CN1566065A - Alpha position heteroatom substituted gamma aryl ketobutyric acid derivative, process, pharmaceutical combination and uses thereof - Google Patents

Alpha position heteroatom substituted gamma aryl ketobutyric acid derivative, process, pharmaceutical combination and uses thereof Download PDF

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CN1566065A
CN1566065A CN 03147933 CN03147933A CN1566065A CN 1566065 A CN1566065 A CN 1566065A CN 03147933 CN03147933 CN 03147933 CN 03147933 A CN03147933 A CN 03147933A CN 1566065 A CN1566065 A CN 1566065A
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oxygen
butyric acid
phenyl
base
xenyl
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杨光中
葛轶昱
杜冠华
贾红
任德成
杨秀颖
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Institute of Materia Medica of CAMS
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Institute of Materia Medica of CAMS
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Abstract

The invention relates to a gamma methyl ethyl ketone acid derivative represented by general formula (I), and contains gamma-aryl-alpha-amido-beta, its preparing process, pharmaceutical compositions containing them and use as medicament, in particular as medicament for treating osteoarthritis and tumor.

Description

γ aryl batanone acid derivative that α position heteroatoms replaces and method for making thereof and its pharmaceutical composition and purposes
Technical field
The present invention relates to the batanone acid derivative, its preparation method contains their pharmaceutical composition, and as medicine, especially as the purposes of treatment osteoarthrosis inflammation and tumour medicine.
Background technology
(Matrix Metalloproteinases is the general name that a class reactive site contains the endopeptidase of zine ion MMPs) to matrix metalloproteinase, is present in extracellular matrix and film surface.Mainly by fibroblast, neutrophil leucocyte, scavenger cell and tumour cell be with the zymogen forms secretion of non-activity, extracellular matrix (Extra Cellular Matrix, ECM) in, activate by corresponding enzyme.MMPs can the different protein substrate of hydrolysis, as: collagen protein, glutin, protein-polysaccharide becomes scleroproein, elastin etc.Regulate by three kinds of modes in vivo: cytokine and somatomedin mediation; The activation of proenzyme; The participation of endogenous inhibitor (TIMPs, Tissue Inhibitorsof Matrix Metalloproteinase).Under the normal physiological state, show as degraded, promote the metabolism of joint cartilage, promote adhering to and adhesion of cell, the effect that promotes vasculogenesis is arranged soft tissue of joint.According to different hydrolysis substrates, MMPs can be divided into four big classes: glutinase, Collagenase, a matter lytic enzyme and film type matrix metalloproteinase.Up to the present, existing about 24 kinds of matrix metalloproteinases are found, and X-ray and nuclear magnetic resonance technique have also been determined its three-dimensional structure basically.Gene molecule is biological to studies show that the homology of hypotype of these MMPs is at 40%-60%.In recent years, pathological research finds that in inflammatory cell, particularly osteoarthrosis inflammation cell reaches in tumor invasion and transfer process, and MMPs has high expression level.The Invasion and Metastasis that shows osteoarthritis and tumour is relevant with the overexpression of MMPs.Research shows that also osteoarthritis may be relevant with MMP-1, MMP-3, and tumour is not only relevant with MMP-1, MMP-3, and also and MMP-2, MMP-9 substantial connection is arranged.
Medicinal design based on structure and hydrolysis mechanism is a method of using maximum MMPs inhibitor designs at present.Existing many documents and patent disclosure have been reported some design and synthetic MMPs inhibitor, as intending peptide class MMPs inhibitor: Marimastat BB-2516 (British BiotechReport and Accounts 1994; Drug Discovery Today, 1996,1,16-26), Barimastat BB-94 (patent No. EP498665; WO9213831), Trocade Ro32-3555 (patent No. EP684240; JP95291938) etc.; Non-peptide class MMPs inhibitor PrinomastatAG-3340 (patent No. US5753653), Bay12-9566 (patent No. 9615096), CGS-27023A (patent No. EP606046; JP94256293) etc.But up to this point, Shang Weiyou is at the listing that goes through of the antitumour drug of MMPs and antiphlogiston, even has that much having entered the MMPs inhibitor of clinical III phase has also stopped clinical trial, stopped clinical development.Clinical trial is found, many antitumour drugs or antiphlogiston as present MMPs inhibitor, there is not significant curative effect with placebo in test, medication does not have significantly antitumor or anti-inflammatory action separately, and ubiquity mainly shows as sore muscle and ankylosis to the damage in skeletal muscle and joint.Thereby to design and develop novel MMPs inhibitor be pressing for of this field as antitumor or antiphlogiston.
Summary of the invention
In order to overcome the deficiencies in the prior art, the object of the present invention is to provide a kind of new derivative;
Another object of the present invention is to provide a kind of preparation method of new derivative;
Another object of the present invention is to provide a kind of new composition that contains derivative;
A further object of the present invention is to provide the application in the antitumor or anti-inflammatory drug of a kind of new derivative and derivative preparation thereof.
In order to finish the present invention's purpose, the present invention takes following technical scheme:
One aspect of the present invention relates to acceptable salt on compound shown in general formula (I) and the pharmacodynamics thereof
Figure A0314793300101
Wherein, R1 is selected from C 1～8Straight chain or branched alkyl and alkoxyl group, alkylthio, alkylamino radical; Cycloalkyl; Halogen, nitro, cyano group, hydroxyl;-COOR 5,-OCOR 6,-NHCOR 7,-CONHR 8, R wherein 5, R 6, R 7, R 8Independently be selected from C 1～C 4Alkyl, cycloalkyl or phenyl
Or
Figure A0314793300102
M is Sauerstoffatom, sulphur atom, amido, methylene radical phenyl, phenoxy group, thiophenyl, anilino, benzyl;
R 9Be selected from C 1～4Alkyl, alkoxyl group, alkylthio, alkylamino radical, hydroxyl, the phenyl that amino, halogen replace, phenoxy group, thiophenyl, anilino, benzyl; Also can be selected from heterocyclic radical and substituted heterocyclic radical;
R2 is selected from O, S ,=NR 9,=NOR 10, R wherein 9, R 10Independently be selected from H, C 1～4Alkyl or cycloalkyl, phenyl;
Z is selected from H, NH, O, S ,=CH 2
Work as Z=NH, O, during S, R3 is selected from H, C 1～6Straight chain or branched alkyl; Cycloalkyl; Phenyl and substituted-phenyl; Heterocyclic radical and substituted heterocyclic radical;-COR 11, R wherein 11Be selected from C 1～4Alkyl, cycloalkyl, phenyl and substituted-phenyl.
Work as Z=CH 2The time, R3 is selected from phthalyl-2-base, succinyl-2-base, glycolylurea-3-base, R 12W[R 12Be selected from H, C 1～6Alkyl; Cycloalkyl; Phenyl and substituted-phenyl; Heterocyclic radical and substituted heterocyclic radical;-COR 13(R 13Be selected from C 1～C 4Alkyl, cycloalkyl, phenyl and substituted-phenyl); W is selected from O, S, NH;
Y is selected from NH, O, S;
R4 is selected from H, C 1～6Straight chain or branched alkyl, cycloalkyl; Phenyl and substituted-phenyl; Benzyl and benzene alkyl;-COR 14, R wherein 14Be selected from C 1～C 4Alkyl, phenyl, the phenyl of benzene alkyl and replacement, benzene alkyl; Also can be selected from heterocyclic radical;
X is selected from OH, NHOH.
Wherein, described heterocyclic radical is selected from pyridyl, pyrryl, and furyl, thienyl, pyranyl is sent the pyridine base, piperazinyl.
According to the present invention, preferred general formula (I) compound includes but not limited to the compound of formula (Ia) expression
Figure A0314793300111
Wherein, R1 and R4 are as defined above.
According to the present invention, preferred general formula (I) compound includes but not limited to the compound of formula (Ib) expression
Figure A0314793300121
Wherein, R1 and R4 are as defined above.
According to the present invention, preferred general formula (I) compound includes but not limited to the compound of formula (Ic) expression
Figure A0314793300122
Wherein, R1 as defined above.
According to the present invention, preferred general formula (I) compound includes but not limited to the compound of formula (Id) expression
Figure A0314793300123
Wherein, R1 as defined above.
According to the present invention, preferred general formula (I) compound includes but not limited to the compound of formula (Ie) expression
Wherein, R1 and R4 are as defined above.
According to the present invention, preferred general formula (I) compound includes but not limited to the compound of formula (If) expression
Wherein, R1, R3 and R4 are as defined above.
According to the present invention, preferred general formula (I) compound includes but not limited to the compound of formula (Ig) expression
Wherein, R1 as defined above.
According to the present invention, preferred compound includes but not limited to the compound that formula is as follows
2-(2-hydroxyethyl amido)-4-oxygen-4-(4 '-xenyl) butyric acid
2,2-benzene methanamine base-4-oxygen-4-(4 '-xenyl) butyric acid
2-n-butylamine-based-4-oxygen-4-(4 '-xenyl) butyric acid
Figure A0314793300135
2-n-octyl amine base-4-oxygen-4-(4 '-xenyl) butyric acid
Figure A0314793300136
2-(2-N, N '-dimethylamino ethyl amido)-4-oxygen-4-(4 '-xenyl) butyric acid
Figure A0314793300137
2-cyclohexyl amido-4-oxygen-4-(4 '-xenyl) butyric acid
2-cyclopropyl amido-4-oxygen-4-(4 '-xenyl) butyric acid
Figure A0314793300142
2-(3-phenyl propyl amido)-4-oxygen-4-(4 '-xenyl) butyric acid
2-(3-N, N '-dimethylamino-propyl amido)-4-oxygen-4-(4 '-xenyl) butyric acid
Figure A0314793300144
2-(4-hydroxyl butylamine base)-4-oxygen-4-(4 '-xenyl) butyric acid
2-(4-morpholinyl)-4-oxygen-4-(4 '-xenyl) butyric acid
Figure A0314793300146
2-(4-hydroxy-n-piperidyl)-4-oxygen-4-(4 '-xenyl) butyric acid
Figure A0314793300147
2-(2-hydroxyethyl amido)-4-oxygen-4-(4 '-Phenoxyphenyl) butyric acid
Figure A0314793300148
2-benzene methanamine base-4-oxygen-4-(4 '-Phenoxyphenyl) butyric acid
2-n-butylamine-based-4-oxygen-4-(4 '-Phenoxyphenyl) butyric acid
2-n-octyl amine base-4-oxygen-4-(4 '-Phenoxyphenyl) butyric acid
Figure A0314793300151
2-(2-N, N '-dimethylamino ethyl amido)-4-oxygen-4-(4 '-Phenoxyphenyl) butyric acid
Figure A0314793300152
2-cyclohexyl amido-4-oxygen-4-(4 '-Phenoxyphenyl) butyric acid
2-cyclopropyl amido-4-oxygen-4-(4 '-Phenoxyphenyl) butyric acid
2-(3-phenyl propyl amido)-4-oxygen-4-(4 '-Phenoxyphenyl) butyric acid
Figure A0314793300155
2-(3-N, N '-dimethylamino-propyl amido)-4-oxygen-4-(4 '-Phenoxyphenyl) butyric acid
Figure A0314793300156
2-(4-hydroxyl butylamine base)-4-oxygen-4-(4 '-Phenoxyphenyl) butyric acid
2-(4-morpholinyl)-4-oxygen-4-(4 '-Phenoxyphenyl) butyric acid
2-(4-piperidyl)-4-oxygen-4-(4 '-Phenoxyphenyl) butyric acid
2-(2-hydroxyethyl amido)-4-oxygen-4-(4 '-p-methoxy-phenyl) butyric acid
2-benzene methanamine base-4-oxygen-4-(4 '-p-methoxy-phenyl) butyric acid
Figure A0314793300162
2-n-butylamine-based-4-oxygen-4-(4 '-p-methoxy-phenyl) butyric acid
2-n-octyl amine base-4-oxygen-4-(4 '-p-methoxy-phenyl) butyric acid
2-(2-N, N '-dimethylamino ethyl amido)-4-oxygen-4-(4 '-p-methoxy-phenyl) butyric acid
2-cyclohexyl amido-4-oxygen-4-(4 '-p-methoxy-phenyl) butyric acid
2-cyclopropyl amido-4-oxygen-4-(4 '-p-methoxy-phenyl) butyric acid
2-(3-phenyl propyl amido)-4-oxygen-4-(4 '-p-methoxy-phenyl) butyric acid
Figure A0314793300168
2-(3-N, N '-dimethylamino-propyl amido)-4-oxygen-4-(4 '-p-methoxy-phenyl) butyric acid
2-(4-hydroxyl butylamine base)-4-oxygen-4-(4 '-p-methoxy-phenyl) butyric acid
2-(4-morpholinyl)-4-oxygen-4-(4 '-p-methoxy-phenyl) butyric acid
2-(2-hydroxyethyl sulfenyl)-4-oxygen-4-(4 '-xenyl) butyric acid
N-hydroxyl-2-(2-hydroxyethyl sulfenyl)-4-oxygen-4-(4 '-xenyl) butyramide
N-hydroxyl-2-[2-(N-succimide base) ethylmercapto group]-4-oxygen-4-(4 '-xenyl) butyramide
Figure A0314793300175
2-propyl group sulfenyl-4-oxygen-4-(4 '-xenyl) butyric acid
Figure A0314793300176
2-(2-hydroxyethyl sulfenyl)-2-methyl-4-oxygen-4-(4 '-xenyl) butyric acid
N-hydroxyl-2-(2 hydroxy ethylamine base)-4-oxygen-4-(4 '-xenyl) butyramide
Figure A0314793300178
N-hydroxyl-2-benzene methanamine base-4-oxygen-4-(4 '-xenyl) butyramide
N-hydroxyl-2-benzene methanamine base-4-oxygen-4-(4 '-p-methoxy-phenyl) butyramide
N-hydroxyl-2-n-octyl amine base-4-oxygen-4-(4 '-p-methoxy-phenyl) butyramide
N-hydroxyl-2-(2 hydroxy ethylamine base)-4-oxygen-4-(4 '-Phenoxyphenyl) butyramide
N-hydroxyl-2-benzene methanamine base-4-oxygen-4-(4 '-Phenoxyphenyl) butyramide
N-hydroxyl-2-(4-hydroxyl butylamine base)-4-oxygen-4-(4 '-Phenoxyphenyl) butyramide
2-(4-morpholinyl)-4-oxygen-4-[4 '-(4 "-chlorine) xenyl] butyric acid
2-(2-hydroxyethyl amido)-4-oxygen-4-[4 '-(4 "-chlorine) xenyl] butyric acid
2-(4-methylbenzene sulfenyl)-4-oxygen-4-(4 '-xenyl) butyric acid
Acceptable hydrochloride on 2-(2-amido ethylamino-)-4-oxygen-4-(4 '-Phenoxyphenyl) butyric acid and the pharmacodynamics.
Figure A0314793300188
Acceptable hydrochloride on N-hydroxyl-2-(4-hydroxyl butylamine base)-4-oxygen-4-(4 '-xenyl) butyramide and the pharmacodynamics.
Acceptable hydrochloride on N-hydroxyl-2-(2 hydroxy ethylamine base)-4-oxygen-4-(4 '-p-methoxy-phenyl) butyramide and the pharmacodynamics.
Figure A03147933001810
N-hydroxyl-2-hydroxyl-3-acetamido 4-oxygen-4-(4 '-xenyl) butyramide.
N-hydroxyl-2-[2-(4-nitrophenoxy) ethylmercapto group]-4-oxygen-4-(4 '-xenyl) butyramide
Figure A0314793300192
Acceptable hydrochloride on 2-(2-hydroxyethyl amido)-4-phenoxy group-3-(4 '-dibenzoyl base) butyric acid and the pharmacodynamics.
Acceptable hydrochloride on 2-benzene methanamine base-4-phenoxy group-3-(4 '-dibenzoyl base) butyric acid and the pharmacodynamics.
Acceptable hydrochloride on 2-n-octyl amine base-4-phenoxy group-3-(4 '-dibenzoyl base) butyric acid and the pharmacodynamics.
Figure A0314793300195
Acceptable hydrochloride on 2-(2-N, N '-dimethylamino ethyl amido)-4-phenoxy group-3-(4 '-dibenzoyl base) butyric acid and the pharmacodynamics.
Acceptable hydrochloride on 2-n-butylamine-based-4-phenoxy group-3-(4 '-dibenzoyl base) butyric acid and the pharmacodynamics.
Figure A0314793300197
Acceptable hydrochloride on 2-cyclohexylamino-4-phenoxy group-3-(4 '-dibenzoyl base) butyric acid and the pharmacodynamics.
Figure A0314793300198
Acceptable hydrochloride on 2-(2-hydroxyethyl amido)-4-(4-toluene sulfenyl)-3-(4 '-dibenzoyl base) butyric acid and the pharmacodynamics.
Acceptable hydrochloride on 2-benzene methanamine base-4-(4-toluene sulfenyl)-3-(4 '-dibenzoyl base) butyric acid and the pharmacodynamics.
Acceptable hydrochloride on 2-(2-N, N '-dimethylamino ethyl amido)-4-(4-toluene sulfenyl)-3-(4 '-dibenzoyl base) butyric acid and the pharmacodynamics.
Figure A0314793300202
Acceptable hydrochloride on 2-n-octyl amine base-4-(4-toluene sulfenyl)-3-(4 '-dibenzoyl base) butyric acid and the pharmacodynamics.
Figure A0314793300203
4-(4-xenyl)-2-(2-hydroxyethyl sulfenyl)-4-hydroxyl imido grpup butyric acid.
Figure A0314793300204
4-(4-xenyl)-2-(2-rosickyite base)-4-hydroxyl imido grpup butyric acid
4-(4-xenyl)-2-(4-methylbenzene sulfenyl)-4-hydroxyl imido grpup butyric acid
According to the invention still further relates to the method for preparing The compounds of this invention, can comprise respectively: method 1:
(A) with Friedel-Crafts reaction gained α, the unsaturated γ aryl of β batanone acid cis-trans mixture and various primary amine or mercaptan carry out the Michael addition in appropriate solvent, obtain corresponding adduct.
Described solvent comprises: various straight chain ethers (as: ether, isopropyl ether, glycol dimethyl ether, ethylene glycol monoemethyl ethers, diethylene glycol dimethyl ether, the only methyl ether of Diethylene Glycol), tetrahydrofuran (THF), benzene or substituted benzene (as: toluene, dimethylbenzene, chlorobenzene), acetone, butanone, methylene dichloride, chloroform, tetracol phenixin, 1, the 2-ethylene dichloride, methyl alcohol, the mixture of ethanol and above-mentioned solvent.
Method 2:
(A) 4-(4-substituted-phenyl)-2-(substituted amido)-4-oxy butyrate is made 4-(4-substituted-phenyl)-2-(substituted amido)-4-oxy butyrate ester hydrochloride with thionyl chloride in alcohol under proper temperature;
(B) resulting ester hydrochloride generates corresponding hydroximic acid with oxammonium hydrochloride and alkali reaction in alcohol.
Alcohol comprises methyl alcohol and ethanol described in the step (A), and temperature range comprises the reflux temperature of room temperature to solvent; Alcohol described in the step (B) is corresponding to alcohol described in (A), and described alkali comprises potassium hydroxide, sodium hydroxide, potassium alcoholate or sodium alkoxide (alcohol is corresponding to alcohol described in (A)).
Method 3:
(A) in appropriate solvent, 2-(2-hydroxyethyl sulfydryl)-4-oxygen-4-(4 '-substituted-phenyl) butyric acid and methyl iodide or methyl-sulfate and salt of wormwood reaction are made corresponding methyl esters;
(B) Mitsunobu reaction, under the effect of triphenyl phosphorus and diethyl azodiformate, on go on foot gained 2-(2-hydroxyethyl sulfydryl)-4-oxygen-4-(4 '-xenyl) methyl-butyrate and succimide or phthalic imidine or fortified phenol reaction and generate corresponding product 2-[2-(2-succimide base) ethyl sulfydryl]-4-oxygen-4-(4 '-substituted-phenyl) methyl-butyrate or 2-[2-(2-phthalimide-based) ethyl sulfydryl]-4-oxygen-4-(4 '-xenyl) methyl-butyrate or 2-[2-(4 "-nitro-phenoxy) ethyl sulfydryl]-4-oxygen-4-(4 '-xenyl) methyl-butyrate;
(C) above-mentioned gained methyl-butyrate is generated corresponding hydroximic acid with oxammonium hydrochloride and alkali reaction in methyl alcohol.
The described alkali of step (C) comprises potassium hydroxide, sodium hydroxide, potassium methylate, sodium methylate.
Method 4:
(A) in alkali alcosol, with mercaptoethanol and trans-α methyl-α, the unsaturated γ aryl of β batanone acid carries out addition, makes corresponding adduct.
Described alkali comprises potassium hydroxide, sodium hydroxide, potassium methylate, sodium methylate; Described alcohol comprises methyl alcohol and ethanol.
Method 5:
(A) in alcohol, the Mannich condensation takes place in substituted acetophenone and oxoethanoic acid monohydrate and all kinds of amine, generates corresponding M annich condensation product.
Described alcohol comprises methyl alcohol and ethanol, and temperature range comprises the reflux temperature of room temperature to solvent for use.
Method 6:
(A) 3-(4 '-substituted benzoyl)-3-butenoic acid is carried out the bromine addition, make 3,4-dibromo 3-(4 '-substituted benzoyl) butyric acid;
(B) to gained 3, the butyro-hydroxyl protection of 4-two bromo-3-(4 '-substituted benzoyl) makes 3,4-two bromo-3-(4 '-substituted benzoyl) butanoic acid derivatives;
(C) with gained 3, β takes place 4-two bromo-3-(4 '-substituted benzoyl) butyric esters eliminates generation 4-bromo-3-(4 '-substituted benzoyl)-2-butylene acid derivative;
(D) gained 4-bromo-3-(4 '-substituted benzoyl)-2-butylene acid derivative and R3H reaction are made corresponding 4-replacement-3-(4 '-substituted benzoyl)-2-butylene acid derivative;
(E) (D) gained is replaced the crotonate deprotection and become corresponding acid;
(F) addition is carried out in gained 4-replacement-3-(4 '-substituted benzoyl)-2-butylene acid and corresponding primary amines, preparation 2-substituted amido-4-replacement-3-(4 '-substituted benzoyl)-2-butyric acid.
The used solvent of step (A) comprises methylene dichloride, trichloromethane, and tetracol phenixin, 1, the 2-ethylene dichloride, chlorobenzene, acetic acid, various straight chain ethers, or be selected from their mixture; Preferred straight chain ethers is an ether, isopropyl ether, and glycol dimethyl ether, diethylene glycol dimethyl ether, preferred solvent is.
Protective reaction in the step (B) preferably 3,4-two bromo-3-(4 '-substituted benzoyl) butyric acid and alcohol carry out esterification; Esterification is preferably under the sulphuric acid catalysis; Preferred alcohol comprises methyl alcohol and ethanol.
It is preferred under the effect of alkali that the β elimination takes place for step (C) 3,4-two bromo-3-(4 '-substituted benzoyl) butyric esters, and preferably under the effect of organic bases, preferred organic bases comprises triethylamine, pyridine, N-methylmorpholine, DBU, DBN.
React the used preferably non-proton property of solvent polar solvent, preferred non-proton property polar solvent comprises methylene dichloride, trichloromethane, tetracol phenixin, 1,2-ethylene dichloride, chlorobenzene, various straight chain ethers; Preferred straight chain ethers is an ether, isopropyl ether, glycol dimethyl ether, diethylene glycol dimethyl ether;
The preferred R3H of step (D) comprises fortified phenol, and substituted benzene thiophenol, phthalic diamide, succimide reaction are preferably carried out under alkaline condition, and preferred alkali comprises salt of wormwood, yellow soda ash, potassium hydroxide, sodium hydroxide, DBU, DBN.
Preferred solvent comprises DMF,
Step (E) ester gets deprotection preferably to carry out under the alkali effect, and preferred alkali comprises potassium hydroxide, sodium hydroxide, lithium hydroxide.
The described solvent of step (F) is with method 1 (A).Used solvent comprises methylene dichloride, trichloromethane, and tetracol phenixin, 1, the 2-ethylene dichloride, chlorobenzene, acetic acid, various straight chain ethers, or be selected from their mixture; Preferred straight chain ethers is an ether, isopropyl ether, and glycol dimethyl ether, diethylene glycol dimethyl ether, preferred solvent is.
Method 7:
(A) 2-hydroxyl-3-acetamido-butyro-carboxylic acid hydroxyl of 4-oxygen-4-(4 '-substituted-phenyl) is methylated.
(B) with the described method of method 2 (B) 2-hydroxyl-3-acetamido-4-oxygen-4-(4 '-substituted-phenyl) methyl-butyrate is made corresponding hydroximic acid.
Preferred methylating reagent is to comprise methyl iodide in the step (A), and methyl-sulfate methylates preferably under alkaline condition, and preferred alkali is salt of wormwood; Reacting preferred solvent is DMF;
Method 8:
(A) in alcoholic solution, 2-thioether replacement-4-(4 '-xenyl)-4 oxy butyrate and oxammonium hydrochloride and alkali reaction are made corresponding condensation product.
Described alcohol comprises methyl alcohol, ethanol, the trimethyl carbinol.Described alkali comprises potassium hydroxide, sodium hydroxide, sodium ethylate, sodium methylate, potassium tert.-butoxide.
The preferred reaction scheme of the whole bag of tricks is as follows:
Method 1
Figure A0314793300231
Method 2
Method 3
Method 4
Figure A0314793300234
Method 5
Method 6:
Method 7:
Figure A0314793300243
Method 8:
Figure A0314793300244
Therefore the present invention also relates to and containing as at least a general formula (I) compound of the effective dose of active ingredient and/or the pharmaceutical composition of its steric isomer and conventional medicine vehicle or assistant agent.Usually pharmaceutical composition of the present invention contains general formula (I) compound and/or its physiologically acceptable salt of 0.1-90 weight %.
Pharmaceutical composition can prepare according to methods known in the art.When being used for this purpose, if desired, general formula (I) compound and/or steric isomer and one or more solids or liquid medicine vehicle and/or assistant agent can be combined, make and can be used as suitable administration form or the dosage form that people's medicine or veterinary drug use.
General formula of the present invention (I) compound or contain its pharmaceutical composition can the unit dosage form administration, route of administration can be enteron aisle or non-enteron aisle, as oral, vein, muscle, subcutaneous, nasal cavity, oral mucosa, skin, peritonaeum or rectum etc.Form of administration is tablet, capsule, dripping pill, aerosol, pill, pulvis, solution, suspensoid, emulsion, granule, suppository, lyophilized injectable powder etc. for example, can be ordinary preparation, sustained release preparation, controlled release preparation and various particulate delivery system.For the unit form of administration is made tablet, can be extensive use of various carrier well known in the art.Example about carrier is, for example thinner and absorption agent are as starch, dextrin, calcium sulfate, lactose, N.F,USP MANNITOL, sucrose, sodium-chlor, glucose, urea, lime carbonate, white bole, Microcrystalline Cellulose, pure aluminium silicate etc.; Wetting agent and tackiness agent are as water, glycerine, polyoxyethylene glycol, ethanol, propyl alcohol, starch slurry, dextrin, syrup, honey, glucose solution, mucialga of arabic gummy, gelatine size, Xylo-Mucine, lac, methylcellulose gum, potassiumphosphate, polyvinylpyrrolidone etc.; Disintegrating agent, for example dry starch, alginates, agar powder, laminaran, sodium bicarbonate and Citric Acid, lime carbonate, polyoxyethylene sorbitol fatty acid ester, sodium laurylsulfonate, methylcellulose gum, ethyl cellulose etc.; Disintegration inhibitor, for example sucrose, Tristearoylglycerol, theobroma oil, hydrogenation wet goods; Absorption enhancer, for example quaternary ammonium salt, sodium lauryl sulphate etc.; Lubricant, for example talcum powder, silicon-dioxide, W-Gum, stearate, boric acid, whiteruss, polyoxyethylene glycol etc.Tablet further can also be made coating tablet, for example sugar coated tablet, thin membrane coated tablet, ECT, or double-layer tablets and multilayer tablet.For pill is made in the administration unit, can be extensive use of various carrier well known in the art.Example about carrier is, for example thinner and absorption agent are as glucose, lactose, starch, theobroma oil, hydrogenated vegetable oil, polyvinylpyrrolidone, Gelucire, kaolin, talcum powder etc.; Tackiness agent is as gum arabic, tragacanth gum, gelatin, ethanol, honey, liquid sugar, rice paste or batter etc.; Disintegrating agent is as agar powder, dry starch, alginates, sodium laurylsulfonate, methylcellulose gum, ethyl cellulose etc.For suppository is made in the administration unit, can be extensive use of various carrier well known in the art.Example about carrier is, for example the ester of polyoxyethylene glycol, Yelkin TTS, theobroma oil, higher alcohols, higher alcohols, gelatin, semi-synthetic glyceryl ester etc.For capsule is made in the administration unit, effective constituent general formula (I) compound or its steric isomer are mixed with above-mentioned various carriers, and the mixture that will obtain thus places hard gelatine capsule or soft capsule.Also effective constituent general formula (I) compound or its steric isomer can be made microcapsule, be suspended in and form suspensoid in the aqueous medium, in the hard capsule of also can packing into or make injection and use.For injection preparation is made in the administration unit, as solution, emulsion, lyophilized injectable powder and suspensoid, can use this area all thinners commonly used, for example, water, ethanol, polyoxyethylene glycol, 1, the isooctadecanol of ammediol, ethoxylation, the isooctadecanol of polyoxyization, Polyoxyethylene Sorbitol Fatty Acid Esters etc.In addition, ooze injection liquid, can in injection preparation, add proper amount of sodium chloride, glucose or glycerine, in addition, can also add conventional solubility promoter, buffer reagent, pH regulator agent etc. in order to prepare etc.
In addition, as needs, also can in pharmaceutical preparation, add tinting material, sanitas, spices, correctives, sweeting agent or other material.
The dosage of general formula of the present invention (I) compound or its steric isomer depends on many factors, for example to prevent or treat the character and the severity of disease, the sex of patient or animal, age, body weight and individual reaction, used particular compound, route of administration and administration number of times etc.Usually to the about 75 kilograms of patients of body weight, the per daily dose of the general formula of giving (I) compound be 0.001mg/kg body weight-100mg/kg body weight, preferred 0.01mg/kg body weight-20mg/kg body weight is more preferably 0.1mg/kg body weight-5mg/kg body weight.Above-mentioned dosage can the single dose form or be divided into several, for example two, three or four dosage form administrations.
The present invention carries out external enzyme inhibition test to MMP1, MMP2, the MMP9 activity screen model of having set up and shows that this compounds has inhibition MMP-1, the activity of MMP-2 and MMP-9, and have selective inhibitory to MMP-2 or MMP-9.Because the Invasion and Metastasis of osteoarthritis and tumour is relevant with the overexpression of MMPs.Osteoarthritis is relevant with MMP-1, MMP-3; Tumour is not only relevant with MMP-1, MMP-3, also and MMP-2, MMP-9 substantial connection is arranged.Therefore, The compounds of this invention can be used for preparing the medicine of treatment osteoarthritis and tumour.
Embodiment
The following examples are used for further specifying the present invention, but this and do not mean that any limitation of the invention.
Embodiment 1:
2-(2-hydroxyethyl the amido)-acrylic acid preparation of 4-oxygen-4-(4 '-xenyl)-butyric acid (A): 3-(4-phenyl benzoyl):
23.13 gram biphenyl and 14.71 gram maleic anhydrides are dissolved in 300 milliliters of methylene dichloride, the ice-water bath cooling down, add 40.00 gram aluminum trichloride (anhydrous)s in four batches, slowly rise to room temperature, continue reaction after 5 hours, be concentrated into driedly, add the mixture of trash ice and concentrated hydrochloric acid in the gained viscous fluid, be hydrolyzed, filter the gained yellow solid, be washed to neutrality, use petroleum ether more several times, after draining, use the Glacial acetic acid recrystallization, get 37.26 gram yellow crystals, yield: 93.19%, fusing point: 168-170 ℃ (literature value: 172-175 ℃).
(B): 2-(2-hydroxyethyl amido)-4-oxygen-4-(4 '-xenyl)-butyro-preparation:
5.045 gram 3-(4-phenyl benzoyl) vinylformic acid are suspended in 100 milliliters of benzene; 10 milliliters of the acetone solns of adding 1.222 gram thanomins; room temperature reaction 1 hour; filter the white precipitate that generates; wash respectively with benzene and acetone, the gained crude product soaks with hot ethanol, washs to such an extent that white powdery solid 6.811 restrains; yield: 86.94%, fusing point: 185-187 ℃ (decomposition).
1HNMR(300MHz，DMSO)：δ(ppm)＝2.827(t，2H，J：5.4Hz)，2.999(t，2H，J：5.4Hz)，3.570(m，3H)，7.491(m，3H，J：7.5Hz)，7.749(d，2H，J：7.5Hz)，7.835(d，2H，J：8.7Hz)，8.029(d，2H，J：8.7Hz)。
Embodiment 2:
2-phenmethyl amido-4-oxygen-4-(4 '-xenyl)-butyric acid
Method is with embodiment 1 (B), and different is to use 5.434 to restrain 3-(4-phenyl benzoyl) vinylformic acid, 2.308 gram benzylamines, and 100 milliliters of ether are made solvent, get white powdery solid 6.877 grams, yield: 88.83%, fusing point: 177-179 ℃ (decomposition).
1HNMR(300MHz，DMSO)：δ(ppm)＝3.361(dd，1H，J：7.5Hz，17.1Hz)，3.456(dd，1H，J：5.4Hz，17.1Hz)，3.654(t，1H，J：5.4Hz，6.9Hz)，3.87(d，1H，J：13.5Hz)，3.968(d，1H，J：13.2Hz)，7.159-8.055(m，14H)。
Embodiment 3:
2-n-butylamine-based-4-oxygen-4-(4 '-xenyl)-butyric acid
Method is with embodiment 1 (B), and different is to use 1.261 to restrain 3-(4-phenyl benzoyl) vinylformic acid, 0.366 gram n-Butyl Amine 99, and 25 milliliters of ether are made solvent, get white powdery solid 1.502 grams, yield: 92.32%, fusing point: 172.6-174.0 ℃ (decomposition).
1HNMR(300MHz，DMSO)：δ(ppm)＝0.867(t，3H，J：7.5Hz)，1.303(q，2H，J：7.5Hz)，1.541(m，2H)，2.742(t，1H，J：7.5Hz)，2.883(dd，1H，J：7.2Hz，13.2Hz)，3.552(m，2H)，3.679(m，1H)，7.486(m，3H，J：7.5Hz)，7.745(d，2H，J：7.5)，7.836(d，2H，J：8.4Hz)，8.039(d，2H，J：8.4Hz)。
Embodiment 4:
2-n-octyl amine base-4-oxygen-4-(4 '-xenyl)-butyric acid
Method is with embodiment 1 (B), and different is to use 1.261 to restrain 3-(4-phenyl benzoyl) vinylformic acid, 0.646 gram n-octyl amine, and 25 milliliters of ether are made solvent, get white powdery solid 1.676 grams, yield: 87.86%, fusing point: 122.4-126.0 ℃ (decomposition).
1HNMR(300MHz，DMSO)：δ(ppm)＝0.833(t，3H，J：6.6Hz)，1.224(s，10H)，1.510(dd，2H，J：7.5Hz，13.5Hz)，2.776(m，2H)，3.326(dd，1H，J：7.2Hz，18.3Hz)，3.478(dd，1H，J：4.2Hz，18.3Hz)，3.631(dd，1H，J：4.5Hz，7.2Hz)，7.024-8.015(m，9H)，8.20(w，1H)。
Embodiment 5:
2-(2-N, N '-dimethylamino ethyl amido)-4-oxygen-4-(4 '-xenyl)-butyric acid
Method is with embodiment 1 (B), and different is to use 1.261 to restrain 3-(4-phenyl benzoyl) vinylformic acid, 0.371 gram 2-N; N '-dimethylamino ethyl amine, 25 milliliters of benzene are made solvent, get white powdery solid 1.655 grams; yield: 97.23%, fusing point: 140.0-143.0 ℃ (decomposition).
1HNMR(300MHz，DMSO)：δ(ppm)＝2.213(s，6H)，2.393(m，1H)，2.830(t，1H)，2.996(t，2H，J：6.0Hz)，3.402-3.692(m，3H)，7.49(m，3H，J：7.5Hz)，7.746(d，2H，7.5Hz)，7.835(d，2H，J：8.4Hz)，8.045(d，2H，J：8.4Hz)。
Embodiment 6:
2-cyclohexylamino-4-oxygen-4-(4 '-xenyl)-butyric acid
Method is with embodiment 1 (B), and different is to use 1.261 to restrain 3-(4-phenyl benzoyl) vinylformic acid, 0.496 gram hexahydroaniline, and 25 milliliters of ether are made solvent, get white powdery solid 1.494 grams, yield: 85.03%, fusing point: 178.6-180.1 ℃ (decomposition).
1HNMR(300MHz，DMSO)：δ(ppm)＝1.196(m，4H)，1.289(d，1H，J：11.7Hz)，1.561(d，1H，J：11.7Hz)，1.701(m，2H)，1.932(m，2H)，2.93(m，1H)，3.430(m，2H)，3.797(s，1H)，7.50(m，3H，J：7.5Hz)，7.757(d，2H，J：7.5Hz)，7.850(d，2H，J：8.4Hz)，8.043(d，2H，J：8.4Hz)。
Embodiment 7:
2-cyclopropyl amino-4-oxygen-4-(4 '-xenyl)-butyric acid
Method is with embodiment 1 (B), and different is to use 1.261 to restrain 3-(4-phenyl benzoyl) vinylformic acid, 0.285 gram cyclopropylamine, and 25 milliliters of ether are made solvent, get white powdery solid 1.476 grams, yield: 95.42%, fusing point: 143.2-146.0 ℃ (decomposition).
1HNMR(300MHz，DMSO)：δ(ppm)＝0.737(m，2H)，0.885(m，2H)，2.809(q，1H，J：3.6Hz)，3.857(dd，1H，J：5.1Hz，18.6Hz)，3.927(dd，1H，J：4.2Hz，18.6Hz)，4.525(t，1H，J：4.8Hz)，7.506(m，3H，J：7.8Hz)，7.764(d，2H，J：7.5)，7.881(d，2H，J：8.4Hz)，8.089(d，2H，J：8.4Hz)。
Embodiment 8:
2-(3-phenyl propyl amido)-4-oxygen-4-(4 '-xenyl) butyric acid
Method is used 0.757 gram 3-(4-phenyl benzoyl) vinylformic acid with embodiment 1 (B), 0.406 gram γ-amphetamine, and 25 milliliters of ether are made solvent, get white powdery solid 1.051 grams, yield: 90.45%, fusing point: 169-170.4 ℃ (decomposition).
1HNMR(300MHz，DMSO)：δ(ppm)＝1.974(m，2H)，2.641(t，2H，J：7.5Hz)，3.056(m，2H)，3.816(dd，1H，J：5.1Hz，18.9Hz)，3.891(dd，1H，J：7.5Hz，18.9Hz)，4.460(t，1H，J：7.5Hz)，7.245(m，5H)，7.506(m，3H)，7.765(d，2H，J：7.2Hz)，7.882(d，2H，J：8.7Hz)，8.082(d，2H，J：8.4Hz)。
Embodiment 9:
2-(3-N, N '-dimethyl amido propyl group amido)-4-oxygen-4-(4 '-xenyl) butyric acid
Method is used 2.523 gram 3-(4-phenyl benzoyl) vinylformic acid with embodiment 1 (B), 1.022 gram 3-N, and N '-dimethyl amido propylamine, 50 milliliters of benzene are made solvent, get white powdery solid.The gained solid is dissolved in 15 milliliters of the methyl alcohol saturated solutions of hydrogenchloride, adds 50 milliliters of anhydrous diethyl ethers, separate out white solid 4.209 grams, yield: 98.49% (in hydrochloride), fusing point: 138-141 ℃ (decomposition).
1HNMR(300MHz，DMSO)：δ(ppm)＝2.151(t，2H，J：7.5Hz)，2.727(s，6H)，3.184(m，4H)，3.881(dd，1H，J：4.8Hz，18.9Hz)，3.994(dd，1H，J：4.8Hz，18.9Hz)，4.459(t，1H，J：4.8Hz)，7.504(m，3H，J：7.8Hz)，7.764(d，2H，J：7.8Hz)，7.879(d，2H，J：8.4Hz)，8.087(d，2H，J：8.4Hz)，10-11(w，2H)。
Embodiment 10:
2-(4-hydroxyl butylamine base)-4-oxygen-4-(4 '-xenyl) butyric acid
Method is with embodiment 1 (B), and different is to use 2.523 to restrain 3-(4-phenyl benzoyl) vinylformic acid, 0.891 gram 4-hydroxyl n-Butyl Amine 99, and 50 milliliters of benzene are made solvent, get white powdery solid.By embodiment 9 described methods this solid is made hydrochloride, white solid 3.017 grams, yield: 79.84% (in hydrochloride), fusing point: 139-142 ℃ (decomposition).
1HNMR(300MHz，DMSO)：δ(ppm)＝1.455(p，2H，J：7.5Hz)，1.720(p，2H，J：7.5Hz)，3.047(m，2H)，3.378(m，2H)，3.833(dd，1H，J：5.1Hz，18.3Hz)，3.871(dd，1H，J：4.5Hz，18.3Hz)，4.428(t，1H，J：4.8Hz)，7.504(m，3H，J：7.5Hz)，7.764(d，2H，J：7.2Hz)，7.88(d，2H，J：8.4Hz)，8.806(d，2H，J：8.4Hz)，9.2(w，1H)。
Embodiment 11:
2-(N-morphine quinoline base)-4-oxygen-4-(4 '-xenyl) butyric acid
Method is with embodiment 1 (B), and different is to use 1.261 to restrain 3-(4-phenyl benzoyl) vinylformic acid, 0.436 gram morphine quinoline, and 25 milliliters of benzene are made solvent, get white powdery solid 1.29 grams, yield: 76.0%, fusing point: 183-186 ℃ (decomposition).
1HNMR(300MHz，DMSO)：δ(ppm)＝2.454(m，4H)，2.729(m，2H)，3.165(dd，1H，J：3.6Hz，16.8Hz)，3.614(dd，1H，J：4.2Hz，16.2Hz)，3.582-3.750(m，3H)，7.458(m，3H)，7，741(dd，2H，J：7.8Hz)，7.811(d，2H，J：8.4Hz)，8.069(d，2H，J：8.4Hz)。
Embodiment 12:
2-(4-hydroxy-n-piperidyl)-4-oxygen-4-(4 '-xenyl) butyric acid
Method is with embodiment 1 (B), and different is to use 1.261 to restrain 3-(4-phenyl benzoyl) vinylformic acid, 0.506 gram 4-hydroxy piperidine, and 25 milliliters of benzene are made solvent, get white powdery solid 1.158 grams, yield: 65.53%, fusing point: 134-137 ℃ (decomposition).
1HNMR(300MHz，DMSO)：6(ppm)＝1.384-1.588(m，2H)，1.726-1.879(m，2H)，2.391(t，1H，J：9.6Hz)，2.675(t，1H，J：9.3Hz)，2.797-2.981(m，2H)，3.139(m，1H)，3.678(m，2H)，3.765(m，1H)，7.478(m，3H，J：7.5Hz)，7.729(d，2H，J：7.5Hz)，7.789(d，2H，J：8.4Hz)，8.026(d，2H，J：8.4Hz)。
Embodiment 13:
2-(2-hydroxyethyl amido)-4-oxygen-4-(4-Phenoxyphenyl)-butyric acid
(A) the acrylic acid preparation of 3-(4-phenoxy group benzoyl):
Method is with embodiment 1 (A), different is to use 17.02 to restrain phenyl ether, 9.806 gram maleic anhydride, reach 26.66 gram aluminum chlorides, 300 milliliters of methylene dichloride, gained pale yellow colored solid body and function methylene dichloride/sherwood oil recrystallization, get 22.69 gram products, yield: 84.59%, fusing point: 115-117 ℃ (literature value: 121 ℃, the benzene recrystallization).
(B) 2-(2-hydroxyethyl amido)-4-oxygen-4-(4-Phenoxyphenyl)-butyro-preparation:
Method is with embodiment 1 (B), and different is to use 1.341 to restrain 3-(4-phenoxy group benzoyl) vinylformic acid, 0.305 gram thanomin, and 25 milliliters of benzene are made solvent, get white powdery solid 1.521 grams, yield: 92.36%, fusing point: 155.0-157.0 ℃ (decomposition).
1HNMR(300MHz，DMSO)：δ(ppm)＝2.961(t，2H，J：5.4Hz)，3.398(dd，1H，J：7.8Hz，18.0Hz)，3.503(dd，1H，J：4.2Hz，18.0Hz)，3.582(t，2H，J：4.8Hz，3.9Hz)，3.675(dd，1H，J：4.5Hz)，7.021(d，2H，J：11.7Hz)，7.105(d，2H，J：7.8Hz)，7.233(t，1H，7.5Hz)，7.447(t，2H，J：7.8Hz)，7.975(d，2H，J：11.7Hz)。
Embodiment 14:
2-phenmethyl amido-4-oxygen-4-(4-Phenoxyphenyl)-butyric acid
Method is with embodiment 1 (B), and different is to use 1.341 to restrain 3-(4-phenoxy group benzoyl) vinylformic acid, 0.536 gram benzylamine, and 25 milliliters of ether are made solvent, get white powdery solid 1.523 grams, yield: 81.13%, fusing point: 173.0-174.4 ℃ (decomposition).
1HNMR(300MHz，DMSO)：δ(ppm)＝3.299(dd，1H，J：6.9Hz，17.4Hz)，3.382(dd，1H，J：5.4Hz，17.4Hz)，3.628(t，1H，J：4.2Hz)3.863(d，1H，J：13.2Hz)，3.956(d，1H，J：13.5Hz)，7.032-8.013(m，14H)。
Embodiment 15:
2-n-butylamine-based-4-oxygen-4-(4-Phenoxyphenyl)-butyric acid
Method is with embodiment 1 (B), and different is to use 1.341 to restrain 3-(4-phenoxy group benzoyl) vinylformic acid, 0.366 gram n-Butyl Amine 99; 25 milliliters of ether are made solvent; get white powdery solid 0.904 gram, yield: 52.96%, fusing point: 164.0-167.0 ℃ (decomposition).
1HNMR(300MHz，DMSO)：δ(ppm)＝0.848(t，3H，J：7.2Hz)，1.283(q，2H，J：14.4Hz)，1.510(p，2H，J：7.2Hz)，2.731(t，1H，J：7.5Hz)，2.838(dd，1H，J：7.5Hz，13.5Hz)，3.345(dd，1H，J：7.8Hz，18.0Hz)，3.481(dd，1H，J：4.5Hz，18.0Hz)，3.652(dd，1H，J：4.5Hz)，6.998-7.993(m，9H)，8.25(w，1H)。
Embodiment 16:
2-n-octyl amine base-4-oxygen-4-(4-Phenoxyphenyl)-butyric acid
Method is with embodiment 1 (B), and different is to use 1.341 to restrain 3-(4-phenoxy group benzoyl) vinylformic acid, 0.646 gram n-octyl amine; 25 milliliters of ether are made solvent; get white powdery solid 0.888 gram, yield: 44.68%, fusing point: 164.0-166.0 ℃ (decomposition).
1HNMR(300MHz，DMSO)：δ(ppm)＝0.830(t，3H，J：6.3Hz)，1.223(s，1?0H)，1.505(dd，2H，J：7.5Hz，13.5Hz)，2.723(t，1H，J：7.5Hz)，2.824(dd，1H，J：7.2Hz，13.2Hz)，3.332(dd，1H，J：7.8Hz，18.3Hz)，3.480(dd，1H，J：4.2Hz，18.3Hz)，3.641(dd，1H，J：4.5Hz，7.2Hz)，7.014-7.988(m，9H)，8.25(w，1H)。
Embodiment 17:
2-(2-N, N '-dimethylamino ethyl amido)-4-oxygen-4-(4-Phenoxyphenyl)-butyric acid
Method is with embodiment 1 (B), and different is to use 1.341 to restrain 3-(4-phenoxy group benzoyl) vinylformic acid, 0.371 gram 2-N; N '-dimethylamino ethyl amine, 25 milliliters of benzene are made solvent, get white powdery solid 1.569 grams; yield: 88.04%, fusing point: 137.0-139.0 ℃ (decomposition).
1HNMR(300MHz，DMSO)：δ(ppm)＝2.143(s，3H)，2.195(s，3H)，2.456(m，2H)，2.959(t，2H，J：5.7Hz)，3.373(dd，1H，J：7.5Hz，18.0Hz)，3.485(dd，1H，J：4.2Hz，18.0Hz)，3.627(dd，1H，J：4.2Hz，7.5Hz)，7.026(d，2H，J：8.7Hz)，7.102(d，2H，J：7.8Hz)，7.232(t，1H，J：7.5Hz)，7.446(t，2H，J：7.8Hz)，7.972(d，2H，J：8.7Hz)。
Embodiment 18:
2-cyclohexylamino-4-oxygen-4-(4-Phenoxyphenyl)-butyric acid
Method is with embodiment 1 (B), and different is to use 1.341 to restrain 3-(4-phenoxy group benzoyl) vinylformic acid, 0.496 gram hexahydroaniline; 25 milliliters of ether are made solvent; get white powdery solid 1.024 grams, yield: 55.74%, fusing point: 184.0-186.5 ℃ (decomposition).
1HNMR(300MHz，DMSO)：δ(ppm)＝1.149(m，4H)，1.275(d，1H，J：11.7Hz)，1.548(d，1H，J：11.7Hz)，1.681(m，2H)，1.919(m，2H)，2.894(m，1H)，3.351(dd，1H，J：7.8Hz，18.0Hz)，3.428(dd，1H，J：4.2Hz，18.0Hz)，3.752(dd，1H，J：4.2Hz，7.8Hz)，6.641-7.980(m，9H)，8.2(w，1H)。
Embodiment 19:
2-cyclopropyl amino-4-oxygen-4-(4-Phenoxyphenyl)-butyric acid
Method is with embodiment 1 (B), and different is to use 1.341 to restrain 3-(4-phenoxy group benzoyl) vinylformic acid, 0.285 gram cyclopropylamine; 25 milliliters of ether are made solvent; get white powdery solid 0.458 gram, yield: 28.15%, fusing point: 171.2-173.2 ℃ (decomposition).
1HNMR(300MHz，DMSO)：δ(ppm)＝0.320(m，4H)，2.240(p，1H，J：3.6Hz)，3.255(d，2H，J：6.6Hz)，3.700(t，1H，J：6.6Hz)，7.022(d，2H，J：8.4Hz)，7.11(d，2H，J：8.4Hz)，7.232(t，1H，J：7.5Hz)，7.446(t，2H，J：7.8Hz)，7.951(d，2H，J：9.0Hz)。
Embodiment 20:
2-(3-phenyl propyl amido)-4-oxygen-4-(4-Phenoxyphenyl) butyric acid
Method is with embodiment 1 (B), and different is to use 2.683 to restrain 3-(4-phenoxy group benzoyl) vinylformic acid, 1.352 gram γ-amphetamines, and 50 milliliters of ether are made solvent, get white powdery solid.By embodiment 9 described methods this solid is made hydrochloride, white solid 2.944 grams, yield: 66.92% (in hydrochloride), fusing point: 140-142 ℃ (decomposition).
1HNMR(300MHz，DMSO)：δ(ppm)＝1.971(p，2H，J：7.5Hz)，2.628(t，2H，J：7.5Hz)，3.029(m，2H)，3.731(dd，1H，J：5.1Hz，18.9Hz)，3.809(dd，1H，J：4.5Hz，18.9Hz)，7.081(d，2H，J：8.7Hz)，7.130(d，2H，J：7.5Hz)，7.194-7.445(m，6H)，7.472(t，2H，J：7.8Hz)，8.018(d，2H，J；8.7Hz)，9.2(w，1H)。
Embodiment 21:
2-(3-N, N '-dimethyl amido Propylamino)-4-oxygen-4-(4-Phenoxyphenyl) butyric acid
Method is with embodiment 1 (B), and different is to use 1.341 to restrain 3-(4-phenoxy group benzoyl) vinylformic acid, 0.511 gram 3-N, and N '-dimethyl amido propylamine, 25 milliliters of benzene are made solvent, get white powdery solid.By embodiment 9 described methods this solid is made hydrochloride, white solid 1.225 grams, yield: 55.26% (in hydrochloride), fusing point: 160-162 ℃ (decomposition).
1HNMR(300MHz，DMSO)：δ(ppm)＝1.902(p，2H，J：7.2Hz)，2.654(s，6H)，2.893(m，2H)，3.021(t，2H，J：7.2Hz)，3.456(m，2H)，3.750(m，1H)，7.048(d，2H，J：9.0Hz)，7.117(d，2H，J：8.1Hz)，7.248(t，1H，J：7.8Hz)，7.46(t，2H，J：7.8Hz)，7.986(d，2H，J：9.0Hz)。
Embodiment 22:
2-(4-hydroxyl butylamine base)-4-oxygen-4-(4-Phenoxyphenyl) butyric acid
Method is with embodiment 1 (B), and different is to use 2.683 to restrain 3-(4-phenoxy group benzoyl) vinylformic acid, 0.891 gram 4-hydroxyl n-Butyl Amine 99, and 50 milliliters of benzene are made solvent, get white powdery solid.By embodiment 9 described methods this solid is made hydrochloride, white solid 2.417 grams, yield: 61.37% (in hydrochloride), fusing point: 130-133 ℃ (decomposition).
1HNMR(300MHz，DMSO)：δ(ppm)＝1.452(m，2H)，1.695(m，2H)，3.022(dd，2H，J：8.1Hz)，3.373(m，2H)，3.764(m，2H)，4.391(m，1H)，7.081(d，2H，J：8.7Hz)，7.130(d，2H，J：7.8Hz)，7.258(t，1H，J：7.5Hz)，7.469(t，2H，J：7.8Hz)，8.023(d，2H，J：8.7Hz)，9.2(w，1H)。
Embodiment 23:
2-(N-morphine quinoline base)-4-oxygen-4-(4-Phenoxyphenyl) butyric acid
Method is with embodiment 1 (B), and different is to use 1.341 to restrain 3-(4-phenoxy group benzoyl) vinylformic acid, 0.436 gram morphine quinoline, and 25 milliliters of benzene are made solvent, get white powdery solid gram, 1.157 yields: 65.11%, fusing point: 176-178 ℃ (decomposition).
1HNMR(300MHz，DMSO)：δ(ppm)＝2.452(m，2H)，2.699(m，2H)，2.878(t，1H，J：4.8Hz)，3.102(dd，2H，J：4.2Hz，17.4Hz)，3.628(dd，2H，J：3.9Hz，9.6Hz)，3.698(dd，2H，J：4.5Hz，9.6Hz)，7.033(d，2H，J：8.7Hz)，7.118(d，2H，J；8.1Hz)，7.239(t，1H，J：7.5Hz)，7.454(t，2H，J：7.8Hz)，8.015(d，2H，J：8.7Hz)。
Embodiment 24:
2-(N-piperidyl)-4-oxygen-4-(4 ' Phenoxyphenyl) butyric acid
Method is with embodiment 1 (B), and different is to use 1.341 to restrain 3-(4-phenoxy group benzoyl) vinylformic acid, 0.426 gram piperidines; 25 milliliters of anhydrous diethyl ethers are made solvent; get white powdery solid 0.201 gram, yield: 11.37%, fusing point: 146.5-149.5 ℃ (decomposition).
1HNMR(300MHz，DMSO)：δ(ppm)＝1.364-1.599(m，8H)，2.568(t，1H，J：5.7Hz)，2.769(t，1H，J：5.7Hz)，2.907(t，2H，J：5.1Hz)，3.671(s，1H)，7.031(d，2H，J：8.7Hz)，7.111(d，2H，J：8.1Hz)，7.233(t，1H，J：7.5Hz)，7.451(t，2H，J：8.1Hz)，7.996(d，2H，J：8.7Hz)。
Embodiment 25:
2-(2-hydroxyethyl amido)-4-oxygen-4-(4-p-methoxy-phenyl)-butyric acid
(A): the acrylic acid preparation of 3-(4-anisoyl):
Method is with embodiment 1 (A), different is to use 10.81 to restrain methyl-phenoxides, 9.806 gram maleic anhydride, reach 26.66 gram aluminum chlorides, 300 milliliters of methylene dichloride, gained pale yellow colored solid body and function recrystallization from ethyl acetate/petroleum ether gets 15.32 gram products, yield: 74.29%, fusing point: 119-122 ℃ (literature value: 108-110 ℃).
(B): 2-(2-hydroxyethyl amido)-4-oxygen-4-(4-p-methoxy-phenyl)-butyro-preparation:
Method is with embodiment 1 (B), and different is to use 1.031 to restrain 3-(4-anisoyl) vinylformic acid, 0.305 gram thanomin, and 25 milliliters of benzene are made solvent, get white powdery solid 1.258 grams, yield: 94.16%, fusing point: 165.2-168.0 ℃ (decomposition).
1HNMR(300MHz，DMSO)：δ(ppm)＝2.956(t，2H，J：5.4Hz)，3.391(dd，1H，J：7.8Hz，18.3Hz)，3.483(dd，1H，J：4.5Hz，18.3Hz)，3.570(dd，2H，J：5.1Hz，8.7Hz)，3.656(dd，1H，J：4.5Hz，7.8Hz)，3.819(s，3H)，7.023(d，2H，9.0Hz)，7.924(d，2H，J：9.0Hz)。
Embodiment 26:
2-phenmethyl amido-4-oxygen-4-(4-p-methoxy-phenyl)-butyric acid
Method is with embodiment 1 (B), and different is to use 1.031 to restrain 3-(4-anisoyl) vinylformic acid, 0.536 gram benzylamine, and 25 milliliters of ether are made solvent, get white powdery solid 1.408 grams, yield: 89.87%, fusing point: 175.7-177.0 ℃ (decomposition).
1HNMR(300MHz，DMSO)：δ(ppm)＝3.298(dd，1H，J：6.9Hz，17.4Hz)，3.370(dd，1H，J：5.4Hz，17.4?Hz)，3.617(t，1H，J：5.4Hz)，3.831(s，3H)，3.867(d，1H，J：13.5Hz)，3.96(d，1H，13.5Hz)，7.004-7.955(m，9H)。
Embodiment 27:
2-n-butylamine-based-4-oxygen-4-(4-p-methoxy-phenyl)-butyric acid
Method is with embodiment 1 (B), and different is to use 1.031 to restrain 3-(4-anisoyl) vinylformic acid, 0.366 gram n-Butyl Amine 99; 25 milliliters of ether are made solvent; get white powdery solid 0.632 gram, yield: 45.25%, fusing point: 162.6-165.0 ℃ (decomposition).
1HNMR(300MHz，DMSO)：δ(ppm)＝0.852(t，3H，J：7.2Hz，7.5Hz)，1.284(q，2H，J：7.2Hz，7.5Hz)，1.533(p，2H)，2.837(m，2H)，3.324(dd，1H，J：7.8Hz，18.0Hz)，3.478(dd，1H，J：4.2Hz，18.0Hz)，3.628(dd，1H，J：4.2Hz，3.9Hz)，3.825(s，3H)，7.033(d，2H，J：11.7Hz)，7.933(d，2H，11.7Hz)，8.2(w，1H)。
Embodiment 28:
2-n-octyl amine base-4-oxygen-4-(4-p-methoxy-phenyl)-butyric acid
Method is with embodiment 1 (B), and different is to use 1.031 to restrain 3-(4-anisoyl) vinylformic acid, 0.646 gram n-octyl amine, and 25 milliliters of ether are made solvent, get white powdery solid 0.96 gram, yield: 57.24%, fusing point: 166.0-168.0 ℃ (decomposition).
1HNMR(300MHz，DMSO)：δ(ppm)＝0.836(t，3H，J：6.0Hz，6.9Hz)，1.225(s，10H)，1.514(t，2H，J：6.9Hz，7.2Hz)，2.778(m，2H)，3.320(dd，1H，J：8.1Hz，18.0Hz)，3.475(dd，1H，J：3.6Hz，18.0Hz)，3.621(dd，1H，J：3.9Hz，4.2Hz，7.8Hz)，3.824(s，3H)，7.033(d，2H，J：9.0Hz)，7.934(d，2H，J：9.0Hz)，8.15(w，1H)。
Embodiment 29:
2-(2-N, N '-dimethylamino ethyl amido)-4-oxygen-4-(4-p-methoxy-phenyl)-butyric acid
Method is with embodiment 1 (B), and different is to use 1.031 to restrain 3-(4-anisoyl) vinylformic acid, 0.371 gram 2-N; N '-dimethylamino ethyl amine, 25 milliliters of benzene are made solvent, get white powdery solid 1.310 grams; yield: 89.01%, fusing point: 126.3-128.7 ℃ (decomposition).
1HNMR(300MHz，DMSO)：δ(ppm)＝2.189(s，6H)，2.455(m，2H)，2.956(t，2H，J：6.0Hz)，3.374(dd，1H，J：7.5Hz，18.0Hz)，3.465(dd，1H，J：4.2Hz，18.0Hz)，3.611(dd，1H，J：3.9Hz，4.2Hz)，3.819(s，3H)，7.022(d，2H，J：9.0Hz)，7.4(w，1H)，7.919(d，2H，J：8.4Hz)。
Embodiment 30:
2-cyclohexylamino-4-oxygen-4-(4-p-methoxy-phenyl)-butyric acid
Method is with embodiment 1 (B), and different is to use 1.031 to restrain 3-(4-anisoyl) vinylformic acid, 0.496 gram hexahydroaniline; 25 milliliters of ether are made solvent; get white powdery solid 1.221 grams, yield: 79.97%, fusing point: 160.0-162.0 ℃ (decomposition).
1HNMR(300MHz，DMSO)：δ(ppm)＝1.155(m，3H)，1.392(t，2H，J：10.8Hz)，1.579(d，1H，J：12.0Hz)，1.748(d，2H，J：12.0Hz)，2.084(m，2H)，3.119(m，1H)，3.732(d，2H，J：5.1Hz)，3.848(s，3H)，4.497(t，1H，J：4.8Hz)，7.079(d，2H，J：8.7Hz)，7.967(d，2H，J：8.7Hz)，9.00(w，1H)。
Embodiment 31:
2-cyclopropyl amino-4-oxygen-4-(4-p-methoxy-phenyl)-butyric acid
Method is with embodiment 1 (B), and different is to use 1.031 to restrain 3-(4-anisoyl) vinylformic acid, 0.285 gram cyclopropylamine; 25 milliliters of ether are made solvent; get white powdery solid 1.257 grams, yield: 95.48%, fusing point: 157.5-159.0 ℃ (decomposition).
1HNMR(300MHz，DMSO)：δ(ppm)＝0.338(m，4H)，2.242(p，1H，J：3.0Hz，3.3Hz，3.6Hz)，3.245(d，2H，J：6.0Hz)，3.696(t，1H，J：6.0Hz)，3.819(s，3H)，7.023(d，2H，J：6.9Hz)，7.907(d，2H，J：6.9Hz)。
Embodiment 32:
2-(3-phenyl propyl amido)-4-oxygen-4-(4-p-methoxy-phenyl) butyric acid
Method is with embodiment 1 (B), and different is to use 2.062 to restrain 3-(4-anisoyl) vinylformic acid, 1.352 gram γ-amphetamines, and 50 milliliters of ether are made solvent, get white powdery solid.By embodiment 9 described methods this solid is made hydrochloride, white solid 2.715 grams, yield: 71.85% (in hydrochloride), fusing point: 125-128 ℃ (decomposition).
1HNMR(300MHz，DMSO)：δ(ppm)＝1.959(t，2H，J：7.5Hz)，2.624(t，2H，J：7.5Hz)，3.026(d，2H，J：7.8Hz)，3.730(t，2H，J：6.3Hz)，3.820(s，3H)，4.401(t，1H，J：4.5Hz)，7.082(d，2H，J：8.7Hz)，7.207(d，3H，J：7.5Hz)，7.291(t，2H，J：7.5Hz)，7.972(d，2H，J：8.7Hz)，9.0(w，1H)。
Embodiment 33:
2-(3-N, N '-dimethyl propylene amido)-4-oxygen-4-(4-p-methoxy-phenyl) butyric acid
Method is with embodiment 1 (B); different is to use 1.031 to restrain 3-(4-anisoyl) vinylformic acid; 0.511 gram 3-N; N '-dimethyl amido propylamine, 25 milliliters of benzene are made solvent, get white powdery solid; by embodiment 9 described methods this solid is made hydrochloride; get white solid 1.304 grams, yield: 68.37% (in hydrochloride), fusing point: 120-123 ℃ (decomposition).
1HNMR(300MHz，DMSO)：δ(ppm)＝1.672(p，2H，J：6.6Hz)，2.113(s，3H)，2.167(s，3H)，2.268(t，1H，J：6.6Hz)，2.373(t，1H，J：6.3Hz)，2.791(t，1H，J：7.2Hz)，2.912(t，1H，J：6.6Hz)，3.462-3.579(m，3H)，3.841(s，3H)，7.05(d，2H，J：9.0Hz)，7.944(d，2H，J：9.0Hz)。
Embodiment 34:
2-(4-hydroxyl butylamine base)-4-oxygen-4-(4-p-methoxy-phenyl) butyric acid
Method is with embodiment 1 (B), and different is to use 2.062 to restrain 3-(4-anisoyl) vinylformic acid, 0.891 gram 4-hydroxyl n-Butyl Amine 99, and 50 milliliters of ether are made solvent, get white powdery solid.By embodiment 9 described methods this solid is made hydrochloride, white solid 2.434 grams, yield: 62.03% (in hydrochloride), fusing point: 150-152 ℃ (decomposition).
1HNMR(300MHz，DMSO)：δ(ppm)＝1.427(p，2H，J：7.2Hz)，1.599(dd，2H，J：7.5Hz，15.3Hz)，2.867(dd，2H，J：7.2Hz，13.2Hz)，3.290-3.477(m，4H)，3.628(m，1H)，3.836(s，3H)，7.045(d，2H，J：9.0Hz)，7.943(d，2H，J：8.7Hz)。
Embodiment 35:
2-(N-morphine quinoline base)-4-oxygen-4-(4-p-methoxy-phenyl) butyric acid
Method is with embodiment 1 (B), and different is to use 1.031 to restrain 3-(4-anisoyl) vinylformic acid, 0.436 gram morphine quinoline, and 50 milliliters of ether are made solvent, get white powdery solid 0.747 gram, yield: 50.93%, fusing point: 167-169 ℃ (decomposition).
1HNMR(300MHz，DMSO)：δ(ppm)＝2.445(m，2H)，2.705(m，2H)，3.085(dd，1H，J：4.2Hz，17.1Hz)，3.540(dd，1H，J：16.2Hz，11.1Hz)，3.617-3.714(m，3H)，3.833(s，3H)，7.026(d，2H，J：8.7Hz)，7.967(d，2H，J：8.7Hz)。
Embodiment 36:
2-(2-hydroxyethyl sulfenyl)-4-oxygen-4-(4 '-xenyl)-butyric acid
12.61 gram 3-(4-phenyl benzoyl) vinylformic acid are suspended in 150 milliliters of ether, add 19.53 gram mercaptoethanols, room temperature reaction spends the night; filter the white precipitate that generates, the ether washing gets white powdery solid 11.56 grams after draining; yield: 69.96%, fusing point: 127.6-129.6 ℃.
1HNMR(300MHz，DMSO)：δ(ppm)＝2.964(dt，1H，J：6.0Hz，14.4Hz)，3.083(dt，1H，J：5.4Hz，14.4Hz)，3.45(dd，1H，J：6.0Hz，118.3Hz)，3.712(dd，1H，J：8.4Hz，18.3Hz)，3.952(t，2H，J：5.7Hz)，4.047(dd，1H，J：6.0Hz，8.4Hz)，7.464(m，3H，J：7.5Hz)，7.625(d，2H，J：7.5Hz)，7.698(d，2H，J：8.1Hz)，8.044(d，2H，J：8.1Hz)。
Embodiment 37:
2-(2-hydroxyl ethylmercapto group)-4-oxygen-4-(4 '-xenyl)-N-maloyl group amine
(A): the preparation of 2-(2-hydroxyethyl sulfenyl)-4-oxygen-4-(4 '-xenyl)-methyl-butyrate:
14.06 gram 2-(2-hydroxyethyl sulfenyl)-4-oxygen-4-(4 '-xenyl)-butyric acid are dissolved among 50 milliliters of DMF, add 7.046 gram Anhydrous potassium carbonates, stir moments later, add 12.08 gram methyl iodide, room temperature reaction is to raw material consumption intact (TLC monitoring), reaction solution is diluted with 400 milliliters of ethyl acetate, water and saturated common salt water washing successively, anhydrous magnesium sulfate drying, filter, be concentrated into driedly, recrystallization from ethyl acetate/petroleum ether gets white solid 12.44 grams, yield: 84.86%, fusing point: 108.5-110.5 ℃.
1HNMR(300MHz，CDCl 3)：δ(ppm)＝2(w，1H)，2.894(m，1H)，3.036(m，1H)，3.429(dd，1H，J：5.7Hz，18.0Hz)，3.718(dd，1H，J：9.0Hz，18.0Hz)，3.798(s，3H)，3.865(m，2H)，4.005(dd，1H，J：5.7Hz，8.7Hz)，7.470(m，3H，J：7.2Hz)，7.630(d，2H，J：7.2Hz)，7.703(d，2H，J：8.4Hz)，8.044(d，2H，J：8.4Hz)。
(B): the preparation of 2-(2-hydroxyl ethylmercapto group)-4-oxygen-4-(4 '-xenyl)-N-maloyl group amine:
Ice-water bath is reduced to 0 ℃, 5 milliliters of methanol solutions that 0.505 gram potassium hydroxide added 0.417 gram oxammonium hydrochloride, reaction is 1 hour under this temperature, remove by filter the white solid of generation, 1.033 gram 2-(2-hydroxyl ethylmercapto group)-4-oxygen-4-(4 '-xenyl) methyl-butyrates are added in the filtrate, and room temperature reaction spends the night.The insolubles that filtering generates, filtrate concentrates, and resistates is dissolved in water, the water extracted with diethyl ether.The concentrated hydrochloric acid acidified aqueous solution is separated out solid to PH=3.Filter, be washed to neutrality, the gained solid gets 655 milligrams of white solids with recrystallization from ethyl acetate/petroleum ether, yield: 63.22%, and fusing point: 138-140 ℃.
1HNMR(300MHz，DMSO)：δ(ppm)＝2.643(td，2H，J：2.4Hz，6.6Hz)，3.161(d，2H，J：7.8Hz)，3.425(t，2H，J：7.2Hz)，3.651(t，1H，J：7.8Hz)，7.379(m，1H)，7.468(t，2H，J：7.2Hz)，7.7(m，6H)，11.5(w，1H)，12.6(w，1H)。
Embodiment 38:
2-[2-(N-succimide base) ethylmercapto group]-4-oxygen-4-(4 '-xenyl)-N-maloyl group amine
(A): 2-[2-(N-succimide base) second sulfydryl]-preparation of 4-oxygen-4-(4 '-xenyl)-methyl-butyrate:
With 0.495 gram succimide, 1.722 gram 2-(2-hydroxyethyl sulfenyl)-4-oxygen-4-(4 '-xenyl)-methyl-butyrate and 1.312 gram triphenyl phosphorus are dissolved in 10 milliliters of tetrahydrofuran (THF)s, drip 10 milliliters of the tetrahydrofuran solutions of 0.871 gram azo-dicarboxylate under the room temperature.Reaction is spent the night under the room temperature.The white solid that filtration is separated out, the ether washing gets white solid 1.49 grams, yield: 70.02%, fusing point: 145.8-147 ℃.
1HNMR(300MHz，CDCl 3)：δ(ppm)＝2.746(s，4H)，2.925(dt，1H，J：7.2Hz，13.8Hz)，3.038(dt，1H，J：6.0Hz，13.8Hz)，3.334(dd，1H，J：4.2Hz，18.0Hz)，3.718(dd，1H，10.8Hz，18.0Hz)，3.798(s，3H)，3.856(t，2H，6.9Hz)，3.975(dd，1H，J：4.2Hz，10.5Hz)，7.466(m，3H，J：7.5Hz)，7.630(d，2H，J：7.5Hz)，7.695(d，2H，J：8.4Hz)，8.04(d，2H，J：8.7Hz)。
(B) 2-[2-(N-succimide base) ethylmercapto group]-preparation of 4-oxygen-4-(4 '-xenyl)-N-maloyl group amine:
Method is with embodiment 37 (B), different is with 1.39 gram 2-[2-(N-succimide base) second sulfydryls]-4-oxygen-4-(4 '-xenyl)-methyl-butyrate reacts with 454 milligrams of oxammonium hydrochlorides and 550 milligrams of potassium hydroxide and makes 340 milligrams of 2-[2-(N-succimide base) ethylmercapto group]-4-oxygen-4-(4 '-xenyl)-N-maloyl group amine, yield: 24.41%, fusing point: 179-181 ℃.
1HNMR(300MHz，DMSO)：δ(ppm)＝2.526(s，4H)，2.639-3.140(m，2H)，3.334-3.718(m，2H)，3.856(t，2H，6.9Hz)，3.975(m，1H)，7.466(m，3H，J：7.5Hz)，7.630(d，2H，J：7.5Hz)，7.695(d，2H，J：8.4Hz)，8.04(d，2H，J：8.7Hz)，10.5(w，1H)，12.9(w，1H)。
Embodiment 39:
2-propyl group sulfenyl-4-oxygen-4-(4 '-xenyl)-butyric acid
Method with 5.045 gram 3-(4-phenyl benzoyl) vinylformic acid and 2.5 equivalent propylmercaptan additions, gets white solid 4.929 grams, yield with embodiment 36: 75.04%, and fusing point: 115-117 ℃.
1HNMR(300MHz，DMSO)：δ(ppm)＝0.925(t，3H，J：7.2Hz)，1.564(hd，2H，J：3.0Hz，7.2Hz)，2.668(t，2H，J：7.2Hz)，3.327(s，1H)，3.618(d，1H，J：10.2Hz)，3.692(d，1H，J：10.2Hz)，7.484(m，3H，J：7.5Hz)，7.737(d，2H，J：7.5Hz)，7.816(d，2H，J：8.7Hz)，8.055(d，2H，J：8.7Hz)。
Embodiment 40:
2-methyl-2-(2-hydroxyethyl sulfenyl)-4-oxygen-4-(4 '-xenyl)-butyric acid
(A): 2-methylene radical-4-oxygen-4-(4 '-xenyl)-butyro-preparation:
Method is with embodiment 1 (A), and the different biphenyl 15.42 that are to use restrain, itaconic anhydride 11.21 grams, 26.66 the gram aluminum chloride, 300 milliliters of ethylene dichloride are made solvent, gained crude product dioxane recrystallization, get light yellow solid 18.06 grams, yield: 67.81%, fusing point: 181.6-183.6 ℃.
1HNMR(300MHz，DMSO)：δ(ppm)＝4.062(s，2H)，5.742(s，1H)，6.216(s，1H)，7.486(m，3H，J：7.5Hz)，7.741(d，2H，J：7.5Hz)，7.826(d，2H，J：8.4Hz)，8.057(d，2H，J：8.4Hz)，12.456(w，1H)。
(B): the acrylic acid preparation of 2-methyl-3-(4-phenyl benzoyl):
15.98 gram 2-methylene radical-4-(4 '-xenyl)-4-oxygen-butyric acid are suspended in 180 milliliters of dry ethers, add 36.43 gram triethylamines, react nearly 70 hours under the room temperature to the reaction solution layering, add 180 ml waters in reaction solution, vigorous stirring makes oily matter water-soluble, tell water, the ether layer with 60 ml waters washing one time, merges water again, is acidified to PH=3 with concentrated hydrochloric acid, the yellow solid that filtration is separated out, be washed to neutrality, crude product ethanol/water recrystallization gets glassy yellow solid 12.56 grams, yield: 78.62%, fusing point: 164-167 ℃.
1HNMR(300MHz，DMSO)：δ(ppm)＝2.045(s，3H)，7.485(m，3H，J：7.5Hz)，7.699(s，1H)，7.733(d，2H，J：7.5Hz)，7.848(d，2H，J：8.4Hz)，8.002(d，2H，J：8.4Hz)，13.077(w，1H)。
(C): 2-methyl-2-(2-hydroxyethyl sulfenyl)-4-oxygen-4-(4 '-xenyl)-butyro-preparation:
10.29 gram 2-methyl-3-(4-phenyl benzoyl) vinylformic acid are dissolved in 100 milliliters of the methanol solutions that contain 2.6 gram potassium hydroxide, add 15.09 gram mercaptoethanols, reflux 4 hours; white crystal is separated out in cooling, filters; the small amount of methanol washing, after draining, solid dissolves with 150 ml waters; the ice bath cooling is used the concentrated hydrochloric acid acidifying down, filters the white solid of separating out; be washed to neutrality; dry to such an extent that white solid 10.32 restrains yield: 77.55%, fusing point: 149-152 ℃.
1HNMR(300MHz，DMSO)：δ(ppm)＝1.524(s，3H)，2.673-2.824(m，2H)，3.440(d，1H，J：17.4Hz)，3.74(d，1H，J：18.3Hz)，4.824(s，1H)，7.487(m，3H，J：8.1Hz)，7.734(d，2H，J：8.1Hz)，7.815(d，2H，J：8.7Hz)，8.039(d，2H，J：8.7Hz)，12.319(w，1H)。
Embodiment 41:
2-(2-hydroxyethyl amido)-4-oxygen-4-(4 '-xenyl)-N-maloyl group amine
(A): the preparation of 2-(2-hydroxyethyl amido)-4-oxygen-4-(4 '-xenyl) methyl-butyrate hydrochloride:
Cryosel is bathed and is reduced to below-10 ℃, drips 1 milliliter of (about 2 equivalents) thionyl chloride in 20 milliliters of anhydrous methanols, and temperature is no more than-10 ℃ in keeping.Drip and finish, stirred 1 hour under the room temperature, add 1.567 gram 2-(2-hydroxyethyl amido)-4-oxygen-4-(4 '-xenyl) butyric acid, raw material dissolves rapidly, stirs after 3 hours reflux 40 minutes under the room temperature.Remove solvent under reduced pressure, the gained solid gets white crystal with the methanol recrystallization: 1.658 grams, and yield: 91.15%, fusing point: 154-156 ℃ (decomposition).
1HNMR(300MHz，DMSO)：δ(ppm)＝3.18(m，2H)，3.704(t，2H，J：5.4Hz)，3.739(s，3H)，3.861(dd，1H，J：5.1Hz，18.9Hz)，3.964(dd，1H，J：4.8Hz，18.9Hz)，4.638(t，1H，J：5.1Hz)，7.508(m，3H，J：7.8Hz)，7.767(d，2H，J：7.5Hz)，7.886(d，2H，J：8.1Hz)，8.074(d，2H，J：8.7Hz)。
(B): the preparation of 2-(2-hydroxyethyl amido)-4-oxygen-4-(4 '-xenyl)-N-maloyl group amine:
Method is with embodiment 37 (B), different is to restrain 2-(2-hydroxyethyl amido)-4-oxygen-4-(4 '-xenyl) methyl-butyrate hydrochlorides and 0.593 gram oxammonium hydrochloride and 0.958 gram potassium hydroxide reaction with 1.553 to make 647 milligrams of 2-(2-hydroxyethyl amido)-4-oxygen-4-(4 '-xenyl)-N-maloyl group amine, white solid, yield: 46.15%, fusing point: 218.9-222 ℃ (decomposition).
1HNMR(300MHz，DMSO)：δ(ppm)＝2.798(dd，2H，J：6.0Hz，13.5Hz)，3.167(t，2H，J：7.5Hz)，3.497(m，4H)，7.376(d，1H，J：7.2Hz)，7.466(t，2H，J：7.5Hz)，7.672(d，2H，J：8.4Hz)，7.685(d，2H，J：6.9Hz)，7.786(d，2H，J：8.7Hz)11-12(w，2H)。
Embodiment 42:
2-benzene methanamine base-4-oxygen-4-(4 '-xenyl)-N-maloyl group amine
(A): the preparation of 2-benzene methanamine base-4-oxygen-4-(4 '-xenyl) methyl-butyrate hydrochloride:
Method is with embodiment 41 (A), different is that 1.797 gram 2-benzene methanamine base-4-oxygen-4-(4 '-xenyl) butyric acid and 1 milliliter of thionyl chloride are made 1.773 gram 2-benzene methanamine base-4-oxygen-4-(4 '-xenyl) methyl-butyrate hydrochlorides, yield: 86.49%, fusing point: 142.5-144 ℃ (decomposition).
1HNMR(300MHz，DMSO)：δ(ppm)＝3.735(s，3H)，3.837(d，1H，J：5.4Hz)，3.899(m，1H)，4.276(d，1H，J：13.2Hz)，4.335(d，1H，J：13.2Hz)，4.394-4.512(m，1H)，7.433-7.567(m，5H)，7.504(m，3H，J：7.8Hz)，7.764(d，2H，J：7.5Hz)，7.881(d，2H，J：8.1Hz)，8.064(d，2H，J：8.4Hz)。
(B): the preparation of 2-benzene methanamine base-4-oxygen-4-(4 '-xenyl)-N-maloyl group amine:
Method is with embodiment 37 (B), different is to restrain 2-benzene methanamine base-4-oxygen-4-(4 '-xenyl) methyl-butyrate hydrochlorides and 0.566 gram oxammonium hydrochloride and 0.914 gram potassium hydroxide reaction with 1.67 to make 686 milligrams of 2-(2-hydroxyethyl amido)-4-oxygen-4-(4 '-xenyl)-N-maloyl group amine, white solid, yield: 44.95%, fusing point: 218-220 ℃ (decomposition).
1HNMR(300MHz，DMSO)：δ(ppm)＝3.116(m，2H)，3.2-4.0(w，1H)，3.463(t，1H，J：7.5Hz)，3.639(d，1H，J：13.8Hz)，3.820(d，1H，J：13.8Hz)，7.225(s，5H)，7.379(t，1H，J：7.2Hz)，7.471(t，2H，J：7.5Hz)，7.640-7.755(m，6H)。
Embodiment 43:
2-benzene methanamine base-4-oxygen-4-(4-p-methoxy-phenyl)-N-maloyl group amine
(A): the preparation of 2-benzene methanamine base-4-oxygen-4-(4-p-methoxy-phenyl) methyl-butyrate hydrochloride:
Method is with embodiment 41 (A), different is that 1.567 gram 2-benzene methanamine base-4-oxygen-4-(4-p-methoxy-phenyl) butyric acid and 2 equivalent thionyl chlorides are made 1.335 gram 2-benzene methanamine base-4-oxygen-4-(4-p-methoxy-phenyl) methyl-butyrate hydrochlorides, yield: 73.39%, fusing point: 128-130 ℃ (decomposition).
1HNMR(300MHz，DMSO)：δ(ppm)＝3.706(s，3H)，3.757-3.828(m，2H)，3.848(s，3H)，4.258(d，1H，J：13.2Hz)，4.303(d，1H，J：13.2Hz)，4.444(t，1H，J：3.3Hz)，7.080(d，2H，J：8.7Hz)，7.423(m，3H)，7.580(m，2H)，7.953(d，2H，J：8.7Hz)。
(B): the preparation of 2-benzene methanamine base-4-oxygen-4-(4-p-methoxy-phenyl)-N-maloyl group amine:
Method is with embodiment 37 (B), different is to restrain 2-benzene methanamine base-4-oxygen-4-(4-p-methoxy-phenyl) methyl-butyrate hydrochlorides and 0.470 gram oxammonium hydrochloride and 0.759 gram potassium hydroxide reaction with 1.230 to make 341 milligrams of 2-benzene methanamine base-4-oxygen-4-(4-p-methoxy-phenyl)-N-maloyl group amine, white solid, yield: 30.72%, fusing point: 192.8-195 ℃ (decomposition).
1HNMR(300MHz，DMSO)：δ(ppm)＝3.035(dd，1H，J：6.6Hz，18.3Hz)，3.075(dd，1H，J：7.8Hz，18.3Hz)，3.389(t，1H，J：7.2Hz)，3.652(d，1H，J：13.8Hz)，3.812(d，1H，J：13.8Hz)，3.759(s，3H)，6.905(d，2H，J：9.0Hz)，7.236(s，5H)，7.584(d，2H，J：9.0Hz)，11.2(w，1H)。
Embodiment 44:
2-n-octyl amine base-4-oxygen-4-(4-p-methoxy-phenyl)-N-maloyl group amine
(A): the preparation of 2-n-octyl amine base-4-oxygen-4-(4-p-methoxy-phenyl) methyl-butyrate hydrochloride:
Method is with embodiment 41 (A), different is that 1.677 gram 2-n-octyl amine base-4-oxygen-4-(4-p-methoxy-phenyl) butyric acid and 2 equivalent thionyl chlorides are made 1.457 gram 2-n-octyl amine base-4-oxygen-4-(4-p-methoxy-phenyl) methyl-butyrate hydrochlorides, yield: 75.5%, fusing point: 122.5-125 ℃ (decomposition).
1HNMR(300MHz，DMSO)：δ(ppm)＝0.850(t，3H，J：6.6Hz)，1.245(s，10H)，1.632(m，2H)，2.965(d，1H，J：6.9Hz)，3.010(d，1H，J：7.2Hz)，3.714(s，3H)，3.781(d，1H，J：4.8Hz)，3.835(d，1H，J：4.8Hz)，3.853(s，3H)，4.482(t，1H，J：4.8Hz)，7.086(d，2H，J：8.7Hz)，7.967(d，2H，J：8.7Hz)。
(B): the preparation of 2-n-octyl amine base-4-oxygen-4-(4-p-methoxy-phenyl)-N-maloyl group amine:
Method is with embodiment 37 (B), different is makes 70 milligrams of 2-n-octyl amine base-4-oxygen-4-(4-p-methoxy-phenyl)-N-maloyl group amine with 485 milligrams of 2-n-octyl amine base-4-oxygen-4-(4-p-methoxy-phenyl) methyl-butyrate hydrochlorides and 175 milligrams of oxammonium hydrochlorides and 282 milligrams of potassium hydroxide reactions, white solid, yield: 15.08%, fusing point: 196-200 ℃ (decomposition).
1HNMR(300MHz，DMSO)：δ(ppm)＝0.836(t，3H，J：6.0Hz，6.9Hz)，1.225(s，10H)，1.514(t，2H，J：6.9Hz，7.2Hz)，2.778(m，2H)，3.320(dd，1H，J：8.1Hz，18.0Hz)，3.475(dd，1H，J：3.6Hz，18.0Hz)，3.621(dd，1H，J：3.9Hz，4.2Hz，7.8Hz)，3.824(s，3H)，7.033(d，2H，J：9.0Hz)，7.934(d，2H，J：9.0Hz)，9.2(w，1H)，11.6(w，1H)。
Embodiment 45:
2-(2-hydroxyethyl amido)-4-oxygen-4-(4-Phenoxyphenyl)-N-maloyl group amine
(A): the preparation of 2-(2-hydroxyethyl amido)-4-oxygen-4-(4-Phenoxyphenyl) methyl-butyrate hydrochloride:
Method is with embodiment 41 (A), different is that 1.573 gram 2-(2-hydroxyethyl amido)-4-oxygen-4-(4-Phenoxyphenyl) butyric acid and 2 equivalent thionyl chlorides are made 1.525 gram 2-(2-hydroxyethyl amido)-4-oxygen-4-(4-Phenoxyphenyl) methyl-butyrate hydrochlorides, yield: 84.06%, fusing point: 133-135 ℃ (decomposition).
1HNMR(300MHz，DMSO)：δ(ppm)＝3.164(m，2H)，3.687(t，2H，J：5.4Hz)，3.723(s，3H)，3.793(d，1H，J：5.4Hz)，3.849(d，1H，J：4.5Hz)，4.598(t，1H，J：4.8Hz)，7.085(d，2H，J：9.0Hz)，7.131(d，2H，J：8.1Hz)，7.264(t，1H，J：7.2Hz)，7.473(t，2H，J：8.1Hz)，8.009(d，2H，J：9.0Hz)。
(B): the preparation of 2-(2-hydroxyethyl amido)-4-oxygen-4-(4-Phenoxyphenyl)-N-maloyl group amine:
Method is with embodiment 37 (B), different is to restrain 2-(2-hydroxyethyl amido)-4-oxygen-4-(4-Phenoxyphenyl) methyl-butyrate hydrochlorides and 0.519 gram oxammonium hydrochloride and 0.838 gram potassium hydroxide reaction with 1.418 to make 509 milligrams of 2-(2-hydroxyethyl amido)-4-oxygen-4-(4-Phenoxyphenyl)-N-maloyl group amine, white solid, yield: 39.58%, fusing point: 187.5-190.5 ℃ (decomposition).
1HNMR(300MHz，DMSO)：δ(ppm)＝2.800(m，2H)，3.077(dd，1H，J：6.0Hz，14.1Hz)，3.155(dd，1H，J：7.5Hz，14.1Hz)，3.483(m，3H)，6.976(d，2H，J：8.4Hz)，7.040(d，2H，J：8.1Hz)，7.160(t，1H，J：7.5Hz)，7.403(t，2H，J：7.8Hz)，7.706(d，2H，J：8.7Hz)，10.9(w，1H)，11.4(w，1H)。
Embodiment 46:
2-benzene methanamine base-4-oxygen-4-(4-Phenoxyphenyl)-N-maloyl group amine
(A): the preparation of 2-benzene methanamine base-4-oxygen-4-(4-Phenoxyphenyl) methyl-butyrate hydrochloride:
Method is with embodiment 41 (A), different is that 1.877 gram 2-benzene methanamine base-4-oxygen-4-(4 '-xenyl) butyric acid and 2 equivalent thionyl chlorides are made 1.698 gram 2-benzene methanamine base-4-oxygen-4-(4-Phenoxyphenyl) methyl-butyrate hydrochlorides, yield: 79.73%, fusing point: 244-250 ℃ (decomposition).
1HNMR(300MHz，DMSO)：δ(ppm)＝3.457(dd，1H，J：6.9Hz，17.4Hz)，3.540(dd，1H，J：5.4Hz，17.4Hz)，3.726(s，3H)，3.785(t，1H，J：4.2Hz)，4.020(d，1H，J：13.2Hz)，4.113(d，1H，J：13.5Hz)，7.189-8.170(m，14H)。
(B): the preparation of 2-benzene methanamine base-4-oxygen-4-(4-Phenoxyphenyl)-N-maloyl group amine:
Method is with embodiment 37 (B), different is to restrain 2-benzene methanamine base-4-oxygen-4-(4-Phenoxyphenyl) methyl-butyrate hydrochlorides and 0.417 gram oxammonium hydrochloride and 0.673 gram potassium hydroxide reaction with 1.278 to make 130 milligrams of 2-benzene methanamine base-4-oxygen-4-(4-Phenoxyphenyl)-N-maloyl group amine, white solid, yield: 11.10%, fusing point: 165-168 ℃ (decomposition).
1HNMR(300MHz，DMSO)：δ(ppm)＝3.043(m，2H)，3.649(d，1H，J：13.8Hz)，3.820(d，1H，J：13.8Hz)，3.998(s，1H)，6.957(d，2H，J：8.7Hz)，7.023(d，2H，J：8.1Hz)，7.160(t，1H，J：7.8Hz)，7.234(s，5H)，7.405(t，2H，J：7.8Hz)，7.656(d，2H，J：8.7Hz)，7.980(d，1H，8.7Hz)。
Embodiment 47:
2-(4-hydroxyl butylamine base)-4-oxygen-4-(4-Phenoxyphenyl)-N-maloyl group amine
(A): the preparation of 2-(4-hydroxyl butylamine base)-4-oxygen-4-(4-Phenoxyphenyl) methyl-butyrate hydrochloride:
Method is with embodiment 41 (A), different is that 10.536 gram 2-(4-hydroxyl butylamine base)-4-oxygen-4-(4-Phenoxyphenyl) butyric acid and 2 equivalent thionyl chlorides are made 10.06 gram 2-(4-hydroxyl Ding Anji)-4-oxygen-4-(4-Phenoxyphenyl) methyl-butyrate hydrochlorides, yield: 83.73%, fusing point: 129.4-131.4 ℃ (decomposition).
1HNMR(300MHz，DMSO)：δ(ppm)＝1.444(p，2H，J：6.9Hz)，1.698(m，2H)，3.025(m，2H)，3.391(t，2H，J：6.3Hz)，3.798(dt，1H，J：4.8Hz，18.6Hz)，3.907(dt，1H，J：5.4Hz，18.6Hz)，4.510(t，1H，J：4.8Hz)，7.083(d，2H，J：8.7Hz)，7.132(d，2H，J：7.8Hz)，7.261(t，1H，J：7.5Hz)，7.471(t，2H，J：7.8Hz)，8.014(d，2H，J：8.7Hz)。
(B): the preparation of 2-(4-hydroxyl butylamine base)-4-oxygen-4-(4-Phenoxyphenyl)-N-maloyl group amine:
Method is with embodiment 37 (B), different is to restrain 2-(4-hydroxyl butylamine base)-4-oxygen-4-(4-Phenoxyphenyl) methyl-butyrate hydrochlorides and 0.695 gram oxammonium hydrochloride and 1.122 gram potassium hydroxide reactions with 2.039 to make 2-(4-hydroxyl butylamine base)-4-oxygen-4-(4-Phenoxyphenyl)-N-maloyl group amine 1.737 grams, yield: 93.29%, fusing point: 179.6-181.6 ℃ (decomposition).
1HNMR(300MHz，DMSO)：δ(ppm)＝1.383(m，2H)，1.507(m，2H)，2.742(t，2H，J：7.5Hz)，3.052(dd，1H，J：6.3Hz，13.8Hz)，3.167(dd，1H，J：7.5Hz，13.8Hz)，3.376(m，3Hz)，6.970(d，2H，J：8.7Hz)，7.037(d，2H，J：8.7Hz)，7.159(，t，1H，J：7.5Hz)，7.401(t，2H，J：8.1Hz)，7.703(d，2H，J：8.7Hz)，10.9(w，1H)，11.5(w，1H)。
Embodiment 48:
2-(N-morphine quinoline base)-4-oxygen-4-[4 '-(4 "-chlorine) xenyl] butyric acid
2.307 gram oxoethanoic acid monohydrates are dissolved in 20ml, and in the dehydrated alcohol, ice bath is chilled to below 4 ℃.Stir down, drip the ethanolic soln 20ml of morphine quinoline 1.742 grams, temperature is no more than 4 ℃ in making.Drip and finish, the gained clear liquor at room temperature stirs moments later, adds 2.307 gram 4-chlordiphenyl ethyl ketones.Being warming up to 60 ℃ of reactions 5 hours all dissolves to solid.Be chilled to room temperature, filter the faint yellow solid of separating out, ethyl alcohol recrystallization gets off-white color solid 0.708 gram, yield: 18.94%, and fusing point: 194-196 ℃.
1HNMR(300MHz，DMSO)：δ(ppm)＝2.429-2.487(m，1H)，2.735(m，2H)，2.912(t，1H，J：4.8Hz)，3.145(d，1H，J：4.2Hz)，3.546(m，4H)，3.651(t，1H，J：4.8Hz)，3.731(d，1H，J：4.2Hz)，7.556(d，2H，J：8.4Hz)，7.784(d，2H，J：8.4Hz)，7.825(d，2H，J：8.7Hz)，8.076(d，2H，J：8.7Hz)。
Embodiment 49:
2-(2-hydroxyethyl amido)-4-oxygen-4-[4 '-(4 "-chlorine) xenyl] butyric acid
Method is with embodiment 1 (B), different 0.634 gram 3-[4-(4 '-chloro-phenyl-) benzoyls that are to use] vinylformic acid, 0.135 gram 2 hydroxy ethylamine, 25 milliliters of benzene are made solvent, white powdery solid.By embodiment 9 described methods this solid is made hydrochloride, white solid 0.664 gram, yield: 78.15% (in hydrochloride), fusing point: 137-140 ℃ (decomposition).
1HNMR(300MHz，DMSO)：δ(ppm)＝3.135(dt，1H，J：7.2Hz，12.6Hz)，3.209(dt，1H，J：7.2Hz，12.6Hz)，3.706(t，2H，J：7.2Hz)，3.823(dd，1H，J：4.8Hz，18.6Hz)，3.916(dd，1H，4.8Hz，18.6Hz)，4.524(t，1H，J：4.8Hz)，7.570(d，2H，J：8.4Hz)，7.802(d，2H，8.4Hz)，7.884(d，2H，J：8.4Hz)，8.079(d，2H，J：8.4Hz)。
Embodiment 50:
2-(4-methylbenzene sulfenyl)-4-oxygen-4-(4 '-xenyl) butyric acid
Method is with embodiment 36, and different is with 1.261 gram 3-(4-phenyl benzoyl) vinylformic acid and 2.5 equivalent toluene-additions, gets white solid 1.086 grams, yield: 57.70%, and fusing point: 160-162 ℃.
1HNMR(300MHz，DMSO)：δ(ppm)＝2.295(s，3H)，3.477(dd，1H，J：4.8Hz，18.0Hz)，3.584(dd，1H，J：9.6Hz，18.0Hz)，4.069(dd，1H，J：4.8Hz，9.6Hz)，7.190(d，2H，J：8.1Hz)，7.420(d，2H，J：8.1Hz)，7.491(m，3H，J：7.5Hz)，7.739(d，2H，J：7.5Hz)，7.821(d，2H，J：8.4Hz)，8.017(d，2H，J：8.4Hz)。
Embodiment 51:
2-(2-amido ethylamino-)-4-oxygen-4-(4 '-Phenoxyphenyl) butyric acid
Method with the embodiment method with embodiment 1 (B); different is to use 1.341 to restrain 3-(4-phenoxy group benzoyl) vinylformic acid; the methanol solution of 1 equivalent ethylenediamine monohydrochloride salt (preparing down at 0 ℃) by 0.665 gram quadrol dihydrochloride and 1 Equivalent Hydrogen potassium oxide; 25 milliliters of benzene are made solvent; make off-white color solid 0.811 gram; yield: 44.46%, fusing point: 167.1-169.1 ℃ (decomposition).By embodiment 9 described methods this solid is made hydrochloride, get white solid 0.746 gram, yield: 37.18% (in hydrochloride), fusing point: 139-142 ℃ (decomposition).
1HNMR(300MHz，DMSO)：δ(ppm)＝3.219-3.608(m，4H)，3.855(dd，1H，J：4.5Hz，15.0Hz)，3.921(dd，1H，J：3.9Hz，15.0Hz)，4.478(t，1H，J：4.2Hz)，7.090(d，2H，J：8.7Hz)，7.140(d，2H，J：7.8Hz)，7.269(t，1H，J：7.5)，7.478(t，2H，J：7.8Hz)，8.035(d，2H，J：8.7Hz).
Embodiment 52:
N-hydroxyl-2-(4-hydroxyl butylamine base)-4-oxygen-4-(4 '-xenyl) butyramide
(A) preparation of 2-(4-hydroxyl butylamine base)-4-oxygen-4-(4 '-xenyl) methyl-butyrate hydrochloride:
Method is with embodiment 41 (A), different is to make 2-(4-hydroxyl butylamine base)-4-oxygen-4-(4 '-xenyl) methyl-butyrate hydrochloride white crystal 1.538 grams with 1.889 gram 2-(4-hydroxyl butylamine base)-4-oxygen-4-(4 '-xenyl) butyrates hydrochlorates with 1 milliliter of thionyl chloride, yield: 78.47%, fusing point: 142-145 ℃ (decomposition).
1HNMR(300MHz，DMSO)：δ(ppm)＝1.454(p，2H，J：7.5Hz)，1.706(p，2HmJ：7.5Hz)，3.060(m，2H)，3.401(t，2H，J：6.3Hz)，3.743(s，3H)，3.845(dd，1H，J：5.1Hz，18.9Hz)，3.931(dd，1H，J：4.5Hz，18.9Hz)，4.555(t，1H，J：4.8Hz)，7.507(m，3H，J：7.5Hz)，7.766(d，2H，J：7.2Hz)，7.887(d，2H，J：8.4Hz)，8.084(d，2H，J：8.4Hz).
(B) preparation of N-hydroxyl-2-(4-hydroxyl butylamine base)-4-oxygen-4-(4 '-xenyl) butyramide:
Method is with embodiment 37 (B), different is with 1.476 gram 2-(4-hydroxyl butylamine base)-4-oxygen-4-(4 '-xenyl) methyl-butyrate hydrochlorides and 0.523 gram oxammonium hydrochloride and 0.844 gram potassium hydroxide reacts and makes 306 milligrams of 686 milligrams of N-hydroxyl-2-(4-hydroxyl butylamine base)-4-oxygen-4-(4 '-xenyl) butyramide white solid, yield: 44.95%, fusing point: 218-220 ℃ (decomposition).
1HNMR(300MHz，DMSO)：δ(ppm)＝1.403(m，2H)，1.533(m，2H)，2.774(t，2H，J：7.5Hz)，3.126(dd，1H，J：6.6Hz，14.1Hz)，3.228(dd，1H，J：7.2Hz，14.1Hz)，3.352(t，2H，J：6.3Hz)，3.441(t，1H，J：6.9Hz)，7.463(m，3H，J：7.5Hz)，7.697(d，2H，J：7.5Hz)，7.681(d，2H，J：8.4Hz)，7.798(d，2H，J：8.4Hz).
Embodiment 53:
N-hydroxyl-2-(2 hydroxy ethylamine base)-4-oxygen-4-(4 '-p-methoxy-phenyl) butyramide
(A) preparation of 2-(2 hydroxy ethylamine base)-4-oxygen-4-(4 '-p-methoxy-phenyl) methyl-butyrate hydrochloride:
Method is with embodiment 41 (A), and different is with 2-(2 hydroxy ethylamine base)-4-oxygen-4-(4 '-p-methoxy-phenyl) butyric acid 1.277 gram and 1 milliliter of SOCl 2Make 2-(2 hydroxy ethylamine base)-4-oxygen-4-(4 '-p-methoxy-phenyl) methyl-butyrate hydrochloride white crystal 1.307 grams, yield: 86.10%, fusing point: 124-126 ℃ (decomposition).
1HNMR(300MHz，DMSO)：δ(ppm)＝3.149(m，2H，CH 2OH)，3.690(t，2H，J：5.1Hz，CH 2NH)，3.714(s，3H，CH 3OAr)，3.768(dd，1H，J：5.1Hz，18.3Hz，COCH 2)，3.875(dd，1H，J：5.4Hz，18.3Hz，COCH 2)，3.852(s，3H，COOCH 3)，4.579(t，1H，J：5.1Hz，CHCOOCH 3)，7.084(d，2H，J：8.7Hz，ArH)，7.963(d，2H，J：8.7Hz，ArH).
(B) preparation of N-hydroxyl-2-(2 hydroxy ethylamine base)-4-oxygen-4-(4 '-p-methoxy-phenyl) butyramide:
Method is with embodiment 37 (B), different is makes 136 milligrams of N-hydroxyl-2-(2 hydroxy ethylamine base)-4-oxygen-4-(4 '-p-methoxy-phenyl) butyramide white solid with 2-(2 hydroxy ethylamine base)-4-oxygen-4-(4 '-p-methoxy-phenyl) methyl-butyrate hydrochloride 1.200 grams and oxammonium hydrochloride 0.525 gram and potassium hydroxide 0.848 gram reaction, yield: 12.76%, fusing point: 176-178 ℃ (decomposition).
1HNMR(300MHz，DMSO)：δ(ppm)＝2.809(m，2H，J：5.4Hz)，3.087(dd，1H，J：5.7Hz，14.1Hz)，3.168(dd，1H，J：7.8Hz，14.1Hz)，3.414(t，1H，J：6.6Hz)，3.495(t，2H，J：5.7Hz)，6.936(d，2H，J：8.7Hz)，7.648(d，2H，J：8.7Hz).
Embodiment 54:
N-hydroxyl-2-hydroxyl-3-acetamido 4-oxygen-4-(4 '-xenyl) butyramide
(A) 2-hydroxyl-butyro-preparation of 3-acetamido 4-oxygen-4-(4 '-xenyl):
Method referenced patent US4453003.
(B) preparation of 2-hydroxyl-3-acetamido 4-oxygen-4-(4 '-xenyl) methyl-butyrate:
4.729 gram 2-hydroxyl-3-acetamido 4-oxygen-4-(4 '-xenyl) butyric acid are dissolved among 30 milliliters of DMF, add 2 gram Anhydrous potassium carbonates, under the stirring at room, add 2 equivalent methyl iodide, reacted 3 hours.After reaction solution dilutes with 200 milliliters of ethyl acetate, water and saturated common salt water washing successively, organic phase anhydrous magnesium sulfate drying.Filter, filtrate is concentrated into dried, and solid gets white crystal 4.758 grams with recrystallization from ethyl acetate/petroleum ether, yield: 96.45%, and 147-149 ℃.
(C) N-hydroxyl-2-hydroxyl-3-acetamido 4-oxygen-4-(4 '-xenyl) butyramide preparation:
Method is with embodiment 37 (B), different is with 2-hydroxyl-3-acetamido 4-oxygen-4-(4 '-xenyl) methyl-butyrate and oxammonium hydrochloride 0.525 restrains and potassium hydroxide 0.848 gram reaction makes N-hydroxyl-2-hydroxyl-3-acetamido 4-oxygen-4-(4 '-xenyl) butyramide 0.551 gram, yield: 53.65%, fusing point: 150.6-153.0 ℃ (decomposition).
1HNMR(300MHz，DMSO)：δ(ppm)＝1.507(s，3H)，4.100(d，1H，J：3.6Hz)，5.004(s，1H)，5.538(d，1H，J：4.2Hz)，7.437(m，3H，J：7.5Hz)，7.558(d，2H，J：8.4Hz)，7.671(d，2H，J：7.5Hz)，7.672(d，2H，J：8.4Hz)，10.986(s，1H)，11.490(s，1H).
Embodiment 55:
N-hydroxyl-2-[2-(4-nitrophenoxy) ethylmercapto group]-4-oxygen-4-(4 '-xenyl) butyramide
(A) 2-[2-(4-nitrophenoxy) ethylmercapto group]-preparation of 4-oxygen-4-(4 '-xenyl) methyl-butyrate:
Method is with embodiment 38 (A), different is with 0.696 gram p-NP, 1.722 gram 2-(2-hydroxyl ethylmercapto group)-4-oxygen-4-(4 '-xenyl) methyl-butyrate and 1.312 gram triphenyl phosphorus and 0.871 gram azo-dicarboxylate reaction, make 2-[2-(4-nitrophenoxy) ethylmercapto group through column chromatography purification (petrol ether/ethyl acetate=4: 1)]-faint yellow semi-solid 2.008 grams of 4-oxygen-4-(4 '-xenyl) methyl-butyrate, yield: 86.25%.
(B) N-hydroxyl-2-[2-(4-nitrophenoxy) ethylmercapto group]-preparation of 4-oxygen-4-(4 '-xenyl) butyramide:
Method is with embodiment 37 (B), with 2.008 gram 2-[2-(4-nitrophenoxy) ethylmercapto groups]-4-oxygen-4-(4 '-xenyl) methyl-butyrate and 0.6 restrains oxammonium hydrochloride and 0.726 gram potassium hydroxide reaction makes faint yellow solid 1.056 grams, yield: 52.49%, fusing point: 162-164 ℃.
1HNMR(300MHz，DMSO)：δ(ppm)＝3.179(t，2H，J：6.0Hz)，3.536(d，2H，J：9.9Hz)，4.373(t，2H，J：6.0Hz)，4.862(t，1H，J：9.6Hz)，7.151(d，2H，J：9.3Hz)，7.468(m，3H，J：7.5Hz)，7.71?5(d，2H，J：7.5Hz)，7.755(s，5H)，8.165(d，2H，J：9.3Hz).
Embodiment 56:
2-(2-hydroxyethyl amido)-4-phenoxy group-3-(4 '-dibenzoyl base) butyric acid
(A): the preparation of 3-(4-benzene dibenzoyl base) propionic acid:
61.68 gram biphenyl and 42.03 gram succinyl oxides are dissolved in 700 milliliters of benzene, the ice-water bath cooling down, add 112 gram aluminum chlorides in four batches, the gained reaction solution slowly rises to room temperature, reheat refluxed 5 hours, be evaporated to dried, the mixture that adds trash ice and concentrated hydrochloric acid is hydrolyzed, filter the gained white solid, be washed to neutrality, again with petroleum ether number time, crude product gets white crystals 83.92 grams with the Glacial acetic acid recrystallization, yield: 82.50%, fusing point: 173-175 ℃ (literature value: 176-178 ℃).
(B): the preparation of 3-(4-dibenzoyl base)-3-butenoic acid:
50.46 gram 3-(4-phenyl benzoyl) propionic acid and 8.8 gram Paraformaldehyde 96s are mixed with 25 milliliters of pyridines; be heated to 55-60 ℃; add 1 milliliter of morphine quinoline; under this temperature, continue reaction 6 hours; be chilled to room temperature, with 800 milliliters of ethyl acetate dilutions, twice of the salt pickling of 6 mol; again successively water and saturated common salt water washing number all over to neutral; anhydrous magnesium sulfate drying filters, the ethyl acetate washing; filtrate merges; be evaporated to driedly, gained white crude product is with methylene dichloride/sherwood oil recrystallization, white solid 40.43 grams; yield: 75.90%, fusing point: 128-130 ℃.
(C): 3-(4-dibenzoyl base)-3, the butyro-preparation of 4-two bromo-:
40 gram 3-(4-phenyl benzoyl)-3-butenoic acids are dissolved in 500 milliliters of chloroforms; drip 24 gram liquid bromines under the stirring at room; drip off back restir 1 hour; be evaporated to dried; gained white crude product gets white products with the toluene recrystallization; 46.39 gram, yield: 72.49%, fusing point: 126.4-128.0 ℃.
(D): 3-(4-dibenzoyl base)-3, the preparation of 4-two bromo-methyl-butyrates:
With 42.61 gram 3-(4-phenyl benzoyl)-3; 4-two bromo-butyric acid are dissolved in 500 milliliters of anhydrous methanols; add 8 milliliters of vitriol oils, reflux 5 hours is chilled to room temperature; separate out white solid; filter, use methanol wash, get 32 gram products after draining; yield: 72.71%, fusing point: 65.3-67 ℃.Not purified, directly carry out the next step.
(E): the preparation of 3-(4-dibenzoyl base)-4-bromo-2-butylene acid methyl esters:
With 32 gram 3-(4-phenyl benzoyl)-3; 4-two bromo-methyl-butyrates are dissolved in 500 milliliters of ether; add 14.71 gram triethylamines; reaction is 4 hours under the room temperature; be diluted to 700 milliliters with ether; the salt pickling twice of 6 mol, more successively water and saturated common salt water washing number all over to neutral, anhydrous magnesium sulfate drying; filter; the ether washing, filtrate merges, and is evaporated to dried; gained light orange crude product dehydrated alcohol recrystallization; get product 14.24 grams, yield: 54.50%, fusing point: 106-109 ℃.
1HNMR(300MHz，CDCl 3)：δ(ppm)＝3.832(s，3H)，4.937(s，2H)，6.166(s，1H)，7.484(m，3H，J：6.5Hz)，7.637(d，2H，J：6.5Hz)，7.721(d，2H，J：9.0Hz)，7.955(d，2H，J：9.0Hz).
(F): the preparation of 4-phenoxy group-3-(4-dibenzoyl base)-2-butylene acid methyl esters:
But 1.179 gram phenol are dissolved among the DMF suspension 15ml of 2.6 Anhydrous potassium carbonates; the triethyl benzyl ammonia chloride (TEBAC) that adds catalytic amount; stir the DMF solution 15ml that moments later adds 4.5 gram 3-(4-dibenzoyl base)-4-bromo-2-butylene acid methyl esters, react under the room temperature to raw material disappearance (TLC detection).Ethyl acetate 250ml dilute reaction solution, water and saturated common salt water washing number time successively, anhydrous magnesium sulfate drying.Filter, filtrate is concentrated into dried, and after the methylene dichloride dissolving, through filtered through silica gel, after filtrate concentrated, the gained solid got yellowish pink solid 4.388 grams with recrystallizing methanol, yield: 94.06%, and fusing point: 110-115 ℃.
(G): the preparation of 4-phenoxy group-3-(4-dibenzoyl base)-2-butylene acid:
4-phenoxy group-3-(4-dibenzoyl base)-2-butylene acid methyl esters 4.388 grams are added in the 10mlNaOH solution (8%), be heated to backflow, all dissolve to suspended substance.Solution is homogeneous phase, and reaction needs 1 hour approximately, is chilled to room temperature, the careful acidifying of concentrated hydrochloric acid, and ethyl acetate 200ml divides 3 extractions, and extraction liquid merges, and water and saturated common salt water washing are to neutrality, anhydrous magnesium sulfate drying successively.Filter, filtrate is concentrated into dried that brown oil 4.05 restrains yield: 96.09%.Not purified, directly drop into the next step.
(H): 2-(2-hydroxyethyl the amido)-butyro-preparation of 4-phenoxy group-3-(4 '-dibenzoyl base):
844.6 milligrams of 4-phenoxy group-3-(4-dibenzoyl base)-2-butylene acid is suspended in the 10ml benzene, adds 1 normal thanomin, room temperature reaction spends the night.The solid that the filter collection is separated out with washing with acetone and dry, gets 416 milligrams of off-white color solids, yield: 48.55%, and fusing point: 80-83 ℃.
1HNMR(300MHz，DMSO)：δ(ppm)＝1.767(s，2H)，2.695(t，2H，J：5.4Hz)，3.450(t，2H，J：5.4Hz)，6.915(d，2H，J：8.1Hz)，6.942(t，1H，J：7.2Hz)，7.285(t，2H，J：8.1Hz)，7.403(t，1H，J：7.2Hz)，7.496(t，2H，J：7.5Hz)，7.720(d，2H，J：7.5Hz)，7.775(d，2H，J：8.4Hz)，7.882(d，2H，J：8.4Hz).
Embodiment 57:
2-benzene methanamine base-4-phenoxy group-3-(4 '-dibenzoyl base) butyric acid
Method is with embodiment 56 (H), and different is to make solvent with ether, makes 421 milligrams of off-white color solids, yield: 38.38%, and fusing point: 174-177 ℃.
1HNMR(300MHz，DMSO)：δ(ppm)＝1.760(s，2H)，3.795(s，2H)，6.915-6.976(m，3H)，7.262-7.332(m，3H)，7.313(s，5H)，7.470(m，3H，7.2Hz)，7.698(d，2H，J：7.2Hz)，7.761(d，2H，J：8.4Hz)，7.866(d，2H，J：8.4Hz).
Embodiment 58:
2-n-octyl amine base-4-phenoxy group-3-(4 '-dibenzoyl base) butyric acid
Method is with embodiment 56 (H), and different is to make solvent with ether, makes 453 milligrams of white solids, yield: 39.42%, and fusing point: 158-161 ℃.
1HNMR(300MHz，DMSO)：δ(ppm)＝0.824(t，3H，J：6.9Hz)，1.147(s，10H)，1.207(p，2H，J：6.9Hz)，1.756(s，2H)，2.483(m，2H)，6.904(d，2H，J：7.8Hz)，6.933(t，1H，J：7.2Hz)，7.273(t，2H，J：7.8Hz)，7.394(t，1H，J：7.2Hz)，7.485(t，2H，J：7.2Hz)，7.711(d，2H，J：7.2Hz)，7.759(d，2H，J：8.7Hz)，7.872(d，2H，J：8.7Hz).
Embodiment 59:
2-(2-N, N '-dimethylamino ethyl amido)-4-phenoxy group-3-(4 '-dibenzoyl base) butyric acid
Method is with embodiment 56 (H), and different is to make solvent with benzene, makes 407 milligrams of white solids, yield: 42.92%, and fusing point: 15.2-154 ℃.
1HNMR(300MHz，DMSO)：δ(ppm)＝1.756(s，2H)，2.084(s，6H)，2.281(t，2H，J：6.0Hz)，2.690(t，2H，J：6.0Hz)，6.917(d，2H，J：8.1Hz)，6.943(t，1H，J：7.5Hz)，7.283(t，2H，J：8.1Hz)，7.401(t，1H，J：7.2Hz)，7.495(t，2H，J：7.5Hz)，7.716(d，2H，J：8.1Hz)，7.763(d，2H，J：8.4Hz)，7.870(d，2H，J：8.4Hz).
Embodiment 60:
2-n-butylamine-based-4-phenoxy group-3-(4 '-dibenzoyl base) butyric acid
Method is made solvent with embodiment 56 (H) with ether, makes 375 milligrams of white solids, yield: 44.49%, and fusing point: 175-178 ℃.
1HNMR(300MHz，DMSO)：δ(ppm)＝0.767(t，3H，J：7.2Hz)，1.164(h，2H，J：7.2Hz)，1.320(p，2H，J：7.2Hz)，1.762(s，2H)，2.510(t，2H，J：7.2Hz)，6.907(d，2H，J：7.8Hz)，6.931(t，1H，J：7.8Hz)，7.274(t，2H，J：7.8Hz)，7.393(t，1H，J：7.2Hz)，7.486(t，2H，J：7.2Hz)，7.708(d，2H，J：7.2Hz)，7.761(d，2H，J：8.4Hz)，7.880(d，2H，J：8.4Hz).
Embodiment 61:
2-cyclohexylamino-4-phenoxy group-3-(4 '-dibenzoyl base) butyric acid
Method is with embodiment 56 (H), and different is to make solvent with ether, makes 543 milligrams of white solids, yield: 69.16%, and fusing point: 216-219 ℃.
1HNMR(300MHz，DMSO)：δ(ppm)＝0.955-1.191(m，5H)，1.469-1.726(m，5H)，1.756(s，2H)，2.708(td，1H，J：3.6Hz，10.5Hz)，6.898(d，2H，J：7.8Hz)，6.925(t，1H，J：7.5Hz)，7.269(t，2H，J：7.8Hz)，7.391(t，1H，J：7.2Hz)，7.486(t，2H，J：7.5Hz)，7.706(d，2H，J：7.2Hz)，7.757(d，2H，J：8.4Hz)，7.877(d，2H，J：8.4Hz).
Embodiment 62:
2-(2-hydroxyethyl amido)-4-(4-toluene sulfenyl)-3-(4 '-dibenzoyl base) butyric acid
(A) preparation of 4-(4-toluene sulfenyl)-3-(4 '-dibenzoyl base)-2-butylene acid methyl esters:
Method is with embodiment 56 (F); use 1.556 gram toluene-s and 4.5 gram 3-(4-dibenzoyl base)-4-bromo-2-butylene acid methyl esters reaction; make 4-(4-toluene sulfenyl)-3-(4 '-dibenzoyl base)-2-butylene acid methyl esters; orange 4.639 grams; yield: 92.01%, not purified direct input the next step.
(B) preparation of 4-(4-toluene sulfenyl)-3-(4 '-dibenzoyl base)-2-butylene acid:
Method is with embodiment 56 (G), and different is that 4.367 gram 4-(4-toluene sulfenyl)-3-(4 '-dibenzoyl base)-2-butylene acid methyl esters hydrolysis is got brown oil 4.05 grams, yield: 96.09%, and not purified direct input the next step.
(C) 2-(2-hydroxyethyl amido)-4-(4-toluene sulfenyl)-butyro-preparation of 3-(4 '-dibenzoyl base):
Method is made solvent with embodiment 56 (H) with benzene, makes 336 milligrams of off-white color solids, yield: 28.80%, and fusing point: 102.2-105.2 ℃.
1HNMR(300MHz，DMSO)：δ(ppm)＝2.230(s，3H)，3.210(s，2H)，2.680(t，2H，J：5.4Hz)，3.109(t，2H，J：5.4Hz)，7.114(s，1H)，7.374-7.714(m，13H).
Embodiment 63:
2-benzene methanamine base-4-(4-toluene sulfenyl)-3-(4 '-dibenzoyl base) butyric acid
Method is with embodiment 56 (H), and different is to make solvent with ether, makes 495 milligrams of white solids, yield: 38.32%, and fusing point: 120-122 ℃.
1HNMR(300MHz，DMSO)：δ(ppm)＝2.235(s，3H)，3.365(s，2H)，3.822(s，2H)，7.043(s，1H)，7.173(d，2HJ：8.7Hz)，7.247-7.386(m，5H)，7.322(d，2H，J：8.7Hz)，7.457(m，3H，J：7.8Hz)，7.698(d，2H，J：7.8Hz)，7.759(s，4H).
Embodiment 64:
2-(2-N, N '-dimethylamino ethyl amido)-4-(4-toluene sulfenyl)-3-(4 '-dibenzoyl base) butyric acid
Method is made solvent with embodiment 56 (H) with benzene,, make 350 milligrams of off-white color solids, yield: 40.75%, fusing point: 94.6-98 ℃.
1HNMR(300MHz，DMSO)：δ(ppm)＝2.115(s，6H)，2.233(s，3H)，2.325(t，2H，J：6.3Hz)，2.728(t，2H，J：6.3Hz)，3.317(s，2H)，3.617(w，3H)，6.971(s，1H)，7.166(d，2H，J：8.4Hz)，7.307(d，2H，8.1Hz)，7.384(t，1H，J：7.2Hz)，7.468(t，2H，H：7.2Hz)，7.696(d，2H，J：7.2Hz)，7.758(s，4H).
Embodiment 65:
2-n-octyl amine base-4-(4-toluene sulfenyl)-3-(4 '-dibenzoyl base) butyric acid
Method is with embodiment 56 (H), and different is to make solvent with ether,, make 160 milligrams of off-white color solids, yield: 18.13%, fusing point: 130-133 ℃.
1HNMR(300MHz，DMSO)：δ(ppm)＝0.815(t，3H，J：6.3Hz)，1.201(s，10H)，1.434(p，2H，J：6.9Hz)，2.232(s，3H)，2.628(t，2H，J：7.5Hz)，3.179(s，2H)，6.918(s，1H)，7.165(d，2H，J：8.1Hz)，7.299(d，2H，J：8.1Hz)，7.384(t，1H，J：7.2Hz)，7.468(t，2H，J：7.2Hz)，7.697(d，2H，J：7.2Hz)，7.760(s，4H).
Embodiment 66:
4-(4-xenyl)-2-(2-hydroxyethyl sulfenyl)-4-hydroxyl imido grpup butyric acid
The 6mmol oxammonium hydrochloride is added in 10 milliliters of anhydrous methanols, and the ice-water bath cooling adds 9mmol potassium hydroxide down, and reaction is 1 hour under this temperature.Filter, solid washs with small amount of methanol, and filtrate adds in 3mmol 2-(2-hydroxyethyl sulfenyl)-(4 '-xenyl)-4-oxy butyrate, and reaction is spent the night under the room temperature.Reaction solution is concentrated into dried, and resistates is dissolved in water, and the white precipitate of separating out is filtered in the careful acidifying of concentrated hydrochloric acid, is washed to neutrality, and is dry that white solid 1.031 restrains yield: 99.52%, fusing point: 138-140 ℃ (decomposition).
1HNMR(300MHz，DMSO)：δ(ppm)＝2.641(td，2H，J：2.4Hz，6.9Hz，CH 2S)，3.160(d，2H，J：7.8Hz，COCH 2)，3.423(t，2H，J：7.2Hz，CH 2OH)，3.651(t，1H，J：7.8Hz，CHS)，7.366(t，1H，J：7.2Hz，ArH)，7.466(t，2H，J：7.5Hz，ArH)，7.663-7.735(m，6H，ArH).
Embodiment 67:4-(4-xenyl)-2-(2-rosickyite base)-4-hydroxyl imido grpup butyric acid
Method gets white solid 0.639 gram, yield with embodiment 66: 93.03%, fusing point: 128-131 ℃ (decomposition).
1HNMR(300MHz，CDCl 3)：δ(ppm)＝0.924(t，3H，J：7.5Hz，CH 3)，1.553(p，2H，J：6.9Hz，CH 2CH 3)，2.585(dt，1H，J：4.8Hz，12.6Hz，SCH 2)，2.655(dt，1H，J：6.3Hz，12.6Hz，SCH 2)，3.304(dd，1H，J：7.8Hz，14.1Hz，COCH 2)，3.426(dd，1H，J：7.8Hz，14.1Hz，COCH 2)，3.893(t，1H，J：7.8Hz，CHS)，7.422(m，3H，J：7.5Hz，ArH)，7.579(d，2H，J：7.5Hz，ArH)，7.613(d，2H，J：8.4Hz，ArH)，7.644(d，2H，J：8.4Hz，ArH).
Embodiment 68:4-(4-xenyl)-2-(4-methylbenzene sulfenyl)-4-hydroxyl imido grpup butyric acid
Method is with embodiment 66, what different is white solid 0.774 gram, and yield: 98.86%, fusing point: 122-125 ℃ (decomposition).
1HNMR(300MHz，DMSO)：δ(ppm)＝2.242(s，3H，CH 3)，3.174(d，2H，J：7.5Hz，COCH 2)，3.949(t，1H，J：7.5Hz，CHS)，7.077(d，2H，J：8.1Hz，ArH)，7.218(d，2H，J：8.1Hz，ArH)，7.361(t，1H，J：7.5Hz，ArH)，7.462(t，2H，J：7.5Hz，ArH)，7.627-7.692(m，6H，ArH).
Compound structure and physical constant see Table 3.2.1.
Table 3.2.1
Numbering structural formula molecular formula molecular weight fusing point (℃)
Gyy21010
Figure A0314793300531
C 18H 18N 2O 5 342.35 150.6-153
Gyy10904 C 18H 18O 4S 330.40 127.6-129.6
Gyy11112 C 19H 20O 4S 344.42 149-152
Gyy20604
Figure A0314793300534
C 19H 20O 3S 328.43 115-117
Gyy30104 C 23H 20O 3S 376.47 160-162
Gyy21009
Figure A0314793300536
C 18H 19NO 4S 345.41 138-140
Gyy21106
Figure A0314793300537
C 22H 22N 2O 5S 426.49 179-181
Gyy21121 C 24H 22N 2O 6S 466.51 106-108
Gyy30314
Figure A0314793300539
C 18H 19NO 4S 345.41 138-140
Gyy30315
Figure A03147933005310
C 23H 21NO 3S 391.48 122-125
Gyy30316
Figure A03147933005311
C 19H 21NO 3S 343.44 128-131
Gyy10404
Figure A03147933005312
C 20H 21NO 4 339.39 183-186
Gyy10407 C 23H 21NO 3 359.42 191.5-193.5
Gyy10408
Figure A0314793300541
C 21H 23NO 4 353.42 171.4-172.4
Gyy10906 C 18H 19NO 4 313.35 185-187
Gyy20201
Figure A0314793300543
C 20H 23NO 3 325.41 173.3-175
Gyy20204 C 24H 31NO 3 381.52 122.4-126.0
Gyy20205 C 22H 25NO 3 351.44 178.6-180.1
Gyy20202
Figure A0314793300546
C 20H 24N 2O 3 340.42 142-143.8
Gyy20206 C 19H 19NO 3 309.36 143.2-146
Gyy20605
Figure A0314793300548
C 25H 25NO 3 387.48 169-170.4
Gyy21112 C 20H 24ClNO 4 377.87 139-142
Gyy21113 C 21H 28Cl 2N 2O 3 427.37 138-141
Gyy20123 C 18H 19NO 5 329.35 155-157
Gyy20207
Figure A03147933005412
C 24H 31NO 4 397.51 164-166
Gyy20208
Figure A03147933005413
C 20H 23NO 4 341.41 164-167
Gyy20209 C 22H 25NO 4 367.44 184-186.5
Gyy20210 C 19H 19NO 4 325.36 171.2-173.2
Gyy20211
Figure A0314793300551
C 23H 21NO 4 375.42 173-174.4
Gyy20215 C 20H 24N 2O 4 356.42 137-139
Gyy20217
Figure A0314793300553
C 20H 21NO 5 355.39 176-178
Gyy20218
Figure A0314793300554
C 21H 23NO 4 353.42 146.5-149.5
Gyy20501
Figure A0314793300555
C 21H 26N 2O 4 370.45 160-162.7
Gyy21110 C 25H 26ClNO 4 439.94 140-142
Gyy30305
Figure A0314793300557
C 18H 21ClN 2O 4 364.82 167.1-169.1
Gyy21111
Figure A0314793300558
C 20H 24ClNO 5 393.87 130-133
Gyy20213 C 18H 19NO 4 313.35 175.7-177
Gyy20113 C 13H 17NO 5 267.28 165.2-168
Gyy20114
Figure A03147933005511
C 19H 29NO 4 335.44 166-168
Gyy20118 C 15H 21NO 4 279.34 162.6-165
Gyy20120 C 15H 22N 2O 4 294.35 126.3-128.7
Gyy20214 C 17H 23NO 4 305.37 160-162
Gyy20216
Figure A03147933005515
C 14H 17NO 4 263.29 157.5-159
Gyy20219
Figure A0314793300561
C 15H 19NO 5 293.32 167-169
Gyy20502
Figure A0314793300562
C 16H 24N 2O 4 308.38 148-150.3
Gyy21108 C 20H 24ClNO 4 377.87 125-128
Gyy21109
Figure A0314793300564
C 17H 25NO 7 355.39 150-152
Gyy10403
Figure A0314793300565
C 20H 20ClNO 4 373.83 194-196
Gyy30105 C 18H 18ClNO 4 347.80 175-177
Gyy20918
Figure A0314793300567
C 23H 22N 2O 3 374.44 218-222
Gyy20919
Figure A0314793300568
C 18H 20N 2O 4 328.37 218.9-222
Gyy30308 C 20H 24N 2O 4 356.42 205.6-208
Gyy20923 C 18H 20N 2O 5 344.37 187.5-190.5
Gyy21011 C 23H 22N 2O 4 390.44 165-168
Gyy20922 C 13H 18N 2O 5 282.30 176-178
Gyy21013 C 18H 20N 2O 4 328.37 192.8-195
Gyy21014 C 19H 30N 2O 4 350.46 196-200
Gyy21132 C 20H 24N 2O 5 372.42 179.6-181.6
Gyy20414 C 30H 27NO 4 465.55 174-177
Gyy20415 C 31H 37NO 4 487.64 158-161
Gyy20417 C 25H 25NO 5 419.48 80-83
Gyy20418
Figure A0314793300574
C 27H 30N 2O 4 446.55 151.2-154
Gyy20419 C 27H 29NO 4 431.53 175-178
Gyy20422 C 29H 31NO 4 457.57 216-219
Gyy20411
Figure A0314793300577
C 26H 27NO 4S 449.56 102.2-105.2
Gyy20412
Figure A0314793300578
C 31H 29NO 3S 495.64 120-122
Gyy20421
Figure A0314793300579
C 32H 39NO 3S 517.73 130-133
Gyy20420 C 28H 32N 2O 3S 476.63 94.6-98
Activity rating
Experimental principle
The MMPs hydrolytic activity suppresses to contain high fluorescence ayapanin group and quenching group in the hydrolysis substrate of choosing simultaneously in the experiment, and activatory MMPs can cut the peptide bond between fluorophor and the quenching group, and the fluorescence of substrate is strengthened.According to the variation observation sample of fluorescence intensity restraining effect to MMPs.
Materials and methods
Instrument: Fluostar galaxy microplate optical detecting instrument and supporting fluorometric assay 384 orifice plates (BMG company product).
Reagent
1, recombinant human MMP-1, MMP-2, MMP-3, MMP-9, fluorogenic substrate II
ProMMP-1: stock solution concentration is 132 μ g/ml, the TCN dissolving, and final concentration is 0.1 μ g/ml.
ProMMP-2: stock solution concentration is 50 μ g/ml, the TCN dissolving, and final concentration is 0.018 μ g/ml.
ProMMP-3: stock solution concentration is 100 μ g/ml, the TCN dissolving, and final concentration is 0.4 μ g/ml.
ProMMP-9: stock solution concentration is 66 μ g/ml, the TCN dissolving, and final concentration is 0.1 μ g/ml.
Fluorogenic substrate II: stock solution concentration is 2mM, DMSO dissolving, final concentration 10mM.
Activator APMA (p-aminophenylmercuric acetate): 100mM is dissolved in DMSO, and working concentration is 1mM.
2, TCN damping fluid: 50mM Tris, PH=7.5,10mM CaCl 2, 150mM NaCl
3, sample to be sieved: testing compound dissolves with DMSO, and the TCN dilution uses final concentration to be 10 μ g/ml, and is stand-by.
Experimental technique
1, the activation of MMPs:
MMP-1: APMA added to make the APMA final concentration in the 132 μ g/ml ProMMP-1 solution be 1mM, 37 ℃ of incubations 2.5 hours.Dilute with the TCN damping fluid during use.
MMP-2: APMA added to make the APMA final concentration in the 50 μ g/ml ProMMP-2 solution be 1mM, 37 ℃ of incubations 2.5 hours.Dilute with the TCN damping fluid during use.
MMP-3: APMA added to make the APMA final concentration in the 100 μ g/ml ProMMP-3 solution be 1mM, 37 ℃ of incubations 24 hours.Dilute with the TCN damping fluid during use.
MMP-9: APMA added to make the APMA final concentration in the 66 μ g/ml ProMMP-9 solution be 1mM, 37 ℃ of incubations 25 hours.Dilute with the TCN damping fluid during use.
2, compound suppresses active mensuration:
(1) 8 holes are in contrast in 384 orifice plates.A1-D1 physiologic saline for substitute sample wherein, the maximum activity of reflection enzyme is as enzyme value contrast (Ke); E1-H1 physiologic saline for substitute sample, reaction buffer replaces enzyme, as positive control (Kc).
(2) add different concns testing sample 5 μ l to all the other holes, activating enzymes 40 μ l (final concentration is 0.4 μ g/ml) measure the gained enzymic activity as experimental value (Ks).
Add 5 μ l fluorogenic substrate II (final concentration is 10 μ M) after (3) 10 minutes at low temperatures, low temperature is of short duration centrifugal fast.
(4) at Ex320nm, the EM405nm place surveys fluorescence, 35 ℃ of temperature of reaction.20 circulations are surveyed in circulation in per 2 minutes altogether.Remove preceding two time points (get rid of the beginning temperature and cross low influence), calculate the variation slope of fluorescent value, as the value of reflection enzymic activity to reaction.
The inhibiting rate %=[(Ke-Kc of sample)-(Ks-Kc)]/(Ke-Kc) * 100%.Testing sample is diluted to 5 different concentration (10,1,0.1,0.01,0.001 μ g/ml) respectively, and working sample is made amount effect curve to the inhibiting rate of enzyme according to inhibiting rate and sample concentration under the mensuration different concns, calculates IC 50(it is listed to the results are shown in following table).
Target compound MMPs suppresses active table look-up
IC 50(μM) IC(μM)
The compound compound
MMP-1 MMP-2 MMP-3 MMP-9 MMP-1 MMP-2 MMP-3 MMP-9
Gyy21010 * 3.45 * * Gyy20217 * 46.70 * *
Gyy10904 * 3.71 * 18.49 Gyy20218 * 3.189 * 14.22
Gyy11112 11.73 4.94 * 53.21 Gyy20501 * 10.32 * 64.76
Gyy20604 15.69 1.86 * * Gyy21110 5.53 4.12 * 14.95
Gyy30104 * 5.94 * 9.496 Gyy30305 * 11.57 * 2.27
Gyy21009 * 0.796 * 46.06 Gyy21111 * 90.71 *
Gyy21106 does not survey not survey and does not survey Gyy20213 * * 22.90 *
Gyy21121 * 2.700 * 53.03 Gyy20113 53.86 45.72 * 77.15
Gyy30314 * 6.47 54.72 79.64 Gyy20114 * 13.25 * *
Gyy30315 37.18 3.07 * 4.626 Gyy20118 * * * *
Gyy30316 * 6.95 * 14.04 Gyy20120 * * * *
Gyy10404 * 4.63 64.23 * Gyy20214 45.65 11.47 * 86.96
Gyy010407 * 5.79 * * Gyy20216 82.01 13.77 * 31.26
Gyy10408 33.59 5.63 * 17.69 Gyy20219 * 16.52 * *
Gyy10906 * 2.645 * 23.64 Gyy20502 9.961 6.04 * 15.01
Gyy20201 * 2.35 46.65 15.16 Gyy21108 * * * *
Gyy20204 does not survey not survey and does not survey Gyy21109 * 31.06 * *
Gyy20205 * 3.12 * 8.494 Gyy10403 * 5.26 * 18.06
Gyy20202 * 1.06 * 13.99 Gyy30105 * 0.364 2.218
Gyy20206 * 2.14 * 15.07 Gyy20918 53.41 75.05 * *
Gyy20605 15.57 9.10 * 12.96 Gyy20919 15.13 5.73 * *
Gyy21112 3.313 4.50 * 9.07 Gyy30308 * 15.91 * *
Gyy21113 2.066 0.709 1.872 9.88 Gyy20923 * 13.52 * 17.47
Gyy20123 * 26.27 * * Gyy21011 * 0.526 69.38 15.93
Gyy20207 * * * * Gyy20922 * * * *
Gyy20208 * 29.74 * 12.40 Gyy21013 * 8.64 71.81 *
Gyy20209 71.68 40.63 * 63.82 Gyy21014 * 17.58 * 86.88
Gyy20210 * 14.04 * 75.84 Gyy21132 * 0.79 * 28.04
Gyy20211 * 10.78 * * Gyy20414 * 2.84 * *
Gyy20215 * 57.63 * * Gyy20415 * 1.14 * *
Gyy20417 does not survey not to survey and does not survey Gyy20411 and do not survey not survey and survey survey
Gyy20418 15.14 3.11 * 57.95 Gyy20412 * 2.37 * *
Gyy20419 10.62 1.24 * 29.08 Gyy20421 * 2.50 * *
Gyy20422 17.59 2.95 * 75.71 Gyy20420 * 2.73 * *
Annotate: * represents the unrestraint activity in the table
MMP1, MMP2, the MMP9 activity screen model of having set up carried out external enzyme inhibition test to be shown, this compounds is to MMP-1, MMP-2, MMP-3 and MMP-9 have inhibition activity in various degree, and have the selective inhibitory in various degree to MMP-2.

Claims (14)

1, acceptable salt on compound shown in general formula (I) and the pharmacodynamics thereof
Figure A031479330002C1
Wherein, R1 is selected from C 1～8Straight chain or branched alkyl and alkoxyl group, alkylthio, alkylamino radical; Cycloalkyl; Halogen, nitro, cyano group, hydroxyl;-COOR 5,-OCOR 6,-NHCOR 7,-CONHR 8R 5, R 6, R 7, R 8Independently be selected from C 1～C 4Alkyl, cycloalkyl or phenyl,
Or
Figure A031479330002C2
M is Sauerstoffatom, sulphur atom, amido, methylene radical phenyl, phenoxy group, thiophenyl, anilino, benzyl;
R 9Be selected from C 1～4Alkyl, alkoxyl group, alkylthio, alkylamino radical, hydroxyl, the phenyl that amino, halogen replace, phenoxy group, thiophenyl, anilino, benzyl; Also can be selected from heterocyclic radical and substituted heterocyclic radical;
R2 is selected from O, S ,=NR 9,=NOR 10R 9, R 10Independently be selected from H, C 1～4Alkyl or cycloalkyl, phenyl;
Z is selected from H, NH, O, S ,=CH 2
Work as Z=NH, O, during S, R3 is selected from H, C 1～6Straight chain or branched alkyl; Cycloalkyl; Phenyl and substituted-phenyl; Heterocyclic radical and substituted heterocyclic radical;-COR 11, R wherein 11Be selected from C 1～4Alkyl, cycloalkyl, phenyl and substituted-phenyl.
Work as Z=CH 2The time, R3 is selected from phthalyl-2-base, succinyl-2-base, glycolylurea-3-base, R 12W[R 12Be selected from H, C 1～6Alkyl; Cycloalkyl; Phenyl and substituted-phenyl; Heterocyclic radical and substituted heterocyclic radical;-COR 13, R wherein 13Be selected from C 1～C 4Alkyl, cycloalkyl, phenyl and substituted-phenyl; W is selected from O, S, NH;
Y is selected from NH, O, S;
R4 is selected from H, C 1～6Straight chain or branched alkyl, cycloalkyl; Phenyl and substituted-phenyl; Benzyl and benzene alkyl;-COR 14, R wherein 14Be selected from C 1～C 4Alkyl, phenyl, the phenyl of benzene alkyl and replacement, benzene alkyl; Also can be selected from heterocyclic radical;
X is selected from OH, NHOH.
According to the compound of claim 1, it is characterized in that 2, described heterocyclic radical is selected from pyridyl, pyrryl, furyl, thienyl, pyranyl is sent the pyridine base, piperazinyl.
According to the compound of claim 1, it is characterized in that 3, described compound is
Wherein, R1 and R4 such as claim 1 definition.
According to the compound of claim 1, it is characterized in that 4, described compound is
Figure A031479330003C2
Wherein, R1 and R4 such as claim 1 definition.
According to the compound of claim 1, it is characterized in that 5, described compound is
Figure A031479330003C3
Wherein, R1 such as claim 1 definition.
According to the compound of claim 1, it is characterized in that 6, described compound is
Wherein, R1 such as claim 1 definition.
According to the compound of claim 1, it is characterized in that 7, described compound is
Figure A031479330003C5
Wherein, R1 and R4 such as claim 1 definition.
According to the compound of claim 1, it is characterized in that 8, described compound is
Figure A031479330004C1
Wherein, R1, R3 and R4 such as claim 1 definition.
According to the compound of claim 1, it is characterized in that 9, described compound is
Wherein, R1 such as claim 1 definition.
According to the compound of claim 1-9, it is characterized in that 10, described compound is selected from
2-(2-hydroxyethyl amido)-4-oxygen-4-(4 '-xenyl) butyric acid
2-benzene methanamine base-4-oxygen-4-(4 '-xenyl) butyric acid
2-n-butylamine-based-4-oxygen-4-(4 '-xenyl) butyric acid
2-n-octyl amine base-4-oxygen-4-(4 '-xenyl) butyric acid
2-(2-N, N '-dimethylamino ethyl amido)-4-oxygen-4-(4 '-xenyl) butyric acid
2-cyclohexyl amido-4-oxygen-4-(4 '-xenyl) butyric acid
2-cyclopropyl amido-4-oxygen-4-(4 '-xenyl) butyric acid
2-(3-phenyl propyl amido)-4-oxygen-4-(4 '-xenyl) butyric acid
2-(3-N, N '-dimethylamino-propyl amido)-4-oxygen-4-(4 '-xenyl) butyric acid
2-(4-hydroxyl butylamine base)-4-oxygen-4-(4 '-xenyl) butyric acid
2-(4-morpholinyl)-4-oxygen-4-(4 '-xenyl) butyric acid
2-(4-hydroxy-n-piperidyl)-4-oxygen-4-(4 '-xenyl) butyric acid
2-(2-hydroxyethyl amido)-4-oxygen-4-(4 '-Phenoxyphenyl) butyric acid
2-benzene methanamine base-4-oxygen-4-(4 '-Phenoxyphenyl) butyric acid
2-n-butylamine-based-4-oxygen-4-(4 '-Phenoxyphenyl) butyric acid
2-n-octyl amine base-4-oxygen-4-(4 '-Phenoxyphenyl) butyric acid
2-(2-N, N '-dimethylamino ethyl amido)-4-oxygen-4-(4 '-Phenoxyphenyl) butyric acid
2-cyclohexyl amido-4-oxygen-4-(4 '-Phenoxyphenyl) butyric acid
2-cyclopropyl amido-4-oxygen-4-(4 '-Phenoxyphenyl) butyric acid
2-(3-phenyl propyl amido)-4-oxygen-4-(4 '-Phenoxyphenyl) butyric acid
2-(3-N, N '-dimethylamino-propyl amido)-4-oxygen-4-(4 '-Phenoxyphenyl) butyric acid
2-(4-hydroxyl butylamine base)-4-oxygen-4-(4 '-Phenoxyphenyl) butyric acid
2-(4-morpholinyl)-4-oxygen-4-(4 '-Phenoxyphenyl) butyric acid
2-(4-piperidyl)-4-oxygen-4-(4 '-Phenoxyphenyl) butyric acid
2-(2-hydroxyethyl amido)-4-oxygen-4-(4 '-p-methoxy-phenyl) butyric acid
2-benzene methanamine base-4-oxygen-4-(4 '-p-methoxy-phenyl) butyric acid
2-n-butylamine-based-4-oxygen-4-(4 '-p-methoxy-phenyl) butyric acid
2-n-octyl amine base-4-oxygen-4-(4 '-p-methoxy-phenyl) butyric acid
2-(2-N, N '-dimethylamino ethyl amido)-4-oxygen-4-(4 '-p-methoxy-phenyl) butyric acid
2-cyclohexyl amido-4-oxygen-4-(4 '-p-methoxy-phenyl) butyric acid
2-cyclopropyl amido-4-oxygen-4-(4 '-p-methoxy-phenyl) butyric acid
2-(3-phenyl propyl amido)-4-oxygen-4-(4 '-p-methoxy-phenyl) butyric acid
2-(3-N, N '-dimethylamino-propyl amido)-4-oxygen-4-(4 '-p-methoxy-phenyl) butyric acid
2-(4-hydroxyl butylamine base)-4-oxygen-4-(4 '-p-methoxy-phenyl) butyric acid
2-(4-morpholinyl)-4-oxygen-4-(4 '-p-methoxy-phenyl) butyric acid
2-(2-hydroxyethyl sulfenyl)-4-oxygen-4-(4 '-xenyl) butyric acid
N-hydroxyl-2-(2-hydroxyethyl sulfenyl)-4-oxygen-4-(4 '-xenyl) butyramide
N-hydroxyl-2-[2-(N-succimide base) ethylmercapto group]-4-oxygen-4-(4 '-xenyl) butyramide
2-propyl group sulfenyl-4-oxygen-4-(4 '-xenyl) butyric acid
2-(2-hydroxyethyl sulfenyl)-2-methyl-4-oxygen-4-(4 '-xenyl) butyric acid
N-hydroxyl-2-(2 hydroxy ethylamine base)-4-oxygen-4-(4 '-xenyl) butyramide
N-hydroxyl-2-benzene methanamine base-4-oxygen-4-(4 '-xenyl) butyramide
N-hydroxyl-2-benzene methanamine base-4-oxygen-4-(4 '-p-methoxy-phenyl) butyramide
N-hydroxyl-2-n-octyl amine base-4-oxygen-4-(4 '-p-methoxy-phenyl) butyramide
N-hydroxyl-2-(2 hydroxy ethylamine base)-4-oxygen-4-(4 '-Phenoxyphenyl) butyramide
N-hydroxyl-2-benzene methanamine base-4-oxygen-4-(4 '-Phenoxyphenyl) butyramide
N-hydroxyl-2-(4-hydroxyl butylamine base)-4-oxygen-4-(4 '-Phenoxyphenyl) butyramide
2-(4-morpholinyl)-4-oxygen-4-[4 '-(4 "-chlorine) xenyl] butyric acid
2-(2-hydroxyethyl amido)-4-oxygen-4-[4 '-(4 "-chlorine) xenyl] butyric acid
2-(4-methylbenzene sulfenyl)-4-oxygen-4-(4 '-xenyl) butyric acid
2-(2-amido ethylamino-)-4-oxygen-4-(4 '-Phenoxyphenyl) butyric acid
N-hydroxyl-2-(4-hydroxyl butylamine base)-4-oxygen-4-(4 '-xenyl) butyramide
N-hydroxyl-2-(2 hydroxy ethylamine base)-4-oxygen-4-(4 '-p-methoxy-phenyl) butyramide
N-hydroxyl-2-hydroxyl-3-acetamido 4-oxygen-4-(4 '-xenyl) butyramide
N-hydroxyl-2-[2-(4-nitrophenoxy) ethylmercapto group]-4-oxygen-4-(4 '-xenyl) butyramide
2-(2-hydroxyethyl amido)-4-phenoxy group-3-(4 '-dibenzoyl base) butyric acid
2-benzene methanamine base-4-phenoxy group-3-(4 '-dibenzoyl base) butyric acid
2-n-octyl amine base-4-phenoxy group-3-(4 '-dibenzoyl base) butyric acid
2-(2-N, N '-dimethylamino ethyl amido)-4-phenoxy group-3-(4 '-dibenzoyl base) butyric acid
2-n-butylamine-based-4-phenoxy group-3-(4 '-dibenzoyl base) butyric acid
2-cyclohexylamino-4-phenoxy group-3-(4 '-dibenzoyl base) butyric acid
2-(2-hydroxyethyl amido)-4-(4-toluene sulfenyl)-3-(4 '-dibenzoyl base) butyric acid
2-benzene methanamine base-4-(4-toluene sulfenyl)-3-(4 '-dibenzoyl base) butyric acid
2-(2-N, N '-dimethylamino ethyl amido)-4-(4-toluene sulfenyl)-3-(4 '-dibenzoyl base) butyric acid
2-n-octyl amine base-4-(4-toluene sulfenyl)-3-(4 '-dibenzoyl base) butyric acid
4-(4-xenyl)-2-(2-hydroxyethyl sulfenyl)-4-hydroxyl imido grpup butyric acid
4-(4-xenyl)-2-(2-rosickyite base)-4-hydroxyl imido grpup butyric acid
4-(4-xenyl)-2-(4-methylbenzene sulfenyl)-4-hydroxyl imido grpup butyric acid
11, a kind of method for preparing compound described in the claim 1 and intermediate thereof is characterized in that, is selected from following method
Method 1:(A) with Friedel-Crafts reaction gained α, the unsaturated γ aryl of β batanone acid cis-trans mixture and various primary amine or mercaptan carry out the Michael addition in appropriate solvent, obtain corresponding adduct;
Method 2:(A) 2-substituted amido-4-oxygen-4-(4 '-substituted-phenyl) butyric acid is made 2-substituted amido-4-oxygen-4-(4 '-substituted-phenyl) butyric ester hydrochloride with thionyl chloride in alcohol under proper temperature;
(B) resulting ester hydrochloride generates corresponding hydroximic acid with oxammonium hydrochloride and alkali reaction in alcohol;
Method 3:(A) 2-(2-hydroxyethyl sulfydryl)-4-oxygen-4-(4 '-substituted-phenyl) butyric acid and methyl iodide or methyl-sulfate and salt of wormwood reaction are made corresponding methyl esters;
(B) Mitsunobu reaction, under the effect of triphenyl phosphorus and diethyl azodiformate or azoformic acid two Bian esters or diisopropyl azodiformate, 2-(2-hydroxyethyl sulfydryl)-4-oxygen-4-(4 '-substituted-phenyl) methyl-butyrate and succimide or phthalic imidine or fortified phenol reaction are generated corresponding product 2-[2-(2-succimide base) ethyl sulfydryl]-4-oxygen-4-(4 '-substituted-phenyl) methyl-butyrate or 2-[2-(2-phthalimide-based) ethyl sulfydryl]-4-oxygen-4-(4 '-substituted-phenyl) methyl-butyrate or 2-[2-(4 "-nitro-phenoxy) the ethyl sulfydryl]-4-oxygen-4-(4 '-substituted-phenyl) methyl-butyrate;
(C) above-mentioned gained methyl-butyrate is generated corresponding hydroximic acid with oxammonium hydrochloride and alkali reaction in methyl alcohol;
Method 4:(A) in alkaline alcohol solution, with mercaptoethanol and trans-α methyl-α, the unsaturated γ aryl of β batanone acid carries out addition, makes corresponding adduct;
Method 5:(A) in alcohol, the Mannich condensation takes place in substituted acetophenone and oxoethanoic acid monohydrate and all kinds of amine, generates corresponding M annich condensation product;
Method 6:(A) 3-(4 '-substituted benzoyl)-3-butenoic acid is carried out the bromine addition, make 3,4-dibromo 3-(4 '-substituted benzoyl) butyric acid;
(B) to gained 3, the butyro-hydroxyl protection of 4-two bromo-3-(4 '-substituted benzoyl) makes 3,4-two bromo-3-(4 '-substituted benzoyl) butanoic acid derivatives;
(C) with gained 3, β takes place 4-two bromo-3-(4 '-substituted benzoyl) butyric esters eliminates generation 4-bromo-3-(4 '-substituted benzoyl)-2-butylene acid derivative;
(D) gained 4-bromo-3-(4 '-substituted benzoyl)-2-butylene acid derivative and R3H reaction are made corresponding 4-replacement-3-(4 '-substituted benzoyl)-2-butylene acid derivative;
(E) (D) gained is replaced the crotonate deprotection and become corresponding acid;
(F) addition is carried out in gained 4-replacement-3-(4 '-substituted benzoyl)-2-butylene acid and corresponding primary amines, preparation 2-substituted amido-4-replacement-3-(4 '-substituted benzoyl)-2-butyric acid;
Method 7:
(A) 2-hydroxyl-3-acetamido-butyro-carboxylic acid hydroxyl of 4-oxygen-4-(4 '-substituted-phenyl) is methylated;
(B) with the described method of method 2 (B) 2-hydroxyl-3-acetamido-4-oxygen-4-(4 '-substituted-phenyl) methyl-butyrate is made corresponding hydroximic acid;
Method 8:
(A) 2-thioether replacement-4-(4 '-xenyl)-4 oxy butyrate and oxammonium hydrochloride and alkali are reacted product 2-thioether replacement-4-(4 '-xenyl)-4-hydroxyl imido grpup butyric acid of making the condensation of 4-azanol in alcoholic solution.
12, a kind of pharmaceutical composition is characterized in that, contain effective dose as the described arbitrary compound of claim 1-10, and acceptable carrier on the pharmacodynamics.
According to the pharmaceutical composition of claim 12, it is characterized in that 13, described pharmaceutical composition can be tablet, capsule, pill, injection, sustained release preparation, controlled release preparation and various particulate delivery system.
14, as the application of the arbitrary compound of claim 1-10 in preparation treatment osteoarthrosis inflammation and tumour medicine.
CN 03147933 2003-06-27 2003-06-27 Alpha position heteroatom substituted gamma aryl ketobutyric acid derivative, process, pharmaceutical combination and uses thereof Pending CN1566065A (en)

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CN105061314A (en) * 2010-12-15 2015-11-18 施万生物制药研发Ip有限责任公司 Neprilysin inhibitors
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WO2007082264A3 (en) * 2006-01-11 2007-12-21 Bristol Myers Squibb Co Human glucagon-like-peptide-1 modulators and their use in the treatment of diabetes and related conditions
CN101503373B (en) * 2009-03-13 2013-07-24 山东大学 2-amino-1-(4-nitro phenyl)-1-ethanol metalloid protease inhibitor, and preparation and use thereof
CN102574801A (en) * 2009-05-28 2012-07-11 诺瓦提斯公司 Substituted aminopropionic derivatives as neprilysin inhibitors
CN102574801B (en) * 2009-05-28 2016-04-27 诺华股份有限公司 As the alanine derivatives of the replacement of enkephalinase inhibitor
EP2521558A1 (en) * 2009-12-30 2012-11-14 Avon Products, Inc. Topical lightening composition and uses thereof
EP2521558A4 (en) * 2009-12-30 2013-07-03 Avon Prod Inc Topical lightening composition and uses thereof
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US9428464B2 (en) 2011-08-30 2016-08-30 Chdi Foundation, Inc. Kynurenine-3-monooxygenase inhibitors, pharmaceutical compositions, and methods of use thereof
US9981918B2 (en) 2011-08-30 2018-05-29 Chdi Foundation, Inc. Kynurenine-3-monooxygenase inhibitors, pharmaceutical compositions, and methods of use thereof
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