CN104418821A - 2,4-substituted 5-(3,4,5-trimethoxyphenyl) thiazole derivative and preparation method and application thereof - Google Patents

Abstract

The invention belongs to chemical medicines, and in particular to 5- (3,4,5- trimethoxyphenyl) thiazole and its preparation method and application of 2,4 substitutions. The present invention provides a kind of 5- (3,4,5- trimethoxyphenyl) thiazole of 2,4 substitutions, as shown in formula I, such compound has effects that inhibit tumour structure.

Description

2,4 5-(3,4,5-trimethoxyphenyl) thiazole derivatives replaced and its production and use

Technical field

The invention belongs to chemical pharmacy field, be specifically related to 2,4 5-(3,4,5-trimethoxyphenyl) thiazole derivatives replaced and its production and use.

Background technology

Tumour is a kind of common disease, the health of the malignant tumour serious threat mankind, and the mankind are positioned at the second of all mortalities, this time in cardiovascular disorder because of the mortality ratio that malignant tumour causes.Antitumor drug ubiquity conventional clinically is at present poor to solid tumor curative effect, toxic side effect large, easy generation buys the features such as the property of medicine.Therefore, research good effect, one of antitumor drug focus remaining new drug research that side effect is little.

Natural product Combretastain(Combretastatin) family is the antineoplastic compound that a class has bright prospects, wherein Compound C ombretastatin A-4 suppress by being incorporated into colchicine site microtubule polymerization and inhibition tumor cell growth, because it has efficient anti-tumor activity, particularly overriding resistance tumor promotion, highly selective, hypotoxicity become study hotspot.Its analog AC-7739, AC-7700, AVE-8082A, CKD-516 and its prodrug phosphoric acid ester disodium salt CA-4P etc. have entered clinical study and have produced good effect, and particularly Compound C A-4P carries out third stage test in American-European countries as tumor vessel inhibitor.

Summary of the invention

The invention provides a kind of 2,4 5-(3,4,5-trimethoxyphenyl) thiazole derivatives replaced, structure is such as formula shown in I:

Wherein, R ₁for the aromatic heterocyclic replaced or do not replace, replacement or the aryl do not replaced, C _{1 ~ 6}alkyl, C _{2 ~ 6}thiazolinyl or C _{2 ~ 6}alkynyl; Described aryl has 5 ~ 11 carbon atoms; The substituting group of described aryl is C _{1 ~ 6}alkyl, C _{2 ~ 6}thiazolinyl, C _{2 ~ 6}alkynyl, C _{3 ~ 6}cycloalkyl, halogen, hydroxyl, cyano group, carboxyl ,-CF ₃, amino or C _{1 ~ 6}alkoxyl group; Described aromatic heterocyclic is for containing 1 ~ 3 heteroatomic 5 ~ 11 ring, and heteroatoms is N, O or S; The substituting group of described aromatic heterocyclic is C _{1 ~ 6}alkyl, halogen, amino or C _{1 ~ 6}alkoxyl group;

R ₂for C _{1 ~ 6}alkyl, C _{2 ~ 6}thiazolinyl, C _{2 ~ 6}alkynyl, C _{3 ~ 6}cycloalkyl, halogen, hydroxyl, cyano group, carboxyl, amino or-NHCOR ₃;

R ₃for-H, C _{1 ~ 6}alkyl, C _{2 ~ 6}thiazolinyl, C _{2 ~ 6}alkynyl, C _{3 ~ 6}cycloalkyl, halogen, hydroxyl, cyano group, carboxyl, amino, C _{3 ~ 6}heterocyclylalkyl or the heteroatoms of described Heterocyclylalkyl is N, O or S;

R ₄for-H, C _{1 ~ 6}alkyl, C _{2 ~ 6}thiazolinyl, C _{2 ~ 6}alkynyl, C _{3 ~ 6}the C that cycloalkyl, aryl replace _{1 ~ 6}the C that alkyl, aromatic heterocyclic replace _{1 ~ 6}alkyl or m=0 ~ 4, n=0 ~ 4.

As preferred embodiments of the present invention, R ₁for aromatic heterocyclic or replacement or the aryl that do not replace; Described aryl has 5 ~ 11 carbon atoms; Described substituting group is C _{1 ~ 6}alkyl, C _{2 ~ 6}thiazolinyl, C _{2 ~ 6}alkynyl, C _{3 ~ 6}cycloalkyl, halogen, hydroxyl, cyano group, carboxyl ,-CF ₃, amino or C _{1 ~ 6}alkoxyl group; Described aromatic heterocyclic is for containing 1 ~ 3 heteroatomic 5 ~ 10 ring, and heteroatoms is N or S;

Preferably, R ₁for the aryl replaced or do not replace, described aryl has 6 ~ 10 carbon atoms; Preferred further, R ₁for the phenyl replaced or do not replace, replacement or the naphthyl that do not replace; Further preferred, R ₁for naphthyl or replacement or the phenyl that do not replace;

Preferably, described substituting group is C _{1 ~ 6}alkyl, C _{2 ~ 6}thiazolinyl, C _{2 ~ 6}alkynyl, C _{3 ~ 6}cycloalkyl, halogen ,-CF ₃, amino or C _{1 ~ 6}alkoxyl group; Preferred further, described substituting group is C _{1 ~ 6}alkyl, halogen ,-CF ₃or C _{1 ~ 6}alkoxyl group; Further preferred, described substituting group is C _{1 ~ 4}alkyl, halogen ,-CF ₃or C _{1 ~ 4}alkoxyl group;

Optimum, R ₁for naphthyl or replacement or the phenyl that do not replace; Described substituting group is R is C _{1 ~ 4}alkyl ,-F ,-Cl ,-CF ₃or C _{1 ~ 4}alkoxyl group.

As preferred embodiments of the present invention, R ₂for C _{1 ~ 6}alkyl, C _{2 ~ 6}thiazolinyl, C _{2 ~ 6}alkynyl, C _{3 ~ 6}cycloalkyl, amino or-NHCOR ₃;

Preferably, R ₂for C _{1 ~ 6}alkyl, C _{3 ~ 6}cycloalkyl, amino or-NHCOR ₃;

Preferred further, R ₂for C _{1 ~ 6}alkyl, amino or-NHCOR ₃;

Optimum, R ₂for C _{1 ~ 4}alkyl, amino or-NHCOR ₃.

As preferred embodiments of the present invention, R ₃for-H, C _{1 ~ 6}alkyl, C _{2 ~ 6}thiazolinyl, C _{2 ~ 6}alkynyl, C _{3 ~ 6}cycloalkyl, amino, C _{3 ~ 6}heterocyclylalkyl or the heteroatoms of described Heterocyclylalkyl is N, O or S;

Preferably, R ₃for-H, C _{1 ~ 6}alkyl, C _{3 ~ 6}cycloalkyl, amino, C _{3 ~ 6}heterocyclylalkyl or

Preferred further, R ₃for-H, C _{1 ~ 6}alkyl, C _{3 ~ 6}heterocyclylalkyl or

Optimum, R ₃for-H, C _{1 ~ 4}alkyl, C _{3 ~ 6}heterocyclylalkyl or the heteroatoms of described Heterocyclylalkyl is N.

As preferred embodiments of the present invention, R ₄for-H, C _{1 ~ 6}alkyl, C _{2 ~ 6}thiazolinyl, C _{2 ~ 6}alkynyl, C _{3 ~ 6}the C that cycloalkyl, aryl replace _{1 ~ 6}the C that alkyl, aromatic heterocyclic replace _{1 ~ 6}alkyl or m=0 ~ 4, n=0 ~ 4;

Preferably, R ₄for-H, C _{1 ~ 6}alkyl, C _{3 ~ 6}the C that cycloalkyl, aryl replace _{1 ~ 6}the C that alkyl, aromatic heterocyclic replace _{1 ~ 6}alkyl or

Preferred further, R ₄for-H, C _{1 ~ 6}the C that alkyl, aryl replace _{1 ~ 6}the C that alkyl, aromatic heterocyclic replace _{1 ~ 6}alkyl or

Optimum, R ₄for-H, C _{1 ~ 4}the C that alkyl, aryl replace _{1 ~ 4}the C that alkyl, aromatic heterocyclic replace _{1 ~ 4}alkyl or m=0 ~ 2, n=0 ~ 3.

As the present invention's preferred scheme further, R ₁for naphthyl or replacement or the phenyl that do not replace; Described substituting group is C _{1 ~ 4}alkyl, halogen ,-CF ₃or C _{1 ~ 4}alkoxyl group;

R ₂for C _{1 ~ 4}alkyl, amino or-NHCOR ₃;

R ₃for-H, C _{1 ~ 4}alkyl, C _{3 ~ 6}heterocyclylalkyl or the heteroatoms of described Heterocyclylalkyl is N;

R ₄for-H, C _{1 ~ 4}the C that alkyl, aryl replace _{1 ~ 4}the C that alkyl, aromatic heterocyclic replace _{1 ~ 4}alkyl or m=0 ~ 2, n=0 ~ 3.

Above-mentioned 2,4 5-(3,4,5-trimethoxyphenyl) thiazole derivatives replaced, work as R ₂during for amino, its structure is such as formula shown in II:

Wherein, R ₁for the aromatic heterocyclic replaced or do not replace, replacement or the aryl do not replaced, C _{1 ~ 6}alkyl, C _{2 ~ 6}thiazolinyl or C _{2 ~ 6}alkynyl; Described aryl has 5 ~ 11 carbon atoms; The substituting group of described aryl is C _{1 ~ 6}alkyl, C _{2 ~ 6}thiazolinyl, C _{2 ~ 6}alkynyl, C _{3 ~ 6}cycloalkyl, halogen, hydroxyl, cyano group, carboxyl ,-CF ₃, amino or C _{1 ~ 6}alkoxyl group; Described aromatic heterocyclic is for containing 1 ~ 3 heteroatomic 5 ~ 11 ring, and heteroatoms is N, O or S; The substituting group of described aromatic heterocyclic is C _{1 ~ 6}alkyl, halogen, amino or C _{1 ~ 6}alkoxyl group.

Preferably, R ₁for aromatic heterocyclic or replacement or the aryl that do not replace; Described aryl has 5 ~ 11 carbon atoms; Described substituting group is C _{1 ~ 6}alkyl, C _{2 ~ 6}thiazolinyl, C _{2 ~ 6}alkynyl, C _{3 ~ 6}cycloalkyl, halogen, hydroxyl, cyano group, carboxyl ,-CF ₃, amino or C _{1 ~ 6}alkoxyl group; Described aromatic heterocyclic is for containing 1 ~ 3 heteroatomic 5 ~ 10 ring, and heteroatoms is N or S.

Preferred further, R ₁for the aryl replaced or do not replace, described aryl has 6 ~ 10 carbon atoms; Preferred further, R ₁for the phenyl replaced or do not replace, replacement or the naphthyl that do not replace; Further preferred, R ₁for naphthyl or replacement or the phenyl that do not replace.

Preferred further, described substituting group is C _{1 ~ 6}alkyl, C _{2 ~ 6}thiazolinyl, C _{2 ~ 6}alkynyl, C _{3 ~ 6}cycloalkyl, halogen ,-CF ₃, amino or C _{1 ~ 6}alkoxyl group; Preferred further, described substituting group is C _{1 ~ 6}alkyl, halogen ,-CF ₃or C _{1 ~ 6}alkoxyl group; Further preferred, described substituting group is C _{1 ~ 4}alkyl, halogen ,-CF ₃or C _{1 ~ 4}alkoxyl group.

Optimum, R ₁for naphthyl or replacement or the phenyl that do not replace; Described substituting group is R is C _{1 ~ 4}alkyl ,-F ,-Cl ,-CF ₃or C _{1 ~ 4}alkoxyl group.

Above-mentioned 2,4 5-(3,4,5-trimethoxyphenyl) thiazole derivatives replaced, work as R ₁for replace or do not replace phenyl time, its structure is as shown in formula III:

Wherein, R is C _{1 ~ 6}alkyl, C _{2 ~ 6}thiazolinyl, C _{2 ~ 6}alkynyl, C _{3 ~ 6}cycloalkyl, halogen, hydroxyl, cyano group, carboxyl ,-CF ₃, amino or C _{1 ~ 6}alkoxyl group.

Preferably, R is C _{1 ~ 6}alkyl, C _{2 ~ 6}thiazolinyl, C _{2 ~ 6}alkynyl, C _{3 ~ 6}cycloalkyl, halogen ,-CF ₃, amino or C _{1 ~ 6}alkoxyl group.

Preferred further, R is C _{1 ~ 6}alkyl, halogen ,-CF ₃or C _{1 ~ 6}alkoxyl group.

Further preferred, R is C _{1 ~ 4}alkyl, halogen ,-CF ₃or C _{1 ~ 4}alkoxyl group.

Optimum, R is C _{1 ~ 4}alkyl ,-F ,-Cl ,-CF ₃or C _{1 ~ 4}alkoxyl group.

Above-mentioned 2,4 5-(3,4,5-trimethoxyphenyl) thiazole derivatives replaced, work as R ₁for during to diethoxy phenyl, its structure is such as formula shown in IV:

Wherein, R ₂for C _{1 ~ 6}alkyl, C _{2 ~ 6}thiazolinyl, C _{2 ~ 6}alkynyl, C _{3 ~ 6}cycloalkyl, halogen, hydroxyl, cyano group, carboxyl, amino or-NHCOR ₃; R ₃for-H, C _{1 ~ 6}alkyl, C _{2 ~ 6}thiazolinyl, C _{2 ~ 6}alkynyl, C _{3 ~ 6}cycloalkyl, halogen, hydroxyl, cyano group, carboxyl, amino, C _{3 ~ 6}heterocyclylalkyl or the heteroatoms of described Heterocyclylalkyl is N, O or S; R ₄for-H, C _{1 ~ 6}alkyl, C _{2 ~ 6}thiazolinyl, C _{2 ~ 6}alkynyl, C _{3 ~ 6}the C that cycloalkyl, aryl replace _{1 ~ 6}the C that alkyl, aromatic heterocyclic replace _{1 ~ 6}alkyl or m=0 ~ 4, n=0 ~ 4.

Preferably, R ₂for C _{1 ~ 6}alkyl, C _{2 ~ 6}thiazolinyl, C _{2 ~ 6}alkynyl, C _{3 ~ 6}cycloalkyl, amino or-NHCOR ₃; Preferred further, R ₂for C _{1 ~ 6}alkyl, C _{3 ~ 6}cycloalkyl, amino or-NHCOR ₃; Further preferred, R ₂for C _{1 ~ 6}alkyl, amino or-NHCOR ₃; Optimum, R ₂for C _{1 ~ 4}alkyl, amino or-NHCOR ₃.

Preferably, R ₃for-H, C _{1 ~ 6}alkyl, C _{2 ~ 6}thiazolinyl, C _{2 ~ 6}alkynyl, C _{3 ~ 6}cycloalkyl, amino, C _{3 ~ 6}heterocyclylalkyl or the heteroatoms of described Heterocyclylalkyl is N, O or S; Preferred further, R ₃for-H, C _{1 ~ 6}alkyl, C _{3 ~ 6}cycloalkyl, amino, C _{3 ~ 6}heterocyclylalkyl or further preferred, R ₃for-H, C _{1 ~ 6}alkyl, C _{3 ~ 6}heterocyclylalkyl or optimum, R ₃for-H, C _{1 ~ 4}alkyl, C _{3 ~ 6}heterocyclylalkyl or the heteroatoms of described Heterocyclylalkyl is N.

Preferably, R ₄for-H, C _{1 ~ 6}alkyl, C _{2 ~ 6}thiazolinyl, C _{2 ~ 6}alkynyl, C _{3 ~ 6}the C that cycloalkyl, aryl replace _{1 ~ 6}the C that alkyl, aromatic heterocyclic replace _{1 ~ 6}alkyl or m=0 ~ 4, n=0 ~ 4; Preferred further, R ₄for-H, C _{1 ~ 6}alkyl, C _{3 ~ 6}the C that cycloalkyl, aryl replace _{1 ~ 6}the C that alkyl, aromatic heterocyclic replace _{1 ~ 6}alkyl or further preferred, R ₄for-H, C _{1 ~ 6}the C that alkyl, aryl replace _{1 ~ 6}the C that alkyl, aromatic heterocyclic replace _{1 ~ 6}alkyl or optimum, R ₄for-H, C _{1 ~ 4}the C that alkyl, aryl replace _{1 ~ 4}the C that alkyl, aromatic heterocyclic replace _{1 ~ 4}alkyl or m=0 ~ 2, n=0 ~ 3.

Optimum, R ₂for C _{1 ~ 4}alkyl, amino or-NHCOR ₃; R ₃for-H, C _{1 ~ 4}alkyl, C _{3 ~ 6}heterocyclylalkyl or the heteroatoms of described Heterocyclylalkyl is N; R ₄for-H, C _{1 ~ 4}the C that alkyl, aryl replace _{1 ~ 4}the C that alkyl, aromatic heterocyclic replace _{1 ~ 4}alkyl or m=0 ~ 2, n=0 ~ 3.

Provided by the invention 2,4 5-(3,4,5-trimethoxyphenyl) thiazole derivatives replaced, its chemical name is:

4-phenyl-5-(3, 4, 5-trimethoxyphenyl)-thiazolamine, 4-(1-naphthyl)-5-(3, 4, 5-trimethoxyphenyl)-thiazolamine, 4-(2-naphthyl)-5-(3, 4, 5-trimethoxyphenyl)-thiazolamine, 4-(2-benzothienyl)-5-(3, 4, 5-trimethoxyphenyl)-thiazolamine, 4-(4-aminomethyl phenyl)-5-(3, 4, 5-trimethoxyphenyl)-thiazolamine, 4-(4-ethylphenyl)-5-(3, 4, 5-trimethoxyphenyl)-thiazolamine, 4-(4-trifluoromethyl)-5-(3, 4, 5-trimethoxyphenyl)-thiazolamine, 4-(4-p-methoxy-phenyl)-5-(3, 4, 5-trimethoxyphenyl)-thiazolamine, 4-(3-p-methoxy-phenyl)-5-(3, 4, 5-trimethoxyphenyl)-thiazolamine, 4-(the fluoro-4-p-methoxy-phenyl of 3-)-5-(3, 4, 5-trimethoxyphenyl)-thiazolamine, 4-(3-chloro-4-methoxy phenyl)-5-(3, 4, 5-trimethoxyphenyl)-thiazolamine, 4-(3, 4-Dimethoxyphenyl)-5-(3, 4, 5-trimethoxyphenyl)-thiazolamine, 4-(3-methyl-4-p-methoxy-phenyl)-5-(3, 4, 5-trimethoxyphenyl)-thiazolamine, 4-(4-ethoxyl phenenyl)-5-(3, 4, 5-trimethoxyphenyl)-thiazolamine, 4-(the chloro-4-ethoxyl phenenyl of 3-)-5-(3, 4, 5-trimethoxyphenyl)-thiazolamine, 4-(4-pyrimidyl)-5-(3, 4, 5-trimethoxyphenyl)-thiazolamine, glycine-4-(4-ethoxyl phenenyl)-5-(3, 4, 5-trimethoxyphenyl)-thiazole-2-acid amides, 2-methyl-alanine-4-(4-ethoxyl phenenyl)-5-(3, 4, 5-trimethoxyphenyl)-thiazole-2-acid amides, leucine-4-(4-ethoxyl phenenyl)-5-(3, 4, 5-trimethoxyphenyl)-thiazole-2-acid amides, methionine(Met)-4-(4-ethoxyl phenenyl)-5-(3, 4, 5-trimethoxyphenyl)-thiazole-2-acid amides, L-PROLINE-4-(4-ethoxyl phenenyl)-5-(3, 4, 5-trimethoxyphenyl)-thiazole-2-acid amides, D-PROLINE-4-(4-ethoxyl phenenyl)-5-(3, 4, 5-trimethoxyphenyl)-thiazole-2-acid amides, L-Phe-4-(4-ethoxyl phenenyl)-5-(3, 4, 5-trimethoxyphenyl)-thiazole-2-acid amides, D-phenylalanine-4-(4-ethoxyl phenenyl)-5-(3, 4, 5-trimethoxyphenyl)-thiazole-2-acid amides, D-trp-4-(4-ethoxyl phenenyl)-5-(3, 4, 5-trimethoxyphenyl)-thiazole-2-acid amides, 1-(4-(4-ethoxyl phenenyl)-5-(3, 4, 5-trimethoxyphenyl)-2-thiazolyl) urea or 4-(4-ethoxyl phenenyl)-5-(3, 4, 5-trimethoxyphenyl)-2-tertiary butyl thiazole.

Second technical problem to be solved by this invention is to provide the preparation method of 5-(3,4, the 5-trimethoxyphenyl) thiazole derivative that 2,4 replace shown in formula I, II, III, IV, and syntheti c route is as follows:

Route one:

Be specially:

(1) first 3,4,5-trimethoxy phenyl acetic acid is prepared into acyl chlorides;

(2) then, acyl chlorides and aryl carry out Friedel-Crafts reaction;

(3) reactor product is by bromo-reaction bromine on the α position of carbonyl;

(4) product is obtained through closing ring with all kinds of thiourea derivative reaction again;

(5) finally product is further modified;

Be thionyl chloride, oxalyl chloride etc. for the reagent of chloride in step (1); Reaction times is 10min ~ 5h, and temperature of reaction is 10 ~ 60 DEG C; Reaction solvent is tetrahydrofuran (THF), ether, toluene, methylene dichloride etc.; Add the DMF(N of catalytic amount, dinethylformamide);

In step (2) solvent be ethers as tetrahydrofuran (THF), ether etc., the inert solvents such as toluene; Use the AlCl of 1 ~ 3 equivalent ₃; Brominated reagent is NBS(N-bromo-succinimide) or bromine, consumption is 1 ~ 3 equivalent;

The mixed solvent, acetonitrile etc. of solvent anhydrous diethyl ether, chloroform and anhydrous diethyl ether and chloroform in step (3); Temperature of reaction is-20 ~ 60 DEG C, and the reaction times is 3 ~ 12h;

Solvent in step (4) selects all kinds of alcoholic solvent as methyl alcohol, ethanol etc.; Temperature of reaction is 30 ~ 120 DEG C, and the reaction times is 0.5 ~ 5h; The consumption of the derivatives such as thiocarbamide is 1 ~ 3 equivalent.

Route two:

Be specially:

(1) 3,4,5-trimethoxy phenylo boric acid and bromethiazole carry out linked reaction;

(2) then by product bromo;

(3) again target product is obtained with aryl boric acid by linked reaction;

(4) finally product is further modified;

In step (1), the mol ratio of 3,4,5-trimethoxy phenylo boric acids and bromethiazole is 1 ︰ 1 ~ 1 ︰ 5; Middle temperature of reaction is 50 ~ 130 DEG C; Reaction solvent is that toluene alcohol mixed solvent, tetrahydrofuran (THF), ethylene dichloride are medium; Basic solution is NaOH, KOH, Na ₂cO ₃, Cs ₂cO ₃deng the aqueous solution;

In step (2), the bromine source of bromo is NBS, bromine etc.; Reaction solvent is ether, acetonitrile, chloroform, toluene equal solvent; Temperature of reaction is-25 ~ 120 DEG C;

In step (3), the mol ratio of the bromo-derivative that aryl boric acid and step (2) obtain is 1 ︰ 1 ~ 1 ︰ 5; Temperature of reaction is 50 ~ 130 DEG C; Reaction solvent is toluene alcohol mixed solvent, tetrahydrofuran (THF), ethylene dichloride etc.; Basic solution is NaOH, KOH, Na ₂cO ₃, Cs ₂cO ₃deng the aqueous solution.

Wherein, R ₁for the aromatic heterocyclic replaced or do not replace, replacement or the aryl do not replaced, C _{1 ~ 6}alkyl, C _{2 ~ 6}thiazolinyl or C _{2 ~ 6}alkynyl; Described aryl has 5 ~ 11 carbon atoms; The substituting group of described aryl is C _{1 ~ 6}alkyl, C _{2 ~ 6}thiazolinyl, C _{2 ~ 6}alkynyl, C _{3 ~ 6}cycloalkyl, halogen, hydroxyl, cyano group, carboxyl ,-CF ₃, amino or C _{1 ~ 6}alkoxyl group; Described aromatic heterocyclic is for containing 1 ~ 3 heteroatomic 5 ~ 11 ring, and heteroatoms is N, O or S; The substituting group of described aromatic heterocyclic is C _{1 ~ 6}alkyl, halogen, amino or C _{1 ~ 6}alkoxyl group;

R ₂for C _{1 ~ 6}alkyl, C _{2 ~ 6}thiazolinyl, C _{2 ~ 6}alkynyl, C _{3 ~ 6}cycloalkyl, halogen, hydroxyl, cyano group, carboxyl, amino or-NHCOR ₃;

R ₃for-H, C _{1 ~ 6}alkyl, C _{2 ~ 6}thiazolinyl, C _{2 ~ 6}alkynyl, C _{3 ~ 6}cycloalkyl, halogen, hydroxyl, cyano group, carboxyl, amino, C _{3 ~ 6}heterocyclylalkyl or the heteroatoms of described Heterocyclylalkyl is N, O or S;

R ₄for-H, C _{1 ~ 6}alkyl, C _{2 ~ 6}thiazolinyl, C _{2 ~ 6}alkynyl, C _{3 ~ 6}the C that cycloalkyl, aryl replace _{1 ~ 6}the C that alkyl, aromatic heterocyclic replace _{1 ~ 6}alkyl or m=0 ~ 4, n=0 ~ 4.

Present invention also offers 2,4 5-(3,4,5-trimethoxyphenyl) thiazole derivatives replaced shown in above-mentioned formula I, II, III, IV and prepare the purposes in antitumor drug.

Preferably, described antitumor drug is anti-lung cancer, colorectal carcinoma, prostate cancer, ovarian cancer, the medicine of mammary cancer.

The target spot of described antitumor drug is human liver cancer cell HePG2, human colon cancer cell (SW480, HCT116), prostate cancer (DU145), ovarian cancer (SK-OV-3), human breast carcinoma (MDA-MB-231, MDA-MB-468, SKBR3), people's lung cancer (A549).

Present invention also offers a kind of pharmaceutical composition, be by shown in above-mentioned formula I, II, III, IV 2,4 replace 5-(3,4,5-trimethoxyphenyl) thiazole derivatives be activeconstituents, add pharmaceutically acceptable carrier composition.

Accompanying drawing explanation

Fig. 1 Compound C LJ-14, the CLJ-17 tumor growth curve on HCT116 human colon carcinoma model.

The tumor growth curve of Fig. 2 Compound C LJ-14 in people's lung cancer model.

Fig. 3 Compound C LJ-14, the CLJ-17 tumor growth curve in human ovarian cancer.

Embodiment:

The preparation method of 2,4 5-(3,4,5-trimethoxyphenyl) thiazole derivatives replaced, syntheti c route is as follows:

Route one:

Be specially:

(1) first 3,4,5-trimethoxy phenyl acetic acid is prepared into acyl chlorides;

(2) then, acyl chlorides and aryl carry out Friedel-Crafts reaction;

(3) reactor product is by bromo-reaction bromine on the α position of carbonyl;

(4) product is obtained through closing ring with all kinds of thiourea derivative reaction again;

(5) finally product is further modified;

Be thionyl chloride, oxalyl chloride etc. for the reagent of chloride in step (1); Reaction times is 10min ~ 5h, and temperature of reaction is 10 ~ 60 DEG C; Reaction solvent is tetrahydrofuran (THF), ether, toluene, methylene dichloride etc.; Add the DMF of catalytic amount;

In step (2) solvent be ethers as tetrahydrofuran (THF), ether etc., the inert solvents such as toluene; Use the AlCl of 1 ~ 3 equivalent ₃; Brominated reagent is NBS or bromine, and consumption is 1 ~ 3 equivalent;

The mixed solvent, acetonitrile etc. of solvent anhydrous diethyl ether, chloroform and anhydrous diethyl ether and chloroform in step (3); Temperature of reaction is-20 ~ 60 DEG C, and the reaction times is 3 ~ 12h;

Solvent in step (4) selects all kinds of alcoholic solvent as methyl alcohol, ethanol etc.; Temperature of reaction is 30 ~ 120 DEG C, and the reaction times is 0.5 ~ 5h; The consumption of the derivatives such as thiocarbamide is 1 ~ 3 equivalent.

Route two:

Be specially:

(1) 3,4,5-trimethoxy phenylo boric acid and bromethiazole carry out linked reaction;

(2) then by product bromo;

(3) again target product is obtained with aryl boric acid by linked reaction;

(4) finally product is further modified;

In step (1), the mol ratio of 3,4,5-trimethoxy phenylo boric acids and bromethiazole is 1 ︰ 1 ~ 1 ︰ 5; Middle temperature of reaction is 50 ~ 130 DEG C; Reaction solvent is that toluene alcohol mixed solvent, tetrahydrofuran (THF), ethylene dichloride are medium; Basic solution is NaOH, KOH, Na ₂cO ₃, Cs ₂cO ₃deng the aqueous solution;

In step (2), the bromine source of bromo is NBS, bromine etc.; Reaction solvent is ether, acetonitrile, chloroform, toluene equal solvent; Temperature of reaction is-25 ~ 120 DEG C;

In step (3), the mol ratio of the bromo-derivative that aryl boric acid and step (2) obtain is 1 ︰ 1 ~ 1 ︰ 5; Temperature of reaction is 50 ~ 130 DEG C; Reaction solvent is toluene alcohol mixed solvent, tetrahydrofuran (THF), ethylene dichloride etc.; Basic solution is NaOH, KOH, Na ₂cO ₃, Cs ₂cO ₃deng the aqueous solution.

Wherein, R ₁for the aromatic heterocyclic replaced or do not replace, replacement or the aryl do not replaced, C _{1 ~ 6}alkyl, C _{2 ~ 6}thiazolinyl or C _{2 ~ 6}alkynyl; Described aryl has 5 ~ 11 carbon atoms; The substituting group of described aryl is C _{1 ~ 6}alkyl, C _{2 ~ 6}thiazolinyl, C _{2 ~ 6}alkynyl, C _{3 ~ 6}cycloalkyl, halogen, hydroxyl, cyano group, carboxyl ,-CF ₃, amino or C _{1 ~ 6}alkoxyl group; Described aromatic heterocyclic is for containing 1 ~ 3 heteroatomic 5 ~ 11 ring, and heteroatoms is N, O or S; The substituting group of described aromatic heterocyclic is C _{1 ~ 6}alkyl, halogen, amino or C _{1 ~ 6}alkoxyl group;

R ₂for C _{1 ~ 6}alkyl, C _{2 ~ 6}thiazolinyl, C _{2 ~ 6}alkynyl, C _{3 ~ 6}cycloalkyl, halogen, hydroxyl, cyano group, carboxyl, amino or-NHCOR ₃;

R ₃for-H, C _{1 ~ 6}alkyl, C _{2 ~ 6}thiazolinyl, C _{2 ~ 6}alkynyl, C _{3 ~ 6}cycloalkyl, halogen, hydroxyl, cyano group, carboxyl, amino, C _{3 ~ 6}heterocyclylalkyl or the heteroatoms of described Heterocyclylalkyl is N, O or S;

R ₄for-H, C _{1 ~ 6}alkyl, C _{2 ~ 6}thiazolinyl, C _{2 ~ 6}alkynyl, C _{3 ~ 6}the C that cycloalkyl, aryl replace _{1 ~ 6}the C that alkyl, aromatic heterocyclic replace _{1 ~ 6}alkyl or m=0 ~ 4, n=0 ~ 4.

The synthesis of embodiment 1:5-(3,4,5-trimethoxyphenyl)-thiazolamine

In reaction flask, add 3,4,5-trimethoxy phenylo boric acid (5mmol), the bromo-thiazolamine of 5-(6mmol) and stirrer, vacuumize and change nitrogen, add solution and the 2M Na of 20mL first benzene ︰ ethanol=1 ︰ 1 successively ₂cO ₃the aqueous solution, be then heated to 80 DEG C, reaction is spent the night.Suction filtered through kieselguhr after reacting completely, decompression removes solvent, obtains target product by silicagel column column chromatography (developping agent Shi You Mi ︰ ethyl acetate=4 ︰ 1).

The synthesis of the bromo-5-of embodiment 2:4-(3,4,5-trimethoxyphenyl)-thiazolamine

5-(3 is added, 4,5-trimethoxyphenyl in reaction flask)-thiazolamine and anhydrous diethyl ether, 0 DEG C time, add the bromine of equivalent, infrared initiation in batches.Use TLC detection reaction, after reacting completely, use water, saturated NaHCO successively ₃, saturated common salt water washing, anhydrous sodium sulfate drying.Filter, decompression removes solvent, obtains target product.

The synthesis of embodiment 3:4-phenyl-5-(3,4,5-trimethoxyphenyl)-thiazolamine (CLJ-1)

In reaction flask, add the bromo-5-of 4-(3,4,5-trimethoxyphenyl)-thiazolamine, phenylo boric acid, vacuumize and change nitrogen, add solution and the 2mL2mol/L Na of 20mL Jia Ben ︰ ethanol=1 ︰ 1 successively ₂cO ₃the aqueous solution, be then heated to 80 DEG C, reaction is spent the night.Suction filtered through kieselguhr after reacting completely, decompression removes solvent, obtains target product by silicagel column column chromatography (developping agent Shi You Mi ︰ ethyl acetate=2 ︰ 1).

¹H-NMR(CDCl ₃)δ:3.36(s,6H),3.84(s,3H),5.24(bs,2H),6.67(s,2H),7.86(m,5H)。

The synthesis of embodiment 4:4-(1-naphthyl)-5-(3,4,5-trimethoxyphenyl)-thiazolamine (CLJ-2)

Operation is as embodiment 3, and just phenylo boric acid is replaced with 1-naphthalene boronic acids, yield is 74%.

¹H-NMR(DMSO-d ₆)δ:3.19(s,6H),3.50(s,3H),6.54(s,2H),7.23(bs,2H),7.54(m,4H),7.72(d,J=8.8Hz,1H),8.01(m,2H)。

The synthesis of embodiment 5:4-(2-naphthyl)-5-(3,4,5-trimethoxyphenyl)-thiazolamine (CLJ-3)

Operation is as embodiment 3, and just phenylo boric acid is replaced with 2-naphthalene boronic acids, yield is 66%.

¹H-NMR(DMSO-d ₆)δ:3.44(s,6H),3.63(s,3H),6.71(s,2H),7.23(bs,2H),7.34(d,J=8.8Hz,1H),7.49(m,2H),7.87(m,4H)。

The synthesis of embodiment 6:4-(2-benzothienyl)-5-(3,4,5-trimethoxyphenyl)-thiazolamine (CLJ-4)

Operation is as embodiment 3, and just phenylo boric acid is replaced with 2-thionaphthene boric acid, yield is 60%.

¹H-NMR(CDCl ₃)δ:3.70(s,6H),3.88(s,3H),6.54(bs,2H),6.80(s,2H),6.95(s,1H),7.33(m,2H),7.68(m,2H)。

The synthesis of embodiment 7:4-(4-aminomethyl phenyl)-5-(3,4,5-trimethoxyphenyl)-thiazolamine (CLJ-5)

Operation is as embodiment 3, and just phenylo boric acid is replaced with 4-methylphenylboronic acid, yield is 67%.

¹H-NMR(CDCl ₃)δ:2.32(s,3H),3.65(s,6H),3.74(s,3H),5.29(bs,2H),6.69(s,2H),7.08(d,J=8.2Hz,2H),7.22(d,J=8.2Hz,2H)。

The synthesis of embodiment 8:4-(4-ethylphenyl)-5-(3,4,5-trimethoxyphenyl)-thiazolamine (CLJ-6)

Operation is as embodiment 3, and just phenylo boric acid is replaced with 4-ethylbenzene boric acid, yield is 73%.

¹H-NMR(CDCl ₃)δ:1.21(t,J=7.4Hz,3H),2.62(q,J=6.8Hz,2H),3.65(s,6H),3.74(s,3H),5.42(bs,2H),6.70(s,2H),7.16(d,J=8.2Hz,2H),7.23(d,J=8.2Hz,2H)。

The synthesis of embodiment 9:4-(4-trifluoromethyl)-5-(3,4,5-trimethoxyphenyl)-thiazolamine (CLJ-7)

Operation is as embodiment 3, and just phenylo boric acid is replaced with 4-trifluoromethylbenzene boronic acid, yield is 68%.

¹H-NMR(CDCl ₃)δ:3.66(s,6H),3.77(s,3H),5.34(bs,2H),6.64(s,2H),7.43(d,J=8.4Hz,2H),7.53(d,J=8.8Hz,2H)。

The synthesis of embodiment 10:4-(4-p-methoxy-phenyl)-5-(3,4,5-trimethoxyphenyl)-thiazolamine (CLJ-8)

Operation is as embodiment 3, and just phenylo boric acid is replaced with 4-methoxyphenylboronic acid, yield is 73%.

¹H-NMR(CDCl ₃)δ:3.67(s,6H),3.74(s,3H),3.82(s,3H),6.68(s,2H),6.84(d,J=8.8Hz,2H),7.22(d,J=8.8Hz,2H),7.29(bs,2H)。

The synthesis of embodiment 11:4-(3-p-methoxy-phenyl)-5-(3,4,5-trimethoxyphenyl)-thiazolamine (CLJ-9)

Operation is as embodiment 3, and just phenylo boric acid is replaced with 3-methoxyphenylboronic acid, yield is 72%.

¹H-NMR(CDCl ₃)δ:3.67(s,6H),3.72(s,3H),3.82(s,3H),6.70(s,2H),6.67(m,6H)。

The synthesis of embodiment 12:4-(the fluoro-4-p-methoxy-phenyl of 3-)-5-(3,4,5-trimethoxyphenyl)-thiazolamine (CLJ-10)

Operation is as embodiment 3, and just phenylo boric acid is replaced with the fluoro-4-methoxyphenylboronic acid of 3-, yield is 75%.

¹H-NMR(CDCl ₃)δ:3.84(s,6H),3.87(s,3H),3.89(s,3H),6.68(s,2H),6.82(m,3H),6.90(d,J=8.6Hz,1H),7.12(d,J=8.6Hz,1H)。

The synthesis of embodiment 13:4-(3-chloro-4-methoxy phenyl)-5-(3,4,5-trimethoxyphenyl)-thiazolamine (CLJ-11)

Operation is as embodiment 3, and just phenylo boric acid is replaced with 3-chloro-4-methoxy phenylo boric acid, yield is 77%.

¹H-NMR(DMSO-d ₆)δ:3.42(bs,2H),3.57(s,6H),3.64(s,3H),3.82(s,3H),6.68(s,2H),7.15(d,J=8.6Hz,1H),7.24(d,J=8.6Hz,1H),7.30(s,1H)。

The synthesis of embodiment 14:4-(3-methyl-4-p-methoxy-phenyl)-5-(3,4,5-trimethoxyphenyl)-thiazolamine (CLJ-12)

Operation is as embodiment 3, and just phenylo boric acid is replaced with 3-methyl-4-methoxyphenylboronic acid, yield is 75%.

¹H-NMR(DMSO-d ₆)δ:2.10(s,3H),3.53(s,6H),3.62(s,3H),3.77(s,3H),6.71(s,2H),6.94(d,J=8.6Hz,1H),7.09(m,4H).

The synthesis of embodiment 15:4-(3,4-Dimethoxyphenyl)-5-(3,4,5-trimethoxyphenyl)-thiazolamine (CLJ-13)

Operation is as embodiment 3, and just phenylo boric acid is replaced with 3,4-dimethoxyphenylboronic, yield is 78%.

¹H-NMR(CDCl ₃)δ:3.68(s,3H),3.72(s,3H),3.82(s,3H),3.83(s,3H),3.87(s,3H),5.52(bs,2H),6.73(s,2H),6.83(m,3H)。

Embodiment 16:4-(4-ethoxyl phenenyl)-5-(3,4,5-trimethoxyphenyl) synthesis of-thiazolamine (CLJ-14)

Operation is as embodiment 3, and just phenylo boric acid is replaced with 4-phenetole boric acid, yield is 76%.

¹H NMR(400MHz,CDCl ₃)δ7.41(d,J=8.7Hz,2H),6.81(d,J=8.7Hz,2H),6.49(s,2H),5.24(br,2H),4.02(q,J=7.0Hz,2H),3.85(s,3H),3.70(s,6H),1.40(t,J=7.0Hz,3H)。

The chloro-4-ethoxyl phenenyl of embodiment 17:4-(3-)-5-(3,4,5-trimethoxyphenyl) synthesis of-thiazolamine (CLJ-15)

Operation is as embodiment 3, and just phenylo boric acid is replaced with 3-chloro-4-phenetole boric acid, yield is 70%.

¹H-NMR(CDCl ₃)δ:1.45(t,J=7.0Hz,3H),3.75(s,6H),3.82(s,3H),4.06(q,J=7.0Hz,2H),5.34(bs,2H),6.69(s,2H),6.79(d,J=8.6Hz,1H),7.09(d,J=8.6Hz,1H),7.34(s,1H)。

Embodiment 18:4-(4-pyrimidyl)-5-(3,4,5-trimethoxyphenyl) synthesis of-thiazolamine (CLJ-16)

Operation is as embodiment 3, and just phenylo boric acid is replaced with 4-pyrimidine phenylo boric acid, yield is 61%.

Embodiment 19:N-Boc-glycine-4-(4-ethoxyl phenenyl)-5-(3,4,5-trimethoxyphenyl) synthesis of-thiazole-2-acid amides

4-(4-ethoxyl phenenyl is added in the reaction flask of 25mL)-5-(3, 4, 5-trimethoxyphenyl)-thiazolamine (193mg, 0.5mmol), Boc-glycine (88mg, 0.5mmol), HOBT(1-hydroxybenzotriazole) (34mg, 0.25mmol), EDCI(1-ethyl-3-(3-dimethylamine propyl) carbodiimide hydrochloride) (192mg, 1mmol) with methylene dichloride (10mL), 5h is reacted under room temperature, after reacting completely, concentration of reaction solution, target product white solid 0.258g is obtained by silicagel column column chromatography (developping agent Shi You Mi ︰ ethyl acetate=5 ︰ 1), yield 95%.

¹H NMR(400MHz,CDCl ₃)δ7.44(d,J=8.7Hz,2H),6.86(d,J=8.7Hz,2H),6.55(s,2H),5.23(s,1H),4.09(d,J=5.5Hz,2H),4.03(q,J=7.0Hz,2H),3.88(s,3H),3.72(s,6H),1.50(s,9H),1.41(t,J=7.0Hz,3H)。

Embodiment 20: glycine-4-(4-ethoxyl phenenyl)-5-(3,4,5-trimethoxyphenyl) synthesis of-thiazole-2-acid amides (CLJ-17)

N-Boc-glycine-4-(4-ethoxyl phenenyl is added in the reaction flask of 25mL)-5-(3,4,5-trimethoxyphenyl)-thiazole-2-acid amides (272mg, 0.5mmol) He 1,4-dioxane (10mL), then passes into HCl gas, after no longer absorbing HCl in system, stop passing into of HCl gas, then stirring at room temperature reaction 1h.Remove solvent after reacting completely, then regulate pH to be alkalescence with saturated sodium bicarbonate, then extraction into ethyl acetate (20mL × 3), merges organic phase, saturated common salt water washing, anhydrous sodium sulfate drying.Decompression removes solvent, obtains target product 188mg, yield 85%.

Embodiment 21:N-Boc-2-methyl-alanine-4-(4-ethoxyl phenenyl)-5-(3,4,5-trimethoxyphenyl) synthesis of-thiazole-2-acid amides

Preparation method is with embodiment 5, and just Boc-glycine replaces with 2-methyl-Boc-L-Ala, obtains product 246mg, yield 86%.

¹H NMR(400MHz,CDCl ₃)δ7.43(d,J=8.8Hz,2H),6.85(d,J=8.8Hz,2H),6.55(s,2H),4.03(q,J=7.0Hz,2H),3.87(s,3H),3.70(d,J=6.7Hz,6H),1.59(s,6H),1.47–1.38(m,12H)。

Embodiment 22:2-methyl-alanine-4-(4-ethoxyl phenenyl)-5-(3,4,5-trimethoxyphenyl) synthesis of-thiazole-2-acid amides (CLJ-18)

Preparation method is with embodiment 6, just by N-Boc-glycine-4-(4-ethoxyl phenenyl)-5-(3,4,5-trimethoxyphenyl)-thiazole-2-acid amides replaces with N-Boc-2-methyl-alanine-4-(4-ethoxyl phenenyl)-5-(3,4,5-trimethoxyphenyl)-thiazole-2-acid amides, obtain product 193mg, yield 82%.

Embodiment 23:N-Boc-leucine-4-(4-ethoxyl phenenyl)-5-(3,4,5-trimethoxyphenyl) synthesis of-thiazole-2-acid amides

Preparation method is with embodiment 5, and just Boc-glycine replaces with Boc-leucine, obtains product 252mg, yield 84%.

¹H NMR(400MHz,CDCl ₃)δ7.44(d,J=7.8Hz,2H),6.85(d,J=8.0Hz,2H),6.55(s,2H),4.89(s,1H),4.40(s,1H),4.03(q,J=7.1Hz,2H),3.87(s,3H),3.71(s,6H),1.69(br,4H),1.48(s,9H),1.41(t,J=6.8Hz,3H),0.98(s,6H)。

Embodiment 23: leucine-4-(4-ethoxyl phenenyl)-5-(3,4,5-trimethoxyphenyl) synthesis of-thiazole-2-acid amides (CLJ19)

Preparation method is with embodiment 6, just by N-Boc-glycine-4-(4-ethoxyl phenenyl)-5-(3,4,5-trimethoxyphenyl)-thiazole-2-acid amides replaces with N-Boc-leucine-4-(4-ethoxyl phenenyl)-5-(3,4,5-trimethoxyphenyl)-thiazole-2-acid amides, obtain product 193mg, yield 82%.

Embodiment 24:N-Boc-methionine(Met)-4-(4-ethoxyl phenenyl)-5-(3,4,5-trimethoxyphenyl) synthesis of-thiazole-2-acid amides

Preparation method is with embodiment 5, and just Boc-glycine replaces with Boc-methionine(Met), obtains product 269mg, yield 87%.

¹H NMR(400MHz,CDCl ₃)δ7.44(d,J=8.7Hz,2H),6.85(d,J=8.7Hz,2H),6.55(s,2H),5.25(d,J=7.5Hz,1H),4.57(s,1H),4.03(q,J=6.9Hz,2H),3.87(s,3H),3.71(s,6H),2.62(t,J=7.0Hz,2H),2.28(m,2H),2.13(s,3H),1.48(s,9H),1.41(t,J=7.0Hz,3H)。

Embodiment 25: methionine(Met)-4-(4-ethoxyl phenenyl)-5-(3,4,5-trimethoxyphenyl) synthesis of-thiazole-2-acid amides (CLJ20)

Preparation method is with embodiment 6, just by N-Boc-glycine-4-(4-ethoxyl phenenyl)-5-(3,4,5-trimethoxyphenyl)-thiazole-2-acid amides replaces with N-Boc-methionine(Met)-4-(4-ethoxyl phenenyl)-5-(3,4,5-trimethoxyphenyl)-thiazole-2-acid amides, obtain product 217mg, yield 84%.

Embodiment 26:N-Boc-L-proline(Pro)-4-(4-ethoxyl phenenyl)-5-(3,4,5-trimethoxyphenyl) synthesis of-thiazole-2-acid amides

Preparation method is with embodiment 5, and just Boc-glycine replaces with Boc-L-proline(Pro), obtains product 251mg, yield 86%.

¹H NMR(400MHz,CDCl ₃)δ7.44(d,J=8.7Hz,2H),6.84(d,J=8.7Hz,2H),6.56(s,2H),4.03(q,J=7.0Hz,2H),3.87(s,3H),3.71(s,6H),3.55(m,2H),3.42(m,1H),1.97(m,2H),1.50(s,9H),1.41(t,J=7.0Hz,3H),1.26(m,2H)。

Embodiment 27:L-proline(Pro)-4-(4-ethoxyl phenenyl)-5-(3,4,5-trimethoxyphenyl) synthesis of-thiazole-2-acid amides (CLJ21)

Preparation method is with embodiment 6, just by N-Boc-glycine-4-(4-ethoxyl phenenyl)-5-(3,4,5-trimethoxyphenyl)-thiazole-2-acid amides replaces with N-Boc-L-proline(Pro)-4-(4-ethoxyl phenenyl)-5-(3,4,5-trimethoxyphenyl)-thiazole-2-acid amides, obtain product 210mg, yield 87%.

Embodiment 28:N-Boc-D-proline(Pro)-4-(4-ethoxyl phenenyl)-5-(3,4,5-trimethoxyphenyl) synthesis of-thiazole-2-acid amides

Preparation method is with embodiment 5, and just Boc-glycine replaces with Boc-D-proline(Pro), obtains product 251mg, yield 86%.

¹H NMR(400MHz,CDCl ₃)δ7.42(d,J=8.0Hz,2H),6.84(d,J=7.2Hz,2H),6.55(s,2H),4.03(q,7.0Hz,2H),3.87(s,3H),3.71(s,6H),3.63(m,2H),3.44(m,1H),2.36(m,2H),1.98(m,2H),1.49(s,9H),1.42(t,J=7.0Hz,3H)。

Embodiment 29:D-proline(Pro)-4-(4-ethoxyl phenenyl)-5-(3,4,5-trimethoxyphenyl) synthesis of-thiazole-2-acid amides (CLJ22)

Preparation method is with embodiment 6, just by N-Boc-glycine-4-(4-ethoxyl phenenyl)-5-(3,4,5-trimethoxyphenyl)-thiazole-2-acid amides replaces with N-Boc-D-proline(Pro)-4-(4-ethoxyl phenenyl)-5-(3,4,5-trimethoxyphenyl)-thiazole-2-acid amides, obtain product 210mg, yield 87%.

Embodiment 30:N-Boc-L-phenylalanine-4-(4-ethoxyl phenenyl)-5-(3,4,5-trimethoxyphenyl) synthesis of-thiazole-2-acid amides

Preparation method is with embodiment 5, and just Boc-glycine replaces with Boc-L-phenylalanine, obtains product 282mg, yield 89%.

¹H NMR(400MHz,CDCl ₃)δ7.39(m,7H),6.81(d,J=7.5Hz,2H),6.53(s,2H),5.56(m,1H),5.38(m,1H),4.02(q,J=7.0Hz,2H),3.86(s,3H),3.70(s,6H),1.45(s,9H),1.40(t,J=7.0Hz,3H)。

Embodiment 31:L-phenylalanine-4-(4-ethoxyl phenenyl)-5-(3,4,5-trimethoxyphenyl) synthesis of-thiazole-2-acid amides (CLJ-23)

Preparation method is with embodiment 6, just by N-Boc-glycine-4-(4-ethoxyl phenenyl)-5-(3,4,5-trimethoxyphenyl)-thiazole-2-acid amides replaces with N-Boc-L-phenylalanine-4-(4-ethoxyl phenenyl)-5-(3,4,5-trimethoxyphenyl)-thiazole-2-acid amides, obtain product 210mg, yield 79%.

Embodiment 32:N-Boc-D-phenylalanine-4-(4-ethoxyl phenenyl)-5-(3,4,5-trimethoxyphenyl) synthesis of-thiazole-2-acid amides

Preparation method is with embodiment 5, and just Boc-glycine replaces with Boc-D-phenylalanine, obtains product 282mg, yield 89%.

¹H NMR(400MHz,CDCl ₃)δ7.41(d,J=7.3Hz,2H),7.31(m,3H),7.20(d,J=8.0Hz,2H),6.83(d,J=7.3Hz,2H),6.56(s,2H),4.88(m,1H),4.64(m,1H),4.02(q,J=7.0Hz,2H),3.87(s,3H),3.71(s,6H),1.45(s,9H),1.40(t,J=7.0Hz,3H)。

Embodiment 33:D-phenylalanine-4-(4-ethoxyl phenenyl)-5-(3,4,5-trimethoxyphenyl) synthesis of-thiazole-2-acid amides (CLJ-24)

Preparation method is with embodiment 6, just by N-Boc-glycine-4-(4-ethoxyl phenenyl)-5-(3,4,5-trimethoxyphenyl)-thiazole-2-acid amides replaces with N-Boc-D-phenylalanine-4-(4-ethoxyl phenenyl)-5-(3,4,5-trimethoxyphenyl)-thiazole-2-acid amides, obtain product 210mg, yield 79%.

Embodiment 34:N-Boc-L-tryptophane-4-(4-ethoxyl phenenyl)-5-(3,4,5-trimethoxyphenyl) synthesis of-thiazole-2-acid amides

Preparation method is with embodiment 5, and just Boc-glycine replaces with Boc-L-tryptophane, obtains product 326mg, yield 97%.

¹H NMR(400MHz,CDCl ₃)δ8.17(s,1H),7.61(d,J=7.9Hz,1H),7.37(t,J=7.9Hz,3H),7.21(t,J=7.3Hz,1H),7.12(t,J=7.4Hz,1H),7.08(s,1H),6.82(d,J=8.7Hz,2H),6.56(s,2H),5.03(m,1H),4.72(m,1H),4.01(q,J=7.0Hz,2H),3.88(s,3H),3.72(s,6H),3.38(s,2H),1.42(s,9H),1.40(t,J=7.0Hz,3H)。

Embodiment 35:D-tryptophane-4-(4-ethoxyl phenenyl)-5-(3,4,5-trimethoxyphenyl) synthesis of-thiazole-2-acid amides (CLJ-25)

Preparation method is with embodiment 6, just by N-Boc-glycine-4-(4-ethoxyl phenenyl)-5-(3,4,5-trimethoxyphenyl)-thiazole-2-acid amides replaces with N-Boc-D-phenylalanine-4-(4-ethoxyl phenenyl)-5-(3,4,5-trimethoxyphenyl)-thiazole-2-acid amides, obtain product 238mg, yield 83%.

Embodiment 36:1-(4-(4-ethoxyl phenenyl)-5-(3,4,5-trimethoxyphenyl)-2-thiazolyl) synthesis of urea (CLJ-26)

4-(4-ethoxyl phenenyl is added in the reaction flask of 10mL)-5-(3,4,5-trimethoxyphenyl)-thiazolamine (209mg, 0.54mmol) with 7ml glacial acetic acid, and then adding potassium cyanate (131mg, 1.62mmol) and water (540 μ L) successively, stirring at room temperature is reacted.After reacting completely, add 30mL water, extraction into ethyl acetate (15mL × 3), merge organic phase, saturated common salt water washing, anhydrous sodium sulfate drying.Decompression removes solvent, obtains target product 162mg, yield 70%.

¹H NMR(400MHz,DMSO)δ10.57(br,1H),9.68(br,1H),7.38(d,J=8.6Hz,2H),6.87(d,J=8.7Hz,2H),6.55(s,2H),4.01(q,J=7.0Hz,2H),3.71(s,3H),3.64(s,6H),1.31(t,J=7.0Hz,3H)。

The synthesis of embodiment 37:3,4,5-trimethoxy phenyllacetyl chloride

3,4,5-trimethoxy phenyl acetic acid (1.13g, 5mmol) and anhydrous THF(20mL is added in 100mL round-bottomed flask), then add oxalyl chloride (0.951mL, 10mmol).Then add rapidly 2 DMF, vigorous stirring, reaction can acutely be carried out, and after 10min, decompression removes solvent, and adds anhydrous THF(50mL again), again concentrate, obtain jonquilleous viscous oil-like liquid.This liquid vacuum pump being taken out 3h, not doing further purifying, being directly used in next step.

Embodiment 38:1-(4-ethoxyl phenenyl)-2-(3,4,5-trimethoxy) synthesis of ethyl ketone

The reaction flask of 50mL is vacuumized and changes nitrogen, then 3,4,5-trimethoxy phenyllacetyl chloride (1.22g, 5mmol) and phenyl ethyl ether (20mL) are injected in reaction flask, then ice-water bath, by anhydrous AlCl under logical nitrogen ₃(0.733g, 5.5mmol) joins in reaction flask in batches.Room temperature reaction spends the night.Be poured in frozen water by reaction solution after reacting completely, then use ethyl acetate (60mL × 3) to extract, organic phase merges, saturated common salt water washing, anhydrous sodium sulfate drying, filters, concentrating under reduced pressure.Add normal hexane in concentrated solution, have a large amount of white solids and separate out, filtration drying obtains target product 1.07g, yield 65%.

¹H NMR(400MHz,CDCl ₃)δ8.02-7.96(m,2H),6.96-6.89(m,2H),6.48(s,2H),4.17(s,2H),4.10(q,J=7.0Hz,2H),3.83(d,J=4.9Hz,9H),1.44(t,J=7.0Hz,3H)。

The bromo-1-(4-ethoxyl phenenyl of embodiment 39:2-)-2-(3,4,5-trimethoxy) synthesis of ethyl ketone

By 1-(4-ethoxyl phenenyl)-2-(3,4,5-trimethoxy) ethyl ketone (4.96g, 15mmol) joins in the reaction flask of 50mL, and then add the mixing solutions (20mL) of ether/chloroform (3/1), be cooled to 0 DEG C.The bromine of 0.92mL is dissolved in 10mL anhydrous diethyl ether, is then added drop-wise in reaction flask.React 2h at such a temperature, after reacting completely, use saturated sodium thiosulfate solution, saturated common salt water washing, then concentrating under reduced pressure successively, obtain target product 1.84g, yield 30% by silicagel column column chromatography (developping agent stone oil ether ︰ ethyl acetate=10 ︰ 1).

¹H NMR(400MHz,CDCl ₃)δ7.97(d,J=8.7Hz,2H),6.91(d,J=8.7Hz,2H),6.75(s,2H),6.31(s,1H),4.09(q,J=7.0Hz,2H),3.87(s,6H),3.84(s,3H),1.44(t,J=7.0Hz,3H)。

Embodiment 40:4-(4'-ethoxyl phenenyl)-5-(3,4,5-trimethoxyphenyl) synthesis of-2-tertiary butyl thiazole (CLJ-27)

The bromo-1-(4-ethoxyl phenenyl of 2-is added in the reaction flask of 100mL)-2-(3,4,5-trimethoxy) ethyl ketone (1.47g, 3.6mmol), tertiary butyl thiocarbamide (468mg, 4mmol) and 50mL ethanol, reflux, after reaction 1h, decompression removes solvent, then uses saturated NaHCO ₃reaction solution is adjusted to about pH=8 by solution, then extraction into ethyl acetate (60mL × 3), merge organic phase, saturated common salt water washing, anhydrous sodium sulfate drying, filters, concentrating under reduced pressure, then product white solid 1.04g is obtained, yield 75% by silicagel column column chromatography (developping agent Shi You Mi ︰ ethyl acetate=5 ︰ 1).

Pharmacodynamics test part

One, external activity experiment

1, cell strain

Human liver cancer cell HepG2, SMMC-7721, human lung cancer cell A549's cell, Humanmachine tumour A375, human leukemia cell etc. purchase in ATCC(American Type Culture Collecti of the U.S.), and conservation is in biotherapy National Key Laboratory of Sichuan University

2, test method

Select man―machine systems, cell culture method is cultivated routinely, adopts tetrazolium MTT reduction method, medicine and co-culture of cells are respectively 48 and 72 hours, and attached cell needs first administration again after adherent 24 hours.Establish the positive and negative control group simultaneously, investigate the anti tumor activity in vitro of Honokiol liposome.

Concrete operations are as follows:

A) select the attached tumor cells of logarithmic phase, after trysinization, be made into the cell suspension of 5000/mL with the corresponding perfect medium containing 10% foetal calf serum (purchased from Lanzhou people's marine life company), be seeded in 96 well culture plates, 200 μ L are inoculated in every hole, 37 DEG C, 5%CO ₂cultivate 24h.The substratum containing different concns sample that experimental group renews, control group then changes the substratum containing equal-volume solvent, and often group establishes 3 ~ 5 parallel holes, 37 DEG C, 5%CO ₂cultivate 2 ~ 3d.

B) abandoning supernatant, every hole adds the freshly prepared serum free medium .37 DEG C of continuation containing 0.2mg/mLMTT of 200 μ L and cultivates 4h.Carefully abandon supernatant, and add 200 μ L DMSO(dimethyl sulfoxide (DMSO)), after the mixing of miniature ultrasonic vibrator, microplate reader is 570nm with tested wavelength, reference wavelength is that 450nm measures optical density value.

C) inhibiting rate of drug on tumor Growth of Cells is calculated as follows:

Growth of tumour cell inhibiting rate %=(1-OD _experiment/ OD _contrast) × 100%

Can dose response curve be obtained with the different concns of same sample to the mapping of growth of tumour cell inhibiting rate, therefrom obtain the half casualty-producing concentrations IC of sample ₅₀, it the results are shown in Table 1.

Table 1 compound is at the IC of kinds of tumor cells ₅₀value

Wherein work as IC ₅₀during >5 μM, be expressed as+; As 5 μMs of >IC ₅₀during >1 μM, be expressed as ++; Work as IC ₅₀during <1 μM, be expressed as +++.As can be seen from Table 1, Compound C LJ-12, CLJ-14, CLJ-15, CLJ-16, CLJ-17, CLJ-18, CLJ-19, CLJ-20, CLJ-22, CLJ-23, CLJ-26 all have good restraining effect to tumour cell.

Two, pharmacodynamics embodiment in body

1, animal-origin: nude mice (Balb/C nu/nu), 4-6 age in week, purchased from Beijing HFK Bio-Technology Co., Ltd., production licence number: SCXK(capital) 2009-0004; Female, raise place: Sichuan University biotherapy National Key Laboratory SPF Animal House (No. 9 room) (laboratory animal occupancy permit number: SYXK(river) 2011-178).

2, tumor cell line, serum and substratum

(1) human lung adenocarcinoma cell line H460, human colon carcinoma HCT116, human ovarian cancer SKVO3 are purchased from ATCC, and conservation is in biotherapy National Key Laboratory of Sichuan University.

(2) modified form RPMI1640 substratum provides for HyClone company, and lot number NWE0416, specification: 500mL, valid until on May 31st, 2012.2-8 DEG C of preservation.

(3) superfine foetal calf serum: grassland, Huhehaote City green field biological engineering material company limited produces, lot number 110318, specification: 100mL, validity period 5 years ,-20 DEG C of cryopreservation

3, cell cultures

H460, HCT116, SKVO3 cell is at the mid-saturated humidity of modified form RPMI1640 substratum, the 5%CO of 37 DEG C ₂cultivate in incubator, in substratum, contain penicillin and the 100 μ g/mL Streptomycin sulphates of 10% foetal calf serum and 100U/mL.The cell of vitro culture, through 0.25% tryptic digestion, is drawn a small amount of suspension and is added drop-wise on blood counting chamber, count under inverted microscope after mixing.Write down the total cellular score of 4 large lattice, after taking the mean, be multiplied by 10 ⁴, then be multiplied by extension rate and obtain cell density, be multiplied by cumulative volume and namely obtain total cellular score.According to counting, be diluted to 6 × 10 with the substratum not containing foetal calf serum ⁷the single cell suspension of individual/mL is for subsequent use.

4, transplanted tumor plantation and pharmacological agent

Mixing cell suspension, with 1mL syringe toward flank position subcutaneous injection 100uL cell suspension (6 × 10 on the right side of nude mice ⁶individual cell).Treat that tumour grows to about 10mm × 10mm, when tumour is not festered, under aseptic condition, cervical dislocation is carried out to mouse and put to death mouse, disinfect operating station skin in alcohol.Cut skin, growth selection is good in tumor tissue that is downright bad or liquefaction, in sterilized petri dishes, tumour is cut into 2 ~ 3mm ³knurl block.The damping fluid of a little sterilizing is placed, to preserve knurl block in plate.Then knurl block is inoculated in the subcutaneous of the right front armpit of nude mice.After knurl block becomes knurl, volume reaches 100mm ³time above, eliminate the tumor bearing nude mice that gross tumor volume is excessive, too small, by qualified animal random packet, only often organize 5-6, start to use pharmacological agent.

Experimental result

Dosage regimen: positive drug 5 FU 5 fluorouracil (5-Fu) (10mg/kg), CLJ-14(20mg/kg), CLJ-14(50mg/kg), CLJ-17 (20mg/kg), intraperitoneal administration, administration every day, successive administration 5 times weekly, altogether administration 4 weeks.In figure, " contrast " is blank.

Compound C LJ-14, the CLJ-17 tumor growth curve on HCT116 human colon carcinoma model is shown in Fig. 1.As can be seen from Fig., the remarkable Tumor suppression growth of Compound C LJ-14, CLJ-17.

The tumor growth curve of Compound C LJ-14 in people's lung cancer model is shown in Fig. 2.Compound C LJ-14 abdominal cavity gives 50mg/kg and show good therapeutic action on H460, its inhibitory rate to 71%, and in whole therapeutic process mouse body weight without obvious reduction.

Compound C LJ-14, the CLJ-17 tumor growth curve in human ovarian cancer is shown in Fig. 3.Compound C LJ-14, CLJ-17 abdominal cavity give 50mg/kg and show good therapeutic action in human ovarian cancer.

Claims (12)

1.2,4 5-(3,4,5-trimethoxyphenyl) thiazole derivatives replaced, its structure is such as formula shown in I:

Wherein, R ₁for the aromatic heterocyclic replaced or do not replace, replacement or the aryl do not replaced, C _{1 ~ 6}alkyl, C _{2 ~ 6}thiazolinyl or C _{2 ~ 6}alkynyl; Described aryl has 5 ~ 11 carbon atoms; The substituting group of described aryl is C _{1 ~ 6}alkyl, C _{2 ~ 6}thiazolinyl, C _{2 ~ 6}alkynyl, C _{3 ~ 6}cycloalkyl, halogen, hydroxyl, cyano group, carboxyl ,-CF ₃, amino or C _{1 ~ 6}alkoxyl group; Described aromatic heterocyclic is for containing 1 ~ 3 heteroatomic 5 ~ 11 ring, and heteroatoms is N, O or S; The substituting group of described aromatic heterocyclic is C _{1 ~ 6}alkyl, halogen, amino or C _{1 ~ 6}alkoxyl group;

R ₂for C _{1 ~ 6}alkyl, C _{2 ~ 6}thiazolinyl, C _{2 ~ 6}alkynyl, C _{3 ~ 6}cycloalkyl, halogen, hydroxyl, cyano group, carboxyl, amino or-NHCOR ₃;

R ₃for-H, C _{1 ~ 6}alkyl, C _{2 ~ 6}thiazolinyl, C _{2 ~ 6}alkynyl, C _{3 ~ 6}cycloalkyl, halogen, hydroxyl, cyano group, carboxyl, amino, C _{3 ~ 6}heterocyclylalkyl or the heteroatoms of described Heterocyclylalkyl is N, O or S;

R ₄for-H, C _{1 ~ 6}alkyl, C _{2 ~ 6}thiazolinyl, C _{2 ~ 6}alkynyl, C _{3 ~ 6}the C that cycloalkyl, aryl replace _{1 ~ 6}the C that alkyl, aromatic heterocyclic replace _{1 ~ 6}alkyl or m=0 ~ 4, n=0 ~ 4.

2. according to claim 12,4 5-(3,4,5-trimethoxyphenyl) thiazole derivatives replaced, is characterized in that: R ₁for aromatic heterocyclic or replacement or the aryl that do not replace; Described aryl has 5 ~ 11 carbon atoms; Described substituting group is C _{1 ~ 6}alkyl, C _{2 ~ 6}thiazolinyl, C _{2 ~ 6}alkynyl, C _{3 ~ 6}cycloalkyl, halogen, hydroxyl, cyano group, carboxyl ,-CF ₃, amino or C _{1 ~ 6}alkoxyl group; Described aromatic heterocyclic is for containing 1 ~ 3 heteroatomic 5 ~ 10 ring, and heteroatoms is N or S;

Preferably, R ₁for the aryl replaced or do not replace, described aryl has 6 ~ 10 carbon atoms; Preferred further, R ₁for the phenyl replaced or do not replace, replacement or the naphthyl that do not replace; Further preferred, R ₁for naphthyl or replacement or the phenyl that do not replace;

Preferably, described substituting group is C _{1 ~ 6}alkyl, C _{2 ~ 6}thiazolinyl, C _{2 ~ 6}alkynyl, C _{3 ~ 6}cycloalkyl, halogen ,-CF ₃, amino or C _{1 ~ 6}alkoxyl group; Preferred further, described substituting group is C _{1 ~ 6}alkyl, halogen ,-CF ₃or C _{1 ~ 6}alkoxyl group; Further preferred, described substituting group is C _{1 ~ 4}alkyl, halogen ,-CF ₃or C _{1 ~ 4}alkoxyl group;

Optimum, R ₁for naphthyl or replacement or the phenyl that do not replace; Described substituting group is R is C _{1 ~ 4}alkyl ,-F ,-Cl ,-CF ₃or C _{1 ~ 4}alkoxyl group.

3. according to claim 1 and 22,4 5-(3,4,5-trimethoxyphenyl) thiazole derivatives replaced, is characterized in that: R ₂for C _{1 ~ 6}alkyl, C _{2 ~ 6}thiazolinyl, C _{2 ~ 6}alkynyl, C _{3 ~ 6}cycloalkyl, amino or-NHCOR ₃;

Preferably, R ₂for C _{1 ~ 6}alkyl, C _{3 ~ 6}cycloalkyl, amino or-NHCOR ₃;

Preferred further, R ₂for C _{1 ~ 6}alkyl, amino or-NHCOR ₃;

Optimum, R ₂for C _{1 ~ 4}alkyl, amino or-NHCOR ₃.

4. according to any one of claims 1 to 32,4 5-(3,4,5-trimethoxyphenyl) thiazole derivatives replaced, is characterized in that: R ₃for-H, C _{1 ~ 6}alkyl, C _{2 ~ 6}thiazolinyl, C _{2 ~ 6}alkynyl, C _{3 ~ 6}cycloalkyl, amino, C _{3 ~ 6}heterocyclylalkyl or the heteroatoms of described Heterocyclylalkyl is N, O or S;

Preferably, R ₃for-H, C _{1 ~ 6}alkyl, C _{3 ~ 6}cycloalkyl, amino, C _{3 ~ 6}heterocyclylalkyl or

Preferred further, R ₃for-H, C _{1 ~ 6}alkyl, C _{3 ~ 6}heterocyclylalkyl or

Optimum, R ₃for-H, C _{1 ~ 4}alkyl, C _{3 ~ 6}heterocyclylalkyl or the heteroatoms of described Heterocyclylalkyl is N.

5. according to any one of Claims 1 to 42,4 5-(3,4,5-trimethoxyphenyl) thiazole derivatives replaced, is characterized in that: R ₄for-H, C _{1 ~ 6}alkyl, C _{2 ~ 6}thiazolinyl, C _{2 ~ 6}alkynyl, C _{3 ~ 6}the C that cycloalkyl, aryl replace _{1 ~ 6}the C that alkyl, aromatic heterocyclic replace _{1 ~ 6}alkyl or m=0 ~ 4, n=0 ~ 4;

Preferably, R ₄for-H, C _{1 ~ 6}alkyl, C _{3 ~ 6}the C that cycloalkyl, aryl replace _{1 ~ 6}the C that alkyl, aromatic heterocyclic replace _{1 ~ 6}alkyl or

Preferred further, R ₄for-H, C _{1 ~ 6}the C that alkyl, aryl replace _{1 ~ 6}the C that alkyl, aromatic heterocyclic replace _{1 ~ 6}alkyl or

Optimum, R ₄for-H, C _{1 ~ 4}the C that alkyl, aryl replace _{1 ~ 4}the C that alkyl, aromatic heterocyclic replace _{1 ~ 4}alkyl or m=0 ~ 2, n=0 ~ 3.

6. according to any one of Claims 1 to 52,4 5-(3,4,5-trimethoxyphenyl) thiazole derivatives replaced, is characterized in that: R ₁for naphthyl or replacement or the phenyl that do not replace; Described substituting group is C _{1 ~ 4}alkyl, halogen ,-CF ₃or C _{1 ~ 4}alkoxyl group;

R ₂for C _{1 ~ 4}alkyl, amino or-NHCOR ₃;

R ₃for-H, C _{1 ~ 4}alkyl, C _{3 ~ 6}heterocyclylalkyl or the heteroatoms of described Heterocyclylalkyl is N;

R ₄for-H, C _{1 ~ 4}the C that alkyl, aryl replace _{1 ~ 4}the C that alkyl, aromatic heterocyclic replace _{1 ~ 4}alkyl or m=0 ~ 2, n=0 ~ 3.

7. according to claim 12,4 5-(3,4,5-trimethoxyphenyl) thiazole derivatives replaced, is characterized in that: R ₂for amino, its structure is such as formula shown in II:

Wherein, R ₁for the aromatic heterocyclic replaced or do not replace, replacement or the aryl do not replaced, C _{1 ~ 6}alkyl, C _{2 ~ 6}thiazolinyl or C _{2 ~ 6}alkynyl; Described aryl has 5 ~ 11 carbon atoms; The substituting group of described aryl is C _{1 ~ 6}alkyl, C _{2 ~ 6}thiazolinyl, C _{2 ~ 6}alkynyl, C _{3 ~ 6}cycloalkyl, halogen, hydroxyl, cyano group, carboxyl ,-CF ₃, amino or C _{1 ~ 6}alkoxyl group; Described aromatic heterocyclic is for containing 1 ~ 3 heteroatomic 5 ~ 11 ring, and heteroatoms is N, O or S; The substituting group of described aromatic heterocyclic is C _{1 ~ 6}alkyl, halogen, amino or C _{1 ~ 6}alkoxyl group;

Preferably, R ₁for aromatic heterocyclic or replacement or the aryl that do not replace; Described aryl has 5 ~ 11 carbon atoms; Described substituting group is C _{1 ~ 6}alkyl, C _{2 ~ 6}thiazolinyl, C _{2 ~ 6}alkynyl, C _{3 ~ 6}cycloalkyl, halogen, hydroxyl, cyano group, carboxyl ,-CF ₃, amino or C _{1 ~ 6}alkoxyl group; Described aromatic heterocyclic is for containing 1 ~ 3 heteroatomic 5 ~ 10 ring, and heteroatoms is N or S;

Preferred further, R ₁for the aryl replaced or do not replace, described aryl has 6 ~ 10 carbon atoms; Preferred further, R ₁for the phenyl replaced or do not replace, replacement or the naphthyl that do not replace; Further preferred, R ₁for naphthyl or replacement or the phenyl that do not replace;

Preferred further, described substituting group is C _{1 ~ 6}alkyl, C _{2 ~ 6}thiazolinyl, C _{2 ~ 6}alkynyl, C _{3 ~ 6}cycloalkyl, halogen ,-CF ₃, amino or C _{1 ~ 6}alkoxyl group; Preferred further, described substituting group is C _{1 ~ 6}alkyl, halogen ,-CF ₃or C _{1 ~ 6}alkoxyl group; Further preferred, described substituting group is C _{1 ~ 4}alkyl, halogen ,-CF ₃or C _{1 ~ 4}alkoxyl group;

Optimum, R ₁for naphthyl or replacement or the phenyl that do not replace; Described substituting group is R is C _{1 ~ 4}alkyl ,-F ,-Cl ,-CF ₃or C _{1 ~ 4}alkoxyl group.

8. according to claim 12,4 5-(3,4,5-trimethoxyphenyl) thiazole derivatives replaced, is characterized in that: R ₁for the phenyl replaced or do not replace, its structure is as shown in formula III:

Wherein, R is C _{1 ~ 6}alkyl, C _{2 ~ 6}thiazolinyl, C _{2 ~ 6}alkynyl, C _{3 ~ 6}cycloalkyl, halogen, hydroxyl, cyano group, carboxyl ,-CF ₃, amino or C _{1 ~ 6}alkoxyl group;

Preferably, R is C _{1 ~ 6}alkyl, C _{2 ~ 6}thiazolinyl, C _{2 ~ 6}alkynyl, C _{3 ~ 6}cycloalkyl, halogen ,-CF ₃, amino or C _{1 ~ 6}alkoxyl group;

Preferred further, R is C _{1 ~ 6}alkyl, halogen ,-CF ₃or C _{1 ~ 6}alkoxyl group;

Further preferred, R is C _{1 ~ 4}alkyl, halogen ,-CF ₃or C _{1 ~ 4}alkoxyl group;

Optimum, R is C _{1 ~ 4}alkyl ,-F ,-Cl ,-CF ₃or C _{1 ~ 4}alkoxyl group.

9. according to claim 12,4 5-(3,4,5-trimethoxyphenyl) thiazole derivatives replaced, is characterized in that: R ₁for to ethoxyl phenenyl, its structure is such as formula shown in IV:

Wherein, R ₂for C _{1 ~ 6}alkyl, C _{2 ~ 6}thiazolinyl, C _{2 ~ 6}alkynyl, C _{3 ~ 6}cycloalkyl, halogen, hydroxyl, cyano group, carboxyl, amino or-NHCOR ₃; R ₃for-H, C _{1 ~ 6}alkyl, C _{2 ~ 6}thiazolinyl, C _{2 ~ 6}alkynyl, C _{3 ~ 6}cycloalkyl, halogen, hydroxyl, cyano group, carboxyl, amino, C _{3 ~ 6}heterocyclylalkyl or the heteroatoms of described Heterocyclylalkyl is N, O or S; R ₄for-H, C _{1 ~ 6}alkyl, C _{2 ~ 6}thiazolinyl, C _{2 ~ 6}alkynyl, C _{3 ~ 6}the C that cycloalkyl, aryl replace _{1 ~ 6}the C that alkyl, aromatic heterocyclic replace _{1 ~ 6}alkyl or m=0 ~ 4, n=0 ~ 4;

Preferably, R ₂for C _{1 ~ 6}alkyl, C _{2 ~ 6}thiazolinyl, C _{2 ~ 6}alkynyl, C _{3 ~ 6}cycloalkyl, amino or-NHCOR ₃; Preferred further, R ₂for C _{1 ~ 6}alkyl, C _{3 ~ 6}cycloalkyl, amino or-NHCOR ₃; Further preferred, R ₂for C _{1 ~ 6}alkyl, amino or-NHCOR ₃; Optimum, R ₂for C _{1 ~ 4}alkyl, amino or-NHCOR ₃;

Preferably, R ₃for-H, C _{1 ~ 6}alkyl, C _{2 ~ 6}thiazolinyl, C _{2 ~ 6}alkynyl, C _{3 ~ 6}cycloalkyl, amino, C _{3 ~ 6}heterocyclylalkyl or the heteroatoms of described Heterocyclylalkyl is N, O or S; Preferred further, R ₃for-H, C _{1 ~ 6}alkyl, C _{3 ~ 6}cycloalkyl, amino, C _{3 ~ 6}heterocyclylalkyl or further preferred, R ₃for-H, C _{1 ~ 6}alkyl, C _{3 ~ 6}heterocyclylalkyl or optimum, R ₃for-H, C _{1 ~ 4}alkyl, C _{3 ~ 6}heterocyclylalkyl or the heteroatoms of described Heterocyclylalkyl is N;

Preferably, R ₄for-H, C _{1 ~ 6}alkyl, C _{2 ~ 6}thiazolinyl, C _{2 ~ 6}alkynyl, C _{3 ~ 6}the C that cycloalkyl, aryl replace _{1 ~ 6}the C that alkyl, aromatic heterocyclic replace _{1 ~ 6}alkyl or m=0 ~ 4, n=0 ~ 4; Preferred further, R ₄for-H, C _{1 ~ 6}alkyl, C _{3 ~ 6}the C that cycloalkyl, aryl replace _{1 ~ 6}the C that alkyl, aromatic heterocyclic replace _{1 ~ 6}alkyl or further preferred, R ₄for-H, C _{1 ~ 6}the C that alkyl, aryl replace _{1 ~ 6}the C that alkyl, aromatic heterocyclic replace _{1 ~ 6}alkyl or optimum, R ₄for-H, C _{1 ~ 4}the C that alkyl, aryl replace _{1 ~ 4}the C that alkyl, aromatic heterocyclic replace _{1 ~ 4}alkyl or m=0 ~ 2, n=0 ~ 3;

Optimum, R ₂for C _{1 ~ 4}alkyl, amino or-NHCOR ₃; R ₃for-H, C _{1 ~ 4}alkyl, C _{3 ~ 6}heterocyclylalkyl or the heteroatoms of described Heterocyclylalkyl is N; R ₄for-H, C _{1 ~ 4}the C that alkyl, aryl replace _{1 ~ 4}the C that alkyl, aromatic heterocyclic replace _{1 ~ 4}alkyl or m=0 ~ 2, n=0 ~ 3.

10.2,4 5-(3,4,5-trimethoxyphenyl) thiazole derivatives replaced, its chemical name is:

4-phenyl-5-(3, 4, 5-trimethoxyphenyl)-thiazolamine, 4-(1-naphthyl)-5-(3, 4, 5-trimethoxyphenyl)-thiazolamine, 4-(2-naphthyl)-5-(3, 4, 5-trimethoxyphenyl)-thiazolamine, 4-(2-benzothienyl)-5-(3, 4, 5-trimethoxyphenyl)-thiazolamine, 4-(4-aminomethyl phenyl)-5-(3, 4, 5-trimethoxyphenyl)-thiazolamine, 4-(4-ethylphenyl)-5-(3, 4, 5-trimethoxyphenyl)-thiazolamine, 4-(4-trifluoromethyl)-5-(3, 4, 5-trimethoxyphenyl)-thiazolamine, 4-(4-p-methoxy-phenyl)-5-(3, 4, 5-trimethoxyphenyl)-thiazolamine, 4-(3-p-methoxy-phenyl)-5-(3, 4, 5-trimethoxyphenyl)-thiazolamine, 4-(the fluoro-4-p-methoxy-phenyl of 3-)-5-(3, 4, 5-trimethoxyphenyl)-thiazolamine, 4-(3-chloro-4-methoxy phenyl)-5-(3, 4, 5-trimethoxyphenyl)-thiazolamine, 4-(3, 4-Dimethoxyphenyl)-5-(3, 4, 5-trimethoxyphenyl)-thiazolamine, 4-(3-methyl-4-p-methoxy-phenyl)-5-(3, 4, 5-trimethoxyphenyl)-thiazolamine, 4-(4-ethoxyl phenenyl)-5-(3, 4, 5-trimethoxyphenyl)-thiazolamine, 4-(the chloro-4-ethoxyl phenenyl of 3-)-5-(3, 4, 5-trimethoxyphenyl)-thiazolamine, 4-(4-pyrimidyl)-5-(3, 4, 5-trimethoxyphenyl)-thiazolamine, glycine-4-(4-ethoxyl phenenyl)-5-(3, 4, 5-trimethoxyphenyl)-thiazole-2-acid amides, 2-methyl-alanine-4-(4-ethoxyl phenenyl)-5-(3, 4, 5-trimethoxyphenyl)-thiazole-2-acid amides, leucine-4-(4-ethoxyl phenenyl)-5-(3, 4, 5-trimethoxyphenyl)-thiazole-2-acid amides, methionine(Met)-4-(4-ethoxyl phenenyl)-5-(3, 4, 5-trimethoxyphenyl)-thiazole-2-acid amides, L-PROLINE-4-(4-ethoxyl phenenyl)-5-(3, 4, 5-trimethoxyphenyl)-thiazole-2-acid amides, D-PROLINE-4-(4-ethoxyl phenenyl)-5-(3, 4, 5-trimethoxyphenyl)-thiazole-2-acid amides, L-Phe-4-(4-ethoxyl phenenyl)-5-(3, 4, 5-trimethoxyphenyl)-thiazole-2-acid amides, D-phenylalanine-4-(4-ethoxyl phenenyl)-5-(3, 4, 5-trimethoxyphenyl)-thiazole-2-acid amides, D-trp-4-(4-ethoxyl phenenyl)-5-(3, 4, 5-trimethoxyphenyl)-thiazole-2-acid amides, 1-(4-(4-ethoxyl phenenyl)-5-(3, 4, 5-trimethoxyphenyl)-2-thiazolyl) urea or 4-(4-ethoxyl phenenyl)-5-(3, 4, 5-trimethoxyphenyl)-2-tertiary butyl thiazole.

Described in 11. any one of claim 1 ~ 10, compound is preparing the purposes in antitumor drug.

12. pharmaceutical compositions are activeconstituents by compound described in any one of claim 1 ~ 10, adds pharmaceutically acceptable carrier composition.