CN104016942B - Thiazolinone analog derivative and pharmaceutical composition thereof and application - Google Patents

Thiazolinone analog derivative and pharmaceutical composition thereof and application Download PDF

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Publication number
CN104016942B
CN104016942B CN201410266754.1A CN201410266754A CN104016942B CN 104016942 B CN104016942 B CN 104016942B CN 201410266754 A CN201410266754 A CN 201410266754A CN 104016942 B CN104016942 B CN 104016942B
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phenyl
thiazolinone
methylene radical
carbethoxy
chloro
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CN104016942A (en
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董卫莉
王润玲
岳海
王树青
邓治荣
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Tianjin Medical University
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Tianjin Medical University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D277/34—Oxygen atoms

Abstract

The invention discloses the 5-substituted methylene-4-thiazolinone compounds of a class chemical structure as shown in general formula (I) or its pharmacy acceptable salt, wherein R 1, R 2, R 3definition with the definition of specification sheets.The present invention also discloses the pharmaceutical composition of compound or its pharmacy acceptable salt and one or more pharmaceutically acceptable carrier, vehicle or the thinner composition comprised as activeconstituents I simultaneously.Shown compound has the inhibit activities of good PTP 1B (PTP-1B) and Protein-tyrosine-phosphatase (SHP-2), particularly as the purposes for the treatment of diabetes and cancer therapy drug aspect.

Description

Thiazolinone analog derivative and pharmaceutical composition thereof and application
Technical field
The present invention relates to organic chemistry technical field of medicine synthesis, be specifically related to the small molecular organic compounds of the new 5-substituted methylene-4-thiazolinone analog derivative of a class, it is as Protein tyrosine phosphatase-1B (proteintyrosinephosphatase1B, PTP-1B) medical usage in treatment and prevent diabetes and complication thereof, and as protein tyrosine phosphatase SHP 2 (Srchomology2 (SH2) domaincontainingphosphotyrosinephosphatase2, SHP-2) inhibitor is in the purposes of anti-tumor aspect, and containing their pharmaceutical composition and the purposes as medicine.The invention still further relates to the preparation method of this compounds.
Background technology
No matter be developed country or developing country, diabetes are just becoming the prevailing disease of modern society with the impetus developed rapidly, serious harm public health.The sickness rate of diabetes is quick ascendant trend in China, and the sickness rate of China adult is risen to the 3.2l% of 1996 by 1% of nineteen eighty-two.It is predicted, 2.46 hundred million examples from 2006 are increased to 3.8 hundred million examples of 2025 by global diabetic subject.According to another World Health Organization's prediction, to the year two thousand thirty, the diabetes B patient number of developing country may account for 76% of the whole world.Oneself becomes the third-largest chronic disease of serious harm human health after cardiovascular and cerebrovascular diseases, tumour to diabetes in the world.Wherein the sickness rate of type II diabetes accounts for 90% ~ 95% of diabetic.The mark of patients with NIDDM is insulin resistant, namely insulin sensitivity declines, there are hypertension, hyperlipidemia, obesity etc. in normal merging, without obvious Ketosis-prone, the medicine of its treatment is divided into sulfourea, biguanides, alpha-glucosidase inhibitor, thialdine alkane diones, blood sugar regulator used during user having meals and Regular Insulin etc.
Protein tyrosine phosphatase-1B (proteintyrosinephosphatase1B, PTP-1B) be a member of Protein-tyrosine-phosphatase family, wide expression in each histocyte in vivo, PTP-1B, by regulating the tyrosine phosphorylation level of its protein substrate with other members in its family and protein tyrosine kinase combined action, is the important component part of Signal Transduction Mechanism.The cellular signal transduction pathways that PTP-1B is different from different substrate-function controllable.Existing certified PTP-1B physiological function mainly contains: 1. with insulin receptor (insulinreceptor, IR), IRS (insulinreceptorsubstrate, the signal protein effect such as IRS), make the tyrosine residues dephosphorylation of these albumen regulatory regions, block the biography down of insulin signaling cascade reaction, therefore in insulin signaling, play negative regulation effect.2. make signal transduction and transcriptional activators dephosphorylation, stop Leptin signaling transduction.3. with multiple somatomedin and substrate interaction, the growth of regulating cell, differentiation.4. the mobility of aortic smooth muscle cells is reduced.In addition, PTP-1B also transduce with prolactin signal transduction, integrin signaling and platelet aggregation etc. in close relations.
PTP-1B plays negative regulation effect in insulin signal transduction chain, the synthesis of glycogen in block cell, Blood Glucose concentration is raised, finally causes diabetes.Therefore, PTP-1B has become the target enzyme of development diabetes medicament.PTP-1B specific inhibitor is expected to the susceptibility improving Regular Insulin, effectively treats type II diabetes, insulin resistant and obesity.
SHP-2 (SH2domain-containingprotein-tyrosinephosphatase-2) molecule is by PTPN11 genes encoding, it is a non-receptor type Protein-tyrosine-phosphatase extensively existed in vivo, both positive regulation downstream signal transduction path can be carried out by the catalytic activity of Phosphoric acid esterase, also positive regulation effect can be played as the adaptor protein of Phosphoric acid esterase dependent/non-dependent, also negative regulation effect can be played under given conditions, thus the regulation and control of the biological functions such as the differentiation of wide participation cell, migration and relevant signal transduction process.PTPN11 sudden change is considered to teenager's myelomonocytic leukemia (juvenilemyelomonocyticleukemia, JMML) high risk factor, meanwhile, in dissimilar leukemia, all there is the abnormal activation of SHP-2 and sudden change because of it and be considered to leukemic proto-oncogene; In prostate cancer, mammary cancer, carcinoma of the pancreas, cancer of the stomach and neurospongioma, SHP-2 is also in the news in overactivity state; In lung cancer, SHP-2 promotes generation, the development of tumour by regulation and control number of mechanisms as oncogene.In During HepatocarcinogenesisIn, SHP-2 but plays the effect of cancer suppressor gene under the impact of specific environment.In a word, as important node molecule, SHP-2 plays important regulating and controlling effect in the process of tumorigenesis, is potential target for cancer therapy.
The present invention passes through 5-aryl methylene-2,4-thiazolidinediones PTP-1B inhibitor (Rosaria, BioorganicMedicinalChemistry, 2007,15,5137) carry out structure of modification, obtain a series of 5-substituted methylene-4-thiazolinone compounds, and determine the inhibit activities to PTP-1B and SHP-2.Have not yet to see with the report of 5-substituted methylene-4-thiazolinone PTP-1B and the SHP-2 inhibitor that is parent nucleus, such inhibitor has good novelty.
Summary of the invention
5-substituted methylene-4-thiazolinone the derivative that first object of the present invention is to provide a class to have general formula I and pharmacy acceptable salt thereof.
Second object of the present invention is to provide preparation to have the compound of general formula I or the method for its pharmacy acceptable salt.
3rd object of the present invention is to provide compound containing general formula I or its pharmacy acceptable salt as effective constituent, using the medicinal compositions of its one or more pharmaceutically acceptable carrier, vehicle or thinner as PTP-1B and SHP-2 inhibitor in the application of hypoglycemic and anticancer aspect.
For achieving the above object, the invention discloses following technology contents:
There is general formula I compound or its medically acceptable salt:
Wherein: n=0 or 1
As n=0
R 1be selected from one to five C 2-C 3ester group, C 3-C 5ester group alkoxyl group, C 3-C 5ester group alkyl, C 2-C 4carboxyalkoxy, C 2-C 4carboxyalkyl;
R 2be selected from phenyl, C 3-C 7cyclic hydrocarbon radical, wherein phenyl not to replace or by one to five halogen, C 1- 4alkyl, nitro, trifluoromethyl, trifluoromethoxy replace;
R 3be selected from phenyl or containing 5 yuan or 6 yuan of fragrant heterocycles of O-, S-, N-, phenyl or be not replace or by one to four halogen, methoxyl group, hydroxyl, C containing O-, S-, N-5 yuan or 6 yuan of fragrant heterocycles 1- 4alkyl, nitro, trifluoromethyl, trifluoromethoxy, OR 4replace;
R 4be selected from benzyl or substituted benzyl, substituting group is selected from one to five halogen, methyl, methoxyl group, nitro;
R defined above 1the C be selected from 2-C 3ester group structure comprises-COOCH 3,-COOC 2h 5,-OCOCH 3,-OCOC 2h 5; C 3-C 5ester group alkoxide comprises-OCH 2cOOCH 3,-OCH 2cOOC 2h 5,-OCH 2cH 2cOOCH 3,-OCH 2cH 2cOOC 2h 5;
C 3-C 5ester group alkyl structure comprises-CH 2cOOCH 3,-CH 2cOOC 2h 5,-CH 2cH 2cOOCH 3,-CH 2cH 2cOOC 2h 5;
C 2-C 4carboxyalkoxy structure comprises-OCH 2cOOH ,-OCH 2cH 2cOOH ,-OCH 2cH 2cH 2cOOH; C 2-C 4carboxyalkyl structure comprises-CH 2cOOH ,-CH 2cH 2cOOH ,-CH 2cH 2cH 2cOOH.
As n=1
R 1be selected from one to five carboxyl, C 2-C 3ester group, amino, hydroxyl, C 2-C 4carboxyalkoxy, C 3-C 5ester group alkoxyl group, C 2-C 4carboxyalkyl, C 3-C 5ester group alkyl, sulfydryl, methylol;
R 2be selected from phenyl, C 3-C 7cyclic hydrocarbon radical, wherein phenyl not to replace or by one to five halogen, methoxyl group, C 1- 4alkyl, nitro, trifluoromethyl, trifluoromethoxy replace;
R 3be selected from phenyl or containing 5 yuan or 6 yuan of fragrant heterocycles of O-, S-, N-, phenyl or be not replace or by one to four halogen, methoxyl group, hydroxyl, C containing O-, S-, N-5 yuan or 6 yuan of fragrant heterocycles 1- 4alkyl, nitro, trifluoromethyl, trifluoromethoxy, OR 4replace;
R 4be selected from benzyl or substituted benzyl, substituting group is selected from one to five halogen, methyl, methoxyl group, nitro;
R defined above 1be selected from one to five C 2-C 3ester group structure comprises-COOCH 3,-COOC 2h 5,-OCOCH 3,-OCOC 2h 5;
C 2-C 4carboxyalkoxy structure comprises-OCH 2cOOH ,-OCH 2cH 2cOOH ,-OCH 2cH 2cH 2cOOH; C 3-C 5ester group alkoxide comprises-OCH 2cOOCH 3,-OCH 2cOOC 2h 5,-OCH 2cH 2cOOCH 3,-OCH 2cH 2cOOC 2h 5;
C 2-C 4carboxyalkyl structure comprises-CH 2cOOH ,-CH 2cH 2cOOH ,-CH 2cH 2cH 2cOOH;
C 3-C 5ester group alkyl structure comprises-CH 2cOOCH 3,-CH 2cOOC 2h 5,-CH 2cH 2cOOCH 3,-CH 2cH 2cOOC 2h 5.
Compound provided by the invention or its medically acceptable salt have general formula I and comprise but do not show in following compounds:
I-1:5-phenylmethylene-2-phenyl-3-(4-ethoxycarbonyl benzyl)-4-thiazolinone;
I-2:5-(2-fluorophenyl methylene radical)-2-phenyl-3-(4-ethoxycarbonyl benzyl)-4-thiazolinone;
I-3:5-(4-fluorophenyl methylene radical)-2-phenyl-3-(4-ethoxycarbonyl benzyl)-4-thiazolinone;
I-4:5-(2-chloro-phenyl-methylene radical)-2-phenyl-3-(4-ethoxycarbonyl benzyl)-4-thiazolinone;
I-5:5-(3-chloro-phenyl-methylene radical)-2-phenyl-3-(4-ethoxycarbonyl benzyl)-4-thiazolinone;
I-6:5-(4-chloro-phenyl-methylene radical)-2-phenyl-3-(4-ethoxycarbonyl benzyl)-4-thiazolinone;
I-7:5-(3-aminomethyl phenyl methylene radical)-2-phenyl-3-(4-ethoxycarbonyl benzyl)-4-thiazolinone;
I-8:5-(4-aminomethyl phenyl methylene radical)-2-phenyl-3-(4-ethoxycarbonyl benzyl)-4-thiazolinone;
I-9:5-(3-anisole methylene)-2-phenyl-3-(4-ethoxycarbonyl benzyl)-4-thiazolinone;
I-10:5-(4-benzyloxy-phenyl methylene radical)-2-phenyl-3-(4-ethoxycarbonyl benzyl)-4-thiazolinone;
I-11:5-phenylmethylene-2-phenyl-3-(4-carbethoxy phenyl)-4-thiazolinone;
I-12:5-(2-fluorophenyl methylene radical)-2-phenyl-3-(4-carbethoxy phenyl)-4-thiazolinone;
I-13:5-(4-fluorophenyl methylene radical)-2-phenyl-3-(4-carbethoxy phenyl)-4-thiazolinone;
I-14:5-(2-chloro-phenyl-methylene radical)-2-phenyl-3-(4-carbethoxy phenyl)-4-thiazolinone;
I-15:5-(3-chloro-phenyl-methylene radical)-2-phenyl-3-(4-carbethoxy phenyl)-4-thiazolinone;
I-16:5-(4-chloro-phenyl-methylene radical)-2-phenyl-3-(4-carbethoxy phenyl)-4-thiazolinone;
I-17:5-(3-aminomethyl phenyl methylene radical)-2-phenyl-3-(4-carbethoxy phenyl)-4-thiazolinone;
I-18:5-(3-anisole methylene)-2-phenyl-3-(4-carbethoxy phenyl)-4-thiazolinone;
I-19:5-(4-aminomethyl phenyl methylene radical)-2-phenyl-3-(4-carbethoxy phenyl)-4-thiazolinone;
I-20:5-(3-benzyloxy-phenyl methylene radical)-2-phenyl-3-(4-carbethoxy phenyl)-4-thiazolinone;
I-21:5-(4-benzyloxy-phenyl methylene radical)-2-phenyl-3-(4-carbethoxy phenyl)-4-thiazolinone;
I-22:5-(3-chloro-phenyl-methylene radical)-2-phenyl-3-(4-carbethoxy phenyl)-4-thiazolinone hydrochloride;
I-23:5-(4-aminomethyl phenyl methylene radical)-2-phenyl-3-(4-carbethoxy phenyl)-4-thiazolinone hydrochloride.
Generalformulaⅰcompound of the present invention, wherein pharmacy acceptable salt means generalformulaⅰcompound and sour salify, comprises mineral acid and organic acid; With alkali salify, alkali is alkali-metal oxyhydroxide.Such as with sodium hydroxide, potassium hydroxide, calcium hydroxide, the pharmacy acceptable salt that the basic cpds such as sodium carbonate are formed, as corresponding sodium salt, sylvite or calcium salt etc.; With suitable organic bases, as the pharmacy acceptable salt that methylamine, triethylamine, meglumine, basic aminoacids etc. generate; And with various mineral acid, such as, hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid etc., or organic acid, such as, the pharmacy acceptable salt that formic acid, acetic acid, citric acid, oxalic acid, fumaric acid, toxilic acid, amino acid etc. generate.
Described compound of Formula I provided by the invention is synthesized by following steps:
With formula II, formula III and Thiovanic acid for starting raw material, with N, N'-dicyclohexyl carbodiimide for dehydrated reagent, under room temperature, one pot reaction is prepared into 4-thiazolidone intermediate, then in sodium alkoxide and alcoholic solution, and formula IV reaction, be prepared into compound of Formula I;
Wherein: n=0 or 1
As n=0
R 1be selected from one to five C 2-C 3ester group, C 3-C 5ester group alkoxyl group, C 3-C 5ester group alkyl, C 2-C 4carboxyalkoxy, C 2-C 4carboxyalkyl;
R 2be selected from phenyl, C 3-C 7cyclic hydrocarbon radical, wherein phenyl not to replace or by one to five halogen, C 1- 4alkyl, nitro, trifluoromethyl, trifluoromethoxy replace;
R 3be selected from phenyl or containing 5 yuan or 6 yuan of fragrant heterocycles of O-, S-, N-, phenyl or be not replace or by one to four halogen, methoxyl group, hydroxyl, C containing O-, S-, N-5 yuan or 6 yuan of fragrant heterocycles 1- 4alkyl, nitro, trifluoromethyl, trifluoromethoxy, OR 4replace;
R 4be selected from benzyl or substituted benzyl, substituting group is selected from one to five halogen, methyl, methoxyl group, nitro;
R defined above 1the C be selected from 2-C 3ester group structure comprises-COOCH 3,-COOC 2h 5,-OCOCH 3,-OCOC 2h 5;
C 3-C 5ester group alkoxide comprises-OCH 2cOOCH 3,-OCH 2cOOC 2h 5,-OCH 2cH 2cOOCH 3,-OCH 2cH 2cOOC 2h 5;
C 3-C 5ester group alkyl structure comprises-CH 2cOOCH 3,-CH 2cOOC 2h 5,-CH 2cH 2cOOCH 3,-CH 2cH 2cOOC 2h 5; C 2-C 4carboxyalkoxy structure comprises-OCH 2cOOH ,-OCH 2cH 2cOOH ,-OCH 2cH 2cH 2cOOH;
C 2-C 4carboxyalkyl structure comprises-CH 2cOOH ,-CH 2cH 2cOOH ,-CH 2cH 2cH 2cOOH.
As n=1
R 1be selected from one to five carboxyl, C 2-C 3ester group, amino, hydroxyl, C 2-C 4carboxyalkoxy, C 3-C 5ester group alkoxyl group, C 2-C 4carboxyalkyl, C 3-C 5ester group alkyl, sulfydryl, methylol;
R 2be selected from phenyl, C 3-C 7cyclic hydrocarbon radical, wherein phenyl not to replace or by one to five halogen, methoxyl group, C 1- 4alkyl, nitro, trifluoromethyl, trifluoromethoxy replace;
R 3be selected from phenyl or containing 5 yuan or 6 yuan of fragrant heterocycles of O-, S-, N-, phenyl or be not replace or by one to four halogen, methoxyl group, hydroxyl, C containing O-, S-, N-5 yuan or 6 yuan of fragrant heterocycles 1- 4alkyl, nitro, trifluoromethyl, trifluoromethoxy, OR 4replace;
R 4be selected from benzyl or substituted benzyl, substituting group is selected from one to five halogen, methyl, methoxyl group, nitro;
R defined above 1be selected from one to five C 2-C 3ester group structure comprises-COOCH 3,-COOC 2h 5,-OCOCH 3,-OCOC 2h 5;
C 2-C 4carboxyalkoxy structure comprises-OCH 2cOOH ,-OCH 2cH 2cOOH ,-OCH 2cH 2cH 2cOOH; C 3-C 5ester group alkoxide comprises-OCH 2cOOCH 3,-OCH 2cOOC 2h 5,-OCH 2cH 2cOOCH 3,-OCH 2cH 2cOOC 2h 5;
C 2-C 4carboxyalkyl structure comprises-CH 2cOOH ,-CH 2cH 2cOOH ,-CH 2cH 2cH 2cOOH;
C 3-C 5ester group alkyl structure comprises-CH 2cOOCH 3,-CH 2cOOC 2h 5,-CH 2cH 2cOOCH 3,-CH 2cH 2cOOC 2h 5.
The invention provides the preparation method of generalformulaⅰcompound, it is characterized in that sodium alkoxide used and alcoholic solution preferred alcohol sodium and ethanolic soln (0.1mol/L), sodium methylate and methanol solution (0.1mol/L).
The invention provides the preparation method of generalformulaⅰcompound, technical process is:
Wherein, the definition of each substituted radical is with mentioned above.
General formula I thiazolinone compounds of the present invention can as Protein tyrosine phosphatase-1B (proteintyrosinephosphatase1B, PTP-1B) medical usage in treatment and prevent diabetes and complication thereof, and as protein tyrosine phosphatase SHP 2 (Srchomology2 (SH2) domaincontainingphosphotyrosinephosphatase2, SHP-2) inhibitor is in the purposes of anti-tumor aspect, and containing their pharmaceutical composition and the purposes as medicine, can as preparing antidiabetic drug and cancer therapy drug effective constituent.
The invention provides a kind of pharmaceutical composition, it is characterized in that it comprises as the general formula I thiazolinone compounds of activeconstituents or its pharmacy acceptable salt at least one and one or more pharmaceutically acceptable carrier, vehicle or thinner.
The pharmaceutical composition of the compounds of this invention is prepared as follows: use standard and conventional technology; the compounds of this invention acceptable solid or liquid vehicle on technology of pharmaceutics are combined, and make it at random on technology of pharmaceutics acceptable auxiliary and vehicle be combined and be prepared into particulate or microballoon.Solid dosage comprises tablet, discrete particles, capsule, slow releasing tablet, sustained release pellet etc.Solid carrier can be at least one material, and it can serve as thinner, flavouring agent, solubilizing agent, lubricant, suspension agent, tackiness agent, disintegrating agent and coating agent.Inert solid carrier comprises trimagnesium phosphate, Magnesium Stearate, smoothers sugar, lactose, pectin, propylene glycol, Polysorbate 80, dextrin, starch, gelatin, cellulose substances such as methylcellulose gum, Microcrystalline Cellulose, low melt point paraffin, polyoxyethylene glycol, N.F,USP MANNITOL, theobroma oil etc.Liquid dosage form comprises solvent, suspension such as injection, pulvis etc.
The amount of the active ingredient (the compounds of this invention) contained in pharmaceutical composition and unit dosage form specifically can be applied according to the situation of the state of an illness of patient, diagnosis, the amount of compound used or concentration regulate in a wider scope, usually, the weight range of active compound is 0.5% ~ 90%(weight of composition).Another preferred scope is 0.5%-70%.
Accompanying drawing illustrates:
Fig. 1 is-substituted methylene-4-thiazolinone analog derivative structural formula.
embodiment:
Below in conjunction with embodiment, the present invention is described further, and embodiment is only indicative, never means that it limits the scope of the invention by any way.Compound of the present invention is through thin-layer chromatography (TLC), and fusing point (m.p) detects, and through proton nmr spectra ( 1hNMR) confirm its structure, can adopt subsequently carbon-13 nmr spectra ( 13etc. CNMR) its structure is further confirmed; Wherein amino-methyl benzoic acid, parathesin, benzyl chlorine, phenyl aldehyde, substituted benzaldehyde, Thiovanic acid, DCC(dicyclohexylcarbodiimide) etc. raw material all have commercially available.
The preparation of embodiment 1 amino-methyl benzoic acid ethyl ester
In 250mL tri-mouthfuls of round-bottomed flasks, add 7.5g(50mmol) paraaminomethyl benzoic acid, add 100mL dehydrated alcohol.Under ice bath, slowly add thionyl chloride 20.8g(175mmol), after dropwising, after stirring at normal temperature 30min, reflux 4h.After heating stops, decompression is sloughed ethanol and is obtained white solid.With 150mL acetic acid ethyl dissolution solid, under ice bath, slowly adding the 35%NaOH aqueous solution to pH is 7 to 8.Stratification, removing water layer, organic layer saturated common salt water washing three times, each 30mL.Anhydrous sodium sulfate drying, filters, and concentrates and obtains yellow solid product, productive rate 90%.
The preparation of embodiment 22-phenyl-3-(4-ethoxycarbonyl benzyl)-4-thiazolinone
By 8.26g(50mmol) parathesin (in embodiment 1 prepare) be dissolved in 300mLTHF after, add 10.61g(100mmol) phenyl aldehyde, dropwise 7.00mL(100mmol is added under ice bath) Thiovanic acid, then add 12.40g(60mmol in batches) DCC.React 3h at normal temperatures.After stopped reaction, the white solid (DCU is DCC and the reacted product of water) in filtering reaction system.Then the THF in underpressure distillation removing system obtains white solid, after this solid of 300mL acetic acid ethyl dissolution, use 5% aqueous citric acid solution successively again, distilled water, 5% sodium bicarbonate aqueous solution and saturated sodium-chloride water solution washing organic layer, anhydrous sodium sulfate drying organic layer, filter, concentrating under reduced pressure obtains white solid.Finally carry out recrystallization with dehydrated alcohol again.Productive rate 90%, white solid, fusing point: 149.2-151.0 DEG C.
1H-NMR（DMSO- d 6 ，400MHz）：7.869（2H，d， J=8Hz，Ar-H）；7.287-7.371（5H，m，Ar-H）；7.206（2H，d， J=8.0Hz，Ar-H）；5.593（1H，s，CH）；4.833（1H，d， J=15.6Hz，Ar-CH 2）；4.295（2H，q， J=7.2Hz，OCH 2）；3.967（1H，d， J=15.6Hz，Ar-CH 2）；3.780（2H，q， J=7.2Hz，CH 2）；1.300（3H，t， J=7.2Hz，CH 3）。MS（ m/z）：342.3（M+1）；364.2（M+Na）；705.1（2M+Na）
Embodiment 3 P-benzyloxybenzaldehyde
By 5.16g(33mmol) p-Hydroxybenzaldehyde is molten in 75mLDMF, then adds Anhydrous potassium carbonate.Dropwise add 3.66g(30mmol with constant pressure funnel) Benzyl Chloride.After, temperature control 55 DEG C heating 3 hours.After reaction terminates, add volume 4 and doubly mix with reaction solution to the water of DMF, then use the organism in 400mL extraction into ethyl acetate water-DMF mixing solutions, extract three times.After merge organic layer and add anhydrous sodium sulfate drying, filter, concentrating under reduced pressure obtains pale yellow oil, and column chromatography is separated, and eluent ratio is 4:1(sherwood oil: ethyl acetate), obtain white solid, productive rate 90%.
Embodiment 4 benzoxybenzaldehyde
Experimental implementation and P-benzyloxybenzaldehyde preparation identical, a benzoxybenzaldehyde is white solid, productive rate 85%.
Embodiment 55-phenylmethylene-2-phenyl-3-(4-ethoxycarbonyl benzyl)-4-thiazolinone (I-1)
By 0.28g(4mmol) sodium Metal 99.5 be cut into little sodium grain and join in 20mL absolute ethanol, reaction generates sodium ethylate.By 4.1g(4mmol) 2-phenyl-3-(4-ethoxycarbonyl benzyl)-4-thiazoline (in embodiment 2 prepare) add in 30mL absolute ethanol in batches, add the phenyl aldehyde of 4mmol, dropwise add the alcoholic solution of sodium ethylate again, continue reflux 30min.After stopped reaction, the crude product of removal of solvent under reduced pressure, column chromatography.Eluent is sherwood oil: ethyl acetate=5:1.Yellow solid, productive rate 90%, fusing point: 124-125 DEG C.
1H-NMR（CDCl-- 3，400MHz）：δ7.246-7.902（14H，m，Ar-H）；6.003（1H，s，CH）；5.044（1H，d， J=15.6Hz，Ar-CH 2）；4.306（2H，q， J=7.2Hz，OCH 2）；4.014（1H，d， J=15.6Hz，Ar-CH 2）；1.308（3H，t， J=7.2Hz，CH 3）。MS（ m/z）：430.3（M+1）；452.2（M+Na）。
Embodiment 65-(2-fluorophenyl methylene radical)-2-phenyl-3-(4-ethoxycarbonyl benzyl)-4-thiazolinone (I-2)
With reference to the operation of embodiment 5, difference is to substitute phenyl aldehyde with 2-fluorobenzaldehyde.Faint yellow solid, fusing point: 135-137 DEG C.
1H-NMR（DMSO- d 6 ，400MHz）：δ7.239-7.891（13H，m，Ar-H）；7.870（1H，s，=CH）；6.028（1H，s，CH）；5.030(1H，d， J=15.6Hz，Ar-CH 2)；4.297（2H，q， J=7.2Hz，OCH 2）；4.025（1H，d， J=15.6Hz，Ar-CH 2）；1.299（3H，t， J=7.2Hz，CH 3）。MS（ m/z）：448.5（M+1）；470.4（M+Na）。
Embodiment 75-(2-chloro-phenyl-methylene radical)-2-phenyl-3-(4-ethoxycarbonyl benzyl)-4-thiazolinone (I-4)
With reference to the operation of embodiment 5, difference is to substitute phenyl aldehyde with 2-chlorobenzaldehyde.Faint yellow solid, fusing point: 150-152 DEG C.
1H-NMR（CDCl-- 3，400MHz）：δ7.213-8.021（13H，m，Ar-H）；7.620（1H，s，=CH）；5.557（1H，s，CH）；5.378（1H，d， J=14.8Hz，Ar-CH 2）；4.403（2H，q， J=6.8Hz，OCH 2）；3.813（1H，d， J=14.8Hz，Ar-CH 2）；1.416（3H，t， J=7.2Hz，CH 3）。MS（ m/z）：464.4（M+1）；486.3（M+Na）。
Embodiment 85-(3-chloro-phenyl-methylene radical)-2-phenyl-3-(4-ethoxycarbonyl benzyl)-4-thiazolinone (I-5)
With reference to the operation of embodiment 5, difference is to substitute phenyl aldehyde with 3-chlorobenzaldehyde.Faint yellow solid, fusing point: 151-152 DEG C.
1H-NMR(DMSO- d 6 ,400MHz)：δ7.234-7.890（13H，m，Ar-H）；7.597（1H，s，=CH）；6.022（1H，s，CH）；5.028（1H，d， J=15.6Hz，Ar-CH 2）；4.297（2H，q， J=7.2Hz，OCH 2）；4.019（1H，d， J=15.6Hz,Ar-CH 2）；1.297（3H，t， J=6.8Hz，CH 3）。MS（ m/z）：464.3（M+1）；486.3（M+Na）。
Embodiment 95-(4-chloro-phenyl-methylene radical)-2-phenyl-3-(4-ethoxycarbonyl benzyl)-4-thiazolinone (I-6)
With reference to the operation of embodiment 5, difference is to substitute phenyl aldehyde with 4-chlorobenzaldehyde.Yellow solid, fusing point: 175-177 DEG C.
1H-NMR（DMSO- d 6 ，400MHz）：δ7.230-7.888（13H，m，Ar-H）；7.573（1H，s，=CH）；6.008（1H，s，CH）；5.030（1H，d， J=15.6Hz，Ar-CH 2）；4.294（2H，q， J=7.2Hz，OCH 2）；4.009（1H，d， J=15.6Hz，Ar-CH 2）；1.296（3H，t， J=7.2Hz，CH 3）。MS（ m/z）：464.4（M+1）；486.3（M+Na）。
Embodiment 105-(3-aminomethyl phenyl methylene radical)-2-phenyl-3-(4-ethoxycarbonyl benzyl)-4-thiazolinone (I-7)
With reference to the operation of embodiment 5, difference is to substitute phenyl aldehyde with 3-tolyl aldehyde.White solid, fusing point: 171-172 DEG C.
1H-NMR（DMSO- d 6 ，400MHz）：δ7.154-7.892（13H，m，Ar-H）；7.481（1H，s，=CH）5.979（1H，s，CH）；5.031（1H，d， J=15.6Hz，Ar-CH 2）；4.296（2H，q， J=7.2Hz，OCH 2）；4.003（1H，d， J=15.6Hz，Ar-CH 2）；2.320（3H，s，Ar-CH 3）；1.298（3H，t， J=6.8Hz，CH 3）8。MS（ m/z）：444.5（M+1）；466.3（M+Na）。
Embodiment 115-(4-aminomethyl phenyl methylene radical)-2-phenyl-3-(4-ethoxycarbonyl benzyl)-4-thiazolinone (I-8)
With reference to the operation of embodiment 5, difference is to substitute phenyl aldehyde with 4-tolyl aldehyde.Faint yellow solid, fusing point: 142-144 DEG C.
1H-NMR（CDCl-- 3，400MHz）：δ7.219-8.019（13H，m，Ar-H）；7.658（1H，s，=CH）；5.544（1H，s，CH）；5.379（1H，d， J=14.8Hz，Ar-CH 2）；4.402（2H，q， J=7.2Hz，OCH 2）；3.804（1H，d， J=14.8Hz，Ar-CH 2）；2.382（3H，s，Ar-CH 3）；1.416（3H，t， J=7.2Hz，CH 3）9。MS（ m/z）：444.3（M+1）；466.3（M+Na）。
Embodiment 125-(3-anisole methylene)-2-phenyl-3-(4-ethoxycarbonyl benzyl)-4-thiazolinone (I-9)
With reference to the operation of embodiment 5, difference is to substitute phenyl aldehyde with m-methoxybenzaldehyde.Faint yellow solid, fusing point: 135-136 DEG C.
1H-NMR（DMSO- d 6 ，400MHz）：δ6.915-7.892（13H，m，Ar-H）；7.507（1H，s，=CH）；5.987（1H，s，CH）；5.031（1H，d， J=15.6Hz，Ar-CH 2）；4.298（2H，q， J=6.8Hz，OCH 2）；4.004（1H，d， J=15.6Hz，Ar-CH 2）；3.764（3H，s，OCH 3）；1.300（3H，t， J=7.2Hz，CH 3）。MS（ m/z）：460.3（M+1）；482.3（M+Na）。
Embodiment 135-(4-benzyloxy-phenyl methylene radical)-2-phenyl-3-(4-ethoxycarbonyl benzyl)-4-thiazolinone (I-10)
With reference to the operation of embodiment 5, difference is to substitute phenyl aldehyde with 4-benzoxybenzaldehyde.White solid, fusing point: 176-177 DEG C.
1H-NMR（DMSO- d 6 ，400MHz）：δ7.091-7.889（19H，m，Ar-H）；5.957(1H，s，CH)；5.137（2H，s，Ar-CH 2-O）；5.025（1H，d， J=15.6Hz，Ar-CH 2）；4.295（2H，q， J=7.2Hz，OCH 2）；3.979（1H，d， J=15.6Hz，Ar-CH 2）；1.297（3H，t， J=6.8Hz，CH 3）。MS（ m/z）：536.2（M+1）；558.2（M+Na）。
Embodiment 142-phenyl-3-(4-carbethoxy phenyl)-4-thiazolinone
By 8.26g(50mmol) parathesin be dissolved in 300mLTHF after, add 10.61g(100mmol) phenyl aldehyde.Dropwise 7.00mL(100mmol is added under ice bath) Thiovanic acid, add 12.40g(60mmol in batches) DCC.Stirring reaction 3 hours at normal temperatures.After stopped reaction, the white solid (DCU) in filtering reaction system.THF in underpressure distillation removing system obtains yellow oil, after this oily matter of 350mL diluted ethyl acetate, then uses 5% aqueous citric acid solution successively, distilled water, 5% sodium bicarbonate aqueous solution and saturated sodium-chloride water solution washing organic layer.Anhydrous sodium sulfate drying, filter, concentrating under reduced pressure obtains pale yellow oil.Finally use ethyl acetate, sherwood oil mixed solution (volume ratio sherwood oil: ethyl acetate=2.5:1) carries out recrystallization, after leaving standstill, must white crystal be separated out.Productive rate 80%, fusing point: 123.9-124.0 DEG C.
1H-NMR（DMSO- d 6 ，400MHz）：δ7.830-7.857（2H，m，Ar-H）；7.486-7.508（2H，q， J=8.8Hz,Ar-H，）；7.359-7.380（2H，t， J=8.4Hz,Ar-H，）；7.190-7.250（3H，m，Ar-H）；6.631（1H，s，CH）；4.241（2H，q， J=7.2Hz，CH 2）；3.890-4.060（2H，m，CH 2）；1.257（3H.，t， J=7.2Hz，CH 3）。MS（ m/z）：328.2（M+1）；350.2（M+Na）；677.1（2M+Na）。
Embodiment 155-phenylmethylene-2-phenyl-3-(4-carbethoxy phenyl)-4-thiazolinone (I-11)
By 0.28g(4mmol) sodium Metal 99.5 be cut into little sodium grain and join in 20mL absolute ethanol, form the alcoholic solution of sodium ethylate.By 4.1g(4mmol) 2-phenyl-3-(4-carbethoxy phenyl)-4-thiazolinone (in embodiment 14 prepare) add in 30mL absolute ethanol gradually, add 4mol phenyl aldehyde, dropwise add the alcoholic solution of sodium ethylate again, continue reflux 30min.After stopped reaction, leave standstill below 0 DEG C, separate out solid, cross and filter solvent.This solid dehydrated alcohol is carried out recrystallization and obtains yellow solid, productive rate 40%, fusing point: 124-125 DEG C.
1H-NMR（CDCl-- 3，400MHz）：δ7.246-7.902（14H，m，Ar-H）；6.003（1H，s，CH）；5.044（1H，d， J=15.6Hz，Ar-CH 2）；4.306（2H，q， J=7.2Hz，OCH 2）；4.014（1H，d， J=15.6Hz，Ar-CH 2）；1.308（3H，t， J=7.2Hz，CH 3）。MS（ m/z）：430.3（M+1）；452.2（M+Na）。
Embodiment 165-(2-fluorophenyl methylene radical)-2-phenyl-3-(4-carbethoxy phenyl)-4-thiazolinone (I-12)
With reference to the operation of embodiment 15, difference is to substitute phenyl aldehyde with 2-fluorobenzaldehyde.Faint yellow solid, fusing point: 155-156 DEG C.
1H-NMR（DMSO- d 6 ，400MHz）：δ7.239-7.912（14H，m，Ar-H）；7.048（1H，s，CH），4.256（2H，q， J=7.2Hz，OCH 2），1.267（3H，t， J=7.2Hz，CH 3）。MS（ m/z）：434.2（M+1）；456.1（M+Na）。
Embodiment 175-(4-fluorophenyl methylene radical)-2-phenyl-3-(4-carbethoxy phenyl)-4-thiazolinone (I-13)
With reference to the operation of embodiment 15, difference is to substitute phenyl aldehyde with 4-fluorobenzaldehyde.Faint yellow solid, fusing point: 190-192 DEG C.
1H-NMR（DMSO- d 6 ，400MHz）：δ7.220-7.909（13H，m，Ar-H）；7.603（1H，s，=CH）；7.029（1H，s，CH）；4.273（2H，q， J=7.2Hz，OCH 2）；1.268（3H，t， J=7.2Hz，CH 3）。MS（ m/z）：456.3（M+Na）。
Embodiment 185-(2-chloro-phenyl-methylene radical)-2-phenyl-3-(4-carbethoxy phenyl)-4-thiazolinone (I-14)
With reference to the operation of embodiment 15, difference is to substitute phenyl aldehyde with 2-chlorobenzaldehyde.White solid, fusing point: 161-162 DEG C.
1H-NMR（DMSO- d 6 ，400MHz）：δ7.242-7.915（13H，m，Ar-H）；7.823（1H，s，=CH）；7.042（1H，s，CH）；4.257（2H，q， J=6.8Hz，OCH 2）；1.273（3H，t， J=7.2Hz，CH 3）。MS（ m/z）：472.4（M+Na）。
Embodiment 195-(3-chloro-phenyl-methylene radical)-2-phenyl-3-(4-carbethoxy phenyl)-4-thiazolinone (I-15)
With reference to the operation of embodiment 15, difference is to substitute phenyl aldehyde with 3-chlorobenzaldehyde.White solid, fusing point: 171-172 DEG C.
1H-NMR（DMSO- d 6 ，400MHz）：δ7.226-7.914（13H，m，Ar-H）；7.633（1H，s，=CH）；7.042（1H，s，CH）；4.260（2H，q， J=7.2Hz，OCH 2）；1.271（3H，t， J=7.2Hz，CH 3）。MS（ m/z）：472.5（M+Na）。
Embodiment 205-(4-chloro-phenyl-methylene radical)-2-phenyl-3-(4-carbethoxy phenyl)-4-thiazolinone (I-16)
With reference to the operation of embodiment 15, difference is to substitute phenyl aldehyde with 4-chlorobenzaldehyde.White solid, fusing point: 210-211 DEG C.
1H-NMR（DMSO- d 6 ，400MHz）：δ7.241-7.911（13H，m，Ar-H）；7.611（1H，s，=CH）；7.038（1H，s，CH）；4.259（2H，q， J=7.2Hz，OCH 2）；1.270（3H，t， J=7.2Hz，CH 3）。MS（ m/z）：472.4（M+Na）。
Embodiment 215-(3-aminomethyl phenyl methylene radical)-2-phenyl-3-(4-carbethoxy phenyl)-4-thiazolinone (I-17)
With reference to the operation of embodiment 15, difference is to substitute phenyl aldehyde with 3-tolyl aldehyde.White solid, fusing point: 173-174 DEG C.
1H-NMR（DMSO- d 6 ，400MHz）：δ7.190-7.909（13H，m，Ar-H）；7.547（1H，s，=CH）；7.022（1H，s，CH）；4.259（2H，q， J=7.2Hz，OCH 2）；1.270（3H，t， J=7.2Hz，CH 3）。MS（ m/z）：428.3（M-1）；452.2（M+Na）。
Embodiment 225-(3-anisole methylene)-2-phenyl-3-(4-carbethoxy phenyl)-4-thiazolinone (I-18)
With reference to the operation of embodiment 15, difference is to substitute phenyl aldehyde with m-methoxybenzaldehyde.White solid, fusing point: 163-165 DEG C.
H-NMR（DMSO- d 6 ，400MHz）：δ7.129-7.910（13H，m，Ar-H）；7.571（1H，s，=CH）；7.019（1H，s，CH）；4.259（2H，q， J=7.2Hz，OCH 2）；3.779（3H，s，Ar-OCH 3）；1.270（3H，t， J=7.2Hz，CH 3）。MS（ m/z）：444.3（M-1）；468.2（M+Na）。
Embodiment 235-(4-aminomethyl phenyl methylene radical)-2-phenyl-3-(4-carbethoxy phenyl)-4-thiazolinone (I-19)
With reference to the operation of embodiment 15, difference is to substitute phenyl aldehyde with 4-tolyl aldehyde.Faint yellow solid, fusing point: 172-174 DEG C.
1H-NMR（DMSO- d 6 ，400MHz）：δ7.251-7.923（13H，m，Ar-H）；7.573（1H，s，=CH）；7.037（1H，s，CH）；4.272（2H，q， J=7.2Hz，OCH 2）；2.342（3H，s，Ar-CH 3）；1.284（3H，t， J=7.2Hz，CH 3）。MS（ m/z）：452.3（M+Na）。
Embodiment 245-(3-benzyloxy-phenyl methylene radical)-2-phenyl-3-(4-carbethoxy phenyl)-4-thiazolinone (I-20)
With reference to the operation of embodiment 15, difference is to substitute phenyl aldehyde with 3-benzoxybenzaldehyde.White solid, fusing point: 165-160 DEG C.
1H-NMR（DMSO- d 6 ，400MHz）：δ6.918-7.968（18H，m，Ar-H）；7.637（1H，s，=CH）；6.340（1H，s，CH）；5.074（2H，s，Ar-CH 2-O）；4.310（2H，q， J=7.2Hz，OCH 2）；1.332（3H，t， J=7.2Hz，CH 3）。MS（ m/z）：544.2（M+Na）。
Embodiment 255-(4-benzyloxy-phenyl methylene radical)-2-phenyl-3-(4-carbethoxy phenyl)-4-thiazolinone (I-21)
With reference to the operation of embodiment 15, difference is to substitute phenyl aldehyde with 4-benzoxybenzaldehyde.Pale solid, fusing point: 172-173 DEG C.
1H-NMR（DMSO- d 6 ，400MHz）：δ7.113-7.903（18H，m，Ar-H）；7.517（1H，s，=CH）；7.008（1H，s，CH）；5.153（2H，s，Ar-CH 2-O）；4.258（2H，q， J=7.2Hz，OCH 2）；1.269（3H，t， J=7.2Hz，CH 3）。MS（ m/z）：544.4（M+Na）。
Table 1 compound structure and physicochemical data
Embodiment 26
The mensuration of the Inhibiting enzyme activity of 5-25 compound:
1, materials and methods
Recombinant human PTP-1B, SHP-2, LARorTCPTP express in Ecoli, obtain pure enzyme through Ni-NTA affinity chromatography column purification.The compound of gradient dilution is joined 96 orifice plates, and add every hole 50 μ l PTPlB, SHP2 containing 0.05 μ g respectively, the 50mM of LAR or TCPTP zymoprotein, the citrate buffer solution of pH6.0 is [containing 0.1M sodium-chlor, 1mMEDTA, with 1mM 3-mercaptoethanol (DTT)], incubated at room temperature is after 15 minutes, add 50 μ l containing 2mM 4-NPP (pNPP) reaction substrate damping fluid.37 DEG C of insulation 30min, add 0.2mol/LNaOH termination reaction, measure the photoabsorption change under 405nm by microplate reader.Wherein PTP-lB and SHP-2 and substrate thereof are purchased from Sigma-Aldrich company.
2, test result
Table 2: the inhibit activities IC of embodiment 5-25 compound for protein tyrosine phosphatase 50(μ g/mL)
From the test result analysis of table 2, embodiment 5-25 compound has the activity suppressing PTP-1B enzyme, and wherein Compound I-20 has the activity suppressing SHP-2 enzyme.Therefore the small molecular organic compounds of the 5-substituted methylene-4-thiazolinone analog derivative that this class is new, have as Protein tyrosine phosphatase-1B (proteintyrosinephosphatase1B, PTP-1B) medical usage in treatment and prevent diabetes and complication thereof, and as protein tyrosine phosphatase SHP 2 (Srchomology2 (SH2) domaincontainingphosphotyrosinephosphatase2, SHP-2) inhibitor is in the purposes of anticancer aspect, and containing their pharmaceutical composition and the purposes as medicine, there is good prospect in medicine.Especially following compounds, has extraordinary inhibit activities:
I-1:5-phenylmethylene-2-phenyl-3-(4-ethoxycarbonyl benzyl)-4-thiazolinone;
I-2:5-(2-fluorophenyl methylene radical)-2-phenyl-3-(4-ethoxycarbonyl benzyl)-4-thiazolinone;
I-5:5-(3-chloro-phenyl-methylene radical)-2-phenyl-3-(4-ethoxycarbonyl benzyl)-4-thiazolinone;
I-7:5-(3-aminomethyl phenyl methylene radical)-2-phenyl-3-(4-ethoxycarbonyl benzyl)-4-thiazolinone;
I-8:5-(4-aminomethyl phenyl methylene radical)-2-phenyl-3-(4-ethoxycarbonyl benzyl)-4-thiazolinone;
I-10:5-(4-benzyloxy-phenyl methylene radical)-2-phenyl-3-(4-ethoxycarbonyl benzyl)-4-thiazolinone;
I-20:5-(3-benzyloxy-phenyl methylene radical)-2-phenyl-3-(4-carbethoxy phenyl)-4-thiazolinone.
Embodiment 27
The compounds of this invention I-5(embodiment 8) active animal measure in the following manner:
experimental animal:
Kunming mouse, male and female dual-purpose, (24 ± 2) g, is provided by Military Medical Science Institute's Experimental Animal Center, credit number SCXK2 (army) 20022001.Raising 1 week is adapted in laboratory, room temperature (22 ± 2) DEG C, relative humidity 65% ~ 70% before experiment.Day illumination 12h, free diet, takes the photograph water.
medicine, reagent and instrument:
Cis and trans potentilla flavone, self-control, its massfraction of high effective liquid chromatography for measuring is respectively 9417%, 9814% (areas of peak normalization method), tetraoxypyrimidine (Sigma company), metformin hydrochloride tablet (Pacific Ocean, Tianjin drugmaker, lot number 061104).Triglyceride level (TG) test kit, total cholesterol (TC) test kit (Zhong Shengbeikong bio tech ltd).Blood glucose meter (Johnson & Johnson of U.S. ONETOUCHUltra), low speed autobalancing centrifuge (Anxin County, Hebei province whizzer factory), UV-240 ultraviolet spectrophotometer (Japanese Shimadzu).
method:
After animal fasting (can't help water) about 12h, the tetraoxypyrimidine solution 70mg/kg of new preparation, fasting again (can't help water) 12h after 60h, cuts tail point and gets blood, survey blood glucose value by blood glucose meter, the mouse that blood glucose value is greater than 14.0mmol/L is Experimental diabetic model.Laboratory animal is divided into 9 groups, wherein diabetic mice, is divided into 7 groups by blood glucose value stratified random, is respectively model group and gives distilled water (10mL/kg), positive (Walaphage, 125mg/kg) and each administration group.Each group of successive administration 15d.Before last administration, water is can't help in fasting, after 12h, cuts tail point and gets blood, and blood glucose meter surveys blood glucose value.
Table 3 is respectively organized Mice Body quality and fasting plasma glucose before and after administration and is compared
Result shows: the compounds of this invention I-5(embodiment 8) there is certain hypoglycemic activity.
Preparation can adopt any one compound in the present invention as activeconstituents, and typical example is as follows:
Embodiment 1
Every sheet is prepared containing the tablet of 100mg activeconstituents:
Mg/ sheet
I-5100
Lactose 50
Microcrystalline Cellulose 80
Starch 50
Hydroxyl methylcellulose 40
Magnesium Stearate 5
By activeconstituents, lactose, starch, Microcrystalline Cellulose cross 100 mesh sieves, and fully mix, the 2% hydroxyl methylcellulose aqueous solution is joined in above-mentioned mixed powder and mixes, cross 20 mesh sieve softwoods, carboxymethylstach sodium, Magnesium Stearate, in 45-55 DEG C of drying, are joined compressing tablet in above-mentioned dried particles by obtained wet granular.
Embodiment 2
Every capsule contains being prepared as follows of the capsule of 100mg activeconstituents:
Consumption/capsule weight concentration (%)
I-19100mg30.0
Polyoxyethylene sorbitan 0.05mg0.02
Sorbitane monooleate
Starch 250mg69.98
Amount to 350.05mg100.00.

Claims (6)

1. compound or its pharmacy acceptable salt, is characterized in that described compound is:
I-1:5-phenylmethylene-2-phenyl-3-(4-ethoxycarbonyl benzyl)-4-thiazolinone;
I-2:5-(2-fluorophenyl methylene radical)-2-phenyl-3-(4-ethoxycarbonyl benzyl)-4-thiazolinone;
I-5:5-(3-chloro-phenyl-methylene radical)-2-phenyl-3-(4-ethoxycarbonyl benzyl)-4-thiazolinone;
I-7:5-(3-aminomethyl phenyl methylene radical)-2-phenyl-3-(4-ethoxycarbonyl benzyl)-4-thiazolinone;
I-8:5-(4-aminomethyl phenyl methylene radical)-2-phenyl-3-(4-ethoxycarbonyl benzyl)-4-thiazolinone;
I-10:5-(4-benzyloxy-phenyl methylene radical)-2-phenyl-3-(4-ethoxycarbonyl benzyl)-4-thiazolinone;
I-11:5-phenylmethylene-2-phenyl-3-(4-carbethoxy phenyl)-4-thiazolinone;
I-12:5-(2-fluorophenyl methylene radical)-2-phenyl-3-(4-carbethoxy phenyl)-4-thiazolinone;
I-13:5-(4-fluorophenyl methylene radical)-2-phenyl-3-(4-carbethoxy phenyl)-4-thiazolinone;
I-14:5-(2-chloro-phenyl-methylene radical)-2-phenyl-3-(4-carbethoxy phenyl)-4-thiazolinone;
I-15:5-(3-chloro-phenyl-methylene radical)-2-phenyl-3-(4-carbethoxy phenyl)-4-thiazolinone;
I-16:5-(4-chloro-phenyl-methylene radical)-2-phenyl-3-(4-carbethoxy phenyl)-4-thiazolinone;
I-17:5-(3-aminomethyl phenyl methylene radical)-2-phenyl-3-(4-carbethoxy phenyl)-4-thiazolinone;
I-18:5-(3-anisole methylene)-2-phenyl-3-(4-carbethoxy phenyl)-4-thiazolinone;
I-19:5-(4-aminomethyl phenyl methylene radical)-2-phenyl-3-(4-carbethoxy phenyl)-4-thiazolinone;
I-20:5-(3-benzyloxy-phenyl methylene radical)-2-phenyl-3-(4-carbethoxy phenyl)-4-thiazolinone.
2. the preparation method of compound described in claim 1, it is characterized in that with formula II, formula (III) and Thiovanic acid for starting raw material, with N, N'-dicyclohexyl carbodiimide is dehydrated reagent, under room temperature, one pot reaction is prepared into 4-thiazolidone intermediate, then in sodium alkoxide and alcoholic solution, and formula IV reaction, be prepared into compound described in claim 1;
Wherein:
As n=0,
R1 is 4-ethoxy carbonyl;
R2 is phenyl;
R3 is selected from phenyl, 2-fluorophenyl, 4-fluorophenyl, 2-chloro-phenyl-, 3-chloro-phenyl-, 4-chloro-phenyl-, 3-aminomethyl phenyl, 3-p-methoxy-phenyl, 4-aminomethyl phenyl, 3-benzyloxy-phenyl;
As n=1,
R1 is 4-ethoxy carbonyl;
R2 is phenyl;
R3 is selected from phenyl, 2-fluorophenyl, 3-chloro-phenyl-, 3-aminomethyl phenyl, 4-aminomethyl phenyl, 4-benzyloxy-phenyl.
3. preparation method described in claim 2, is characterized in that sodium alkoxide used and alcoholic solution are selected from sodium ethylate and ethanolic soln, sodium methylate and methanol solution.
4. a pharmaceutical composition, is characterized in that it comprises at least one as the compound according to claim 1 of activeconstituents or its pharmacy acceptable salt, and one or more pharmaceutically acceptable carrier, vehicle or thinners.
5. compound described in claim 1 or the application of its pharmacy acceptable salt in preparation treatment diabetes medicament.
6.5-(3-benzyloxy-phenyl methylene radical)-2-phenyl-3-(4-carbethoxy phenyl)-4-thiazolinone or its pharmacy acceptable salt are preparing the application in cancer therapy drug.
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An efficient method for the transformation of 5-ylidenerhodanines into 2,3,5-trisubstituted-4-thiazolidinones;Danylo Kaminskyy等;《Tetrahedron Letters》;20111125;第53卷;第557-559页 *

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