CN101768133A - Diphenylethlene derivative and use thereof - Google Patents

Abstract

The invention discloses a diphenylethlene derivative with the structure shown as the formula 1 and a pharmaceutically-acceptable salt thereof. Since the compounds have the property of PPAR gamma agonist, the compounds have insulin hypersensitivity and blood sugar reducing activity and can be used for preventing and treating II-type diabetes mellitus. The invention also provides a preparation method of the compounds, a pharmaceutics composition containing the compounds and application of the compounds for preparing hypoglycaemic drugs, wherein Z represents the formula (I) or the formula (II).

Description

Diphenylethlene analog derivative and uses thereof

Technical field

The present invention relates to novel diphenylethlene derivatives quasi-compound and pharmacy acceptable salt thereof, described compound has PPAR gamma agonist character, therefore has insulin sensitivity enhancing and hypoglycemic activity; The invention still further relates to the preparation method of described compound, contain the medicinal compositions and the purposes of these compounds in the hypoglycemic drug preparation of these compounds.

Technical background

Along with the propelling of growth in the living standard, life pattern modernization and aging population process, diabetes have become one of main killer of human health.No matter be developed country or developing country, the sickness rate of diabetes is all increasing year by year.Mostly be non insulin dependent diabetes among the diabetic subject, i.e. type ii diabetes.Threaten type ii diabetes patient life and the factor that influences its life quality to transfer chronic complicating diseases to by its acute complications, the multiple diabetic vascular complications that produces on capillary blood vessel and macroangiopathy basis becomes the deadly major cause of morbidity of diabetic subject.Prevent and treat diabetes especially type ii diabetes be an extremely urgent hot job.

Diabetes often cause many food, many drinks, diuresis, become thin, weak, blood sugar increasing and glucose in urine.Diabetics such as hyperglycemia be Be Controlled not for a long time, can cause coronary heart disease, cerebro-vascular diseases, peripheral angiopathy (causing cutting a toe or an amputation), retinopathy (causing losing one's sight), nephropathy (causing uremia), serious threat patient's health and life.

The method of treatment diabetes has multiple, as sitotherapy, and kinesitherapy etc.Mainly be to adopt pharmacotherapy to the treatment of type ii diabetes clinically at present.The drug main of clinical treatment type ii diabetes will be divided into five big class, i.e. sulfonylurea, non-sulfonylurea, biguanides, alpha-glucosidase inhibitor and thiazolidinedioneses.

Thiazolidinediones (thiaolidinediones, TZDs) medicine is the new in recent years up-and-coming euglycemic agent of developing, and can strengthen the susceptibility of tissue to Regular Insulin, improves the utilization of cell to glucose; Improve the insulin resistant state, it is unusual to correct sugar and metabolism of fat; The glycolated hemoglobin level also there is the reduction effect.Represent medicine that troglitazone (troglitazone), rosiglitazone (rosiglitazone) and pioglitazone (pioglitazone) are arranged.Troglitazone improves insulin resistance and glucose tolerance, and do not lose weight or cause the hypoglycemia relevant with medicine, this medicine is the oral therapeutic drug that first listing is used for the type ii diabetes patient in the thiazolidine diketone derivative, it is evident in efficacy to improve insulin resistant, but found afterwards that it has serious liver toxicity, was cancelled by majority state.Rosiglitazone can reduce the generation of basal insulin secretion and basic liver glycogen, strengthen the restraining effect that Regular Insulin produces glycogen and the skeletal muscle carbohydrate metabolism of insulin stimulating, do not see at present serious hepatic injury is arranged, cardiac side effects or the report relevant with hypoglycemia.Pioglitazone is the medicine of in July, 1999 through drugs approved by FDA, and its range of application is wider, both can use separately, also can with sulfonylurea, N1,N1-Dimethylbiguanide coupling.

The pharmaceutical composition and preparation method thereof that contains thiazolidinedione is in U.S. patent Nos.6,133,295,6,133,293,6,130,216,6,121,295,6,121,294,6,117,893,6,114,526,6,110,951,6,110,948,6,107,323,6,103,742,6,080,765,6,046,222,6,034,110,6,030,973, GE36,575,6,011,036,6,011,031,6,008,237,5,990,139,5,985,884,5, describe to some extent in 972,973 grades.

In recent years, the segmental thiazolidine diketone derivative of toluylene that contains with hypoglycemic activity sees report, and the patent of these compounds and preparation method thereof is found in US 2,002,025,975,2,004,259,938,2,004,097,593,2,003,181,494,2,006,235,062,2,008,188,654,2,008,103,302,2,008,293,949,2,008,108,825,2,002,032,225,2,004,186,299,6,245,814,6,331,633,6,525,093,6,624,197,7,105,552 and EP 1,007,039,1,251,738,1,360,178,1,448,515,1,549,625, AU 200,133,332, and WO 0,156, and 382 etc.

The present invention relates to a series of have a new constitutional features contain the segmental thiazolidine diketone derivative of toluylene, its compound that mainly shows as segmental mode of connection of chemical constitution such as the thiazolidinedione fragment of toluylene fragment, replacement of its replacement and the aromatic ring fragment that replaces and above-mentioned patent report there are differences, the present invention is surprised to find, the novel cpd that obtains by these differences has outstanding PPAR gamma agonist character, can be used as euglycemic agent thus and produces hypoglycemic activity.

Summary of the invention

An object of the present invention is to provide the compound of following general formula (1):

Wherein Z is formula (I)

Or formula (II)

N wherein, q represents 0～4 integer respectively independently, condition is n≤4 and q≤4; A, b represent to exist or non-existent pair of key independently; When two keys existed, formula (I) compound was E or Z configuration, and when two keys did not exist, the three-dimensional center of formula (I) compound had R-or S-configuration;

R and R ' represent H respectively independently; C ₁-C ₂₀The straight or branched alkyl; C ₂-C ₂₀The straight or branched thiazolinyl ,-CO ₂Z ', wherein Z ' is H, sodium, potassium or other pharmaceutically acceptable gegenion such as calcium, magnesium, ammonium, tromethane, tetramethyl-ammonium etc.;-CO ₂R ' ";-NH ₂-NHR ' ";-NR ₂' ";-OH; Halogen; The C that replaces ₁-C ₂₀The C of straight or branched alkyl or replacement ₂-C ₂₀The straight or branched thiazolinyl;-OR ' ", wherein R ' " represents C ₁-C ₂₀Straight or branched alkyl, straight or branched thiazolinyl or aralkyl-(CH ₂) x-Ar, wherein x is 1～6 integer;-CO ₂R " ", wherein R " " represents H, the C that can replace arbitrarily ₁-C ₂₀Alkyl, the C that can replace arbitrarily ₁-C ₂₀Straight or branched alkyl, the preferably C that can replace arbitrarily ₁-C ₆Alkoxyl group (for example methoxyl group, oxyethyl group or propoxy-), the C that can replace arbitrarily ₂-C ₂₀Thiazolinyl or the C that can replace arbitrarily ₆-C ₁₀Aryl or expression circular part such as morpholine, piperidines, piperazine etc.;

A, " expression is single to be replaced or polysubstituted group, can be H, C independently for A ' and A ₁-C ₂₀Amido, C ₁-C ₂₀Acyloxy, C ₁-C ₂₀Alkyloyl, C ₁-C ₂₀Carbalkoxy, C ₁-C ₂₀Alkoxyl group, C ₁-C ₂₀Alkylamino, C ₁-C ₂₀Alkane carboxylic amino, aroyl, aralkanoyl, carboxyl, cyano group, halogen, hydroxyl or nitro; Perhaps A, A ' and A " also can represent to replace arbitrarily straight or branched C ₁-C ₂₀Alkyl or C ₂-C ₂₀Thiazolinyl; Or formation methylene-dioxy or ethylenedioxy group;

X and X ' difference represent independently-NH ,-NR ' ", O or S.

Further aspect of the present invention provides the preferred compound of formula (1) compound:

The compound of following general formula (1):

Wherein Z is formula (I)

Or formula (II)

Wherein:

N, q represent 0～4 integer respectively independently, and condition is n≤4 and q≤4; A, b represent to exist or non-existent pair of key; When two keys exist, can be for E or Z configuration, when two keys did not exist, the three-dimensional center of acquisition can have R-or S-configuration;

R and R ' represent H respectively independently;-CO ₂Z ', wherein Z ' is H, sodium, potassium or other pharmaceutically acceptable gegenion such as calcium, magnesium, ammonium, tromethane, tetramethyl-ammonium etc.;-CO ₂R " ", wherein R " " be separately H, the C that can replace arbitrarily ₁-C ₂₀Alkyl, the C that can replace arbitrarily ₁-C ₂₀Straight or branched alkyl, the preferably C that can replace arbitrarily ₁-C ₆Alkoxyl group (for example methoxyl group, oxyethyl group or propoxy-), the C that can replace arbitrarily ₂-C ₂₀Thiazolinyl or the C that can replace arbitrarily ₆-C ₁₀Aryl or wherein NR " " expression circular part such as morpholine, piperidines, piperazine etc.;

A, " expression is single to be replaced or polysubstituted group, can represent H, C separately for A ' and A ₁-C ₂₀Amido, C ₁-C ₂₀Acyloxy, C ₁-C ₂₀Alkyloyl, C ₁-C ₂₀Carbalkoxy, C ₁-C ₂₀Alkoxyl group, C ₁-C ₂₀Alkylamino, C ₁-C ₂₀Alkane carboxylic amino, aroyl, aralkanoyl, carboxyl, cyano group, halogen, hydroxyl, nitro;

A, A ' and A " also can represent to replace arbitrarily straight or branched C ₁-C ₂₀Alkyl or C ₂-C ₂₀Thiazolinyl; Or formation methylene-dioxy or ethylenedioxy group;

X and X ' be separately-NH ,-NR ' ", O or S.

Preferred compound: representative compounds of the present invention comprises:

[1] 3-(3, the 5-Dimethoxyphenyl)-2-{3-[4-(2,4-dioxo thiazolidine-5-ylidenemethyl)-phenoxy group]-phenyl }-methyl acrylate (10);

[2] 3-(3, the 5-Dimethoxyphenyl)-2-{3-[4-(2,4-dioxo thiazolidine-5-ylmethyl)-phenoxy group]-phenyl }-methyl acrylate (11);

[3] 3-(3, the 5-Dimethoxyphenyl)-2-{3-[4-(2,4-dioxo thiazolidine-5-ylmethyl)-phenoxy group]-phenyl }-vinylformic acid (14);

[4] 3-(3, the 5-Dimethoxyphenyl)-2-{3-[4-(2,4-dioxo thiazolidine-5-ylidenemethyl)-phenoxy group]-phenyl }-methyl propionate (17);

[5] 3-(3, the 5-Dimethoxyphenyl)-2-{3-[4-(2,4-dioxo thiazolidine-5-ylmethyl)-phenoxy group]-phenyl }-methyl propionate (18);

[6] Z-3-(3, the 5-Dimethoxyphenyl)-2-{3-[4-(2,4-dioxo thiazolidine-5-ylidenemethyl)-phenoxy group]-phenyl }-methyl acrylate (22);

[7] Z-3-(3, the 5-Dimethoxyphenyl)-2-{3-[4-(2,4-dioxo thiazolidine-5-ylmethyl)-phenoxy group]-phenyl }-methyl acrylate (23);

[8] 2-{3-[4-(2,4-dioxo thiazolidine-5-ylidenylmethyl)-phenoxy group]-phenyl }-3-p-methylphenyl vinylformic acid (40);

[9] 2-{3-[4-(2,4-dioxo thiazolidine-5-ylmethyl)-phenoxy group]-phenyl }-3-p-methylphenyl vinylformic acid (41);

[10] 2-{3-[4-(2,4-dioxo thiazolidine-5-ylmethyl)-phenoxy group]-phenyl }-3-p-methylphenyl methyl acrylate (42);

[11] 3-(3, the 5-3,5-dimethylphenyl)-2-{3-[4-(2,4-dioxo thiazolidine-5-ylidenemethyl)-phenoxy group]-phenyl }-vinylformic acid (46);

[12] 3-(3, the 5-3,5-dimethylphenyl)-2-{3-[4-(2,4-dioxo thiazolidine-5-ylmethyl)-phenoxy group]-phenyl }-vinylformic acid (47);

[13] 3-(3, the 5-3,5-dimethylphenyl)-2-{3-[4-(2,4-dioxo thiazolidine-5-ylmethyl)-phenoxy group]-phenyl }-methyl acrylate (49);

[14] 5-(3-{4-[2-(3, the 5-3,5-dimethylphenyl)-1-(morpholine-4-carbonyl)-vinyl]-phenoxy group-benzyl)-thiazolidine-2,4-diketone (50);

[15] 5-(3-{4-[2-(4-p-methoxy-phenyl)-vinyl] phenoxy group }-benzyl)-thiazolidine-2,4-diketone (54).

Secondly, the present invention further provides the preparation method of the compound of general formula 1, hereinafter is the preparation method of example explanation The compounds of this invention with representative compounds of the present invention.

Representative compounds of the present invention can be synthetic by following synthetic route 1～6 disclosed method, wherein:

Z is that formula 1 compound of formula (I) can adopt method shown in the route 1 synthetic, representative compounds 10,11 for example of the present invention and 14 etc.;

Z is that formula 1 compound of formula (I) can also adopt method shown in the route 2 synthetic, representative compounds 17 for example of the present invention and 18 etc.;

Z is that formula 1 compound of formula (I) also can adopt method shown in the route 3 synthetic, representative compounds 22 for example of the present invention and 23 etc.;

Z is that formula 1 compound of formula (II) can adopt method shown in the route 4 synthetic, representative compounds 40,41 for example of the present invention and 42 etc.;

The present invention's formula 1 compound also can adopt method shown in the route 5 synthetic, representative compounds 46,47,49 for example of the present invention and 50 etc.;

The present invention's formula 1 compound can also adopt method shown in the route 6 synthetic, representative compounds 54 for example of the present invention etc.

Being illustrated as of the present invention's synthetic route 1～6:

Route 1:

^aReagent and condition: (a) diacetyl oxide, Et ₃N, 6h, 130 ℃, 46%; (b) MeOH, H ₂SO ₄, 20h refluxes 95%; (c) 4-fluorobenzaldehyde, NaH, DMF, 18h, 80 ℃, 73%; (d) 2, the 4-thiazolidinedione, piperidines, phenylformic acid, toluene, 5h refluxes 84%; (e) Pd/C (10%), HCOONH ₄/ AcOH, 48h refluxes 46%; (f) NaBH ₄, EtOH, 1h, 25 ℃, quantitative; (g) PBr ₃, CH ₂Cl ₂, 25 ℃, 1h, 98%; (h) BuLi, 2,4-thiazolidinedione, THF, 0 ℃, 45min, 16%; (i) aqueous NaOH, MeOH, 15h, 25 ℃, 76%.

Route 2:

^aReagent and condition: (a) Pd/C (10%), H ₂, 18h, 25 ℃, quantitative; (b) 4-fluorobenzaldehyde, NaH, DMF, 18h, 80 ℃, 68%; (c) 2, the 4-thiazolidinedione, piperidines, phenylformic acid, toluene, 5h refluxes 82%; (d) Pd/C (10%), H ₂(60psi), 34h, 25 ℃, 40%.

Route 3:

^aReagent and condition: (a) diacetyl oxide, Et ₃N, 24h, 125 ℃, 14%; (b) MeOH, H ₂SO ₄, 18h refluxes 36%; (b) 4-fluorobenzaldehyde, NaH, DMF, 18h, 80 ℃, 72%; (c) 2, the 4-thiazolidinedione, piperidines, phenylformic acid, toluene, 5h refluxes 90%; (e) Pd/C (10%), ammonium formiate, acetate, 20h refluxes.

Route 4:

Route 5:

Route 6:

With reference to route 1, aldehyde 5 and acid 6 can be in diacetyl oxide and triethylamine condensation to form unsaturated acid 7.After the acid estersization that compound 8 is provided, form the ether 9 that has p-Fluorobenzenecarboxaldehyde by phenolic hydroxyl group.Aldehyde 9 and 2 then, the condensation of 4-thiazolidinedione to be to provide compound 10, then by hydrogen with reduction formation of the key beyond the heterocycle in the compound 10 target compound 11.

As indicated previously, when a wherein, b represented two key, compound of the present invention can have E or Z configuration; And work as a, when b was singly-bound, the compound of acquisition can be R-and/or S steric isomer.The present invention imagines the racemic mixture of such steric isomer and separately, isolating steric isomer.Can obtain independent steric isomer by using optical resolution agent.Alternatively, can use the optical purity starting raw material of known conception by the required enantiomorph of the synthetic acquisition of stereoselectivity.

Below with reference to route 1 compound 11 is described, be 5-(4-(3-(1-methoxycarbonyl)-2-(3, the 5-Dimethoxyphenyl)-vinyl)-phenoxy group)-benzyl)-2, the 4-thiazolidinedione (is also referred to as 3-(3,5-dimethoxy-phenyl)-2-{4-[3-(2,4-dioxo-thiazolidine-5-ylmethyl)-phenoxy group]-phenyl-methyl acrylate) preparation.3,5-dimethoxy benzaldehyde 5 and 3-hydroxyphenyl acetate 6 obtain uniquely styracin 7 for the α of E-isomer-phenyl replacement through the condensation reaction of handkerchief gold.By with the report compound ¹H-NMR relatively confirms the geometry (Pettit etc., J Nat Prod 51:517-27,1998) of two keys.7 esterification and the condensation with the 4-fluorobenzaldehyde subsequently obtain 9.Having in the presence of the phenylformic acid piperidines that the water azeotropic removes, aldehyde 9 and 2, the Nuo Wengeer of 4-thiazolidinedione (Knoevenagel) condensation obtains 10 of good yield.

Main challenge is the two key selective hydrations for production compound 11,17 and 18.Magnesium/methyl alcohol is nonselective and obtains mixture of products 10 reduction.Zinc-alcoholic acid reduction can obtain the polarity mixture of products.1, be 6: 4 11 and 18 mixture by using hydrogenation as the 10% palladium/carbon of catalyzer to obtain ratio in the 4-dioxan.Only by the separating compound in the mixture from then on of the reverse-phase chromatography on C-18 silicon-dioxide.Can adopt several modes to overcome these problems.Use as the ammonium formiate of hydrogen donor in the presence of palladium catalyst to 10 hydrogenation (Hudlicky, ACS Vonograph188:46-7,1996; Ram and Ehrenkaufer, Synthesis 91-5,1988) produce the over reduction product 18 of minimum, and might separate by carry out highly purified 11 from the repetition crystallization of methyl alcohol.In the preferred variation of this route, platinum catalyst substitutes palladium, and from methylene dichloride the recrystallize crude product; The quantity and the reaction times of adopting these improved procedures obviously to reduce required catalyzer, improve overall yield on the certain degree simultaneously.In the another kind of preparation 11 was attempted, aldehyde 9 was reduced into alcohol 12, and it is using PBr ₃Obtain bromo compound 13 with high yield during processing.Bromo compound with produce by BuLi 2, the condensation of 4-thiazolidinedione negatively charged ion obtains 11 with low yield.

Because in the molecule 2,4-thiazolidinedione part is difficult to be combined to 18 with good yield by the catalytic hydrogen of palladium from 10 or 11 to the murder by poisoning of catalyzer, the mixture of acquisition comprises as 18 of low amounts of product.Be head it off (as shown in Scheme 2), at first quantitatively be reduced into 15 by using 10% carbon as catalyzer to carry palladium with 8, subsequently with 4-fluorobenzaldehyde and 2, the coupling of 4-thiazolidinedione obtains 17 of good yield.Adopt carbon-containing palladium catalyst to reduce 17, and, obtain 18 of suitable yield subsequently by the chromatographic refining of C-18 reverse phase silica gel with the longer time.

The synthesis strategy of the corresponding Z-isomer of preparation 23,11 is described in route 3.7 obtain the corresponding Z-isomer 19 of 13% yield with the prolongation heating (Kessar etc., Indian J Chem 20B:1-3,1981) of diacetyl oxide and triethylamine.With interest, be used to produce 22 2, the minimum isomerization of 4-thiazolidinedione and 21 two keys of reaction and display styracin and generate E-respectively and the ratio of Z-isomer is 1: 7 a mixture.Do not have to react under the further purified situation and by the refining final product of chiral column HPLC to obtain 23.

Its three, the present invention further provides the medicinal compositions that contains general formula (1) compound, described composition comprises acceptable carrier on general formula (1) compound for the treatment of significant quantity and the physiology.

Described treatment significant quantity is meant that the amount of the contained general formula of medicinal compositions (1) compound is enough to produce clinical desired therapeutic effect, and medication person's glucose level is reduced in the clinical acceptable scope.

Medicinal compositions of the present invention can pass through intravenously, intracutaneous, intramuscular, administration such as subcutaneous, oral, the formulation of its medicinal compositions can be gi tract medication preparation such as tablet, capsule, pill etc., also can be stomach and intestine external application preparation such as injection, external preparation etc.

In addition, the present invention also provides the method for treatment diabetes and relative disease, and this method comprises the general formula 1 described compound that the patient who suffers from diabetes or related conditions is used the treatment significant quantity.

Description of drawings

Fig. 1 shows the influence to db/db mouse body weight of compound 11,23,42 and rosiglitazone;

Fig. 2 shows the influence to the db/db mouse blood sugar of compound 11,23,42 and rosiglitazone; Wherein Fig. 2 a is the comparison of rosiglitazone positive controls and normal control group fasting plasma glucose; Fig. 2 b is that compound 11 high dose group and normal control group fasting plasma glucose compare; Fig. 2 c is dosage group and the comparison of normal control group fasting plasma glucose in the compound 23; Fig. 2 d is that compound 42 low dose group and normal control group fasting plasma glucose compare; Fig. 2 e totally shows the influence to the db/db mouse blood sugar of compound 11,23,42 and rosiglitazone.

Specific embodiment

Hereinafter further specify the present invention, but scope of the present invention is not formed any restriction with specific embodiment.

Universal method: measure fusing point on RT-1 fusing point instrument (Tianjin analytical instrument factory) equipment, temperature is calibrated.Record 1HNMR spectrum and it is described with 1,000,000 of TMS/portion (ppm) downfield in Bruker AV400 (400MHz) spectrograph.Pay on the upright leaf spectrophotometer at Nicolet Magna 550FT-IR and to write down infrared spectra.With HP1100 Esquire2000 liquid chromatography/mass spectrometry combined instrument record mass spectrum.At Tianjin, island UV2410 ultraviolet spectrophotometer record UV spectrum.On the efficient plate of silica GF254 (Yantai City Zhifu silica gel development experiments factory), carry out TLC.Carry out polarimetry on the WZZ-1S polarimetry instrument (Shanghai Precision Scientific Apparatus Co., Ltd).

Embodiment 1 is according to route 1 synthesis type 1 (wherein Z is formula I) compound

1.13-(3, the 5-Dimethoxyphenyl)-2-(3-hydroxyphenyl)-vinylformic acid (7) is synthetic

To 3,5-dimethoxy benzaldehyde 5 (10g, 0.06mol) and 3-hydroxyphenyl acetate 6 (9.14g, add in mixture 0.06mol) diacetyl oxide (20mL, 0.212mol) and triethylamine (8.4mL, 0.06mol).After 130-140 ℃ is stirred 6h down, with the mixture cool to room temperature.Dense HCl (20mL) was slowly joined in the reaction mixture with the time more than 50min, temperature is remained on 20-30 ℃ simultaneously.With the faint yellow sedimentation and filtration that obtains and wash with water.Solid is dissolved in 3N NaOH (100mL) and stirs 1h and filtration.With dense HCl filtrate being acidified to pH is 1, keeps 25-30 ℃ temperature simultaneously.Sedimentary product is filtered and washes with water to obtain crude product, with crude product from MeOH/H ₂Among the O recrystallize and 40 ℃ down dry 6h to obtain compound 7 (10.38g, 57%).mp：220-222℃； ¹HNMR(400MHz，DMSO-d ₆)δ3.53(s，6H)，6.31(d，J＝2.2Hz，2H)，6.39(t，J＝2.2Hz，1H)，6.76(d，J＝7.8Hz，2H)，6.95(d，J＝7.8Hz，2H)，7.59(s，1H)，9.42(s，1H)，12.48(br?s，1H)；MS(EI)m/z?229[M] ⁺。

1.23-(3, the 5-Dimethoxyphenyl)-2-(3-hydroxyphenyl)-methyl acrylate (8) is synthetic

Under argon gas, methyl alcohol (3.0L) joined thorough drying 7 (8.55g, 2.84mol) in.In the suspension of this stirring, add the vitriol oil (2mL) and, heat 20h under the condition of nitrogen gas refluxing.In decompression, 30 ℃ evaporate methyl alcohol down.Absorption of residual excess and water in ethyl acetate (60mL) (2 * 20mL), saturated aqueous NaHCO ₃(2 * 20mL), salt solution (2 * 20mL) washings.Organic phase by anhydrous sodium sulfate drying, is filtered and evaporating solvent.The resistates thorough drying under high vacuum that obtains is obtained white solid 8 (8.68g, 98%).mp：105-106℃； ¹HNMR(400MHz，CDCl ₃)δ3.53(s，6H)，3.70(s，3H)，6.30(d，J＝2.2Hz，2H)，6.38(t，J＝2.2Hz，1H)，6.56-6.58(m，1H)，6.60-6.62(m，1H)，6.76-6.78(m，1H)，7.20-7.23(t，J＝7.8Hz，1H)，7.66(s，1H)，9.45(s，1H)；MS(EI)m/z?337[M+Na] ⁺。

1.3 3-(3, the 5-Dimethoxyphenyl)-2-[3-(4-formyl radical phenoxy group)-phenyl]-methyl acrylate (9) synthetic

Under argon gas, (8.66g 27.4mmol) is dissolved in dry DMF (28mL) and add the 4-fluorobenzaldehyde in this material (3.7mL is 34.2mmol) and at 80 ℃ of heating 18h down with 8.With the reaction mixture cool to room temperature, (3 * 20mL), (1 * 20mL) extracts salt solution then to use ethyl acetate (60mL) dilution and water.Organic layer by anhydrous sodium sulfate drying, is filtered and evaporating solvent.Resistates is suspended in methyl alcohol (60mL) and stir and spend the night.With solid filtering and in vacuum, 40 ℃ dry down is 9 (8.9g, 78%) of faint yellow solid to obtain.mp：108-110℃； ¹HNMR(400MHz，CDCl ₃)δ3.54(s，6H)，3.71(s，3H)，6.28(d，J＝2.2Hz，2H)，6.39(t，J＝2.2Hz，1H)，7.07(dd，J＝9.0Hz，2H)，7.12(dd，J＝9.0Hz，2H)，7.29(d，J＝8.6Hz，2H)，7.83(s，1H)，7.88(d，J＝8.6Hz，2H)，9.96(s，1H)。

(1.43-3, the 5-Dimethoxyphenyl)-2-{3-[4-(2,4-dioxo thiazolidine-5-ylidenemethyl)-phenoxy group]- Phenyl }-methyl acrylate (10) synthetic

To 9 (7.04g, 16.4mmol) dry toluene stirred suspension (50mL) in, be sequentially added into 2,4-thiazolidinedione (1.97g, 16.4mmol), phenylformic acid (2.68g, 22mmol) and piperidines (2.15g, heating and 25.2mmol) and under reflux temperature by means of Dean-Stark equipment dehydration 5h.Toluene (20mL) removed from reaction mixture and 4 ℃ of following cool overnight.The solid of filtering separation and vapourisation under reduced pressure mother liquor are to dry.With the resistates that obtains be dissolved in again the MeOH-ether (1: 1, in mixture 60mL).When 4 ℃ of following standing over night, solution can produce more solid.Will be from two batches of solid bond that obtain and vacuum drying oven, 40 ℃ of following dried overnight are 10 (7.26,97%) of yellow solid to obtain.mp：176-178℃； ¹HNMR(400MHz，CDCl ₃)δ3.66(s，6H)，3.81(s，3H)，6.25(d，J＝2.4Hz，2H)，6.40(t，J＝2.4Hz，1H)，7.04-7.08(m，1H)，7.12-7.16(m，1H)，7.40-7.44(m，3H)，7.78-7.81(d，J＝5.5Hz，2H)，8.31(br?s，1H)；MS(EI)m/z?518[M] ⁺。

(1.53-3, the 5-Dimethoxyphenyl)-2-{3-[4-(2,4-dioxo thiazolidine-5-ylmethyl)-phenoxy group]-benzene Base }-methyl acrylate (11) synthetic

To 10 (11.98g, in glacial acetic acid solution 23.2mmol) (230mL), add ammonium formiate (80g, 1.26mol) and stir 30min.With carbon carry palladium (10%, drying, 6g) stasis of blood in glacial acetic acid (10mL) slurry joins that (note: heat release may become problem in extensive reaction in the flask; The oxygen strictness need be got rid of) and under 120 ℃, heat 24h, at room temperature stir 48h subsequently.By

Bed filters the mixture that obtains.With in the water (240mL) of the slow impouring vigorous stirring of filtrate and with isolating solid filtering and drying.Make solid slurryization twice in hot methanol of acquisition, subsequently in methyl alcohol slurryization once and refining be pure 11 (5.96g, 50%) of white solid to obtain.mp：165-166℃。 ¹HNMR(400MHz，DMSO-d ₆)δ3.10(dd，J＝14.2，9.2Hz，1H)，3.38(d，J＝4.3Hz，1H)，3.59(s，6H)，3.74(s，3H)，4.92(dd，J＝9.2，4.4Hz，1H)，6.28(d，J＝2.2Hz，2H)，6.41-6.58(m，1H)，6.81-6.88(m，2H)，6.95-7.06(m，2H)，7.13-7.30(m，2H)，7.42-7.46(m，1H)，7.72(s，1H)，12.00(br?s，1H)；IR(KBr)v(max)：3215，2956，2846，1706，1607，1500，1154，853cm ^-1；MS(EI)m/z[M-H] ^-518。

1.6 3-(3, the 5-Dimethoxyphenyl)-2-{3-[4-(2,4-dioxo thiazolidine-5-ylmethyl)-phenoxy group]-benzene Base }-methyl acrylate (11) synthetic

With 10 (0.4g, 0.77mol), ammonium formiate (3g, 4.76mol), 10%Pt/C (drying, 0.08g) and acetate (11.2mL) be mixed to join and be equipped with reflux exchanger, in the round-bottomed flask of thermometer and mechanical stirrer.Reactor found time and with nitrogen purge three times, be heated to stable state reflux (about 124 ℃) then.Be reflected to finish in the 15h and make and react by stirring cool to room temperature.After the cooling, mixture is passed through

(1g) pad filters and (2 * 5mL) wash with fresh acetate with filter cake.With mother liquor and washes mixing and concentrated.Use methylene dichloride (8mL) dilution resistates then, and with blended organism water (8mL) and 5% supercarbonate (8mL) extracting twice.Then that organic moiety is dry and pour into and (2 * 8mL) wash with methylene dichloride by silica gel (30g).Mix and the thickening and washing thing.Use the alcohol dilution resistates, make resistates be cooled to 60 ℃ and add crystal seed, under 50 ℃,, make its cooling be determined as 98.1% compound 11 (0.257g, 64%) then to obtain HPLC with this slurry stir about 30min.

1.7 3-(3, the 5-Dimethoxyphenyl)-2-[3-(4-hydroxymethyl phenoxy group)-phenyl]-methyl acrylate (12) Synthetic

At room temperature, with compound 9 (3.0g, 7.1mmol) be suspended in the dehydrated alcohol (36mL) and add sodium borohydride (0.14g, 3.66mmol), simultaneously with enough stirrings.Be reflected in the 1h and finish, evaporating solvent also is dissolved in ethyl acetate with resistates.Water (30mL), salt solution (15mL) extraction organic layer by anhydrous magnesium sulfate drying, filters and the title compound 12 (3.1g, 100%) of evaporating solvent to obtain white solid.mp：112-113℃； ¹HNMR(400MHz，DMSO-d ₆)δ3.59(s，6H)，3.77(s，3H)，4.54(d，J＝4.8Hz，2H)，5.20(t，J＝6.4Hz，1H)，6.32(d，J＝2.0Hz，2H)，6.42(t，J＝2.4Hz，1H)，7.04(dd，J＝8.4Hz，2H)，7.04(dd，J＝8.4Hz，2H)，7.20(d，J＝8.8Hz，2H)，7.38(d，J＝8.8Hz，2H)，7.89(s，1H)；MS(EI)m/z?315[M] ⁺。

1.8 2-[3-(4-hydroxymethyl phenoxy group)-phenyl]-3-(3, the 5-Dimethoxyphenyl)-methyl acrylate (13) Synthetic

Under-5 ℃ of temperature, adopt good stirring with PBr ₃(2.9mL is at CH for solution ₂Cl ₂In 1.0M) be added drop-wise to and be dissolved in CH ₂Cl ₂(12mL) 12 (3.0g, 7.1mmol) in.After the 1h, water (2 * 36mL) and salt solution (12mL) extraction solution.Organic phase is passed through anhydrous magnesium sulfate drying, by little silica gel bed (12g) drying and evaporating solvent.In high vacuum, under the room temperature with the dry 48h of the viscous syrup that obtains, to obtain title compound 13 (3.4g, 98%).Mp:79-81 ℃; ¹HNMR (400MHz, DMSO-d ₆) δ 3.58 (s, 6H), 3.68 (s, 3H), 4.73 (d, J=4.8Hz, 2H), 6.28 (d, J=2.0Hz, 2H), 6.42 (t, J=2.4Hz, 1H), 7.00 (dd, J=8.4Hz, 2H), 7.07 (dd, J=8.4Hz, 2H), 7.22 (d, J=8.4Hz, 2H), 7.49 (d, J=8.8Hz, 2H), 7.73 (s, 1H); Anal. (C ₂₅H ₂₃BrO ₅) C: calculated value: 61.12; Discovery value 62.26; H: calculated value: 4.80; Discovery value 4.88.

1.9 3-(3, the 5-Dimethoxyphenyl)-2-{3-[4-(2,4-dioxo thiazolidine-5-ylmethyl)-phenoxy group]-benzene Base }-methyl acrylate (11) synthetic

With 2, (2.26g 19.4mmol) is dissolved among the exsiccant THF (136mL) and under argon gas and is cooled to 0 ℃ the 4-thiazolidinedione.Splash into butyllithium (1.6M in hexane, 24mL, 38.4mmol).Continue to stir 0.5h down at 0 ℃.Under argon gas, (4.56g 9.4mmol) is dissolved among the exsiccant THF (24mL) and adopts to stir fast and joins fast in the above suspension by syringe with 13.Moisture HCl (5%, 32mL) before the quenching, temperature is remained on 0 ℃ of following 45min.Add other H ₂O (32mL) also uses ethyl acetate (3 * 24mL) extractions.Organic layer is mixed, use the salt water washing, obtain title compound 11 (0.76g, 18%) as eluting solvent by flash chromatography with hexane-ethyl acetate (3: 2).Compound 11 prepared by this method ¹The compound 11 that H-NMR and the above-mentioned route of synthesis that begins from compound 10 are produced ¹H-NMR is identical.

1.10 3-(3, the 5-Dimethoxyphenyl)-2-{3-[4-(2,4-dioxo thiazolidine-5-ylmethyl)-phenoxy group]-benzene Base }-vinylformic acid (14) synthetic

((6g 11.56mmol) also stirs, and is cooled to also at room temperature stir in the methanol suspension (30mL) below 10 ℃ 15h 40.4mmol) to join 11 for 2N, 20.2mL with aqueous NaOH.With the yellow solution that obtains be cooled to 10 ℃ and with moisture HCl (5%, 69mL) acidifying.With isolating solid filtering and water (3 * 18mL) washings obtain 14 (4.30g, 74%): MS (EI) m/z[M-H into white solid by the ethanol recrystallize] ^-504.

Embodiment 2 is according to route 2 synthesis types 1 (wherein Z is formula I) compound

2.1 3-(3, the 5-Dimethoxyphenyl)-2-(3-hydroxyphenyl)-methyl acrylate (15) is synthetic

(adding carbon among the 3.77g, alcohol suspension 12.0mmol) (120mL) carries palladium (10%, humidity is 0.38g) and at H to 8 ₂, normal atmosphere stirs 18h under the room temperature.Is 15 (3.79g, 100%) of white solid by filtration of Celite bed and vapourisation under reduced pressure solvent to obtain with catalyzer.Mp:83-84 ℃; ¹HNMR (400MHz, DMSO-d ₆) δ 7.20 (d, J=7.8Hz, 2H), 6.79 (d, J=7.8Hz, 2H), 6.30 (t, J=2.2Hz, 1H), 6.25 (d, J=2.2Hz, 2H), 3.78 (t, J=8.7Hz, 1H), 3.71 (s, 3H), 3.53 (s, 6H), 3.34 (dd, J=13.5 and 8.4Hz, 1H), 2.90 (dd, J=13.5 and 6.9Hz, 1H); MS (EI) m/z 317[M] ⁺

2.2 3-(3, the 5-Dimethoxyphenyl)-2-[3-(4-formyl radical phenoxy group)-phenyl]-methyl propionate (16) synthetic

Under argon gas, to sodium hydride (in oil 60%, 0.30g, be added in the DMF suspension (2.4mL) 7.56mmol) 15 among the dry DMF (3.6mL) (2.4g, 7.56mmol).In the yellow solution that obtains, (0.82mL 7.56mmol) and at 80 ℃ heats 18h down to add the 4-fluorobenzaldehyde.With the reaction mixture cool to room temperature, add entry (24mL) and use ethyl acetate (3 * 36mL) extractions.Organic layer by anhydrous sodium sulfate drying, is filtered and evaporating solvent.The ethyl acetate solution of crude product is filtered to obtain oily matter 16 (2.21g, 70%) by little silica gel bed. ¹HNMR (400MHz, DMSO-d ₆) δ 9.95 (s, 1H), 7.88 (d, J=8.7Hz, 2H), 7.35 (d, J=8.7Hz, 2H), 7.08 (d, J=5.4Hz, 2H), 7.03 (d, J=5.4Hz, 2H), 6.35 (t, J=2.2Hz, 1H), 6.30 (d, J=2.2Hz, 2H), 3.90 (d, J=7.8Hz, 1H), 3.70 (s, 3H), 3.53 (s, 6H), 3.38 (dd, J=12.6 and 8.1Hz, 1H), 2.98 (dd, J=13.5 and 7.5Hz, 1H); MS (EI) m/z 421[M] ⁺

2.3 3-(3, the 5-Dimethoxyphenyl)-2-{3-[4-(2,4-dioxo thiazolidine-5-ylidenemethyl)-phenoxy group]- Phenyl }-methyl propionate (17) synthetic

To 16 (2.72g, 6.45mmol) dry toluene stirred suspension (37.5mL) in, be sequentially added into 2,4-thiazolidinedione (0.84g, 7.11mmol), phenylformic acid (1.02g, 8.40mmol) and piperidines (0.90mL, heating and use Dean-Stark equipment to remove water 2h 9.05mmol) and under reflux temperature.With hexane-eluent ethyl acetate (1: 1) to obtain 17 (2.74g, 82%).Mp:108-109 ℃; ¹HNMR (400MHz, DMSO-d ₆) δ 12.50 (br s, 1H), 7.72 (s, 1H), 7.62 (d, J=8.7Hz, 2H), 7.36 (d, J=8.7Hz, 2H), 7.09 (d, J=4.8Hz, 2H), 7.05 (d, J=4.8Hz, 2H), 6.35-6.29 (m, 3H), 4.05 (t, J=7.5Hz, 1H), 3.70 (s, 3H), 3.56 (s, 6H), 3.22 (dd, J=13.8 and 8.4Hz, 1H), 2.90 (dd, J=13.8 and 7.2Hz, 1H); MS (EI) m/z520[M] ⁺, Anal. (C ₂₈H ₂₅NO ₇S) C: calculated value 64.73; Discovery value 65.00; H: calculated value 4.85; Discovery value 4.98; N: calculated value 2.70; Discovery value 2.59.

2.4 3-(3, the 5-Dimethoxyphenyl)-2-{3-[4-(2,4-dioxo thiazolidine-5-ylmethyl)-phenoxy group]-benzene Base }-methyl propionate (18) synthetic

With 17 (2.4g 4.62mmol) is dissolved in the dioxan (67.5mL), in the hydrogenation bottle, add carbon carry palladium (10%, 1.5g).34h is carried out in hydrogenation under 65psi.After at this moment, add other carbon carry palladium (10%, 0.9g) and make hydrogenation continue another 18h.Catalyzer is passed through

Bed filters and evaporating solvent.Resistates is gone up use acetonitrile-water (1: 1) mixture by column chromatography at reverse phase silica gel (C-18) make with extra care wash-out white solid 18 (0.95g, 40%).Mp:136-138 ℃; ¹HNMR (400MHz, DMSO-d ₆) δ 12.05 (br s, 1H), 7.30 (d, J=8.4Hz, 2H), 7.24 (d, J=8.4Hz, 2H), 6.90 (d, J=8.6Hz, 4H), 6.31 (d, J=2.0Hz, 2H), 6.28 (t, J=2.0Hz, 2H), 4.92 (dd, J=9.2 and 4.4Hz, 1H), 3.99 (t, J=8.0Hz, 1H), 3.69 (s, 6H), 3.53 (s, 3H), 3.38 (dd, J=13.6 and 4.0Hz, 1H), 3.20 (dd, J=14.0 and 8.8Hz, 1H), 3.12 (dd, J=14.0 and 9.2Hz, 1H); MS (EI) m/z 522[M] ⁺

Embodiment 3 is according to route 3 synthesis types 1 (wherein Z is formula I) compound

3.1 Z-3-(3, the 5-Dimethoxyphenyl)-2-(3-hydroxyphenyl)-vinylformic acid (19) is synthetic

With E-3-(3, the 5-Dimethoxyphenyl)-2-(4-hydroxyphenyl)-vinylformic acid 7 (6.0g, 19.98mmol) be dissolved in diacetyl oxide (24mL, 0.25mol) and triethylamine (24mL is in mixture 0.17mol) and at 125 ℃ of following heating 24h.With the mixture cool to room temperature.Add ethyl acetate (90mL), further be cooled to 5 ℃, with dense HCl (24mL) acidifying and under this temperature, stir 90min.Separate organic layer and with ethyl acetate (60mL) aqueous layer extracted.With bonded organic layer water (2 * 30mL) washings and with aqueous NaOH (5M, 3 * 42mL) extract.To be acidified to pH be 5.2 and stir down 30min at 0 ℃ with glacial acetic acid (40mL) with the aqueous alkaline layer.The solid of filtering separation, and mother liquor stirred down 1h with dense HCl (54mL) acidifying and at 5 ℃.With isolating solid filtering, with cold water (2 * 30mL) washings and 45 ℃ down dry 6h to obtain 19 (0.82g, 15%).Mp:131-133 ℃; ¹HNMR (400MHz, DMSO-d ₆) δ 13.28 (br s, 1H), 7.36 (d, J=8.4Hz, 2H), 7.28 (d, J=8.4Hz, 2H), 6.90 (d, J=8.6Hz, 4H), 6.32 (d, J=2.0Hz, 2H), 6.28 (t, J=2.0Hz, 2H), 4.92 (dd, J=9.2 and 4.4Hz, 1H), 3.99 (t, J=8.0Hz, 1H), 3.70 (s, 3H), 3.53 (s, 6H), 3.37 (dd, J=13.6 and 4.0Hz, 1H), 3.21 (dd, J=14.0 and 8.8Hz, 1H), 3.11 (dd, J=14.0 and 9.2Hz, 1H); MS (EI) m/z 522[M] ⁺

3.2 Z-3-(3, the 5-Dimethoxyphenyl)-2-(3-hydroxyphenyl)-methyl acrylate (20) is synthetic

Under argon gas, with the vitriol oil (15) join thorough drying 19 (0.90g heats 18h in agitated methanol suspension 3.0mmol) and under refluxing.Vapourisation under reduced pressure methyl alcohol, absorption of residual excess and water (30mL) in ethyl acetate (30mL), saturated aqueous NaHCO ₃(15mL) and salt solution (15mL) debris.Organic layer is dry on anhydrous magnesium sulfate, filter and evaporating solvent.With the crude product that obtains by chromatogram by silica gel refining and with hexane-ethyl acetate (7: 3) wash-out to obtain white solid 20 (0.38g, 36%). ¹HNMR(400MHz，CDCl ₃)：δ7.28(d，J＝8.4Hz，2H)，6.80(s，1H)，6.74(d，J＝8.4Hz，2H)，6.46(d，J＝2.0Hz，2H)，6.38(t，J＝2.0Hz，1H)，4.98(s，1H)，3.73(s，3H)，3.56(s，6H)。

3.3 Z-3-(3, the 5-Dimethoxyphenyl)-2-[3-(4-formyl radical phenoxy group)-phenyl]-methyl acrylate (21) Synthetic

Under argon gas, with 20 (3.0g, 9.5mmol) be dissolved in add among the dry DMF (20mL) and in this material sodium hydride (in oil 60%, 0.45g, 11.4mmol).In the orange solution that obtains, (1.25mL 11.4mmol) and at 80 ℃ heats 18h down to add the 4-fluorobenzaldehyde.With the reaction mixture cool to room temperature, add entry (50mL) and with ethyl acetate (3 * 100mL) extraction mixtures.By the crude product that obtains after the evaporation of the chromatographic refining by silica gel and with the mixture wash-out of hexane-ethyl acetate (4: 1) to obtain white solid 21 (3.0g, 75%). ¹HNMR (400MHz, CDCl ₃): δ 9.93 (s, 1H), 7.86 (d, J=8.8Hz, 2H), 7.49 (d, J=8.8Hz, 2H), 7.10 (eclipsed d, J=8.8Hz, 2H), 7.08 (eclipsed d, J=8.8Hz, 2H), 6.96 (s, 1H), 6.53 (dd, J=2.8Hz, 2H), 6.43 (t, J=2.0Hz, 1H), 3.80 (s, 3H), 3.79 (s, 6H).

3.4 Z-3-(3, the 5-Dimethoxyphenyl)-2-{3-[4-(2,4-dioxo thiazolidine-5-ylidenemethyl)-benzene oxygen Base]-phenyl }-methyl acrylate (22) synthetic

To 21 (2.12g, 5.20mmol) dry toluene suspension (40mL) in, be sequentially added into 2,4-thiazolidinedione (0.60g, 5.20mmol), phenylformic acid (0.84g, 6.76mmol) and piperidines (0.76g, heating removes water 5h continuously by means of Dean-Stark equipment simultaneously 7.80mmol) and under reflux temperature.Evaporation toluene and the chromatographic refining resistates by silica gel and be 7: 1 22 and 10 mixture to obtain on the basis of NMR analysis ratio with hexane-ethyl acetate (1: 1) wash-out. ¹HNMR (400MHz, DMSO-d ₆): δ 12.50 (br s, 1H), 7.81 (s, 1H), 7.68 (d, J=8.8Hz, 2H), 7.56 (d, J=8.8Hz, 2H), 7.19 (eclipsed d, J=8.8Hz, 2H), 7.15 (eclipsed d, J=8.8Hz, 2H), 7.13 (eclipsed s, 1H), 6.58 (d, J=2.0Hz, 2H), 6.53 (t, J=2.0Hz, 2H), 3.73 (s, 3H), 3.69 (s, 6H).

3.5 Z-3-(3, the 5-Dimethoxyphenyl)-2-{3-[4-(2,4-dioxo thiazolidine-5-ylmethyl)-phenoxy group]-benzene Base }-methyl acrylate (23) synthetic.

To 22 (add among the 2.40g, acetic acid solution 6.40mmol) (60mL) carbon carry palladium (10%, 1.20g) and ammonium formiate (17.2g, 223.2mmol) (note: heat release may become problem in reacting on a large scale; The oxygen strictness need be got rid of) and under 120 ℃, heat 20h.By

Bed filtering catalyst and vapourisation under reduced pressure acetate.Water (200mL) joined in the resistates and the solid of filtering separation.Use is used the methyl alcohol that comprises formic acid (0.05%): acetonitrile with the Intersil-ODS-3 amboceptor post (250 * 4.6mM, 5 μ n) of the speed operation of 15mL per minute by amboceptor HPLC: water (3: 3: 2) separation obtains pure Z-isomer 23.Mp 78-79 ℃; ¹HNMR (400MHz, DMSO-d ₆): δ 12.01 (br s, 1H), 7.49 (d, J=8.8Hz, 2H), 7.32 (d, J=8.4Hz, 2H), 7.15 (s, 1H), 7.04 (eclipsed d, J=8.8Hz, 2H), 7.00 (eclipsed d, J=8.4Hz, 2H), 6.58 (d, J=2.0Hz, 2H), 6.48 (t, J=2.0Hz, 2H), 4.88 (dd, J=9.2,4.4Hz, 1H), 3.79 (s, 3H), 3.59 (s, 6H), 3.39 (dd, J=14.8,4.8Hz, 1H), 3.15 (dd, J=14.4,9.2Hz, 1H); MS (EI) m/z 300[M] ⁺

Embodiment 4

4.1 3-(3, the 5-Dimethoxyphenyl)-2-{3-[4-(2,4-dioxo thiazolidine-5-ylmethyl)-phenoxy group]-benzene Base }-acrylamide (24) synthetic

The compound 24 that can represent by following structural formula:

Below from compound 14 preparation compounds 24.(2.12g is 4.18mmol) with exsiccant DMF (50mL) to add compound 14 in the dry flask of the cleaning with stirring rod.Then along with stirring, (1.36g 8.35mmol) and in by oily bubbler discharging, will react and heat 1h to 60 ℃ to add N,N'-carbonyldiimidazole.Then reaction mixture is cooled to 0 ℃ and add the 2M ammonia be dissolved in the methyl alcohol (10.5mL, 21mmol).By using 10% citric acid (50mL), ethyl acetate (250mL), and water (200mL) carries out cancellation to reaction, separates, extracts mixture then.Then in order water (2 * 150mL), (1 * 150mL) cleans organic phase and uses anhydrous MgSO salt solution ₄Dry.Organic concentrating provides crude product.Ethyl acetate-the hexane (1: 1) that comprises 1% acetate by use is made with extra care crude product to the ethyl acetate-hexane that comprises 1% acetate (3: 2) gradient elution by silica gel chromatography.It is solid white-faint yellow primary amide that concentrated suitable composition obtains 1.05g (49%).Analyze: ¹HNMR (400MHz, DMSO-d ₆): δ 12.05 (br s, 1H), 7.41 (s, H), 7.36 (br s, 1H), 7.25 (d, J=8.4Hz, 2H), 7.19 (d, J=8.4Hz, 2H), 7.06 (d, J=8.8Hz, 2H), 6.98 (d, J=8.4Hz, 2H), 6.94 (br s, 1H), 6.38 (m, 1H), 6.22 (s, 1H), 6.20 (s, 1H), 4.90 (dd, J=4.0,4.0Hz, 1H), 3.58 (s, 6H), 3.14 (dd, J=9.2,9.2Hz, 1H).

4.2 3-(3, the 5-Dimethoxyphenyl)-2-{3-[4-(2,4-dioxo thiazolidine-5-ylmethyl)-phenoxy group]-benzene Base }-N,N-DMAA (25) synthetic

The compound 25 that can represent by following structural formula:

Be prepared as follows: (2.11g is 4.18mmol) with exsiccant DMF (5mL) to add compound 14 in the dry flask of the cleaning with stirring rod.Then along with stirring, (1.36g 8.35mmol) and in by oily bubbler discharging, will react and heat 1h to 60 ℃ to add N,N'-carbonyldiimidazole.Then reaction mixture is cooled to 0 ℃ and also adds 2M dimethylamine (10.5mL, 21mmol) solution that is dissolved among the THF.By using 10% citric acid (50mL), ethyl acetate (250mL), and water (200mL) carries out cancellation to reaction; Separate, extract mixture then.Then in order water (2 * 150mL), (1 * 100mL) cleans organic phase and uses anhydrous MgSO salt solution ₄Dry.Organic concentrating provides crude product.Ethyl acetate-hexane (1: the 1) wash-out that comprises 1% acetate by use is by the refining crude product of silica gel chromatography.The concentrated 1.91g (86%) that obtains of composition is a solid pale uncle dimethylformamide.Analyze: ¹HNMR (400MHz, DMSO-d ₆): δ 11.99 (br, 1H), 7.30 (d, J=8.8Hz, 2H), 7.28 (d, J=8.8Hz, 2H), 6.98 (d, J=8.8Hz, 2H), 6.96 (d, J=8.8Hz, 2H), 6.59 (s, 1H), 6.36 (m, 1H), 6.30 (s, 1H), 6.26 (s, 1H), 4.90 (dd, J=4.4,4.4Hz, 1H), 3.53 (s, 6H), 3.14 (dd, J=9.2,9.2Hz, 1H), 3.08 (br, 3H), 2.95 (s, 3H).

4.3 3-(3, the 5-Dimethoxyphenyl)-2-{3-[4-(2,4-dioxo thiazolidine-5-ylmethyl)-phenoxy group]-benzene Base }-the N-methoxyl group ,-N methacrylamide (26) synthetic

The compound 26 that can represent by following structural formula:

Be prepared as follows: (0.90g is 1.78mmol) with exsiccant DMF (2mL) to add compound 14 in the dry flask of the cleaning with stirring rod.Then along with stirring, (0.58g 3.56mmol) and in by oily bubbler discharging, will react and heat 1h to 60 ℃ to add N,N'-carbonyldiimidazole.Then reaction mixture is cooled to 0 ℃ and add N-methyl-N-methoxyl group hydroxy amine hydrochloric acid salt (0.87g, 8.90mmol) and add triethylamine (1.24mL) and stir and spend the night.By using 10% citric acid (20mL), ethyl acetate (100mL), and water (80mL) carries out cancellation to reaction; Separate, extract mixture then.Then in order water (2 * 60mL), (1 * 40mL) cleans organic phase and uses anhydrous MgSO salt solution ₄Dry.Organic concentrating provides crude product.By using ethyl acetate-chloroform (1: 5) wash-out by the refining crude product of silica gel chromatography.Composition concentrated obtains being solid pale uncle N-methyl-N-methoxyamide 26 (840mg, 86%).Analyze: ¹HNMR (400MHz, DMSO-d ₆): δ 12.08 (br s, 1H), 7.29 (d, J=9.2Hz, 2H), 7.25 (d, J=8.8Hz, 2H), 7.04 (d, J=8.8Hz, 2H), 6.96 (d, J=8.4Hz, 2H), 6.58 (s, 1H), 6.36 (m, 1H), 6.28 (s, 1H), 6.25 (s, 1H), 4.90 (dd, J=4.4,4.4Hz, 1H), 3.53 (s, 6H), 3.10 (dd, J=9.2,9.2Hz, 1H), 3.06 (br, 3H), 2.90 (s, 3H).

Embodiment 5 is according to route 4 synthesis types 1 (wherein Z is formula II) compound

5.1 2-(4-acetoxyl group phenyl)-3-p-methylphenyl vinylformic acid (37) is synthetic

To (4-hydroxyphenyl) acetate (11.0g, 72.2mmol) and the 4-tolyl aldehyde (7.20g, add in the mixture of 150mL solution of acetic anhydride 60mmol) salt of wormwood (7.14g, 72.7mmol).Before with its cool to room temperature, reaction mixture is remained on 80 ℃ up to all ethyl acetate of evaporation.Throw out is filtered and water and hexane wash.With filter cake recrystallize from toluene, filter, with hexane wash and dry to obtain pale yellow powder 37 (12.6g, 70.9%) under vacuum. ¹HNMR(400MHz，DMSO-d ₆)：δ12.52(brs，1H)，7.76(s，1H)，7.18(d，J＝8.8Hz，2H)，7.12(d，J＝8.8Hz，2H)，7.04(d，J＝8.0Hz，2H)，6.96(d，J＝8.4Hz，2H)，2.29(s，3H)，2.23(s，3H)。

5.2 2-(3-hydroxyphenyl)-3-p-methylphenyl vinylformic acid (38) is synthetic

(4.03g adds 20mL lithium hydroxide (1.14g, 47.5mmol) aqueous solution in 20mL THF solution 13.62mmol) to compound 37.Stirring reaction 16h at room temperature, add then the 5%HCl aqueous solution to pH be 1.Yellow solid filtered and from toluene recrystallize, with hexane wash and under vacuum drying to obtain white solid 38 (2.9g, 83.7%). ¹HNMR(400MHz，DMSO-d ₆)：δ12.48(br?s，1H)，9.45(br?s，1H)，7.65(s，1H)，7.03(d，J＝8.0Hz，2H)，6.98(d，J＝8.4Hz，2H)，6.92(d，J＝8.4Hz，2H)，6.76(d，J＝8.8Hz，2H)，2.23(s，3H)。

5.3 2-[3-(4-formyl radical phenoxy group)-phenyl]-3-p-methylphenyl vinylformic acid (39) synthetic

To compound 38 (4.36g, 17.2mmol) and salt of wormwood (5.21g, add in 120mL N,N-dimethylacetamide solution 37.7mmol) the 4-fluorobenzaldehyde (2.34mL, 21.8mmol).Under argon gas, reaction mixture is heated 1.5h to 190 ℃, cool to room temperature then, add the 5%HCl aqueous solution to pH be 1 so that product separate, as oil.About 30mL ethyl acetate is joined in the mixture, stir this mixture 16h.With solid collection and from toluene recrystallize, clean and dry to obtain yellow powder 39 (5.00g, 81.0%) under vacuum with hexane. ¹HNMR(400MHz，DMSO-d ₆)：δ12.68(s，1H)，9.95(s，1H)，7.99(d，J＝8.8Hz，2H)，7.78(s，1H)，7.26(d，J＝8.4Hz，2H)，7.19(d，J＝6.8Hz，2H)，7.14(d，J＝6.4Hz，2H)，7.09(d，J＝8.0Hz，2H)，6.99(d，J＝8.4Hz，2H)，2.25(s，3H)。

5.4 2-{3-[4-(2,4-dioxo thiazolidine-5-ylidenylmethyl)-phenoxy group]-phenyl }-3-p-methylphenyl propylene Synthesizing of acid (40)

To 39 (3.2g, 8.96mmol), thiazolidine-2, the 4-diketone (1.05g, 8.96mmol), and phenylformic acid (1.31g, add in 80mL toluene solution 10.7mmol) piperidines (1.33mL, 13.44mmol).Under argon gas with mixture with Dean Stark equipment vigorous reflux 1.5h cool to room temperature then in backflow.Adding 5%HCl is 1 to pH.With solid filtering, recrystallize from toluene filters, and before vacuum-drying with hexane wash to obtain yellow solid 40 (quantitative). ¹HNMR(400MHz，DMSO-d ₆)：δ12.68(br?s，1H)，12.53(br?s，1H)，7.79(s，1H)，7.74(s，1H)，7.69(d，J＝8.8Hz，2H)，7.24(d，J＝9.2Hz，2H)，7.19(d，J＝7.6Hz，2H)，7.14(d，J＝9.2Hz，2H)，7.09(d，J＝8.0Hz，2H)，6.98(d，J＝8.0Hz，2H)，2.25(s，3H)。

5.5 2-{3-[4-(2,4-dioxo thiazolidine-5-ylmethyl)-phenoxy group]-phenyl }-3-p-methylphenyl vinylformic acid Synthesizing (41)

To 40 (0.8g, 1.76mmol) and ammonium formiate (6.66g adds 5%Pd/C (1.0g) in 20mL glacial acetic acid solution 105.6mmol).With the mixture 7.5h that refluxes, cool to room temperature also filters by Celite.Enriched mixture joins in the 160mL water then in a vacuum.Product is filtered and uses hexane wash.With solid recrystallize from toluene, cool to room temperature and with supersound process up to observing solid.And then the 16h that stirs the mixture under the room temperature.The collecting precipitation thing and with hexane wash to obtain white solid 41 (0.50g, 61.0%). ¹HNMR(400MHz，DMSO-d ₆)：δ12.66(s，1H)，12.04(br?s，1H)，7.76(s，1H)，7.33(d，J＝8.8Hz，2H)，7.18(d，J＝8.4Hz，2H)，7.03(d，J＝8.4Hz，2H)，7.00(d，J＝8.4Hz，2H)，6.97(d，J＝9.2Hz，2H)，6.95(d，J＝8.0Hz，2H)，4.90(dd，J＝4.4，9.6Hz，1H)，3.39(dd，J＝4.4，14.0Hz，1H)，3.20(dd，J＝9.2，14.0Hz，1H)，2.25(s，3H)。

5.6 2-{3-[4-(2,4-dioxo thiazolidine-5-ylmethyl)-phenoxy group]-phenyl }-3-p-methylphenyl vinylformic acid Synthesizing of methyl esters (42)

To 41 (0.1g, 0.218mmol) and BOP[Castro ' s Reagent, benzotriazole-1-base-oxygen-three-(dimethylamino)-phosphorus hexafluorophosphate] (0.173g, add in 6mL dichloromethane mixture 0.391mmol) triethylamine (0.080mL, 0.572mmol).Mixture is stirred 1h, and (the 0.5M solution in the methyl alcohol, 0.08mL 0.042mmol) adds with 6mLMeOH with sodium methylate then.Stirring reaction 16h at room temperature.It is 0 and with 30mL dichloromethane extraction mixture three times that 5%HCl is joined pH.Use the salt water washing, pass through MgSO ₄Drying is filtered and concentrated bonded organic layer.Resistates is loaded on the silicagel column as the solution in methylene dichloride.With hexane-ethyl acetate (3: 2) eluted product.Concentration components is to obtaining white solid 42 (46.8mg, 38.4%) in a vacuum. ¹HNMR(400MHz，DMSO-d ₆)：δ12.03(br?s，1H)，7.76(s，1H)，7.32(d，J＝8.8Hz，2H)，7.20(d，J＝8.8Hz，2H)，7.08(d，J＝8.0Hz，2H)，7.00(d，J＝8.8Hz，2H)，6.98(d，J＝8.8Hz，2H)，6.95(d，J＝8.0Hz，2H)，4.90(dd，J＝4.8，9.6Hz，1H)，3.70(s，3H)，3.38(dd，J＝4.0，13.6Hz，1H)，3.12(dd，J＝9.2，14.0Hz，1H)，2.25(s，3H)。

Embodiment 6 is according to route 5 synthesis types 1 (wherein Z is formula I) compound

6.1 3,5-dimethylbenzaldehyde (43) synthetic

To 3, the 5-mesitylenic acid (1.50g, 10mmol) and triethylamine (4.2mL, add in methylene dichloride 30mmol) (40mL) mixture BOP medicament (4.42g, 10mmol).Solution is at room temperature stirred 20min, add N then, and O-dimethyl hydroxyl amine hydrochlorate (1.0g, 10mmol).After other 10min, (1.4mL 10mmol) and with mixture stirs other 0.5h to add triethylamine.Except that desolvating and mixture being dissolved in ethyl acetate (60mL) again, use 1N HCl (40mL) in a vacuum, 1N NaOH (40mL), water, salt water washing, dry then (MgSO ₄), filter and concentrate to obtain colourless syrup (1.25g) in a vacuum.This material is dissolved in THF (50mL) and is cooled to 0 ℃ under argon gas atmosphere.In 5min with the DIBAL[diisobutylaluminium hydride] (be dissolved among the THF, 1M, solution 10mL) joins in the solution of stirring.After the stirring of 20min, add other DIBAL (4mL).After other 15min, extract in ethyl acetate (75mL) with other 1NHCl (75mL) quenching reaction and with product, water (2 * 40mL), salt solution (40mL) washing, dry (MgSO ₄), filter and concentrate to obtain 43 (1.04g, 77% is overall) in a vacuum.

6.2 3-(3, the 5-3,5-dimethylphenyl)-2-(3-hydroxyphenyl)-vinylformic acid (44) is synthetic

To 43 (2.58g, 19.2mmol), the 4-hydroxyphenyl acetic acid (2.93g, 19.2mmol) and potassium acetate (2.26g adds diacetyl oxide (80mL) in mixture 22.4mmol).Mixture heating up 4h is cooled to room temperature, then in the impouring water (320mL) to refluxing.After stirring 1.5h, solid gums is deposited to bottom and decantation supernatant liquor.In resistates, add THF (80mL) and 1N NaOH (120mL) and mixture is stirred 30min.In ethyl acetate (240mL), extract water (180mL), salt solution (180mL) washing, dry (MgSO with 1N HCl (160mL) acidifying mixture and with product ₄), filter and concentrate in a vacuum.The thick solid of crystallization is to obtain faint yellow solid 44 (2.41g, 47.5%) in toluene.

6.3 3-(3, the 5-3,5-dimethylphenyl)-2-[3-(4-formyl radical phenoxy group)-phenyl]-vinylformic acid (45) synthetic

To 44 (add among the 2.26g, DMF solution (14mL) 16.8mmol) sodium hydride (60% dispersion in mineral oil, 0.62g, 15.4mmol), after gas release stops, adding the 4-fluorobenzaldehyde (1.12g, 10.5mmol) and stirring reaction 16h.In mixture impouring 10% citric acid (70mL), form the glassy yellow solid thereafter.Wash with water solid and then from toluene the wet solid of azeotropic and recrystallize to obtain yellow solid 45 (2.13g, 81%).

6.4 3-(3, the 5-3,5-dimethylphenyl)-2-{3-[4-(2,4-dioxo thiazolidine-5-ylidenemethyl)-phenoxy group]-benzene Base }-vinylformic acid (46) synthetic

In the 100mL round-bottomed flask of assembling Dean-Stark equipment, under vigorous reflux, with 45 (1.24g, 3.36mmol), 2,4-thiazolidinedione (0.4g, 3.36mmol), phenylformic acid (0.5g, 4.0mmol) and piperidines (0.50mL, mixture 5.04mmol) is blend 45min in toluene (48mL).Reaction mixture also stirs up to forming the glassy yellow solid in impouring 10% citric acid (32mL) then.With solid filtering and wash with water and from toluene the wet solid of azeotropic and recrystallize to obtain 46 (1.48g, 94%). ¹HNMR(400MHz，DMSO-d ₆)：δ12.70(br?s，1H)，12.56(br?s，1H)，7.79(s，1H)，7.72(s，1H)，7.65(d，J＝8.8Hz，2H)，7.20(d，J＝8.4Hz，2H)，7.16(d，J＝8.4Hz，2H)，7.14(d，J＝8.8Hz，2H)，6.90(s，1H)，6.68(s，2H)，2.18(s，6H)。

6.5 3-(3, the 5-3,5-dimethylphenyl)-2-{3-[4-(2,4-dioxo thiazolidine-5-ylmethyl)-phenoxy group]-phenyl }- Synthesizing of vinylformic acid (47)

With 46 (2.20g, 4.68mmol), ammonium formiate (0.6g, 5.04mmol) and the mixture backflow 15h of 10% carrying alumina Pd (2.4g).Reaction mixture is to room temperature and leach catalyzer.Adding entry comes separated product and crosses filter solid.The wet solid of azeotropic and recrystallize is to obtain 47 (1.08g, 48%) from toluene. ¹HNMR(400MHz，DMSO-d ₆)：δ12.69(br?s，1H)，12.06(br?s，1H)，7.69(s，1H)，7.28(d，J＝8.8Hz，2H)，7.16(d，J＝8.4Hz，2H)，7.01(d，J＝8.4Hz，2H)，6.99(d，J＝8.8Hz，2H)，6.90(s，1H)，6.61(s，2H)，4.92(dd，J＝8.8，4.4Hz，1H)，3.39(dd，J＝14.0，4.4Hz，1H)，3.10(dd，J＝14.0，8.8Hz，1H)，2.15(s，6H)。

6.6 3-(3, the 5-3,5-dimethylphenyl)-2-{3-[4-(2,4-dioxo thiazolidine-5-ylmethyl)-phenoxy group]-phenyl }- Synthesizing of vinylformic acid benzotriazole-1-base ester (48)

With 47 (0.97g, 2.04mmol) and N, the N-diisopropylethylamine (0.396mL, methylene dichloride 2.28mmol) (24mL) mixture add the BOP medicament (0.91g, 2.04mmol).At room temperature stir after the 45min, mixture is used 1N HCl (120mL) then with ethyl acetate (180mL) dilution, water (120mL), salt solution (120mL) washing, dry (MgSO ₄), filter and concentrate in a vacuum.By using hexane-ethyl acetate (3: 2) by the refining crude product of flash chromatography.The solid that will obtain after concentrating is further used hexane: ethyl acetate (4: 1) is developed to obtain 48 (0.92g, 78%).

6.7 3-(3, the 5-3,5-dimethylphenyl)-2-{3-[4-(2,4-dioxo thiazolidine-5-ylmethyl)-phenoxy group]-phenyl }- Synthesizing of methyl acrylate (49)

With 48 (add among the 192mg, methanol solution 0.32mmol) (8mL) sodium methylate (0.5N in methyl alcohol, 1.6mL).After 10min, in ethyl acetate (40mL), extract water (80mL), salt solution (80mL) washing, dry (MgSO with 1N HCl (1.6mL) diluted mixture thing and with product ₄), filter and concentrate in a vacuum.Use hexane: ethyl acetate (3: 2) is made with extra care crude product to obtain 49 (104mg, 66%) of white foam shape by flash chromatography. ¹HNMR(400MHz，DMSO-d ₆)：δ12.10(br?s，1H)，7.71(s，1H)，7.28(d，J＝8.8Hz，2H)，7.18(d，J＝8.8Hz，2H)，7.03(d，J＝8.8Hz，2H)，6.97(d，J＝8.8Hz，2H)，6.92(s，1H)，6.68(s，2H)，4.91(dd，J＝8.8，4.4Hz，1H)，3.73(s，3H)，3.37(dd，J＝14.0，4.4Hz，1H)，3.12(dd，J＝14.0，8.8Hz，1H)，2.12(s，6H)。

6.8 5-(3-{4-[2-(3, the 5-3,5-dimethylphenyl)-1-(morpholine-4-carbonyl)-vinyl]-phenoxy group }-benzyl)-thiazole Alkane-2,4-diketone (50) synthetic

At room temperature, to 48 (add among the 104mg, methylene dichloride suspension (4.5mL) 1.8mmol) morpholine (78.3mL, 0.9mmol).Solution becomes is clear.After 10min, with 10% citric acid (3.6mL) treating mixture.With dichloromethane layer drying (MgSO ₄) and directly reprint on the pillar, use hexane: ethyl acetate (2: 3) wash-out pillar is to obtain 50 (93.6mg, 86%) of white foam shape. ¹HNMR(400MHz，DMSO-d ₆)：δ12.10(br?s，1H)，7.27(d，J＝8.8Hz，2H)，7.26(d，J＝8.8Hz，2H)，6.98(d，J＝8.8Hz，2H)，6.96(d，J＝8.8Hz，2H)，6.85(s，1H)，6.72(s，2H)，6.61(s，1H)，4.91(dd，J＝8.8，4.4Hz，1H)，3.59(br?s，8H)，3.37(dd，J＝14.0，4.4Hz，1H)，3.12(dd，J＝14.0，8.8Hz，1H)，2.13(s，6H)。

Embodiment 7 is according to route 6 synthesis types 1 (wherein Z is formula I) compound

7.1 5-(3-hydroxyl benzylidene)-thiazolidine-2,4-diketone (51) synthetic

To the 3-hydroxy benzaldehyde (2.20g, 18mmol), 2, the 4-thiazolidinedione (2.11g, 18mmol), phenylformic acid (2.64g, 21.6mmol) toluene (60mL) mixture in add piperidines (2.7mL be 27mmol) and with pack into Dean-Strark equipment and introduce vigorous reflux of mixture.After 45min, mixture is cooled off in ice bath and the decantation supernatant liquor.The glassy yellow solid is become suspension and filter to obtain faint yellow solid 51 (3.66g, 91.5%) by adding glacial acetic acid (60mL) by B. ¹HNMR(400MHz，DMSO-d ₆)：δ12.45(br?s，1H)，10.30(s，1H)，7.70(s，1H)，7.45(d，J＝8.8Hz，2H)，6.91(d，J＝8.8Hz，2H)。

7.2 5-(3-hydroxybenzyl)-thiazolidine-2,4-diketone (52) synthetic.

To 51 (add among the 3.60g, glacial acetic acid suspension (60mL) 16.2mmol) ammonium formiate (3.76g, 60mmol) and 10% carbon carries Pd (3.48g) and with mixture heating up 16h to vigorous reflux.Mixture is cooled to room temperature, filters by Celite then.Remove most of acetate in a vacuum, then crude product is dissolved in ethyl acetate (150mL), (salt solution (150mL) washing is used in 2 * 150mL) washings to water then.With organic layer drying (MgSO4), filter and concentrate to obtain beige solid 52 (3.33g, 88%) in a vacuum. ¹HNMR(400MHz，DMSO-d ₆)：δ11.98(br?s，1H)，9.32(s，1H)，7.02(d，J＝8.4Hz，2H)，6.68(d，J＝8.4Hz，2H)，4.82(dd，J＝8.4，4.0Hz，1H)，3.25(dd，J＝14.4，4.4Hz，1H)，2.99(dd，J＝14.0，9.2Hz，1H)。

7.3 3-[4-(2,4-dioxo thiazolidine-5-ylmethyl)-phenoxy group]-phenyl aldehyde (53) synthetic

To 52 (add among the 3.21g, DMF solution (90mL) 14.4mmol) the 4-fluorobenzaldehyde (1.80g, 14.4mmol) and Cs ₂CO ₃(12g, 37.2mmol) and 2h to 100 ℃ of heated mixt.In 10% citric acid (120mL) and ethyl acetate (120mL) with mixture impouring vigorous stirring.With organic layer water (180mL), salt solution (180mL) washing, dry (MgSO4) filters and concentrates in a vacuum.The development crude product is to obtain white solid 53 (3.21g, 67.5%) in hexane-ethyl acetate (2: 1). ¹HNMR(400MHz，DMSO-d ₆)：δ12.08(br?s，1H)，9.90(s，1H)，7.93(d，J＝8.8Hz，2H)，7.36(d，J＝8.4Hz，2H)，7.14(d，J＝8.4Hz，2H)，7.08(d，J＝8.4Hz，2H)，4.95(dd，J＝8.4，4.4Hz，1H)，3.40(dd，J＝14.4，4.4Hz，1H)，3.19(dd，J＝14.4，9.2Hz，1H)。

7.4 5-(3-{4-[2-(4-p-methoxy-phenyl)-vinyl] phenoxy group }-benzyl)-thiazolidine-2,4-diketone (54) Synthetic

Under 0 ℃, to chlorination 4-methoxy-benzyl triphenyl phosphorus (377mg, in the THF suspension (9mL) 0.9mmol), add solid potassium tert-butoxide (202mg, 1.8mmol).Orange-the red solution that obtains is stirred 15min down at 0 ℃, be cooled to-45 ℃ then.(294mg 0.9mmol) and with reaction mixture stirs 30min under this temperature to add solid chemical compound 53.(54mL 0.9mmol) and in a vacuum removes and desolvates to add glacial acetic acid to this yellow solution.The crude product that suspends in methylene dichloride makes it be adsorbed onto on the silica gel and uses hexane-ethyl acetate (7: 3) refining by flash chromatography, obtains white solid 54 (165mg, 42%) after dry then in high vacuum. ¹HNMR(400MHz，DMSO-d ₆)：δ12.05(br?s，1H)，7.28(d，J＝8.0Hz，2H)，7.25(d，J＝8.4Hz，2H)，7.19(d，J＝8.4Hz，2H)，6.98(d，J＝8.4Hz，2H)，6.89(d，J＝8.8Hz，2H)，6.85(d，J＝8.8Hz，2H)，6.55(d，J＝12.4Hz，2H)，6.49(d，J＝12.0Hz，2H)，4.92(dd，J＝9.2，4.4Hz，1H)，3.38(dd，J＝14.0，4.4Hz，1H)，3.12(dd，J＝14.0，8.8Hz，1H)。

Embodiment 8

8.1 5-(3-{4-[2-(3, the 5-Dimethoxyphenyl)-vinyl] phenoxy group }-benzyl)-thiazolidine-2, the 4-diketone Synthesizing (55)

Under 0 ℃, to bromination 3,5-dimethoxy-benzyl triphenyl phosphorus (0.98g, in the THF suspension (12mL) 2.4mmol), the adding solid potassium tert-butoxide (269mg, 2.4mmol).The red solution that obtains is stirred 15min down at 0 ℃, be cooled to-78 ℃ then.(0.36g 1.08mmol) and with reaction is warmed up to room temperature to add solid chemical compound 53.After 30min, add 10% citric acid (60mL).And mixture distributed between water (60mL) and ethyl acetate (90mL).With organic layer water (60mL) and the dry then (MgSO of salt solution (60mL) washing ₄), filter and concentrate in a vacuum.Use hexane-ethyl acetate (7: 3) by the refining crude product of flash chromatography, and under high vacuum, obtain slight opaque coating 55 (72mg, 14.4%) after the concentrate drying. ¹HNMR(400MHz，DMSO-d ₆)：δ12.05(br?s，1H)，7.28(d，J＝8.8Hz，2H)，7.30(d，J＝8.8Hz，2H)，6.95(d，J＝8.4Hz，2H)，6.90(d，J＝8.4Hz，2H)，6.63(d，J＝12.4Hz，2H)，6.50(d，J＝12.0Hz，2H)，6.39(d，J＝2.4Hz，1H)，6.36(d，J＝2.4Hz，1H)，6.32(t，J＝2.4Hz，1H)，4.92(dd，J＝9.2，4.4Hz，1H)，3.52(s，6H)，3.46(dd，J＝14.0，4.4Hz，1H)，3.13(dd，J＝14.4，8.8Hz，1H)。

Embodiment 9

9.1 the picked-up of glucose

The 3T3-L1 adipocyte that adopts differentiation with improved Tafuri method (Endocrinology, 1996,137,4706-4712) detect basic glucose uptake.

In this experiment, at first adopt Forst and Lane method (J Biol Chem, 1985,260,2646-2652) obtain adipocyte by the differentiation of 3T3-L1 inoblast.Then, in 24 orifice plates, the adipocyte of differentiation is being contained 10% foetal calf serum (GibcoBRL, gaithersburg, MD) and in DMEM (the Eagle Modified Essential Medium) substratum of the compound 11 of series concentration or carrier (0.1%DMSO) hatch 48h, triplicate.Phosphoric acid buffer (PBS, 150mM NaCl, 1mM KH ₂PO ₄, 3mM Na ₂PO ₄PH 7.4) hatch 2h among washed cell and the no glucose DMEM under 37 ℃.With Ke-Lin Shi phosphoric acid buffer (KRP) washed cell 3 times.By in each hole, adding 0.25 μ Ci2- ¹⁴C (U)-DDG (300 μ Ci/mmol, American Radiolabeled Chemicals Inc., St Louis MO) causes glucose uptake, under the room temperature cell is hatched 10min under the situation of the 2-deoxy-D-glucose existence of cold (heterotope mark).At last, cell with the ice-cold PBS washing that comprises the cold glucose of 10mM three times, with the 0.5%SDS dissolving, and is counted in scintillometer (Beckman LS6500).

9.2 the mensuration of transfection and uciferase activity

The 3T3-L1 adipocyte that adopts differentiation with improved Tafuri method (Endocrinology, 1996,137,4706-4712) detect basic glucose uptake.

In this experiment, at first adopt Forst and Lane method (J Biol Chem, 1985,260,2646-2652) obtain adipocyte by the differentiation of 3T3-L1 inoblast.Then, in 24 orifice plates, the adipocyte of differentiation is being contained 10% foetal calf serum (GibcoBRL, gaithersburg, MD) and in DMEM (the Eagle Modified Essential Medium) substratum of the compound 11 of series concentration or carrier (0.1%DMSO) hatch 48h, triplicate.Phosphoric acid buffer (PBS, 150mM NaCl, 1mM KH ₂PO ₄, 3mM Na ₂PO ₄PH 7.4) hatch 2h among washed cell and the no glucose DMEM under 37 ℃.With Ke-Lin Shi phosphoric acid buffer (KRP) washed cell 3 times.By in each hole, adding 0.25 μ Ci2-14C (U)-DDG (300 μ Ci/mmol, American Radiolabeled Chemicals Inc., St Louis MO) causes glucose uptake, under the room temperature cell is hatched 10min under the situation of the 2-deoxy-D-glucose existence of cold (heterotope mark).At last, cell with the ice-cold PBS washing that comprises the cold glucose of 10mM three times, with the 0.5%SDS dissolving, and is counted in scintillometer (Beckman LS6500).

9.3 result

The preparation and in the 3T3-L1 cell, 0.001uM, having three kinds of two keys under 0.01uM, 0.1uM, 1uM, 5uM and the 10uM concentration on the different positions of test compounds 11 in the extracorporeal glucose picked-up may methyl ester analogue (10,11,17), and adjacent methyl ester analogue (42), methyl ester 18 without any two keys, free acid analogue 14 and 11 Z-isomer 23 (people such as Tafuri, Endocrinology, 137:4706-12,1996; Frost and Lane, J Biol Chem 260:2646-52,1985) (table 1).Under the concentration of 10uM, compound 10,11,42 can increase to glucose uptake the degree that can compare with the level of rosiglitazone, wherein under high density (10uM) compound 10,11 activity be respectively rosiglitazone near 2 to 3 times.Compound 17 and 18 demonstrates appropriate activity under 10uM concentration and compound 23 is inactive basically.Under the concentration of 1uM, compound 10 and 11 keeps active, but compound 10 is less than the activity of rosiglitazone.The compound 10 that comprises two two keys demonstrates the increase of the low glucose uptake of comparing with 11.Only have a compound 17 and a double reductive product 18 that is attached to two keys of TZD ring and under 10uM, show lower activity.We infer that thus the existence that does not exist with TZD ring bonded both shoulders and the two keys of styracin is important for the glucose uptake that increases in this system.The geometric position that 23,11 corresponding Z-isomer, active shortage demonstrate two keys is crucial for activity.Compare with methyl ester 11, the more low activity of free acid 14 may be because the lipophilic difference of compound.

The antidiabetic compound of TZD classification passes through the sensitivity of the activity increase of PPAR-γ to the peripheral tissue of Regular Insulin.Our target is to improve as introducing this extra mechanism of action in the diphenylethylene compounds by chemistry.In vitro system, use by with human ppar γ 2 cells transfected of Photinus pyralis LUC ligation as the report element, study agonist activity to PPAR-γ.The result who measures alive is summarised in the table 2 to this external commentaries on classics of test compound.The most virtuous compound is thought the 11 (EC of 0.28uM in this series ₅₀), it has by the rosiglitazone of the identical mensuration (EC of 0.009uM ₅₀) about a thirtieth activity.The compound 42 that the ortho position replaces has also showed stronger activity.Compound 10 (two two keys) and compound 14 (11 free acids) also demonstrate rational effectiveness, although it is less than the effectiveness of compound 11.The compound 17 and 18 of the two keys of the styracin that wherein reduces is inactive basically.In this measured, Z-isomer 23 demonstrated the effectiveness less than compound 11.According to these in vitro results, assessing compound 11 in two widely used NIDDM mouse models.

Table 1:3T3-L1 adipocyte ^aIn extracorporeal glucose picked-up

% substrate with non-treatment cell is expressed ^aBasis glucose uptake (each point is the mean value ± SD value of four times of measured values).

Table 2: by thiazolidinedione ^aThe uciferase activity of PPAR-γ mediation induce

A result is based on the several separate test.Each test comprises at least 8 different pharmacological agent concentration (0.1-3.0 μ M), and each concentration is carried out three times.Use GraphPad Prism computed in software EC50 value by nonlinear regression analysis. ^bN=independently tests.

The in vivo test of the hypoglycemic effect of embodiment 10 test compounds

All processes of carrying out all meet animal welfare bill (Animal Welfare Act) and USDA standard (U.S.Department of Agriculture regulations) and can be shown loving care for and the use council (Calyx Therapeutics Institutional Animal Care and UseCommittee) approval by animal by the Calyx refrigeration.Under the situation of 22 ℃ and 50% relative humidity, adopt 12h illumination and dark cycle to raise animal, and (Harlan Teklad, Madison WI) and arbitrarily drink water to bestow the tooth animal diet followed of rule.When its age was 5 weeks, (Barharbor Maine) obtained male C57BL/KsJ-db/db and C57BL/6J-ob/ob mouse from Jackson Laboratories.With compound 11, ((σ, St Louis MO) raise oral administration once a day by force to seven all big animals to 0.5% carboxymethyl cellulose aqueous solution for rosiglitazone maleate (from the marketed tablet recrystallize) or carrier.Before using next time dosage and on the feed under the state, with the glucose meter of simple operations (LifeScan, Inc., Milpitas, CA) and/or the glucose oxidase enzymatic determination (St Louis MO) carries out blood glucose measurement for Glucose Trinder, Sigma.

10.1 experimental procedure

54 8 week type ii diabetes mouse in age (db/db mouse) are divided into five groups according to their blood sugar and body weight.First group: normal control group, the normal feed of feeding; Second group: positive controls, give the antidiabetic drug rosiglitazone; The 3rd group: low dose compounds 42 test group (8mg/kg); The 4th group: middle dosage compound 23 test group (20mg/kg); The 5th group: high doses of compounds 11 test group (50mg/kg).Every day gastric infusion.Weigh weekly, survey blood sugar, duration of test runs: 4 weeks.

10.2 result

Fig. 1 shows the influence to db/db mouse body weight of compound 11,23,42 and rosiglitazone.As shown in Figure 1, the positive control drug rosiglitazone can significantly increase the body weight of db/db mouse, and compound 11 high dose group 50mg/kg can increase the mouse body weight around the after treatment.

Fig. 2 shows the influence to the db/db mouse blood sugar of compound 11,23,42 and rosiglitazone, the wherein comparison of positive control group of Fig. 2 a and normal control group fasting plasma glucose; Fig. 2 b is that compound 11 high dose group and normal control group fasting plasma glucose compare; Fig. 2 c is dosage group and the comparison of normal control group fasting plasma glucose in the compound 23; Fig. 2 d is that compound 11 low dose group and normal control group fasting plasma glucose compare.

As shown in Figure 2, property contrast medicine rosiglitazone is at the slight lowering blood glucose of the first week energy, and second week can significantly be reduced the fasting plasma glucose of db/db mouse.The 3rd week began to lose blood sugar reducing function; Compound 11 high dosages (50mg/kg/day) can significantly reduce the fasting plasma glucose of db/db mouse; Dosage in the compound 23 (20mg/kg/day) is at the slight lowering blood glucose of the first week energy, but no difference of science of statistics; The no hypoglycemic effect of compound 42 low dosages (8mg/kg/day).

10.3 conclusion

With compound 11 high dosages (50mg/kg/day) treatment type ii diabetes mouse (db/db mouse) 4 weeks, the obvious functions of blood sugar effect is arranged, but this medicine there is the side effect of the body weight of remarkable increase mouse.Dosage in the compound 23 (20mg/kg/day) and compound 42 low dosages (20mg/kg/day) do not have obvious hypoglycemic activity to type ii diabetes mouse (db/db mouse).

Embodiment 11 co-administereds

Can combine with physiology acceptable carrier or media so that pharmaceutical composition to be provided according to compound of the present invention, be tablet or the capsular lyophilized powder that contains various fillers and binding agent as form.Similarly, compound can with other medicament co-administered, co-administered should be represented to use two kinds of medicaments so that two kinds of medicament bonded beneficial effects to be provided to the patient at least.For example, can be within a certain period of time simultaneously or make with medicament in order.Can select experience to determine the effective dose of compound in the composition by those skilled in the art widely.In addition, according to indication and required result of treatment, compound of the present invention can use separately or be used in combination with one or more extra medicaments.For example; in diabetes; insulin resistance and related conditions or complication; comprise under the situation of obesity and hyperlipidaemia; this additional agent can be selected from: Regular Insulin or insulin-mimickers, and sulfonylurea is (as the own urea of vinegar ring sulphur; P-607; glimepiride; Glipizide; Glyburide) or other Regular Insulin succagoga (as the Na Gelie naphthalene; Rui Gelie naphthalene etc.); thiazolidinedione is (as U-721017E; rosiglitazone) or other peroxisome Proliferator-activated receptor (PPAR)-the exciting flesh of γ; Bei Te is (as Ben Zhabeite; clofibrate; fenofibrate; gemfibrozol etc.) or other PPAR-o excitomotor; the PPAR-delta agonists; biguanides (as buformin); statin is (as fluvastatin; lovastatin; Pravastatin; simvastatin etc.) or other hydroxymethyl penta and acyl group (HMG) CoA-reductase inhibitors; alpha-glucosidase inhibitor is (as acarbose; miglitol; voglibose etc.); the cholic acid binding resin is (as Colestyramine; colestipol etc.); high-density lipoprotein (HDL) (HDL)-depressant such as apolipoprotein A-1 (apoA1); nicotinic acid etc.; Pu Luobukao and niacin.Combination therapy by the present invention imagination comprises, for example, and use and the use in formula of medicine separately of The compounds of this invention and additional agent in the single medicine prescription of The compounds of this invention and additional agent.

11.1 contain the pharmaceutical composition of compound 11

Prescription 1:

Compound 11 100mg

Microcrystalline Cellulose 40mg

Lactose 50mg

Low-substituted hydroxypropyl cellulose 8mg

Magnesium Stearate 2mg

Total amount 200mg

Prescription 2:

Compound 11 100mg

Microcrystalline Cellulose 40mg

Lactose 50mg

Croscarmellose sodium 8mg

Magnesium Stearate 2mg

Total amount 200mg

Prescription 3:

Compound 11 100mg

Microcrystalline Cellulose 40mg

Lactose 50mg

Polyvinylpolypyrrolidone 8mg

Magnesium Stearate 2mg

Total amount 200mg

Prescription 4:

Compound 11 100mg

Lactose 94mg

Polyvinylpolypyrrolidone 4mg

Magnesium Stearate 2mg

Total amount 200mg

Prescription 5:

Compound 11 100mg

Microcrystalline Cellulose 40mg

Lactose 58mg

Magnesium Stearate 2mg

Total amount 200mg

Prescription 6:

Compound 11 200mg

Microcrystalline Cellulose 41mg

Lactose 50mg

Polyvinylpolypyrrolidone 6mg

Magnesium Stearate 3mg

Total amount 300mg

Prescription 7:

Compound 11 300mg

Microcrystalline Cellulose 40mg

Lactose 48mg

Polyvinylpolypyrrolidone 8mg

Magnesium Stearate 4mg

Total amount 400mg

The preparation method of preparation of the present invention is as follows: get active compound of the present invention, disintegrating agent and weighting agent in proportion and cross 60～100 mesh sieves, mix, the ethanolic soln system softwood of 30 POVIDONE K 30 BP/USP 30 with 2～20%, cross 20～50 mesh sieves and granulate, 40～90 ℃ of dryings, pellet moisture is controlled in 3%, whole grain back adds proper amount of lubricating agent, mix, compressing tablet, promptly.

Particularly, the pharmaceutical composition of the foregoing description also can prepare by the following method: take by weighing compound 11, weighting agent and disintegrating agent by 50 times of recipe quantities and cross 60,80 mesh sieves successively, mix, with 50% ethanolic soln system softwood of 2～20% 30 POVIDONE K 30 BP/ USPs 30,30 mesh sieves are granulated, 60 ℃ of dryings, pellet moisture is controlled in 3%, and the whole grain of 20 mesh sieves back adds proper amount of lubricating agent, mixes, compressing tablet promptly gets product.

Can carry out various improvement as mentioned above and among the present invention as following claim definition.

Claims (9)

1. the compound of following general formula (1) expression:

Wherein Z is formula (I)

Or formula (II)

N, q represent 0～4 integer separately, and condition is n≤4 and q≤4; A, b represent to exist or non-existent pair of key; When two keys existed, formula (1) compound was E or Z configuration, and when two keys did not exist, the three-dimensional center of formula (1) compound had R-or S-configuration;

R and R ' represent H separately; C ₁-C ₂₀The straight or branched alkyl; C ₂-C ₂₀The straight or branched thiazolinyl;-CO ₂Z ', wherein Z ' is that H, sodium, potassium or other are selected from the pharmaceutically acceptable gegenion of calcium, magnesium, ammonium, tromethane, tetramethyl-ammonium;-CO ₂R ' ";-NH ₂-NHR ' ";-NR ₂' ";-OH; Halogen; The C that replaces ₁-C ₂₀The C of straight or branched alkyl or replacement ₂-C ₂₀The straight or branched thiazolinyl;-OR ' ", wherein R ' " represents C separately ₁-C ₂₀Straight or branched alkyl, straight or branched thiazolinyl or aralkyl-(CH ₂) x-Ar, wherein x is 1～6 integer;-CO ₂R " ", wherein R " " represents H, the C that can replace arbitrarily separately ₁-C ₂₀Alkyl, the C that can replace arbitrarily ₁-C ₂₀Straight or branched alkyl, the C that can replace arbitrarily ₂-C ₂₀Thiazolinyl or the C that can replace arbitrarily ₆-C ₁₀Aryl or expression are selected from the circular part of morpholine, piperidines, piperazine;

A, " expression is single to be replaced or polysubstituted group, represents H, C separately for A ' and A ₁-C ₂₀Amido, C ₁-C ₂₀Acyloxy, C ₁-C ₂₀Alkyloyl, C ₁-C ₂₀Carbalkoxy, C ₁-C ₂₀Alkoxyl group, C ₁-C ₂₀Alkylamino, C ₁-C ₂₀Alkane carboxylic amino, aroyl, aralkanoyl, carboxyl, cyano group, halogen, hydroxyl, nitro; Perhaps

A, " representative can replace arbitrarily, straight or branched C for A ' and A ₁-C ₂₀Alkyl or C ₂-C ₂₀Thiazolinyl; Or formation methylene-dioxy or ethylenedioxy group;

X and X ' separately expression-NH ,-NR ' ", O or S.

2. the compound of general formula as claimed in claim 1 (1) expression:

Wherein Z is formula (I)

Or formula (II)

Wherein:

N, q represent 0～4 integer separately, and condition is n≤4 and q≤4; A, b represent to exist or non-existent pair of key independently; When two keys existed, formula (1) compound can be for E or Z configuration, and when two keys did not exist, the three-dimensional center of formula (1) compound can have R-or S-configuration;

R and R ' represent H separately;-CO ₂Z ', wherein Z ' is that H, sodium, potassium or other are selected from the pharmaceutically acceptable gegenion of calcium, magnesium, ammonium, tromethane, tetramethyl-ammonium;-CO ₂R " ", wherein R " " be separately H, the C that can replace arbitrarily ₁-C ₂₀Alkyl, the C that can replace arbitrarily ₁-C ₂₀Straight or branched alkyl, the C that can replace arbitrarily ₂-C ₂₀Thiazolinyl or the C that can replace arbitrarily ₆-C ₁₀Aryl;

A, " expression is single to be replaced or polysubstituted group, represents H, C separately for A ' and A ₁-C ₂₀Amido, C ₁-C ₂₀Acyloxy, C ₁-C ₂₀Alkyloyl, C ₁-C ₂₀Carbalkoxy, C ₁-C ₂₀Alkoxyl group, C ₁-C ₂₀Alkylamino, C ₁-C ₂₀Alkane carboxylic amino, aroyl, aralkanoyl, carboxyl, cyano group, halogen, hydroxyl, nitro; Perhaps

A, A ' and A " the straight or branched C that expression can replace arbitrarily ₁-C ₂₀Alkyl or C ₂-C ₂₀Thiazolinyl; Or formation methylene-dioxy or ethylenedioxy group;

X and X ' separately expression-NH ,-NR ' ", O or S.

3. compound as claimed in claim 1 is selected from:

3-(5-Dimethoxyphenyl)-2-{3-[4-(2,4-dioxo thiazolidine-5-ylidenemethyl)-phenoxy group]-phenyl }-methyl acrylate (10);

3-(5-Dimethoxyphenyl)-2-{3-[4-(2,4-dioxo thiazolidine-5-ylmethyl)-phenoxy group]-phenyl }-methyl acrylate (11);

3-(5-Dimethoxyphenyl)-2-{3-[4-(2,4-dioxo thiazolidine-5-ylmethyl)-phenoxy group]-phenyl }-vinylformic acid (14);

3-(5-Dimethoxyphenyl)-2-{3-[4-(2,4-dioxo thiazolidine-5-ylidenemethyl)-phenoxy group]-phenyl }-methyl propionate (17);

3-(5-Dimethoxyphenyl)-2-{3-[4-(2,4-dioxo thiazolidine-5-ylmethyl)-phenoxy group]-phenyl }-methyl propionate (18);

Z-3-(3, the 5-Dimethoxyphenyl)-2-{3-[4-(2,4-dioxo thiazolidine-5-ylidenemethyl)-phenoxy group]-phenyl }-methyl acrylate (22);

Z-3-(3, the 5-Dimethoxyphenyl)-2-{3-[4-(2,4-dioxo thiazolidine-5-ylmethyl)-phenoxy group]-phenyl }-methyl acrylate (23);

2-{3-[4-(2,4-dioxo thiazolidine-5-ylidenylmethyl)-phenoxy group]-phenyl }-3-p-methylphenyl vinylformic acid (40);

2-{3-[4-(2,4-dioxo thiazolidine-5-ylmethyl)-phenoxy group]-phenyl }-3-p-methylphenyl vinylformic acid (41);

2-{3-[4-(2,4-dioxo thiazolidine-5-ylmethyl)-phenoxy group]-phenyl }-3-p-methylphenyl methyl acrylate (42);

3-(5-3,5-dimethylphenyl)-2-{3-[4-(2,4-dioxo thiazolidine-5-ylidenemethyl)-phenoxy group]-phenyl }-vinylformic acid (46);

3-(5-3,5-dimethylphenyl)-2-{3-[4-(2,4-dioxo thiazolidine-5-ylmethyl)-phenoxy group]-phenyl }-vinylformic acid (47);

3-(5-3,5-dimethylphenyl)-2-{3-[4-(2,4-dioxo thiazolidine-5-ylmethyl)-phenoxy group]-phenyl }-methyl acrylate (49);

5-(3-{4-[2-(3, the 5-3,5-dimethylphenyl)-1-(morpholine-4-carbonyl)-vinyl]-phenoxy group }-benzyl)-thiazolidine-2,4-diketone (50);

5-(3-{4-[2-(4-p-methoxy-phenyl)-vinyl] phenoxy group }-benzyl)-thiazolidine-2,4-diketone (54).

4. as the application of each described compound of claim 1 to 3 in the medicine of preparation treatment diabetes.

Each described compound of claim 1 to 3 be selected from following medicament and unite the application of use in preparation treatment diabetes medicament:

Regular Insulin or insulin-simulated dose;

Sulfonylurea or other Regular Insulin succagoga;

Thiazolidinedione;

The special class of shellfish or other PPAR-α excitomotor;

The PPAR-delta agonists;

Biguanides;

Si Dating or other hydroxymethyl glutaryl base (HMG) CoA reductase inhibitor;

Alpha-glucosidase inhibitor;

The cholic acid binding resin;

apoA1；

Nicotinic acid;

Probucol;

Niacin.

6. pharmaceutical composition comprises acceptable carrier on each described compound of claim 1 to 3 for the treatment of significant quantity and the physiology.

7. medicinal compositions as claimed in claim 6, it is characterized in that, described pharmaceutical composition is by intravenously, intracutaneous, intramuscular, subcutaneous, oral administration, and the formulation of described pharmaceutical composition is the stomach and intestine external application preparation that is selected from the gi tract medication preparation of tablet, capsule and pill or is selected from injection, external preparation.

8. one kind with the tablet of each described compound of claim 1 to 3 as activeconstituents, it is characterized in that, comprises that weight ratio is 30～80% activeconstituents, 2～20% disintegrating agent, and 0.2～2% lubricant, all the other are weighting agent.

9. method for preparing the described tablet of claim 8, it is characterized in that, described compound, disintegrating agent and weighting agent are crossed 60～100 mesh sieves, mix, the ethanolic soln system softwood of the 30 POVIDONE K 30 BP/USP 30 with 2～20% is crossed 20～50 mesh sieves and is granulated, 40～90 ℃ of dryings, add lubricant, mix, compressing tablet promptly.

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