described alkoxyl group can be do not replace or be substituted base replacement.The limiting examples of alkoxyl group includes but not limited to methoxyl group, oxyethyl group, propoxy-, isopropoxy, n-butoxy, isobutoxy, uncle-butoxy, n-pentyloxy, 2-methyl butoxy, neopentyl oxygen, positive hexyloxy, 2-methyl hexyloxy etc.
Term " cycloalkyl " refers to saturated or undersaturated non-aromatic ring-type hydrocarbon ring, preferably comprises 1,2 or 3 ring, and each ring has 3-7 carbon atom.Described cycloalkyl can be do not replace or be substituted base replacement.The limiting examples of cycloalkyl includes but not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and suberyl etc.
Term " thiazolinyl " refers to the alkylene of straight chain or side chain, preferably contains the straight chain of 2-4 carbon atom or the alkylene of side chain.Described thiazolinyl can be do not replace or be substituted base replacement.The limiting examples of thiazolinyl includes but not limited to vinyl, 1-propenyl, 2-propenyl, 1-butylene base, isobutenyl.
Term " alkynyl " refers to the alkynes base of straight chain or side chain, preferably contains the straight chain of 2-4 carbon atom or the alkylene of side chain.Described thiazolinyl can be do not replace or be substituted base replacement.The limiting examples of alkynyl includes but not limited to ethynyl, 1-proyl, 2-propynyl.
Refer to-NH of term " amino " 2group, hydrogen atom wherein can be substituted base and replace.
Term " aryl " refers to the full carbon monocycle of the π-electron system with conjugation or the aromatic group of fused polycycle, preferably has 6-14 carbon atom, more preferably has 6-12 carbon atom, most preferably has 6 carbon atoms.Described aryl can be do not replace or be substituted base replacement.The limiting examples of aryl includes but not limited to phenyl, naphthyl and anthryl.
Term " heteroaryl " refers to monocycle or the fused rings with 5,6,7,8,9,10,11 or 12 annular atomses, wherein contains 1,2,3 or 4 annular atoms that is selected from N, O, S, and all the other annular atomses are C, and has the π-electron system of total conjugated.Described heteroaryl preferably has 5 or 6 rings, is more preferably 5 rings.Described heteroaryl can be do not replace or be substituted base replacement.The limiting examples of heteroaryl includes but not limited to pyrryl, furyl, thienyl, imidazolyl, oxazolyl, pyrazolyl, pyridyl, pyrimidyl, pyrazinyl, quinolyl, isoquinolyl, tetrazyl, triazolyl, triazinyl.
Term " Heterocyclylalkyl " refers to monocycle or the fused rings with 3,4,5,6,7,8,9,10,11 or 12 annular atomses, and wherein 1,2 or 3 annular atoms is to be selected from N, O, S (O) nthe heteroatoms of (wherein n is 0,1 or 2), all the other annular atomses are C.Such ring can be saturated or unsaturated (for example having one or more pairs of keys), but does not have the π-electron system of total conjugated.Described Heterocyclylalkyl can be do not replace or be substituted base replacement.The example of 3 yuan of heterolipid cyclic groups includes but not limited to Oxyranyle, thiirane base, azirane base, the example of 4 yuan of heterolipid rings includes but not limited to azetidine base, Evil fourth cyclic group, thiophene fourth cyclic group, the example of 5 yuan of heterolipid cyclic groups includes but not limited to tetrahydrofuran base, tetrahydro-thienyl, pyrrolidyl, isoxazole alkyl, oxazolidinyl, isothiazole alkyl, 1, 1-dioxo isothiazole alkyl, thiazolidyl, imidazolidyl, tetrahydro-pyrazole base, pyrrolinyl, dihydrofuran base, dihydro-thiophene base, the example of 6 yuan of heterolipid cyclic groups includes but not limited to piperidyl, THP trtrahydropyranyl, tetrahydro thiapyran base, morpholinyl, piperazinyl, 1, 4-thioxane base, 1, 4-dioxane base, thio-morpholinyl, 1, 2-, 1, 4-dithiane base, dihydropyridine base, tetrahydro pyridyl, dihydro pyranyl, THP trtrahydropyranyl, dihydro thiapyran base, the example of 7 yuan of heterolipid rings includes but not limited to azepan base, oxepane alkyl, thia suberane base.Be preferably the monocyclic heterocycles alkyl with 5 or 6 annular atomses.
Except as otherwise noted, term " being substituted base replaces " means that this group is replaced by one or more substituting group, this substituent limiting examples includes but not limited to halogen, alkyl, the alkyl that halogen replaces, thiazolinyl, alkynyl, alkoxyl group, the alkoxyl group that halogen replaces, cycloalkyl, hydroxyl, sulfydryl, alkyl thiol, nitro, cyano group,=O, alkyl acyl, carboxyl, alkyl acyloxy, alkyl amido, alkyl sulphinyl, alkyl sulphonyl, amino, formamyl, aryl, aralkyl, Heterocyclylalkyl, Heterocyclylalkyl alkyl, heteroaryl or heteroarylalkyl.
Term " treatment significant quantity " refers to works as Mammals, and during preferably to people's administration, the compounds of this invention is enough to effectively treat the amount of the disease (the particularly relevant disease of diabetes) that mammiferous (preferred people's) is relevant to GPR40.The amount that forms the compounds of this invention of " treatment significant quantity " depends on this compound, morbid state and seriousness thereof, administering mode and mammiferous age to be treated and changes, but can be determined according to the knowledge of himself and present disclosure by those skilled in the art to routine.
Term " treatment " mean by compound of the present invention or preparation carry out administration with prevention, improve or eliminate a disease or with one or more symptoms of described disease-related, and comprise:
(i) preventing disease or morbid state occur in Mammals, particularly when this class Mammals easily suffers from this morbid state, but are not yet diagnosed as while having suffered from this morbid state;
(ii) suppress disease or morbid state, contain its development;
(iii) alleviate disease or morbid state, even if this disease or morbid state disappear.
Term " pharmaceutical composition " refer to one or more compound or its salts of the present invention with conventionally accept in the art for example, for bioactive compounds being delivered to the preparation of carrier, vehicle and/or medium of organism (people).The object of pharmaceutical composition is to be conducive to organism to give compound of the present invention.
Term " pharmaceutically acceptable carrier " refers to organism without obvious stimulation effect, and can not damage those carriers and the thinner of biological activity and the performance of this active compound." pharmaceutically acceptable carrier " includes but not limited to that by the license of state food drug administration be acceptable any carrier for people or livestock animals, vehicle, medium, glidant, sweetener, thinner, sanitas, dyestuff/tinting material, flavoring toughener, tensio-active agent, wetting agent, dispersion agent, disintegrating agent, suspending agent, stablizer, isotonic agent, solvent or emulsifying agent.The limiting examples of described vehicle comprises calcium carbonate, calcium phosphate, various sugar and each kind of starch, derivatived cellulose, gelatin, vegetables oil and polyoxyethylene glycol etc.
Brief description of the drawings
Fig. 1, glucose tolerance test (blood sugar concentration-time)
Fig. 2, glucose tolerance test (blood sugar AUC-dosage)
Embodiment
Specific embodiment below, its objective is and make those skilled in the art can more clearly understand and implement the present invention.They should not be considered to limitation of the scope of the invention, and are exemplary illustration of the present invention and Typical Representative.Those skilled in the art should understand that: form in addition other route of synthesis of the compounds of this invention, provide nonrestrictive embodiment below.
The all operations of all raw materials that relates to oxidizable or facile hydrolysis all carries out under nitrogen protection.The raw material that the present invention uses can be directly to buy on market, without being further purified direct use, or adopts similar approach to prepare according to existing document.
The silica gel (200-300 order) that column chromatography chromatogram adopts Qingdao Chemical Co., Ltd. to produce.The precoated plate (silica gel 60PF254,0.25 millimeter) that thin-layer chromatography adopts E.Merck company to produce.Nucleus magnetic resonance chromatogram (NMR) is used Varian VNMRS-400 nmr determination; LC-MS (LC/MS) is used FINNIGAN Thermo LCQ Advantage MAX, Agilent LC1200series(pillar: Waters Symmetry C18,4.6 × 50 millimeters of Φ, 5 microns, 35 DEG C), adopt ESI (+) ion mode.
intermediate 1:(S)-6-hydroxyl-2,3-Dihydrobenzofuranes-3-methyl acetate synthetic
Synthesizing of step 1:4-chloromethyl-umbelliferone
Under frozen water is cooling, 4-chloroacetyl acetacetic ester (28.0g, 0.17mol) is dissolved in to (60mL) in the vitriol oil, then adds wherein in multiple times on a small quantity Resorcinol (18.7g, 170mmol), add after by reaction mixture stirring at room temperature 2 hours.Reaction mixture is poured in frozen water, filtered the solid producing, gained solid, through water washing, obtains 4-chloromethyl-umbelliferone (32.2g, yield 90.0%) after vacuum-drying. 1H NMR(400MHz，CDCl 3-d 3)：10.63(1H,s),7.64(1H,d,J=8.8Hz),6.80(1H,dd,J=8.8Hz,2.4Hz),6.72(1H,d,J=2.4Hz),6.39(1H,s),4.92(2H,s)。
Synthesizing of step 2:6-hydroxyl benzofuran-3-acetic acid
4-chloromethyl-umbelliferone (23.0g, 0.11mol) is dissolved in the aqueous solution of 1M sodium hydroxide (600mL), by mixture reflux 2 hours.Be 5-6 by regulating pH value with the vitriol oil after reaction solution cool to room temperature.Mixture is extracted with ethyl acetate (500mL × 2), merges organic phase, with the concentrated 6-hydroxyl benzofuran-3-acetic acid (19.9g, yield 95.0%) that obtains after anhydrous sodium sulfate drying. 1H NMR(400MHz，CDCl 3-d 3)：12.35-12.45(1H,brs),9.48(1H,s),7.65(1H,s),7.33(1H,d,J=8.0Hz),6.85(1H,d,J=2.0Hz),6.72(1H,dd,J=8.4Hz,2.0Hz),3.58(2H,s)。
Synthesizing of step 3:6-hydroxyl benzofuran-3-methyl acetate
In the mixed solution of 6-hydroxyl benzofuran-3-acetic acid (22.0g, 0.11mol) and methyl alcohol (200mL), add the vitriol oil (8mL).By mixture reflux 8 hours.Concentrating under reduced pressure after reaction solution cool to room temperature.In residue, add water (500mL), mixture is extracted with ethyl acetate (500mL × 2), merge organic phase, with using anhydrous sodium sulfate drying after saturated sodium bicarbonate solution washing, the concentrated 6-hydroxyl benzofuran-3-methyl acetate (22.0g, yield 93.2%) that obtains. 1H NMR(400MHz，CDCl 3-d 3)：7.50(1H,s),7.34(1H,d,J=8.4Hz),6.91(1H,d,J=2.4Hz),6.76(1H,dd,J=8.4Hz,2.0Hz),5.62(1H,s),3.74(3H,s),3.67(2H,s)。
Step 4:6-hydroxyl-2,3-Dihydrobenzofuranes-3-methyl acetate synthetic
6-hydroxyl benzofuran-3-methyl acetate (22.0g, 0.11mol), the mixture of 10% palladium-carbon (water content 50%, 8.0g) and methyl alcohol (500mL) is (1 normal atmosphere) stirred overnight at room temperature under hydrogen atmosphere.Reaction solution, by diatomite filtration, obtains 6-hydroxyl-2,3-Dihydrobenzofuranes-3-methyl acetate (21.0g, yield 94.6%) after filtrate is concentrated. 1H NMR(400MHz，CDCl 3-d 3)：6.92(1H,d,J=7.6Hz),6.31-6.33(2H,m),6.10-6.14(1H,brs),4.71(1H,t,J=8.8Hz),4.22(1H,dd,J=9.2Hz,6.0Hz),3.73-3.79(1H,m),3.70(3H,s),2.72(1H,dd,J=16.4Hz,5.6Hz),2.53(1H,dd,J=16.4Hz,5.6Hz)。
Step 5:6-hydroxyl-2,3-Dihydrobenzofuranes-3-acetic acid synthetic
To 6-hydroxyl-2,3-Dihydrobenzofuranes-3-methyl acetate (20.8g, 0.10mol), in the solution of methyl alcohol (100mL) and tetrahydrofuran (THF) (100mL) mixed solvent, drip 2M aqueous sodium hydroxide solution (100mL), dropwise rear mixture stirred overnight at room temperature.By reaction mixture dilute with water, with dilute hydrochloric acid adjusting pH to 6.Filter the solid of separating out, wash with water, dry 6-hydroxyl-2,3-Dihydrobenzofuranes-3-acetic acid (17.9g, 92.3%) of obtaining.
Step 6:(S)-6-hydroxyl-2,3-Dihydrobenzofuranes-3-acetic acid synthetic
Under room temperature, (S)-1-phenyl-ethyl amine (22.6g, 0.19mol) is added to 6-hydroxyl-2 in batches, in the acetone soln of 3-Dihydrobenzofuranes-3-acetic acid (52.4g, 0.27mol) (1.5L).By mixed solution reflux 1 hour, cool to room temperature.Filter and collect the solid of separating out, solid acetone recrystallization 2 times.Dissolution of solid in water, with dilute hydrochloric acid adjusting pH to 6, mixture is extracted with ethyl acetate (500mL × 3), merge organic phase and use anhydrous sodium sulfate drying, concentrated (S)-6-hydroxyl-2 that obtain, 3-Dihydrobenzofuranes-3-acetic acid (10.5g, yield 20.0%).
Step 7:(S)-6-hydroxyl-2,3-Dihydrobenzofuranes-3-methyl acetate synthetic
To (S)-6-hydroxyl-2,3-Dihydrobenzofuranes-3-acetic acid (11.0g, 57mmol)) and the mixed solution of methyl alcohol (200mL) in add the vitriol oil (4mL).By mixture reflux 8 hours.Concentrating under reduced pressure after reaction solution cool to room temperature.In residue, add water (500mL), mixture is extracted with ethyl acetate (500mL × 2), merge organic phase, with using anhydrous sodium sulfate drying after saturated sodium bicarbonate solution washing, concentrated (S)-6-hydroxyl-2 that obtain, 3-Dihydrobenzofuranes-3-methyl acetate (11.0g, yield 93.2%). 1H NMR(400MHz，CDCl 3-d 3):6.95(1H,d,J=8.0Hz),6.29-6.32(2H,m),4.81(1H,s),4.73(1H,t,J=8.8Hz),4.25(1H,dd,J=9.2Hz,6.0Hz),3.72-3.81(1H,m),3.70(3H,s),2.72(1H,dd,J=16.4Hz,5.6Hz),2.54(1H,dd,J=16.4Hz,9.2Hz)。
embodiment 1:2-(6-((4'-(3-(dimethyl phosphine acyl group) propoxy-)-2', 6'-dimethyl diphenyl-3-yl) methoxyl group)-2,3-dihydrobenzo furan mutter-3-yl) acetic acid synthetic
Step 1:4 '-hydroxyl-2 ', 6 '-dimethyl diphenyl-3-formaldehyde synthetic
3; 5-dimethyl-4-bromophenol (10.0g; 49.7mmol); 3-formylphenylboronic acid (8.9g, 59.7mmol), cesium carbonate (24.3g; 74.6mmol) with [1; two (diphenylphosphine) ferrocene of 1'-] palladium chloride (1.8g, 2.5mmol) is added to (250mL) in Isosorbide-5-Nitrae-dioxane.By this mixture reflux cool to room temperature after 8 hours.Reaction mixture is by diatomite filtration, and with the washing of ethyl ester ethyl ester, after concentrating filter liquor, residue obtains 4 '-hydroxyl-2 ' by silica gel column chromatography separating purification, 6 '-dimethyl diphenyl-3-formaldehyde (8.4g, yield 75.0%). 1H NMR(400MHz，CDCl 3-d 3)：10.05(2H,s),7.86(1H,d,J=7.6Hz),7.67(1H,t,J=1.6Hz),7.59(1H,t,J=7.6Hz),7.42(1H,d,J=7.6Hz),6.64(2H,s),1.97(6H,s)。
Step 2:4 '-(tertiary butyl dimethyl-silicon alcoxyl base)-2 ', 6 '-dimethyl diphenyl-3-formaldehyde synthetic
Under ice-water bath is cooling, to 4 '-hydroxyl-2 ', 6 '-dimethyl diphenyl-3-formaldehyde (2.0g, 8.8mmol) and imidazoles (1.2g, in dichloromethane solution 17.6mmol), (50mL) drips the dichloromethane solution (50mL) of TERT-BUTYL DIMETHYL CHLORO SILANE (2.0g, 13.2mmol).After dropwising, reaction solution is slowly raised to room temperature and stirs and spend the night.Filtering reacting liquid, after filtrate is concentrated, residue obtains 4 '-(tertiary butyl dimethyl-silicon alcoxyl base)-2 ', 6 '-dimethyl diphenyl-3-formaldehyde (2.6g, yield 86.7%) by silicagel column column chromatographic isolation and purification. 1H NMR(400MHz，CDCl 3-d 3)：10.05(1H,s),7.84(1H,d,J=7.6Hz),7.67(1H,s),7.58(1H,t,J=7.6Hz),7.42(1H,d,J=7.6Hz),6.60(2H,s),1.96(6H,s),1.01(9H,s),0.24(6H,s)。
Step 3:(4 '-(t-butyldimethylsilyloxy base)-2', 6'-dimethyl diphenyl-3-yl) methyl alcohol synthetic
Under ice-water bath is cooling, to 4 '-(t-butyldimethylsilyloxy base)-2 ', 6 '-dimethyl diphenyl-3-formaldehyde (3.0g, 8.8mmol) in the solution of tetrahydrofuran (THF) (40mL) and methyl alcohol (20mL), add in multiple times on a small quantity sodium borohydride (0.67g, 17.6mmol).After adding, reaction solution is slowly raised to room temperature and stirs and spend the night.After reaction solution is concentrated, add wherein water (200mL), mixture is extracted with ethyl acetate (250mL × 3), merge organic phase and use anhydrous sodium sulfate drying, concentrated (4 '-(t-butyldimethylsilyloxy the base)-2' that obtains, 6'-dimethyl diphenyl-3-yl) methyl alcohol (2.6g, yield 86.7%). 1H NMR(400MHz，CDCl 3-d 3)：7.40(1H,t,J=7.6Hz),7.32(1H,d,J=7.6Hz),7.13(1H,s),7.07(1H,d,J=7.2Hz),6.58(2H,s),4.73(2H,s),1.97(6H,s),1.00(9H,s),0.23(6H,s)。
Synthesizing of step 4:2-(6-((4'-(t-butyldimethylsilyloxy base)-2', 6'-dimethyl diphenyl-3-yl) methoxyl group)-2,3-Dihydrobenzofuranes-3-yl) methyl acetate
Under ice-water bath is cooling, to (4 '-(t-butyldimethylsilyloxy base)-2', 6'-dimethyl diphenyl-3-yl) methyl alcohol (2.0g, 5.8mmol), 6-hydroxyl-2,3-Dihydrobenzofuranes-3-methyl acetate (in intermediate 1, the product of step 5 prepares according to the method for step 7) (1.5g, 7.2mmol) and triphenylphosphine (2.4g, in tetrahydrofuran solution 9.0mmol), (150mL) drips diisopropyl azodiformate (1.8g, 9.0mmol).After dropwising, reaction solution is slowly raised to room temperature and stirs and spend the night.Reaction solution residue after concentrated obtains 2-(6-((4'-(t-butyldimethylsilyloxy base)-2' by silica gel column chromatography separating purification, 6'-dimethyl diphenyl-3-yl) methoxyl group)-2,3-Dihydrobenzofuranes-3-yl) methyl acetate (2.1g, yield 67.7%). 1H NMR(400MHz，CDCl 3-d 3)：7.42(1H,t,J=7.6Hz),7.37(1H,d,J=8.0Hz),7.18(1H,s),7.09(1H,d,J=7.2Hz),7.02(1H,d,J=8.4Hz),6.59(2H,s),6.45-6.51(2H,m),5.06(2H,s),4.75(1H,t,J=8.8Hz),4.27(1H,dd,J=9.2Hz,6.4Hz),3.76-3.85(1H,m),3.72(3H,s),2.75(1H,dd,J=16.4Hz,5.2Hz),2.56(1H,dd,J=16.4Hz,5.2Hz),1.96(6H,s),1.02(9H,s),0.24(6H,s)。
Synthesizing of step 5:2-(6-((4'-hydroxyl-2', 6'-dimethyl diphenyl-3-yl) methoxyl group)-2,3-Dihydrobenzofuranes-3-yl) methyl acetate
Under ice-water bath is cooling, to 2-(6-((4'-(t-butyldimethylsilyloxy base)-2', 6'-dimethyl diphenyl-3-yl) methoxyl group)-2,3-Dihydrobenzofuranes-3-yl) methyl acetate (1.1g, in tetrahydrofuran solution 2.1mmol), (50mL) adds tetrabutyl ammonium fluoride (1.3g, 5.0mmol).After adding, reaction solution is slowly raised to room temperature and stirs and spend the night.Add 50mL saturated aqueous ammonium chloride termination reaction, mixture is extracted with ethyl acetate (50mL × 3), merge organic phase and use anhydrous sodium sulfate drying, concentrated 2-(the 6-((4'-hydroxyl-2' that obtains, 6'-dimethyl diphenyl-3-yl) methoxyl group)-2,3-Dihydrobenzofuranes-3-yl) methyl acetate (0.75g, yield 87%). 1H NMR(400MHz，CDCl 3-d 3)：7.42(1H,t,J=7.2Hz),7.37(1H,d,J=8.0Hz),7.16(1H,s),7.07(1H,d,J=7.2Hz),7.01(1H,d,J=8.0Hz),6.60(2H,s),6.45-6.50(2H,m),5.06(2H,s),4.75(1H,t,J=9.2Hz),4.26(1H,dd,J=9.2Hz,6.4Hz),3.75-3.87(1H,m),3.72(3H,s),2.74(1H,dd,J=16.4Hz,5.6Hz),2.55(1H,dd,J=16.4Hz,5.6Hz),1.97(6H,s)。
Synthesizing of step 6:2-(6-((4'-(allyloxy)-2', 6'-dimethyl diphenyl-3-yl) methoxyl group)-2,3-Dihydrobenzofuranes-3-yl) methyl acetate
Salt of wormwood (3.3g, 23.9mmol) add 2-(6-((4'-hydroxyl-2', 6'-dimethyl diphenyl-3-yl) methoxyl group)-2,3-Dihydrobenzofuranes-3-yl) methyl acetate (5.0g, 11.9mmol) and in the acetonitrile of allyl iodide (4.0g, 23.8mmol) (100mL) solution.By this mixture stirred overnight at room temperature, filter, residue after filtrate is concentrated obtains 2-(6-((4'-(allyloxy)-2' through silica gel column chromatography separating purification, 6'-dimethyl diphenyl-3-yl) methoxyl group)-2,3-Dihydrobenzofuranes-3-yl) methyl acetate (4.1g, yield 74.5%). 1H NMR(400MHz，CDCl 3-d 3)：7.40(1H,t,J=7.6Hz),7.35(1H,d,J=7.6Hz),7.16(1H,s),7.06(1H,d,J=7.2Hz),6.99(1H,d,J=8.4Hz),6.66(2H,s),6.43-6.48(2H,m),6.02-6.12(1H,m),5.42(1H,d,J=16.8Hz),5.27(1H,d,J=10.4Hz),5.04(2H,s),4.73(1H,t,J=8.8Hz),4.53(2H,d,J=5.2Hz),4.24(1H,dd,J=9.2Hz,2.0Hz),3.75-3.82(1H,m),3.70(3H,s),2.73(1H,dd,J=16.4Hz,5.6Hz),2.53(1H,dd,J=16.4Hz,9.2Hz),1.97(6H,s)。
Synthesizing of step 7:2-(6-((4'-(3-(dimethyl phosphine acyl group) propoxy-)-2', 6'-dimethyl diphenyl-3-yl) methoxyl group)-2,3-Dihydrobenzofuranes-3-yl) methyl acetate
Dimethyl oxidation phosphine (1.0g, 12.8mmol) be added to 2-(6-((4'-(allyloxy)-2', 6'-dimethyl diphenyl-3-yl) methoxyl group)-2,3-Dihydrobenzofuranes-3-yl) in the methanol solution of methyl acetate (4.1g, 9.0mmol) (100mL).This reaction solution stirring at room temperature, after 10 minutes, adds diethyl methoxyl group borine (1.3g, 13.0mmol) wherein.This reaction mixture is heated to 80 DEG C of reactions to spend the night.By reaction solution cool to room temperature; concentrated; through column chromatography silicagel column, separation and purification obtains 2-(6-((4'-(3-(dimethyl phosphine acyl group) propoxy-)-2' to residue; 6'-dimethyl diphenyl-3-yl) methoxyl group)-2; 3-Dihydrobenzofuranes-3-yl) methyl acetate (3.0g, yield 62.5%). 1H NMR(400MHz，CDCl 3-d 3)：7.41(1H,t,J=7.2Hz),7.36(1H,d,J=8.0Hz),7.15(1H,s),7.06(1H,d,J=7.2Hz),7.00(1H,d,J=8.0Hz),6.64(2H,s),6.44-6.48(2H,m),5.05(2H,s),4.73(1H,t,J=9.2Hz),4.24(1H,dd,J=9.2Hz,6.0Hz),4.06(2H,t,J=6.0Hz),3.76-3.82(1H,m),3.71(3H,s),2.73(1H,dd,J=16.4Hz,5.2Hz),2.54(1H,dd,J=16.4Hz,9.2Hz),2.04-2.16(2H,m),1.98(6H,s),1.88-1.97(2H,m),1.53(6H,d,J=12.4Hz)。
Synthesizing of step 8:2-(6-((4'-(3-(dimethyl phosphine acyl group) propoxy-)-2', 6'-dimethyl diphenyl-3-yl) methoxyl group)-2,3-Dihydrobenzofuranes-3-yl) acetic acid
To 2-(6-((4'-(3-(dimethyl phosphine acyl group) propoxy-)-2'; 6'-dimethyl diphenyl-3-yl) methoxyl group)-2; 3-Dihydrobenzofuranes-3-yl) methyl acetate (3.0g; 5.6mmol) in the solution of the mixed solvent of methyl alcohol (50mL) and tetrahydrofuran (THF) (100mL); drip 2M aqueous sodium hydroxide solution (8mL), dropwise rear mixture stirred overnight at room temperature.By reaction mixture dilute with water, with 10% aqueous citric acid solution acidifying, and be extracted with ethyl acetate (150mL × 3).Organic phase is with concentrated after anhydrous sodium sulfate drying.Residue obtains 2-(6-((4'-(3-(dimethyl phosphine acyl group) propoxy-)-2' by silica gel column chromatography separating purification; 6'-dimethyl diphenyl-3-yl) methoxyl group)-2; 3-Dihydrobenzofuranes-3-yl) acetic acid (2.3g, yield 78.0%). 1H NMR(400MHz，DMSO-d 6)：12.19-12.38(1H,brs),7.41(1H,t,J=7.2Hz),7.34(1H,d,J=7.6Hz),7.10(1H,s),7.06(1H,d,J=8.0Hz),7.02(1H,d,J=7.6Hz),6.66(2H,s),6.41-6.45(2H,m),5.06(2H,s),4.64(1H,t,J=9.2Hz),4.14(1H,dd,J=9.2Hz,6.8Hz),4.00(2H,t,J=6.0Hz),3.59-3.67(1H,m),2.65(1H,dd,J=16.4Hz,5.6Hz),2.40-2.43(1H,m),1.90-1.97(2H,m),1.72-1.78(2H,m),1.36(6H,d,J=12.8Hz)。
embodiment 2:2-(6-((2', 6'-dimethyl-4'-(2-(methylsulfonyl amino) oxyethyl group) biphenyl-3-yl) methoxyl group)-2,3-dihydrobenzo furan mutter-3-yl) acetic acid synthetic
Synthesizing of step 1:2-(6-((4 '-(cyano group methoxyl group)-2 ', 6 '-dimethyl diphenyl-3-yl) methoxyl group)-2,3-Dihydrobenzofuranes-3-yl) methyl acetate
Salt of wormwood (2.0g, 14.5mmol) add 2-(6-((4'-hydroxyl-2', 6'-dimethyl diphenyl-3-yl) methoxyl group)-2,3-Dihydrobenzofuranes-3-yl) methyl acetate (3.0g, 7.2mmol) and in the acetonitrile of bromoacetonitrile (1.8g, 15.0mmol) (100mL) solution.By this mixture stirred overnight at room temperature, filter, residue after filtrate is concentrated obtains 2-(6-((4'-(cyano group methoxyl group)-2' through silica gel column chromatography separating purification, 6'-dimethyl diphenyl-3-yl) methoxyl group)-2,3-Dihydrobenzofuranes-3-yl) methyl acetate (2.2g, yield 66.7%).MS m/z[ESI] +:458.0[M+1]。
Synthesizing of step 2:2-(6-((4'-(2-amino ethoxy)-2', 6'-dimethyl diphenyl-3-yl) methoxyl group)-2,3-Dihydrobenzofuranes-3-yl) methyl acetate
2-(6-((4'-(cyano group methoxyl group)-2', 6'-dimethyl diphenyl-3-yl) methoxyl group)-2,3-Dihydrobenzofuranes-3-yl) methyl acetate (2.2g, 4.8mmol), the mixture of Raney's nickel (5.0g) and methyl alcohol (100mL) (1 normal atmosphere) stirred overnight at room temperature under hydrogen atmosphere.Reaction solution passes through diatomite filtration, after filtrate is concentrated, obtain 2-(6-((4'-(2-amino ethoxy)-2', 6'-dimethyl diphenyl-3-yl) methoxyl group)-2,3-Dihydrobenzofuranes-3-yl) methyl acetate (2.1g, yield 95.0%).MS m/z[ESI] +:462.0[M+1]。
Synthesizing of step 3:2-(6-((2', 6'-dimethyl-4'-(2-(methylsulfonyl amino) oxyethyl group) biphenyl-3-yl) methoxyl group)-2,3-Dihydrobenzofuranes-3-yl) methyl acetate
To 2-(6-((4'-(2-amino ethoxy)-2', 6'-dimethyl diphenyl-3-yl) methoxyl group)-2,3-Dihydrobenzofuranes-3-yl) methyl acetate (0.5g, in dichloromethane solution 1.1mmol), (50mL) adds methylsulfonyl chloride (0.19g successively, 1.6mmol) and triethylamine (0.22g, 2.2mmol).By this reaction mixture stirred overnight at room temperature.Reaction is poured into water (50mL); with dichloromethane extraction (100mL × 2); organic phase anhydrous sodium sulfate drying; concentrated; residue obtains 2-(6-((2' through silica gel column chromatography separating purification; 6'-dimethyl-4'-(2-(methylsulfonyl amino) oxyethyl group) biphenyl-3-yl) methoxyl group)-2,3-Dihydrobenzofuranes-3-yl) methyl acetate (0.44g, yield 75.0%). 1H NMR(400MHz，CDCl 3-d 3)：7.44(1H,t,J=7.6Hz),7.40(1H,d,J=7.6Hz),7.18(1H,s),7.09(1H,d,J=7.2Hz),7.03(1H,d,J=8.0Hz),6.66(2H,s),6.47-6.52(2H,m),5.08(2H,s),4.77-4.79(2H,m),4.28(1H,dd,J=9.2Hz,6.0Hz),4.14(2H,t,J=4.8Hz),3.78-3.85(1H,m),3.74(3H,s),3.58(2H,q,J=5.6Hz),3.06(3H,s),2.76(1H,dd,J=16.8Hz,5.2Hz),2.57(1H,dd,J=16.8Hz,9.6Hz),2.01(6H,s)。
Synthesizing of step 4:2-(6-((2', 6'-dimethyl-4'-(2-(methylsulfonyl amino) oxyethyl group) biphenyl-3-yl) methoxyl group)-2,3-Dihydrobenzofuranes-3-yl) acetic acid
To 2-(6-((2'; 6'-dimethyl-4'-(2-(methylsulfonyl amino) oxyethyl group) biphenyl-3-yl) methoxyl group)-2; 3-Dihydrobenzofuranes-3-yl) methyl acetate (0.44g; 0.8mmol) in the solution of the mixed solvent of methyl alcohol (25mL) and tetrahydrofuran (THF) (50mL); drip 2M aqueous sodium hydroxide solution (2mL), dropwise rear mixture stirred overnight at room temperature.By reaction mixture dilute with water, with 10% aqueous citric acid solution acidifying, and be extracted with ethyl acetate (50mL × 3).Organic phase is with concentrated after anhydrous sodium sulfate drying; residue obtains 2-(6-((2' by silica gel column chromatography separating purification; 6'-dimethyl-4'-(2-(methylsulfonyl amino) oxyethyl group) biphenyl-3-yl) methoxyl group)-2; 3-Dihydrobenzofuranes-3-yl) acetic acid (0.28g, yield 65.0%). 1H NMR(400MHz，DMSO-d 6)：7.43(1H,t,J=7.6Hz),7.36(1H,d,J=7.6Hz),7.25(1H,t,J=6.0Hz),7.12(1H,s),7.08(1H,d,J=8.0Hz),7.04(1H,d,J=7.2Hz),6.70(2H,s),6.43-6.47(2H,m),5.08(2H,s),4.66(1H,t,J=9.2Hz),4.16(1H,dd,J=8.8Hz,6.8Hz),4.02(2H,t,J=6.0Hz),3.58-3.70(1H,m),3.32-3.34(2H,m),2.95(3H,s),2.66(1H,dd,J=16.4Hz,5.6Hz),2.43-2.45(1H,m),1.90(6H,s)。
embodiment 3:2-(6-((2', 6'-dimethyl-4'-(2-(ethylsulfonyl amino) oxyethyl group) biphenyl-3-yl) methoxyl group)-2,3-dihydrobenzo furans-3-yl) acetic acid synthetic
According to the method for embodiment 2, replace Methanesulfonyl chloride with ethyl chloride, prepare title compound. 1H NMR(400MHz，DMSO-d 6)：7.43(1H,t,J=7.6Hz),7.36(1H,d,J=7.6Hz),7.28(1H,t,J=6.4Hz),7.12(1H,s),7.08(1H,d,J=8.0Hz),7.04(1H,d,J=7.2Hz),6.69(2H,s),6.43-6.47(2H,m),5.08(2H,s),4.66(1H,t,J=8.8Hz),4.16(1H,dd,J=9.6Hz,6.8Hz),4.00(2H,t,J=5.6Hz),3.61-3.69(1H,m),3.34-3.37(2H,m),3.05(2H,q,J=7.6Hz),2.67(1H,dd,J=16.8Hz,6.0Hz),2.42-2.45(1H,m),1.90(6H,s),1.20(3H,t,J=7.2Hz)。
embodiment 4:2-(6-((2', 6'-dimethyl-4'-(2-(cyclopropyl sulfuryl amino) oxyethyl group) biphenyl-3-yl) methoxyl group)-2,3-dihydrobenzene and furans-3-yl) acetic acid synthetic
According to the method for embodiment 2, with cyclopropyl SULPHURYL CHLORIDE replacement Methanesulfonyl chloride, prepare title compound. 'HNMR(400MHz，CDCl 3-d 3)：7.40(1H,t,J=7.6Hz),7.35(1H,d,J=7.6Hz),7.14(1H,s),7.02-7.06(2H,m),6.63(2H,s),6.47(1H,dd,J=8.0Hz,2.0Hz),6.44(1H,d,J=2.4Hz),5.04(2H,s),4.71-4.79(2H,m),4.26(1H,dd,J=9.2Hz,6.0Hz),4.11(2H,t,J=6.0Hz),3.74-3.82(1H,m),3.55(2H,q,J=6.0Hz),2.78(1H,dd,J=16.8Hz,5.2Hz),2.59(1H,dd,J=16.8Hz,9.2Hz),2.40-2.51(1H,m),1.97(6H,s),1.18-1.22(2H,m),0.98-1.03(2H,m)。
embodiment 5:2-(6-((2', 6'-dimethyl-4'-(2-(1,1-dioxo-isothiazolidine-2-yl) oxyethyl group) biphenyl-3-yl) methoxyl group)-2,3- dihydrobenzofuranes-3-yl) acetic acid synthetic
Synthesizing of step 1:2-(6-((4'-(2-(3-chloropropyl sulfuryl amino) oxyethyl group)-2', 6'-dimethyl diphenyl-3-yl) methoxyl group)-2,3-Dihydrobenzofuranes-3-yl) methyl acetate
To 2-(6-((4'-(2-amino ethoxy)-2', 6'-dimethyl diphenyl-3-yl) methoxyl group)-2,3-Dihydrobenzofuranes-3-yl) methyl acetate (0.66g, in dichloromethane solution 1.4mmol), (50mL) adds the chloro-1-sulfonyl propyl of 3-chlorine (0.38g successively, 2.1mmol) and triethylamine (0.29g, 2.9mmol).By this reaction mixture stirred overnight at room temperature.Reaction is poured into water (50mL), with dichloromethane extraction (100mL × 2), organic phase anhydrous sodium sulfate drying, concentrated, residue obtains 2-(6-((4'-(2-(3-chloropropyl sulfonamido) oxyethyl group)-2' through silicagel column column chromatographic isolation and purification, 6'-dimethyl diphenyl-3-yl) methoxyl group)-2,3-Dihydrobenzofuranes-3-yl) methyl acetate (0.64g, yield 75.0%).MS m/z[ESI] +:602.0[M+1]。
Step 2:2-(6-((4'-(2-(1,1-dioxo-isothiazolidine-2-yl) oxyethyl group)-2', 6'-dimethyl diphenyl-3-yl) methoxyl group)-2,3-Dihydrobenzofuranes-3-yl) methyl acetate synthetic
To 2-(6-((4'-(2-(3-chloropropyl sulfuryl amino) oxyethyl group)-2'; 6'-dimethyl diphenyl-3-yl) methoxyl group)-2; 3-Dihydrobenzofuranes-3-yl) methyl acetate (60.0mg; N 0.1mmol); in dinethylformamide solution, (10mL) adds salt of wormwood (28.0mg, 0.2mmol).80 DEG C of stirrings of this reaction mixture are spent the night.Reaction is poured into water (50mL), be extracted with ethyl acetate (100mL × 2), organic phase anhydrous sodium sulfate drying, concentrated, residue obtains 2-(6-((4'-(2-(1,1-dioxo-isothiazolidine-2-yl) oxyethyl group)-2', 6'-dimethyl diphenyl-3-yl) methoxyl group)-2 through purification by silica gel column chromatography, 3-Dihydrobenzofuranes-3-yl) methyl acetate (50.0mg, yield 88.8%).MS m/z[ESI] +:566.0[M+1]。
Step 3:2-(6-((4'-(2-(1,1-dioxo-isothiazolidine-2-yl) oxyethyl group)-2', 6'-dimethyl diphenyl-3-yl) methoxyl group)-2,3-Dihydrobenzofuranes-3-yl) acetic acid synthetic
To 2-(6-((4'-(2-(1,1-dioxo-isothiazolidine-2-yl) oxyethyl group)-2', 6'-dimethyl diphenyl-3-yl) methoxyl group)-2,3-Dihydrobenzofuranes-3-yl) methyl acetate (50.0mg, 0.09mmol) in the solution of the mixed solvent of methyl alcohol (10mL) and tetrahydrofuran (THF) (20mL), drip 2M aqueous sodium hydroxide solution (1mL), dropwise rear mixture stirred overnight at room temperature.By reaction mixture dilute with water, with 10% aqueous citric acid solution acidifying, and be extracted with ethyl acetate (50mL × 3).Organic phase is with concentrated after anhydrous sodium sulfate drying, residue obtains 2-(6-((4'-(2-(1 by silica gel column chromatography separating purification, 1-dioxo-isothiazolidine-2-yl) oxyethyl group)-2', 6'-dimethyl diphenyl-3-yl) methoxyl group)-2,3-Dihydrobenzofuranes-3-yl) acetic acid (22.0mg, yield 45.1%). 1HNMR(400MHz，CDCl 3-d 3)：7.43(1H,t,J=7.2Hz),7.37(1H,d,J=7.6Hz),7.16(1H,s),7.04-7.09(2H,m),6.66(2H,s),6.49(1H,dd,J=8.0Hz,2.0Hz),6.48(1H,d,J=2.0Hz),5.07(2H,s),4.78(1H,t,J=8.8Hz),4.29(1H,dd,J=9.2Hz,6.0Hz),4.20(2H,t,J=4.2Hz),3.79-3.84(1H,m),3.48-3.53(4H,m),3.16(2H,t,J=7.6Hz),2.80(1H,dd,J=17.2Hz,5.6Hz),2.61(1H,dd,J=16.8Hz,9.2Hz),2.37(2H,quin,J=6.8Hz),1.99(6H,s)。
embodiment 6:2-(6-((2', 6'-dimethyl-4'-(3-(N, N-dimethylamino-sulfonyl) propoxy-) biphenyl-3-yl) methoxyl group)-2,3-bis- hydrogen cumarone-3-yl) acetic acid synthetic
Step 1:3-(4-bromo-3,5-dimethyl phenoxy) propyl group-1-sodium sulfonate synthetic
In the mixed solution of the bromo-MX of 4-(20.2g, 0.1mol) and water (250mL), add sodium hydroxide (5.0g, 0.12mol).This reaction mixture is stirred 1 hour.By 2,2-dioxo-1, the Isosorbide-5-Nitrae-dioxane solution of 2-oxa-sulfo-pentamethylene (15.3g, 0.12mol) (200mL) is added drop-wise in above-mentioned reaction solution.After reaction solution stirred overnight at room temperature, filter and collect the solid that generates, solid drying is obtained to 3-(4-bromo-3,5-dimethyl phenoxy) propyl group-1-sodium sulfonate (29.3g, yield 85.0%). 1H NMR(400MHz，DMSO-d 6)：6.77(2H,s),3.92-4.05(2H,m),2.49-2.53(2H,m),1.90-1.97(2H,m)。
Step 2:3-(4-bromo-3,5-dimethyl phenoxy) propyl group-1-SULPHURYL CHLORIDE synthetic
Under ice-water bath is cooling, in DMF (150mL) solution of 3-(4-bromo-3,5-dimethyl phenoxy) propyl group-1-sodium sulfonate (10.0g, 29.0mmol), drip thionyl chloride (15mL).After dropwising by this reaction mixture stirring at room temperature 4 hours.Reaction solution is poured into water (500mL), filters and collect the solid that generates, solid drying is obtained to 3-(4-bromo-3,5-dimethyl phenoxy) propyl group-1-SULPHURYL CHLORIDE (7.5g, yield 75.8%). 1H NMR(400MHz，CDCl 3-d 3)：6.62(2H,s),4.08(2H,t,J=5.2Hz),3.88(2H,t,J=7.2Hz),2.46-2.50(2H,m),2.37(3H,s)。
Step 3:N, N-dimethyl-3-(4-bromo-3,5-dimethyl phenoxy) propyl group-1-sulphonamide synthetic
To 3-(4-bromo-3,5-dimethyl phenoxy) in tetrahydrofuran (THF) (150mL) solution of propyl group-1-SULPHURYL CHLORIDE (4.0g, 11.7mmol), drip dimethylamine agueous solution (33.0%, 10mL), dropwise rear mixture stirred overnight at room temperature.After solvent is concentrated, residue obtains N by silica gel column chromatogram separating purification, N-dimethyl-3-(4-bromo-3,5-dimethyl phenoxy) propyl group-1-sulphonamide (4.0g, yield 97.6%). 1H NMR(400MHz，CDCl 3-d 3)：6.65(2H,s),4.06(2H,t,J=6.0Hz),3.14-3.15(2H,m),2.91(6H,s),2.39(6H,s),2.26-2.39(2H,m)。
Step 4:4 '-(3-(N, N-dimethylamino-sulfonyl) propoxy-)-2 ', 6 '-dimethyl diphenyl-3-formaldehyde synthetic
N; N-dimethyl-3-(4-bromo-3; 5-dimethyl phenoxy) propyl group-1-sulphonamide (4.0g, 11.4mmol), 3-formylphenylboronic acid (2.1g; 13.7mmol); cesium carbonate (5.5g, 17.1mmol) and [two (diphenylphosphine) ferrocene of 1,1'-] palladium chloride (0.4g; 0.6mmol) be added to (150mL) in Isosorbide-5-Nitrae-dioxane.By this mixture reflux cool to room temperature after 8 hours.Reaction mixture passes through diatomite filtration; wash with ethyl ester ethyl ester; after concentrating filter liquor, residue obtains 4 '-(3-(N by the separation and purification of column chromatography silicagel column; N-dimethylamino-sulfonyl) propoxy-)-2 '; 6 '-dimethyl diphenyl-3-formaldehyde (2.75g, yield 64.3%). 1H NMR(400MHz，CDCl 3-d 3)：10.05(1H,s),7.86(1H,d,J=7.6Hz),7.66(1H,s),7.59(1H,t,J=7.6Hz),7.41(1H,d,J=7.6Hz),6.67(2H,s),4.12(2H,t,J=6.0Hz),3.16(2H,t,J=7.6Hz),2.92(6H,s),2.28-2.37(2H,m),1.99(6H,s)。
Synthesizing of step 5-7:2-(6-((2', 6'-dimethyl-4'-(3-(N, N-dimethylamino-sulfonyl) propoxy-) biphenyl-3-yl) methoxyl group)-2,3-Dihydrobenzofuranes-3-yl) acetic acid
With the 4 '-(3-(N that step 4 was obtained; N-dimethylamino-sulfonyl) propoxy-)-2 '; 6 '-dimethyl diphenyl-3-formaldehyde is raw material; successively according to step 3 in similar embodiment 1; 4 and 8 method prepares 2-(6-((2'; 6'-dimethyl-4'-(3-(N, N-dimethylamino-sulfonyl) propoxy-) biphenyl-3-yl) methoxyl group)-2,3-Dihydrobenzofuranes-3-yl) acetic acid. 1H NMR(400MHz，CDCl 3-d 3)：7.40(1H,t,J=8.0Hz),7.35(1H,d,J=8.0Hz),7.14(1H,s),7.02-7.07(2H,m),6.63(2H,s),6.47(1H,dd,J=8.0Hz,2.0Hz),6.44(1H,d,J=2.0Hz),5.04(2H,s),4.74(1H,t,J=9.2Hz),4.26(1H,dd,J=9.2Hz,6.0Hz),4.09(2H,t,J=5.2Hz),3.75-3.83(1H,m),3.14(2H,t,J=7.6Hz),2.90(6H,s),2.79(1H.dd,J=16.8Hz,5.2Hz),2.59(1H,dd,J=16.8Hz,9.2Hz),2.26-2.32(2H.m),1.97(6H,s)。
embodiment 7:2-(6-((2', 6'-dimethyl-4'-(3-(N-methylamino alkylsulfonyl) propoxy-) biphenyl-3-yl) methoxyl group)-2,3-dihydrobenzene and furans-3-yl) acetic acid synthetic
According to the method for embodiment 6, replace dimethylamine with methylamine, prepare title compound. 1H NMR(400MHz，CDCl 3-d 3)：7.42(1H,t,J=7.6Hz),7.37(1H,d,J=7.6Hz),7.15(1H,s),7.04-7.08(2H,m),6.64(2H,s),6.49(1H,dd,J=8.0Hz,2.0Hz),6.46(1H,d,J=2.0Hz),5.06(2H,s),4.76(1H,t,J=9.2Hz),4.28(1H,dd,J=9.2Hz,6.0Hz),4.07-4.12(3H,m),3.77-3.84(1H,m),3.26(2H,t,J=7.2Hz),2.84(3H,d,J=5.6Hz),2.80(1H,dd,J=16.8Hz,5.2Hz),2.60(1H,dd,J=16.8Hz,9.2Hz),2.24-2.33(2H,m),1.99(6H,s)。
embodiment 8:2-(6-((4'-(2-(1,1-dioxo-isothiazolidine-2-yl) oxyethyl group)-2', 6'-dimethyl diphenyl-3-yl) methyl ammonia base)-2,3-Dihydrobenzofuranes-3-yl) acetic acid synthetic
Step 1:6-trifluoro-methanesulfonyl oxy-2,3-Dihydrobenzofuranes-3-methyl acetate synthetic
To 6-hydroxyl-2,3-Dihydrobenzofuranes-3-methyl acetate (2.08g, 10.0mmol) and triethylamine (2.02g, in mixture 20.0mmol), add methylene dichloride (50mL), mixture is cooled to zero degree, in mixture, slowly drip trifluoromethanesulfanhydride anhydride (3.4g, 12.0mmol).Mixture was raised to room temperature, stirring at room temperature 2 hours.By lower reaction mixture decompression concentrated, the residue obtaining obtains 6-trifluoro-methanesulfonyl oxy 2 by silica gel column chromatography separating purification, 3-Dihydrobenzofuranes-3-methyl acetate (2.1g, yield 63.0%). 1H NMR(400MHz，CDCl 3-d 3)：7.18(1H,d,J=8.4Hz),6.76(1H,dd,J=8.4Hz,2.0Hz),6.70(1H,d,J=2.0Hz),4.84(1H,t,J=9.2Hz),4.34(1H,dd,J=9.2Hz,6.4Hz),3.82-3.94(1H,m),3.73(3H,s),2.78(1H,dd,J=16.8Hz,5.6Hz),2.61(1H,dd,J=16.8Hz,8.4Hz)。
Step 2:6-amino-2,3-Dihydrobenzofuranes-3-methyl acetate synthetic
Under nitrogen is fully replaced, to 6-trifluoro-methanesulfonyl oxy-2,3-Dihydrobenzofuranes-3-methyl acetate (2.1g, 6.17mmol), benzophenone imine (1.5g, 8.3mmol), three (dibenzalacetone) two palladium (0.56g, 0.6mmol), 2-dicyclohexylphosphontetrafluoroborate-2,4,6-tri isopropyl biphenyl (0.7g, 1.5mmol) and in the mixture of cesium carbonate (4.0g, 12.0mmol), add tetrahydrofuran (THF) (50mL), mixture reflux is spent the night.After reaction mixture cool to room temperature, filter, filtrate is under reduced pressure concentrated.In the residue obtaining, add tetrahydrofuran (THF) (50mL), then add the hydrochloric acid (10mL) of 3M, mixture stirring at room temperature 2 hours.By (100mL) soluble in water after reaction mixture concentrating under reduced pressure, pH value is adjusted between 8-9 with the aqueous solution of sodium hydroxide, be extracted with ethyl acetate.By organic phase anhydrous sodium sulfate drying, natural filtration, and under reduced pressure concentrated.The residue obtaining silica gel chromatography column purification, obtains 6-amino-2,3-Dihydrobenzofuranes-3-methyl acetate (0.4g, yield 32.0%). 1H NMR(400MHz，CDCl 3-d 3)：6.88(1H,d,J=8.0Hz),6.17(1H,dd,J=8.0Hz,1.6Hz),6.15(1H,d,J=1.6Hz),4.69(1H,t,J=9.2Hz),4.20(1H,dd,J=9.2Hz,6.4Hz),3.71-3.77(1H,m),3.69(3H,s),3.51-3.70(2H,brs),2.70(1H,dd,J=16.8Hz,5.6Hz),2.51(1H,dd,J=16.8Hz,9.2Hz)。
Synthesizing of step 3:2-(6-((4'-hydroxyl-2', 6'-dimethyl diphenyl-3-yl) methylamino)-2,3-Dihydrobenzofuranes-3-yl) methyl acetate
To 6-amino-2,3-Dihydrobenzofuranes-3-methyl acetate (0.41g, 1.98mmol) with 4 '-hydroxyl-2 ', 6 '-dimethyl diphenyl-3-formaldehyde (0.45g, in ethanol (20mL) solution 1.98mmol), add acetic acid (0.1ml), mixture stirring at room temperature 2 hours.In reaction mixture, add sodium triacetoxy borohydride (0.84g, 3.96mmol).Reaction mixture stirring at room temperature 3 hours.By saturated aqueous ammonium chloride solution cancellation for reaction mixture, with the extraction of ethyl acetate separatory.Organic phase is used to saturated sodium bicarbonate aqueous solution and saturated common salt water washing successively, with anhydrous sodium sulfate drying, filter.The residue silica gel chromatography column purification obtaining after filtrate is concentrated, obtain product 2-(6-((4'-hydroxyl-2', 6'-dimethyl diphenyl-3-yl) methylamino)-2,3-Dihydrobenzofuranes-3-yl) methyl acetate (0.4g, yield 50.0%).MS m/z[ESI] +:418.0[M+1]。
Step 4-8:2-(6-((2', 6'-dimethyl-4'-(2-(1,1-dioxo-isothiazolidine-2-yl) oxyethyl group) biphenyl-3-yl) methylamino)-2,3-Dihydrobenzofuranes-3-yl) acetic acid synthetic
With 2-(6-((4'-hydroxyl-2', 6'-dimethyl diphenyl-3-yl) methylamino)-2,3-Dihydrobenzofuranes-3-yl) methyl acetate is raw material, successively with reference to the step 1 in embodiment 2,2 and embodiment 5 in step 1,2 and 3 method prepare target compound. 1H NMR(400MHz，DMSO-d 6)：7.43(1H,t,J=7.6Hz),7.36(1H,d,J=7.6Hz),7.12(1H,s),7.07(1H,d,J=8.0Hz),7.03(1H,d,J=8.4Hz),6.70(2H,s),6.42-6.47(2H,m),5.08(2H,s),4.66(1H,t,J=8.8Hz),4.09-4.18(3H,m),3.61-3.69(1H,m),3.2-3.35(4H,m),3.18(2H,t,J=7.6Hz),2.66(1H,dd,J=17.2Hz,5.6Hz),2.42-2.49(1H,m),2.21(2H,quint,J=6.8Hz),1.90(6H,s)。
embodiment 9:2-(6-((4'-(3-(dimethyl phosphine acyl group) propoxy-)-2', 6'-dimethyl diphenyl-3-yl) methylamino)-2,3-dihydrobenzo furans-3-yl) acetic acid synthetic
Be that raw material prepares title compound with reference to the method for embodiment 1 with 2-(6-((4'-hydroxyl-2', 6'-dimethyl diphenyl-3-yl) methylamino)-2,3-Dihydrobenzofuranes-3-yl) methyl acetate. 1H NMR(400MHz，CDCl 3-d 3)：7.40(1H,t,J=7.6Hz),7.35(1H,d,J=7.6Hz),7.12(1H,s),7.02-7.06(2H,m),6.64(2H,s),6.46(1H,dd,J=8.4Hz,2.4Hz),6.42(1H,d,J=2.4Hz),5.05(2H,s),4.74(1H,t,J=8.8Hz),4.26(1H,dd,J=9.2Hz,6.0Hz),4.07(2H,t,J=5.2Hz),3.74-3.82(1H,m),2.72(1H,dd,J=16.8Hz,5.6Hz),2.53(1H,dd,J=16.8Hz,9.2Hz),2.09-2.16(2H,m),1.93-2.00(8H,m),1.56(6H,d,J=13.2Hz)。
embodiment 10:2-(6-((4'-((4-methylsulfonyl) piperazine-1-yl)-2', 6'-dimethyl diphenyl-3-yl) methoxyl group)-2,3-dihydrobenzo furan mutter-3-yl) acetic acid synthetic
With 2-(6-((4'-hydroxyl-2'; 6'-dimethyl diphenyl-3-yl) methoxyl group)-2; 3-Dihydrobenzofuranes-3-yl) methyl acetate and 1-methylsulfonyl piperazine be raw material; wherein step 1 is reacted with reference to step 1 in embodiment 8, step 2 with reference to step 6 in embodiment 8 react, step 3 prepares title compound with reference to the method for the step 8 in embodiment 8.MS m/z[ESI] +:551.0[M+1]。
embodiment 11:(S)-2-(6-((2', 6'-dimethyl-4'-(2-(1,1-dioxo-isothiazolidine-2-yl) oxyethyl group) biphenyl-3-yl) methoxy base)-2,3-Dihydrobenzofuranes-3-yl) acetic acid synthetic
Step 1:(S)-2-(6-((4'-(t-butyldimethylsilyloxy base)-2', 6'-dimethyl diphenyl-3-yl) methoxyl group)-2,3-Dihydrobenzofuranes-3-yl) methyl acetate synthetic
Under ice-water bath is cooling, to (4 '-(t-butyldimethylsilyloxy base)-2', 6'-dimethyl diphenyl-3-yl) methyl alcohol (2.0g, 5.8mmol), (S)-6-hydroxyl-2,3-Dihydrobenzofuranes-3-methyl acetate (1.5g, 7.2mmol) and triphenylphosphine (2.4g, in tetrahydrofuran solution 9.0mmol), (150mL) drips diisopropyl azodiformate (1.8g, 9.0mmol).After dropwising, reaction solution is slowly raised to room temperature and stirs and spend the night.Reaction solution residue after concentrated obtains (S)-2-(6-((4'-(t-butyldimethylsilyloxy base)-2' by silica gel column chromatography separating purification, 6'-dimethyl diphenyl-3-yl) methoxyl group)-2,3-Dihydrobenzofuranes-3-yl) methyl acetate (2.3g, yield 75.5%). 1H NMR(400MHz，CDCl 3-d 3)：7.42(1H,t,J=7.6Hz),7.37(1H,d,J=7.6Hz),7.18(1H,s),7.09(1H,d,J=7.2Hz),7.03(1H,d,J=8.0Hz),6.59(2H,s),6.47-6.51(2H,m),5.06(2H,s),4.76(1H,t,J=9.2Hz),4.26(1H,dd,J=9.2Hz,6.0Hz),3.77-3.85(1H,m),3.72(3H,s),2.75(1H,dd,J=16.8Hz,5.6Hz),2.56(1H,dd,J=16.8Hz,9.6Hz),1.96(6H,s),1.02(9H,s),0.24(6H,s)。
Step 2:(S)-2-(6-((4'-hydroxyl-2', 6'-dimethyl diphenyl-3-yl) methoxyl group)-2,3-Dihydrobenzofuranes-3-yl) methyl acetate synthetic
Under ice-water bath is cooling, to (S)-2-(6-((4'-(t-butyldimethylsilyloxy base)-2', 6'-dimethyl diphenyl-3-yl) methoxyl group)-2,3-Dihydrobenzofuranes-3-yl) methyl acetate (1.1g, in tetrahydrofuran solution 2.1mmol), (50mL) adds tetrabutyl ammonium fluoride (1.3g, 5.0mmol).After adding, reaction solution is slowly raised to room temperature and stirs and spend the night.Add 50mL saturated aqueous ammonium chloride termination reaction, mixture is extracted with ethyl acetate (50mL × 3), merge organic phase and use anhydrous sodium sulfate drying, concentrated (S)-2-(6-((4'-hydroxyl-2' that obtains, 6'-dimethyl diphenyl-3-yl) methoxyl group)-2,3-Dihydrobenzofuranes-3-yl) methyl acetate (0.82g, yield 95.0%). 1H NMR(400MHz，CDCl 3-d 3)：7.44(1H,t,J=7.6Hz),7.39(1H,d,J=7.6Hz),7.17(1H,s),7.07(1H,d,J=7.2Hz),7.03(1H,d,J=8.0Hz),6.73(2H,s),6.49(1H,dd,J=8.0Hz,2.4Hz),6.47(1H,s),5.05(2H,s),4.75(1H,t,J=9.2Hz),4.26(1H,dd,J=9.2Hz,6.0Hz),3.77-3.84(1H,m),3.72(3H,s),2.75(1H,dd,J=16.4Hz,4.2Hz),2.55(1H,dd,J=16.4Hz,9.2Hz),2.01(6H,s)。
Step 3:(S)-2-(6-((4'-(cyano group methoxyl group)-2', 6'-dimethyl diphenyl-3-yl) methoxyl group)-2,3-Dihydrobenzofuranes-3-yl) methyl acetate synthetic
Salt of wormwood (2.0g, 14.5mmol) add (S)-2-(6-((4'-hydroxyl-2', 6'-dimethyl diphenyl-3-yl) methoxyl group)-2,3-Dihydrobenzofuranes-3-yl) methyl acetate (3.0g, 7.2mmol) and in the acetonitrile of bromoacetonitrile (1.8g, 15.0mmol) (100mL) solution.By this mixture stirred overnight at room temperature, filter, residue after filtrate is concentrated obtains (S)-2-(6-((4'-(cyano group methoxyl group)-2' through silica gel column chromatography separating purification, 6'-dimethyl diphenyl-3-yl) methoxyl group)-2,3-Dihydrobenzofuranes-3-yl) methyl acetate (2.4g, yield 72.5%).MS m/z[ESI] +:458.0[M+1]。
Step 4:(S)-2-(6-((4'-(2-amino ethoxy)-2', 6'-dimethyl diphenyl-3-yl) methoxyl group)-2,3-Dihydrobenzofuranes-3-yl) methyl acetate synthetic
(S)-2-(6-((4'-(cyano group methoxyl group)-2', 6'-dimethyl diphenyl-3-yl) methoxyl group)-2,3-Dihydrobenzofuranes-3-yl) methyl acetate (2.2g, 4.8mmol), the mixture of Raney's nickel (5.0g) and methyl alcohol (100mL) (1 normal atmosphere) stirred overnight at room temperature under hydrogen atmosphere.Reaction solution passes through diatomite filtration, after filtrate is concentrated, obtain (S)-2-(6-((4'-(2-amino ethoxy)-2', 6'-dimethyl diphenyl-3-yl) methoxyl group)-2,3-Dihydrobenzofuranes-3-yl) methyl acetate (2.2g, yield 100.0%).MSm/z[ESI] +:462.0[M+1]。
Step 5:(S)-2-(6-((4'-(2-(3-chloropropyl sulfuryl amino) oxyethyl group)-2'; 6'-dimethyl diphenyl-3-yl) methoxyl group)-2,3-Dihydrobenzofuranes-3-yl) methyl acetate synthetic
To (S)-2-(6-((4'-(2-amino ethoxy)-2', 6'-dimethyl diphenyl-3-yl) methoxyl group)-2,3-Dihydrobenzofuranes-3-yl) methyl acetate (0.66g, in dichloromethane solution 1.4mmol), (50mL) adds the chloro-1-sulfonyl propyl of 3-chlorine (0.38g successively, 2.1mmol) and triethylamine (0.29g, 2.9mmol).By this reaction mixture stirred overnight at room temperature.Reaction is poured into water (50mL), with dichloromethane extraction (100mL × 2), organic phase anhydrous sodium sulfate drying, concentrated, residue obtains (S)-2-(6-((4'-(2-(3-chloropropyl sulfonamido) oxyethyl group)-2' through silicagel column column chromatographic isolation and purification, 6'-dimethyl diphenyl-3-yl) methoxyl group)-2,3-Dihydrobenzofuranes-3-yl) methyl acetate (0.73g, yield 85.0%). 1H NMR(400MHz，CDCl 3-d 3)：7.42(1H,t,J=7.2Hz),7.38(1H,d,J=7.6Hz),7.16(1H,s),7.07(1H,d,J=7.2Hz),7.02(1H,d,J=7.6Hz),6.45(2H,s),6.45-6.50(2H,m),5.06(2H,s),4.75(2H,t,J=8.8Hz),4.25(1H,dd,J=9.2Hz,6.0Hz),3.77-3.84(1H,m),3.72(3H,s),3.69(2H,t,J=6.0Hz),3.56(2H,q,J=4.2Hz),3.28(2H,t,J=7.6Hz),2.74(2H,dd,J=16.4Hz,5.6Hz),2.55(1H,dd,J=16.4Hz,9.2Hz),2.29-2.36(2H,m),1.99(6H,s)。
Step 6:(S)-2-(6-((4'-(2-(1,1-dioxo-isothiazolidine-2-yl) oxyethyl group)-2', 6'-dimethyl diphenyl-3-yl) methoxyl group)-2,3-Dihydrobenzofuranes-3-yl) methyl acetate synthetic
To (S)-2-(6-((4'-(2-(3-chloropropyl sulfuryl amino) oxyethyl group)-2'; 6'-dimethyl diphenyl-3-yl) methoxyl group)-2; 3-Dihydrobenzofuranes-3-yl) methyl acetate (60.0mg; N 0.1mmol); in dinethylformamide solution, (10mL) adds salt of wormwood (28.0mg, 0.2mmol).80 DEG C of stirrings of this reaction mixture are spent the night.Reaction is poured into water (50mL), be extracted with ethyl acetate (100mL × 2), organic phase anhydrous sodium sulfate drying, concentrated, residue obtains (S)-2-(6-((4'-(2-(1 through purification by silica gel column chromatography, 1-dioxo-isothiazolidine-2-yl) oxyethyl group)-2', 6'-dimethyl diphenyl-3-yl) methoxyl group)-2,3-Dihydrobenzofuranes-3-yl) methyl acetate (50.0mg, yield 88.8%).MS m/z[ESI] +:566.0[M+1]。
Step 7:(S)-2-(6-((4'-(2-(1,1-dioxo-isothiazolidine-2-yl) oxyethyl group)-2', 6'-dimethyl diphenyl-3-yl) methoxyl group)-2,3-Dihydrobenzofuranes-3-yl) acetic acid synthetic
To (S)-2-(6-((4'-(2-(1,1-dioxo-isothiazolidine-2-yl) oxyethyl group)-2', 6'-dimethyl diphenyl-3-yl) methoxyl group)-2,3-Dihydrobenzofuranes-3-yl) methyl acetate (50.0mg, 0.09mmol) in the solution of the mixed solvent of methyl alcohol (10mL) and tetrahydrofuran (THF) (20mL), drip 2M aqueous sodium hydroxide solution (1mL), dropwise rear mixture stirred overnight at room temperature.By reaction mixture dilute with water, with 10% aqueous citric acid solution acidifying, and be extracted with ethyl acetate (50mL × 3).Organic phase is with concentrated after anhydrous sodium sulfate drying, residue obtains (S)-2-(6-((4'-(2-(1 by silica gel column chromatography separating purification, 1-dioxo-isothiazolidine-2-yl) oxyethyl group)-2', 6'-dimethyl diphenyl-3-yl) methoxyl group)-2,3-Dihydrobenzofuranes-3-yl) acetic acid (36.7mg, yield 75.2%). 1H NMR(400MHz，CDCl 3-d 3)：7.38-7.42(2H,m),7.16(1H,s),7.05-7.15(2H,m),6.65(2H,s),6.39-6.55(2H,m),5.06(2H,s),4.76(1H,t,J=7.6Hz),4.24-4.39(1H,m),4.13-4.19(2H,m),3.74-3.89(1H,m),3.38-3.58(4H,m),3.07-3.23(2H,m),2.73-2.83(1H,m),2.53-2.64(1H,m),2.28-2.37(2H,m),1.99(6H,s)。
embodiment 12:2-(6-((2', 6'-dimethyl-4'-(3-(methylsulfonyl) propoxy-) biphenyl-3-yl) ethynyl)-2,3-Dihydrobenzofuranes-3- base) acetic acid synthetic
Trimethyl silicon based ethynyl-2 of step 1:6-, 3-Dihydrobenzofuranes-3-methyl acetate synthetic
Under nitrogen is fully replaced, to 6-trifluoro-methanesulfonyl oxy-2,3-Dihydrobenzofuranes-3-methyl acetate (1.0g, 2.9mmol), trimethyl silicane ethyl-acetylene (0.43g, 4.4mmol), tetra-triphenylphosphine palladium (0.16g, 0.15mmol), in the mixture of cuprous iodide (0.03g, 0.15mmol) and triethylamine (0.59g, 5.8mmol), add N, dinethylformamide (50mL), reacts mixture 5 hours at 70 DEG C.After reaction mixture cool to room temperature, filter, filtrate is under reduced pressure concentrated.Residue is poured into water (100mL), is extracted with ethyl acetate.By organic phase anhydrous sodium sulfate drying, natural filtration, and under reduced pressure concentrated.The residue obtaining silica gel chromatography column purification, obtains trimethyl silicon based ethynyl-2 of 6-, 3-Dihydrobenzofuranes-3-methyl acetate (0.55g, yield 65.3%). 1H NMR(400MHz，CDCl 3-d 3)：7.06(1H,d,J=7.6Hz),6.98(1H,dd,J=7.6Hz,1.2Hz),6.86(1H,s),4.74(1H,t,J=9.2Hz),4.24(1H,dd,J=9.6Hz,6.4Hz),3.81-3.89(1H,m),3.71(3H,s),2.75(1H,dd,J=16.8Hz,5.6Hz),2.56(1H,dd,J=16.8Hz,9.6Hz),0.23(9H,s)。
Step 2:6-ethynyl-2,3-Dihydrobenzofuranes-3-methyl acetate synthetic
To trimethyl silicon based ethynyl-2 of 6-, in methyl alcohol (100mL) solution of 3-Dihydrobenzofuranes-3-methyl acetate (0.5g, 1.7mmol), add salt of wormwood (0.47g, 3.4mmol), by mixture room temperature reaction 2 hours.Filter, by under reduced pressure concentrated 6-ethynyl-2 that obtain of filtrate, synthetic (0.33g, the yield 89.0%) of 3-Dihydrobenzofuranes-3-methyl acetate. 1H NMR(400MHz，CDCl 3-d 3)：7.09(1H,d,J=7.6Hz),7.02(1H,dd,J=7.6Hz,1.2Hz),6.90(1H,s),4.76(1H,t,J=9.6Hz),4.26(1H,dd,J=9.2Hz,6.4Hz),3.83-3.90(1H,m),3.72(3H,s),2.77(1H,dd,J=16.8Hz,5.6Hz),2.58(1H,dd,J=16.8Hz,9.6Hz)。
Step 3:2-is bromo-1,3-dimethyl-5-(3-(methyl sulphonyl) propoxy-) benzene synthetic
At 0 DEG C, to 3-first mercaprol (57.14g, 0.54mol) and triethylamine (81.6g, in dichloromethane solution 0.81mol) (250mL), drip trifluoromethanesulfchloride chloride (136.5g, 0.81mol), dropwise rear mixture stirred overnight at room temperature.By reaction mixture dilute with water, and with dichloromethane extraction (150mL × 3).Organic phase is with concentrated after anhydrous sodium sulfate drying, and residue obtains 1,1,1-trifluoromethanesulfonic acid-3-first sulfydryl propyl ester (126.0g, yield 98.0%) by silica gel column chromatography separating purification.
At 0 DEG C, to 1,1, in the methanol solution of 1-trifluoromethanesulfonic acid-3-first sulfydryl propyl ester (23.8g, 0.1mol) (250mL), drip potassium hydrogen persulfate (30g, the aqueous solution (500mL) 0.2mol), dropwises rear mixture stirred overnight at room temperature.After methyl alcohol is removed with Rotary Evaporators, residue is extracted with ethyl acetate (250mL × 3).Organic phase is with concentrated after anhydrous sodium sulfate drying, and residue is with obtaining 1,1,1-trifluoromethanesulfonic acid-3-methylsulfonyl propyl ester (26.5g, yield 98.1%) after petroleum ether.
3; 5-dimethyl-4-bromophenol (4.0g; 19.9mmol) He 1; 1; in DMF (150mL) solution of 1-trifluoromethanesulfonic acid-3-methylsulfonyl propyl ester (5.9g, 21.9mmol), add salt of wormwood (4.1g; 29.9mmol), mixture is reacted 1 hour at 100 DEG C.Reaction mixture is poured in frozen water, filters, and solid is washed with water, obtains 2-after dry bromo-1,3-dimethyl-5-(3-(methyl sulphonyl) propoxy-) benzene (6.0g, yield 94.0%). 1H NMR(400MHz，DMSO-d 6)：6.78(2H,s),4.02(2H,t,J=6.8Hz),3.23(2H,t,J=6.8Hz),2.99(3H,s),2.30(6H,s),2.03-2.16(2H,m)。
Step 4:2 ', 6 '-dimethyl-4 '-(3-(methyl sulphonyl) propoxy-)-biphenyl-3-phenol synthetic
2-bromo-1; 3-dimethyl-5-(3-(methyl sulphonyl) propoxy-) benzene (0.35g; 1.1mmol); 3-hydroxybenzene boric acid (0.18g; 1.3mmol), cesium carbonate (0.54g, 1.65mmol) and tetra-triphenylphosphine palladium (0.13g; 0.11mmol) be added to (150mL) in Isosorbide-5-Nitrae-dioxane.By this mixture reflux cool to room temperature after 8 hours.Reaction mixture passes through diatomite filtration; wash with ethyl ester ethyl ester; after concentrating filter liquor, residue obtains 2 ' by the separation and purification of column chromatography silicagel column; 6 '-dimethyl-4 '-(3-(methyl sulphonyl) propoxy-)-biphenyl-3-phenol (0.36g, yield 99.0%). 1H NMR(400MHz，CDCl 3-d 3)：7.27(1H,t,J=8.0Hz),6.80(1H,dd,J=8.0Hz,2.8Hz),6.68(1H,d,J=7.2Hz),6.63(2H,s),6.60(1H,t,J=1.2Hz),4.12(2H,t,J=5.6Hz),3.27(2H,t,J=8.0Hz),2.97(3H,s),2.32-2.38(2H,m),2.02(6H,s)。
Step 5:2 ', 6 '-dimethyl-4 '-(3-(methyl sulphonyl) propoxy-)-3-trifluoro-methanesulfonyl oxy-biphenyl synthetic
To 2 '; 6 '-dimethyl-4 '-(3-(methyl sulphonyl) propoxy-)-biphenyl-3-phenol (0.36g; 1.1mmol) and triethylamine (0.22g; in mixture 2.2mmol), add methylene dichloride (50mL); mixture is cooled to zero degree; in mixture, slowly drip trifluoromethanesulfanhydride anhydride (0.46g, 1.6mmol).Mixture was raised to room temperature, stirring at room temperature 2 hours.By lower reaction mixture decompression concentrated; the residue obtaining obtains 2 ' by silica gel column chromatography separating purification; 6 '-dimethyl-4 '-(3-(methyl sulphonyl) propoxy-)-3-trifluoro-methanesulfonyl oxy-biphenyl (0.43g, yield 85.0%). 1H NMR(400MHz，CDCl 3-d 3)：7.50(1H,t,J=8.0Hz),7.26(1H,dd,J=8.0Hz,2.4Hz),7.17(1H,d,J=7.6Hz),7.07(1H,s),6.66(2H,s),4.13(2H,t,J=6.0Hz),3.27(2H,t,J=8.0Hz),2.97(3H,s),2.33-2.39(2H,m),1.99(6H,s)。
Synthesizing of step 6:2-(6-((2', 6'-dimethyl-4'-(3-(methylsulfonyl) propoxy-) biphenyl-3-yl) ethynyl)-2,3-Dihydrobenzofuranes-3-yl) methyl acetate
Under nitrogen is fully replaced, to 2 ', 6 '-dimethyl-4 '-(3-(methyl sulphonyl) propoxy-)-3-trifluoro-methanesulfonyl oxy--biphenyl (50mg, 0.1mmol), 6-ethynyl-2, 3-Dihydrobenzofuranes-3-methyl acetate (30mg, 0.12mmol), three (dibenzalacetone) two palladium (10mg, 0.01mmol), 2-dicyclohexyl phosphine-2', 4', 6'-tri isopropyl biphenyl (10mg, 0.2mmol), cuprous iodide (2.0mg, 0.01mmol) and cesium carbonate (52mg, in mixture 0.15mmol), add N, dinethylformamide (50mL), mixture is reacted 5 hours at 130 DEG C.After reaction mixture cool to room temperature, filter, filtrate is under reduced pressure concentrated.Residue is poured into water (100mL), is extracted with ethyl acetate.By organic phase anhydrous sodium sulfate drying, natural filtration, and under reduced pressure concentrated.The residue obtaining silica gel chromatography column purification; obtain 2-(6-((2'; 6'-dimethyl-4'-(3-(methylsulfonyl) propoxy-) biphenyl-3-yl) ethynyl)-2; 3-Dihydrobenzofuranes-3-yl) methyl acetate (30.0mg, yield 53.0%). 1H NMR(400MHz，CDCl 3-d 3)：7.49(1H,d,J=7.6Hz),7.39(1H,t,J=7.6Hz),7.30(1H,s),7.04-7.13(3H,m),6.94(1H,s),6.65(2H,s),4.78(1H,t,J=9.6Hz),4.28(1H,t,J=8.0Hz),4.13(2H,t,J=5.6Hz),3.85-3.92(1H,m),3.73(3H,s),3.28(2H,t,J=8.0Hz),2.97(3H,s),2.80(1H,dd,J=16.4Hz,5.2Hz),2.60(1H,dd,J=16.4Hz,9.2Hz),2.32-2.40(2H,m),2.02(6H,s)。
Synthesizing of step 7:2-(6-((2', 6'-dimethyl-4'-(3-(methylsulfonyl) propoxy-) biphenyl-3-yl) ethynyl)-2,3-Dihydrobenzofuranes-3-yl) acetic acid
To 2-(6-((2'; 6'-dimethyl-4'-(3-(methylsulfonyl) propoxy-) biphenyl-3-yl) ethynyl)-2; 3-Dihydrobenzofuranes-3-yl) methyl acetate (30.0mg; 0.056mmol) in the solution of the mixed solvent of methyl alcohol (10mL) and tetrahydrofuran (THF) (20mL); drip 2M aqueous sodium hydroxide solution (1mL), dropwise rear mixture stirred overnight at room temperature.By reaction mixture dilute with water, with 10% aqueous citric acid solution acidifying, and be extracted with ethyl acetate (50mL × 3).Organic phase is with concentrated after anhydrous sodium sulfate drying; residue obtains 2-(6-((2' by silica gel column chromatography separating purification; 6'-dimethyl-4'-(3-(methylsulfonyl) propoxy-) biphenyl-3-yl) ethynyl)-2; 3-Dihydrobenzofuranes-3-yl) acetic acid (21.7mg, yield 74.2%). 1H NMR(400MHz，CDCl 3-d 3)：7.49(1H,d,J=8.0Hz),7.39(1H,t,J=8.0Hz),7.30(1H,s),7.15(1H,d,J=7.2Hz),7.05-7.10(2H,m),6.95(1H,s),6.65(2H,s),4.79(1H,t,J=9.6Hz),4.31(1H,t,J=8.4Hz),4.13(2H,t,J=5.2Hz),3.83-3.94(1H,m),3.28(2H,t,J=7.6Hz),2.97(3H,s),2.85(1H,dd,J=16.8Hz,4.0Hz),2.66(1H,dd,J=16.8Hz,9.6Hz),2.30-2.39(2H,m),2.02(6H,s)。
embodiment 13:2-(6-((2', 6'-dimethyl-4'-(dimethyl phosphine acyl group) biphenyl-3-yl) methoxyl group)-2,3-Dihydrobenzofuranes-3-yl) synthesizing of acetic acid
Synthesizing of step 1:2-(6-((4'-trifluoro-methanesulfonyl oxy-2', 6'-dimethyl diphenyl-3-yl) methoxyl group)-2,3-Dihydrobenzofuranes-3-yl) methyl acetate
To 2-(6-((4'-hydroxyl-2', 6'-dimethyl diphenyl-3-yl) methoxyl group)-2,3-Dihydrobenzofuranes-3-yl) methyl acetate (0.46g, 1.1mmol) and triethylamine (0.22g, in mixture 2.2mmol), add methylene dichloride (50mL), mixture is cooled to zero degree, in mixture, slowly drips trifluoromethanesulfanhydride anhydride (0.46g, 1.6mmol).Mixture was raised to room temperature, stirring at room temperature 2 hours.By lower reaction mixture decompression concentrated, the residue obtaining obtains 2-(6-((4'-trifluoro-methanesulfonyl oxy-2' by silica gel column chromatography separating purification, 6'-dimethyl diphenyl-3-yl) methoxyl group)-2,3-Dihydrobenzofuranes-3-yl) methyl acetate (0.51g, yield 85.0%). 1HNMR(400MHz，CDCl 3-d 3)：7.46(1H,t,J=7.6Hz),7.42(1H,d,J=8.0Hz),7.16(1H,s),7.06(1H,d,J=7.2Hz),7.02(1H,d,J=8.0Hz),7.00(2H,s),6.48(1H,dd,J=8.0Hz,2.0Hz),5.07(2H,s),4.75(1H,t,J=8.8Hz),4.26(1H,dd,J=9.2Hz,6.0Hz),3.76-3.84(1H,m),3.72(3H,s),2.74(1H,dd,J=16.4Hz,5.6Hz),2.55(1H,dd,J=16.4Hz,9.2Hz),2.03(6H,s)。
Synthesizing of step 2:2-(6-((2', 6'-dimethyl-4'-(dimethyl phosphine acyl group) biphenyl-3-yl) methoxyl group)-2,3-Dihydrobenzofuranes-3-yl) methyl acetate
Under nitrogen is fully replaced, to 2-(6-((4'-trifluoro-methanesulfonyl oxy-2', 6'-dimethyl diphenyl-3-yl) methoxyl group)-2,3-Dihydrobenzofuranes-3-yl) methyl acetate (500mg, 0.9mmol), dimethyl oxidation phosphorus ( 142mg, 1.8mmol), palladium (20mg, 0.09mmol), 9,9-dimethyl-4, in the mixture of two (di-t-butyl phosphine) dibenzo-γ-pyrans (100mg, 0.18mmol) of 5-and potassiumphosphate (220mg, 0.99mmol), add N, dinethylformamide (50mL), reacts mixture 5 hours at 130 DEG C.After reaction mixture cool to room temperature, filter, filtrate is under reduced pressure concentrated.Residue is poured into water (100mL), is extracted with ethyl acetate.By organic phase anhydrous sodium sulfate drying, natural filtration, and under reduced pressure concentrated.The residue obtaining silica gel chromatography column purification; obtain 2-(6-((2'; 6'-dimethyl-4'-(dimethyl phosphine acyl group) biphenyl-3-yl) methoxyl group)-2; 3-Dihydrobenzofuranes-3-yl) methyl acetate (331mg, yield 76.1%). 1H NMR(400MHz，CDCl 3-d 3)：7.40-7.48(4H,m),7.16(1H,s),7.07(1H,d,J=7.6Hz),7.02(1H,d,J=8.0Hz),6.47(1H,dd,J=8.0Hz,1.6Hz),6.45(1H,d,J=1.6Hz),5.07(2H,s),4.75(1H,t,J=9.2Hz),4.26(1H,dd,J=9.2Hz,1.6Hz),3.77-3.84(1H,m),3.71(3H,s),2.74(1H,dd,J=16.4Hz,5.2Hz),2.55(1H,dd,J=16.4Hz,9.2Hz),2.05(6H,s),1.75(6H,d,J=13.2Hz)。
Synthesizing of step 3:2-(6-((2', 6'-dimethyl-4'-(dimethyl phosphine acyl group) biphenyl-3-yl) methoxyl group)-2,3-Dihydrobenzofuranes-3-yl) acetic acid
To 2-(6-((2'; 6'-dimethyl-4'-(dimethyl phosphine acyl group) biphenyl-3-yl) methoxyl group)-2; 3-Dihydrobenzofuranes-3-yl) in the solution of mixed solvent of methyl acetate (0.056mmol) methyl alcohol (10mL) and tetrahydrofuran (THF) (20mL); drip 2M aqueous sodium hydroxide solution (1mL), dropwise rear mixture stirred overnight at room temperature.By reaction mixture dilute with water, with 10% aqueous citric acid solution acidifying, and be extracted with ethyl acetate (50mL × 3).Organic phase is with concentrated after anhydrous sodium sulfate drying; residue obtains 2-(6-((2' by silica gel column chromatography separating purification; 6'-dimethyl-4'-(dimethyl phosphine acyl group) biphenyl-3-yl) methoxyl group)-2,3-Dihydrobenzofuranes-3-yl) acetic acid (yield 49.0%). 1H NMR(400MHz，CDCl 3-d 3)：7.38-7.49(4H,m),7.14(1H,s),7.03-7.07(2H,m),6.43-6.46(2H,m),5.08(2H,s),4.74(1H,t,J=8.8Hz),4.27(1H,dd,J=9.2Hz,6.4Hz),3.73-3.86(1H,m),2.75(1H,dd,J=16.4Hz,5.2Hz),2.55(1H,dd,J=16.4Hz,9.2Hz),2.04(3H,s),1.79(6H,d,J=12.8Hz)。
embodiment 14:N-methylsulfonyl-2-(6-((2', 6'-dimethyl-4'-(3-(methyl sulphonyl) propoxy-) biphenyl-3-yl) methoxyl group)-2,3- dihydrobenzofuranes-3-yl) ethanamide synthetic
Step 1:2 ', 6 '-dimethyl-4 '-(3-(methyl sulphonyl) propoxy-)-biphenyl-3-formaldehyde synthetic
2-bromo-1; 3-dimethyl-5-(3-(methyl sulphonyl) propoxy-) benzene (0.35g; 1.1mmol); 3-formylphenylboronic acid (0.19g; 1.3mmol), cesium carbonate (0.54g, 1.65mmol) and tetra-triphenylphosphine palladium (0.13g; 0.11mmol) be added to (150mmol) in Isosorbide-5-Nitrae-dioxane.By this mixture reflux cool to room temperature after 8 hours.Reaction mixture passes through diatomite filtration; wash with ethyl ester ethyl ester; after concentrating filter liquor, residue obtains 2 ' by the separation and purification of column chromatography silicagel column; 6 '-dimethyl-4 '-(3-(methyl sulphonyl) propoxy-)-biphenyl-3-formaldehyde (0.32g, yield 85.0%). 1H NMR(400MHz，CDCl 3-d 3)：10.03(1H,s),7.84(1H,d,J=7.6Hz),7.64(1H,s),7.58(1H,t,J=7.6Hz),7.39(1H,d,J=7.6Hz),6.65(2H,s),4.12(2H,t,J=6.0Hz),3.26(2H,t,J=7.6Hz),2.96(3H,s),2.31-2.38(2H,m),1.97(6H,s)。
Step 2:2 ', 6 '-dimethyl-4 '-(3-(methyl sulphonyl) propoxy-)-biphenyl-3-methyl alcohol synthetic
Under ice-water bath is cooling; to 2 '; 6 '-dimethyl-4 '-(3-(methyl sulphonyl) propoxy-)-biphenyl-3-formaldehyde (3.0g; 8.8mmol) in the solution of tetrahydrofuran (THF) (40mL) and methyl alcohol (20mL); add in multiple times on a small quantity sodium borohydride (0.67g, 17.6mmol).After adding, reaction solution is slowly raised to room temperature and stirs and spend the night.After reaction solution is concentrated, add wherein water (200mL); mixture is extracted with ethyl acetate (250mL × 3); merge organic phase and use anhydrous sodium sulfate drying; concentrate and obtain 2 '; 6 '-dimethyl-4 '-(3-(methyl sulphonyl) propoxy-)-biphenyl-3-methyl alcohol (3.0g, yield 100%). 1H NMR(400MHz，CDCl 3-d 3)：7.43(1H,t,J=7.6Hz),7.36(1H,d,J=7.6Hz),7.14(1H,s),7.08(1H,d,J=7.2Hz),6.67(2H,s),4.75(2H,d,J=6.0Hz),4.15(2H,t,J=6.0Hz),3.30(2H,t,J=7.6Hz),2.99(3H,s),2.35-2.39(2H,m),2.03(6H,s),1.73(1H,t,J=6.0Hz)。
Synthesizing of step 3:2-(6-((2', 6'-dimethyl-4'-(3-(methyl sulphonyl) propoxy-) biphenyl-3-yl) methoxyl group)-2,3-Dihydrobenzofuranes-3-yl) methyl acetate
Under ice-water bath is cooling; to 2 '; 6 '-dimethyl-4 '-(3-(methyl sulphonyl) propoxy-)-biphenyl-3-methyl alcohol (2.0g; 5.8mmol); 6-hydroxyl-2,3-Dihydrobenzofuranes-3-methyl acetate (1.5g, 7.2mmol) and triphenylphosphine (2.4g; in tetrahydrofuran solution 9.0mmol), (150mL) drips diisopropyl azodiformate (1.8g, 9.0mmol).After dropwising, reaction solution is slowly raised to room temperature and stirs and spend the night.Reaction solution residue after concentrated obtains 2-(6-((2' by silica gel column chromatography separating purification; 6'-dimethyl-4'-(3-(methyl sulphonyl) propoxy-) biphenyl-3-yl) methoxyl group)-2; 3-Dihydrobenzofuranes-3-yl) methyl acetate (2.33g, yield 75.5%).MS m/z[ESI] +:539.0[M+1]。
Synthesizing of step 4:2-(6-((2', 6'-dimethyl-4'-(3-(methyl sulphonyl) propoxy-) biphenyl-3-yl) methoxyl group)-2,3-Dihydrobenzofuranes-3-yl) acetic acid
To 2-(6-((2'; 6'-dimethyl-4'-(3-(methyl sulphonyl) propoxy-) biphenyl-3-yl) methoxyl group)-2; 3-Dihydrobenzofuranes-3-yl) methyl acetate (30.2mg; 0.056mmol) in the solution of the mixed solvent of methyl alcohol (10mL) and tetrahydrofuran (THF) (20mL); drip 2M aqueous sodium hydroxide solution (1mL), dropwise rear mixture stirred overnight at room temperature.By reaction mixture dilute with water, with 10% aqueous citric acid solution acidifying, and be extracted with ethyl acetate (50mL × 3).Organic phase is with concentrated after anhydrous sodium sulfate drying; residue obtains 2-(6-((2' by silica gel column chromatography separating purification; 6'-dimethyl-4'-(3-(methyl sulphonyl) propoxy-) biphenyl-3-yl) methoxyl group)-2; 3-Dihydrobenzofuranes-3-yl) acetic acid (47.7mg, yield 85.0%). 1H NMR(400MHz，CDCl 3-d 3)：7.42(1H,t,J=7.6Hz),7.38(1H,d,J=7.6Hz),7.16(1H,s),7.04-7.08(2H,m),6.65(2H,s),6.49(1H,dd,J=7.6Hz,2.4Hz),6.46(1H,d,J=2.0Hz),5.06(2H,s),4.76(1H,t,J=8.8Hz),4.28(1H,dd,J=9.2Hz,6.0Hz),4.13(2H,t,J=5.6Hz),3.78-3.83(1H,m),3.28(2H,t,J=8.0Hz),2.98(3H,s),2.81(1H,dd,J=16.8Hz,5.2Hz),2.61(1H,dd,J=16.8Hz,9.2Hz),2.32-2.39(2H,m),1.99(6H,s)。
Step 5:N-methylsulfonyl-2-(6-((2'; 6'-dimethyl-4'-(3-(methyl sulphonyl) propoxy-) biphenyl-3-yl) methoxyl group)-2,3-Dihydrobenzofuranes-3-yl) ethanamide synthetic
To 2-(6-((2'; 6'-dimethyl-4'-(3-(methyl sulphonyl) propoxy-) biphenyl-3-yl) methoxyl group)-2; 3-Dihydrobenzofuranes-3-yl) acetic acid (0.2mmol); methylsulfonamides (28.5mg; 0.3mmol); 2-(7-azo benzotriazole)-N; N; N'; in DMF (50mL) solution of N'-tetramethyl-urea phosphofluoric acid ester (114mg, 0.3mmol), drip diisopropyl ethyl amine (51.6mg; 0.4mmol), by mixture room temperature reaction 5 hours.Reaction mixture is poured into water (100mL), is extracted with ethyl acetate.By organic phase anhydrous sodium sulfate drying, natural filtration, and under reduced pressure concentrated.The residue obtaining silica gel chromatography column purification; obtain N-methylsulfonyl-2-(6-((2'; 6'-dimethyl-4'-(3-(methyl sulphonyl) propoxy-) biphenyl-3-yl) methoxyl group)-2; 3-Dihydrobenzofuranes-3-yl) ethanamide (61.2mg, yield 52.0%). 1H NMR(400MHz，CDCl 3-d 3)：7.44(1H,t,J=7.6Hz),7.38(1H,d,J=7.6Hz),7.16(1H,s),7.09(1H,d,J=7.6Hz),7.06(1H,d,J=8.0Hz),6.66(2H,s),6.50(1H,dd,J=8.0Hz,2.0Hz),6.47(1H,d,J=2.0Hz),5.07(2H,s),4.75(1H,t,J=9.2Hz),4.29(1H,dd,J=9.2Hz,5.2Hz),4.14(2H,t,J=6.0Hz),3.83-3.90(1H,m),3.29(2H,t,J=6.0Hz),2.98(3H,s),2.90(3H,s),2.74(1H,dd,J=16.4Hz,5.6Hz),2.61(1H,dd,J=16.4Hz,8.4Hz),2.32-2.39(2H,m),2.00(6H,s)。
Biological activity determination
the foundation of GPR40 stable expression cell line
1. gene clone: GPR40 full-length gene derives from Non-small cell lung carcinoma cell line A549 (sequence: NCBI ReferenceSequence:NT_077812.2).Extract A549 cell total rna, by reverse transcription-polymerase chain reaction (RT-PCR) method, the full-length gene of GPR40 is cloned out, and add BamHI and these two DNA restriction restriction enzyme sites of EcoRV at 5 '-end and 3 '-end respectively in the time of design primer.
2. the structure of expression plasmid: vector plasmid pcDNA3.1 purchased from company.Utilize these two DNA restriction restriction enzyme sites of BamHI and EcoRV, the GPR40 full-length gene of having cloned is linked to enzyme by T4DNA to be connected on pCDNA3.1 carrier, then be transfected in DH5 α competent cell, and be added with microbiotic Ampilline(1 μ g/mL) LB nutrient agar on the mono-clonal of transfection chosen successfully, extract plasmid and also determine gene order by DNA sequencing method.
3. the foundation of stably express cell: extract highly purified pCDNA3.1-GPR40 plasmid, with FugeneHD reagent ratio with 2(μ g): 6(μ L) is mixed, be transfected in human embryonic kidney epithelial cells HEK293, in the DMEM nutrient solution that is supplemented with 10% foetal calf serum, be 400 μ g/mL by microbiotic G418(final concentration) filter out GPR40 express cell, in 96 porocyte culture plates, gradient dilution is with picking mono-clonal, determine the expression of GPR40 albumen by Western blot method, by the monoclonal cell amplification culture of stably express, set up GPR40 stable expression cell line.
The foundation of GPR40 stable expression cell line also can prepare with reference to the disclosed method of existing document, for example Koener B, Hermans E.Inducible expression of G protein-coupled receptors in transfected cells.Methods in Molecular Biology.2011 (746): 3-20 and Schucht R, Lydford S, Andzinski L, Zauers J, Cooper J, method in .Rapid Establishment of G-Protein-Coupled ReceptorExpressing Cell Lines by Site-Specific Integration.Journal of Biomolecular Screening.2011 (16): the 3230-331 such as Hauser H or CN102421739A specification sheets 24-25/106 test method(s) 1:GPR40 agonist activity mensuration obtains GPR40 stable expression cell line.
the mensuration of GPR40 agonist activity
The present invention adopts calcium current method, measures the castering action of compound to GPR40 stably express intracellular calcium concentration, thereby reflects the agonism to GPR40.This agonist activity adopts EC 50this index represents, corresponding compound concentration when the activity of GPR40 is excited to peaked 50%.
Materials and methods:
1, material:
1), saturating Tissue Culture Plate at the bottom of 96 hole black ( cat.No.3603)
2), transparent reaction plate at the bottom of 96 hole V ( cat.No.3897)
3), Fluo-4 calcium current test kit ( cat.No.F10471), comprise FLuo-4 calcium dyestuff, Probenecid and Fluo-4 calcium current reaction buffer.
4), poly-lysine
5), DMEM cell culture fluid ( cat.No.C11995500B)
6), foetal calf serum ( cat.No.SV30087)
7)、G418sulfate( Cat.No.345810)
8)、DMSO( Cat.No.A3672)
9), embodiment of the present invention compound
2, carry out the mensuration of compound agonist activity according to following working order:
1), be at the bottom of the coated 96 hole black of poly-lysine of 20 μ g/mL in saturating Tissue Culture Plate with final concentration, hatch two hours for 37 DEG C, remove liquid, air-dry, to strengthen the adherent property of cell.
2), GPR40 stably express cell is taped against at the bottom of the 96 hole black that have been coated with poly-lysine in saturating Tissue Culture Plate, density is 2 × 10 4cells/well, supplements and adds the G418sulfate of 10% foetal calf serum and 400 μ g/mL in DMEM nutrient solution, incubated overnight in 37 DEG C, 5% carbonic acid gas incubator.
3), remove cell culture fluid, change the DMEM nutrient solution of 50 μ L/ hole serum-frees and 50 μ L/ holes into and add the FLuo-4 calcium dyestuff of Probenecid, 37 DEG C of lucifuges are hatched 1 hour.
4), all compounds to be detected all dissolve with DMSO the storage liquid that is mixed with 10mM.In transparent reaction plate at the bottom of 96 hole V, carry out gradient dilution with DMSO, in the 8th hole, insert DMSO as blank.And then unified with 200 times of Fluo-4 calcium current reaction buffer dilutions, 5 times of reacting final concentration, stand-by.
5), under 37 DEG C of constant temperatures, with FlexStation3 (Molecular ) instrument, the testing compound of drawing 25 μ L/ holes from the good compound plate of gradient dilution joins in Tissue Culture Plate, makes that the final concentration of the contained compound of reaction solution in 8 holes is followed successively by 0,1nM, 3nM, 10nM, 30nM, 100nM, 300nM, 1000nM.From dosing, read fluorescent signal value (495nm excitation wavelength and 520nm emission wavelength) once every two seconds, continuous recording 150 seconds, obtains the fluorescent signal value of each time point.
6), by the each sample Kongzui high (Max) and minimum (Min) fluorescent signal value that read, calculate the Δ F/F value in this hole, (Max-Min)/Min value, passes through calcium ion concn change curve is drawn by 5 statistical softwares, calculates the EC of the compound of surveying 50value.
Table 1: the agonist activity of embodiment of the present invention compound to GPR40
Embodiment EC 50(nM) Embodiment EC 50(nM)
1 10.0 8 8.5
2 3.3 9 74.4
3 57.0 10 7.6
4 12.9 11 6.1
5 6.7 12 31.9
6 18.7 13 1235.0
7 4.3 14 1100.0
activity in vivo research
The present invention adopts the method for mouse oral glucose tolerance experiment (OGTT), measures the interior hypoglycemic effect of body of compound.
1, material: 7-8 week male C 57 BL/6 J mouse.
2, carry out the mensuration of mouse blood sugar concentration according to following working order:
1), mouse fasting is weighed after 16 hours and is measured fasting blood sugar (G 0), according to G 0carry out random packet, 5 mouse/groups.
2), administration by gavage takes the compound to be detected of different concns to mouse, the polyoxyethylene glycol stearate (HS-15) taking 25%, as solvent, takes 25% HS-15 to blank mouse.
3), administration is after 15 minutes, by 2.0g/kg body weight to the mouse stomach oral glucose aqueous solution.
4), by getting the method for tail vein, measure after mouse oral glucose the blood glucose value of 15 minutes, 30 minutes, 60 minutes, 120 minutes by blood glucose meter, be designated as respectively G 15, G 30, G 60and G 120.
5), draw mouse blood sugar change curve, and by formula AUC 0-120=7.5 (G 0+ 2G 15+ 3G 30+ 6G 60+ 4G 120) calculating mouse blood sugar AUC value.
Experimental result is shown in Fig. 1 and Fig. 2, shows that the compound of embodiments of the invention 11 has significant hypoglycemic activity in normal C57 Mice Body, and the compound of embodiments of the invention 11 hypoglycemic effect in the time of 30-50mg/kg has significant advantage.

Claims (18)

1. formula I compound or its salt:
Wherein,
R 1, R 2, R 3, R 4, R 5, R 6, R 7, R 8be selected from independently of one another hydrogen, halogen, cyano group, hydroxyl, nitro, amino, alkyl, alkoxyl group, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl ,-NHCO-alkyl ,-NHCO-cycloalkyl ,-SO 2-alkyl ,-SO 2-cycloalkyl ,-SO-alkyl ,-SO-cycloalkyl ,-N (alkyl)-SO 2-alkyl ,-N (alkyl)-SO 2-cycloalkyl ,-N (alkyl)-SO 2-aryl ,-N (alkyl)-SO 2-heteroaryl ,-NHSO 2-alkyl ,-NHSO 2-cycloalkyl ,-NHSO 2-aryl ,-NHSO 2-heteroaryl ,-SO 2-NH 2,-SO 2-NH-alkyl ,-SO 2n-(alkyl) 2,-CO-alkyl ,-COO-alkyl ,-CONH-alkyl ,-CON-(alkyl) 2,-CONH 2;
L 1for-CH 2o-,-CH 2nH-or
L 2for key, O or-NR 12-;
R 9, R 10be selected from independently of one another hydrogen, halogen, alkyl, hydroxyl, alkoxyl group, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl, cyano group;
N is 0,1,2,3,4 or 5;
L 3for key or-NR 13-;
R 12, R 13be selected from independently of one another hydrogen, alkyl, cycloalkyl, aryl, heteroaryl ,-SO 2-alkyl ,-SO 2-cycloalkyl ,-SO-alkyl ,-SO-cycloalkyl ,-CO-alkyl ,-CO-cycloalkyl ,-CO-aryl ,-CO-heteroaryl, or R 12with R 13and connected N atom forms the Heterocyclylalkyl that at least contains two N atoms together;
L 4for-P (O) (R 14)-or-SO 2-;
R 11for-NR 15r 16, halogen, hydroxyl, cyano group, nitro, alkyl, alkoxyl group, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl, or R 11with R 13connect at least Heterocyclylalkyl containing a nitrogen-atoms;
Z 1be selected from hydrogen, halogen, hydroxyl, cyano group, nitro, amino, alkyl, alkoxyl group, thiazolinyl, alkynyl;
Z 2be selected from-(CR 17r 18) mcOL 5r 19;
R 14, R 15, R 16, R 17, R 18be selected from independently of one another hydrogen, halogen, hydroxyl, alkyl, alkoxyl group, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl;
L 5for-NH-,-N (alkyl)-,-N (cycloalkyl)-or-O-;
M is 0,1,2,3,4 or 5;
R 19be selected from hydrogen, alkyl, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl, amino ,-SO 2-alkyl ,-SO 2-cycloalkyl ,-SO 2-aryl ,-SO 2-heteroaryl ,-SO-alkyl ,-SO-cycloalkyl ,-SO-aryl ,-SO-heteroaryl;
Condition is: work as L 1for-CH 2o-or-CH 2nH-, and L 2for O, R 9=R 10=hydrogen, n=2 or 3, L 3for key, L 4for-SO 2-and R 11for methyl or ethyl, Z 2for CH 2cOOR 19time, R 19be selected from cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl, amino ,-SO 2-alkyl ,-SO 2-cycloalkyl ,-SO 2-aryl ,-SO 2-heteroaryl ,-SO-alkyl ,-SO-cycloalkyl ,-SO-aryl ,-SO-heteroaryl.
2. the formula I compound or its salt of claim 1, wherein R 1, R 2, R 3, R 4, R 5, R 6, R 7, R 8be selected from independently of one another hydrogen, halogen, cyano group, hydroxyl, alkyl, alkoxyl group, amino; Preferably, R 1, R 4, R 5, R 6, R 7and R 8for hydrogen, R 2and R 3for methyl.
3. the formula I compound or its salt of claim 1 or 2, wherein R 9and R 10be selected from hydrogen.
4. the formula I compound or its salt described in arbitrary claim in claim 1-3, wherein L 2for O, n is 1,2,3 or 4, L 3for key, L 4for-SO 2-, R 11for-NR 15r 16, alkyl, alkoxyl group, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl; Preferably, L 2for O, n is 2 or 3, L 3for key, L 4for-SO 2-, R 11for-NR 15r 16, alkyl, cycloalkyl; More preferably, L 2for O, n is 3, L 3for key, L 4for-SO 2-, R 11for-NR 15r 16, alkyl; Preferred, L 2for O, n is 3, L 3for key, L 4for-SO 2-, R 11for-N (alkyl) 2,-NH (alkyl), alkyl; Most preferred, L 2for O, n is 3, L 3for key, L 4for-SO 2-, R 11for-N (CH 3) 2,-NHCH 3,-CH 3.
5. the formula I compound or its salt described in arbitrary claim in claim 1-4, wherein L 2for O, n is 1,2,3 or 4, L 3for-NR 13-, L 4for-SO 2-, R 11for-NR 15r 16, alkyl, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl, or R 11with R 13connect at least Heterocyclylalkyl containing a nitrogen-atoms; Preferably, L 2for O, n is 2 or 3, L 3for-NR 13-, L 4for-SO 2-, R 11for-NR 15r 16, alkyl, cycloalkyl, Heterocyclylalkyl, or R 11with R 13connect into the Heterocyclylalkyl that at least contains the 3-12 unit of a nitrogen-atoms; Preferred, L 2for O, n is 2 or 3, L 3for-NR 13-, L 4for-SO 2-, R 11with R 13connect at least 3,4,5 or 6 yuan of Heterocyclylalkyls containing a nitrogen-atoms, or R 11for alkyl, cycloalkyl, Heterocyclylalkyl; Most preferred, L 2for O, n is 2, L 3for-NR 13-, L 4for-SO 2-, R 11with R 13connect at least 5 or 6 Heterocyclylalkyls containing a nitrogen-atoms, or L 2for O, n is 2, L 3for-NH-, L 4for-SO 2-, R 11for alkyl, cycloalkyl.
6. the formula I compound or its salt described in arbitrary claim in claim 1-5, wherein L 2and L 3for key, n is 0, L 4for-P (O) (R 14)-, R 11for alkyl, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl; Preferably, L 2and L 3for key, n is 0, L 4for-P (O) (alkyl)-, R 11for alkyl, cycloalkyl, Heterocyclylalkyl; Preferred, L 2and L 3for key, n is 0, L 4for-P (O) (CH 3)-, R 11for methyl, ethyl, sec.-propyl ,-CH 2-cyclopropyl, cyclopropyl.
7. the formula I compound or its salt described in arbitrary claim in claim 1-6, wherein L 2for O, n is 1,2,3 or 4, L 3for key, L 4for-P (O) (R 14)-, R 11for alkyl, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl; Preferably, L 2for O, n is 3, L 3for key, L 4for-P (O) (alkyl)-, R 11for alkyl, cycloalkyl, Heterocyclylalkyl; Preferred, L 2for O, n is 3, L 3for key, L 4for-P (O) (CH 3)-, R 11for methyl, ethyl, sec.-propyl ,-CH 2-cyclopropyl, cyclopropyl, cyclopropyl.
8. the formula I compound or its salt described in arbitrary claim in claim 1-7, wherein L 2for-NR 12-, L 3for-NR 13-and L 4for-SO 2-, R 12with R 13and connected N atom forms the Heterocyclylalkyl that at least contains two N atoms together; Preferably, L 2for-NR 12-, L 3for-NR 13-and L 4for-SO 2-, R 12with R 13and connected N atom forms piperazinyl together.
9. the formula I compound or its salt described in arbitrary claim in claim 1-7, wherein L 1for-CH 2o-.
10. the formula I compound or its salt described in arbitrary claim in claim 1-9, wherein L 1for-CH 2nH-.
Formula I compound or its salt in 11. claim 1-8 described in arbitrary claim, wherein L 1for
12. the formula I compound or its salt described in claim 11, wherein Z 1for hydrogen, Z 2for-CH 2cOL 5r 19.
Formula I compound or its salt in 13. claim 1-12 described in arbitrary claim, wherein L 5for-NH-, R 19be selected from alkyl, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl ,-SO 2-alkyl ,-SO 2-cycloalkyl ,-SO 2-aryl ,-SO 2-heteroaryl ,-SO-alkyl ,-SO-cycloalkyl ,-SO-aryl ,-SO-heteroaryl; Preferably, R 19be selected from-SO 2-alkyl ,-SO 2-cycloalkyl ,-SO 2-aryl ,-SO 2-heteroaryl ,-SO-alkyl ,-SO-cycloalkyl ,-SO-aryl ,-SO-heteroaryl; More preferably, R 19be selected from-SO 2-alkyl ,-SO 2-cycloalkyl; Most preferably, R 19be selected from-SO 2-methyl ,-SO 2-ethyl ,-SO 2-cyclopropyl ,-SO 2-CH 2-cyclopropyl.
Formula I compound or its salt in 14. claim 1-13 described in arbitrary claim, wherein L 5for-O-, R 19be selected from hydrogen, alkyl, cycloalkyl; Preferably, R 19be selected from hydrogen, methyl, ethyl, propyl group, sec.-propyl, cyclopropyl, cyclobutyl, cyclohexyl.
15. formula I compound or its salts claimed in claim 1, it is selected from:
。
16. 1 kinds of pharmaceutical compositions, it comprises the compound or its salt described in any one and pharmaceutically acceptable carrier in claim 1-15.
Compound or its salt in 17. claim 1-15 described in any one is in the purposes for the preparation for the treatment of and/or preventing in the medicine of the disease relevant to GPR40.
Compound or its salt in 18. claim 1-15 described in any one is in the purposes for the preparation for the treatment of and/or preventing in the medicine of diabetes.
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