CN101402587B - Substituted acethydrazide derivatives, preparation method and application thereof - Google Patents
Substituted acethydrazide derivatives, preparation method and application thereof Download PDFInfo
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- CN101402587B CN101402587B CN2008101804866A CN200810180486A CN101402587B CN 101402587 B CN101402587 B CN 101402587B CN 2008101804866 A CN2008101804866 A CN 2008101804866A CN 200810180486 A CN200810180486 A CN 200810180486A CN 101402587 B CN101402587 B CN 101402587B
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- AWNFAJUMMQLMMT-NDZAJKAJSA-N CC(C)(C)c1ccc(CN(C)CCCN(C)CC(N/N=C/c(c(cccc2)c2cc2)c2O)=O)cc1 Chemical compound CC(C)(C)c1ccc(CN(C)CCCN(C)CC(N/N=C/c(c(cccc2)c2cc2)c2O)=O)cc1 AWNFAJUMMQLMMT-NDZAJKAJSA-N 0.000 description 1
- 0 CC(C)CC(C)(C)CN(C)CC(NN)=* Chemical compound CC(C)CC(C)(C)CN(C)CC(NN)=* 0.000 description 1
- GMBXYBQNCHBVSG-OVVQPSECSA-N CCN(CC)c1cc(O)c(/C=N/NC(CN(C)CCCN(C)Cc(cc2)ccc2OC)=O)cc1 Chemical compound CCN(CC)c1cc(O)c(/C=N/NC(CN(C)CCCN(C)Cc(cc2)ccc2OC)=O)cc1 GMBXYBQNCHBVSG-OVVQPSECSA-N 0.000 description 1
- PRSATUWOQZCFHK-UHFFFAOYSA-N CN(CCN(C)Cc(cc1)ccc1OC)CC(NN)=O Chemical compound CN(CCN(C)Cc(cc1)ccc1OC)CC(NN)=O PRSATUWOQZCFHK-UHFFFAOYSA-N 0.000 description 1
- BDUWVJQXEYQZGD-UZWMFBFFSA-N CN(CCN(C)Cc(cc1)ccc1OCc1ccccc1)CC(N/N=C/c1c(cccc2)c2ccc1O)=O Chemical compound CN(CCN(C)Cc(cc1)ccc1OCc1ccccc1)CC(N/N=C/c1c(cccc2)c2ccc1O)=O BDUWVJQXEYQZGD-UZWMFBFFSA-N 0.000 description 1
- XZJVKBFAGWAHGF-UHFFFAOYSA-N CN(CCN(C)Cc(cc1)ccc1OCc1ccccc1)CC(NN)=O Chemical compound CN(CCN(C)Cc(cc1)ccc1OCc1ccccc1)CC(NN)=O XZJVKBFAGWAHGF-UHFFFAOYSA-N 0.000 description 1
- ACYBVNYNIZTUIL-UHFFFAOYSA-N NCCNCc1ccccc1 Chemical compound NCCNCc1ccccc1 ACYBVNYNIZTUIL-UHFFFAOYSA-N 0.000 description 1
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C251/00—Compounds containing nitrogen atoms doubly-bound to a carbon skeleton
- C07C251/72—Hydrazones
- C07C251/86—Hydrazones having doubly-bound carbon atoms of hydrazone groups bound to carbon atoms of six-membered aromatic rings
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- C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
- C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
- C07D241/06—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having one or two double bonds between ring members or between ring members and non-ring members
- C07D241/08—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having one or two double bonds between ring members or between ring members and non-ring members with oxygen atoms directly attached to ring carbon atoms
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Abstract
The invention relates to an acethydrazide derivative having the function of inhibiting tumor cells and substituted by general formula I and a formula a-c compound as well as medicinal salt or a solvate, a preparation method for the compounds, a medicament composition containing the compounds, and application of the compounds for preparing medicament used for treating cancer.
Description
Technical field
The present invention relates to novel substituted acethydrazide derivatives that can activation procaspase-3, the preparation method of these compounds comprise the pharmaceutical composition of above-claimed cpd, and said compound is used to prepare the purposes of the medicine of treating cancer.
Technical background
Apoptosis claims that again (programmed cell death PCD) is a multicellular animals development and a homeostatic important and basic process in programmed cellization death.1972, three scientists such as kerr proposed apoptotic notion first: apoptosis (apoptosis) but be the cell removal mechanisms at work of the many processes of a kind of participation organism, by the cell of the gene programming regulation and control process of initiatively committing suiside.A common characteristic of cancer is exactly the apoptotic signal of opposing nature, and this resistivity is with the rise of some the key protein factors in the apoptotic process or reduce relevantly, and wherein caspase-3 is exactly the execution albumen of apoptosis.
The topmost substrate of Caspase-3 is poly (ADP-ribose) polysaccharase PARP, and PARP repairs with DNA, the monitoring of gene complete property is relevant, is the startup enzyme of apoptosis program.Caspase-3 is synthesized with the zymogen forms of non-activity, and through a safety catch---the 3-aspartic acid is kept this dormant state.Safety catch is arranged in the collar of a flexibility of big small subunit junction, interacts through polyion, forms salt bridge, and IETD175 protects with the hydrolysis site.Procaspase-3 in the normal cell can auto-activation become caspase-3 be depend on pH value in the born of the same parents [
17], after cell was accepted apoptotic signal, the pH value in the born of the same parents can be reduced to 6.8 by original 7.4, has destroyed the formation of salt bridge, thereby has exposed the hydrolysis site, carries out auto-activation.So can find that in most tumour cell the procaspase-3 level is very high, cell can not start automatic apoptosis system, and sick cell is finally built up into tumour.If can help procaspase-3 to change into activated apoptosis enzyme caspase-3 through extraneous strength, cell death inducing just can reach the purpose of treating cancer.Therefore, exploitation procaspase-3 acvator has a good application prospect.
Summary of the invention
The objective of the invention is to seek and develop directly to act on the also micromolecular compound of activation procaspase-3, reach inducing apoptosis of tumour cell, be used to treat cancer.The inventor has been found that the compound of structural formula a-c has the effect that suppresses tumour cell, and the inventor finds that also compound of Formula I has the effect that suppresses tumour cell, the present invention is based on above-mentioned discovery and is accomplished.
Summary of the invention:
First aspect present invention provides compound of Formula I,
Wherein:
N is 1 or 2;
Ar
1Be aromatic carbocyclic or aromatic heterocycle, it is optional to be selected from following substituting group list-or many-replacement: halogen, itrile group, trifluoromethyl, trifluoromethoxy, hydroxyl, nitro, carboxyalkyl, alkoxyl group, carbalkoxy, alkoxycarbonyl alkyl, alkoxy aromatic yl, carboxamide, carboxamido alkyl, alkyl, naphthenic base, alkylthio, alkyl sulphinyl, alkyl sulphonyl, sulfamyl, amidino groups, cyanic acid, amino, amido, alkylamino, dialkylamino, alkyl amino alkyl, allyl group, alkynyl;
Ar
2Be quilt-OR at the ortho position of its tie point
2Substituted aromatic carbocyclic of group or aromatic heterocycle, wherein said aromatic carbocyclic or aromatic heterocycle be optional to be selected from following substituting group list-or many-replacement: halogen, itrile group, trifluoromethyl, trifluoromethoxy, hydroxyl, nitro, carboxyalkyl, carbalkoxy, alkoxycarbonyl alkyl, carboxamide, carboxamido alkyl, alkyl, naphthenic base, alkylthio, alkyl sulphinyl, alkyl sulphonyl, sulfamyl, amidino groups, cyanic acid, amino, amido, alkylamino, dialkylamino, alkyl amino alkyl, allyl group, alkynyl;
A is O or S;
R
2And R
3Be selected from hydrogen, C independently of one another
1-C
6Alkyl group;
And pharmacologically acceptable salt and solvate.
According to the compound of first aspect present invention, wherein said aromatic carbocyclic is selected from: benzene, naphthalene, anthracene, phenanthrene, indenes, fluorenes, acenaphthene.
According to the compound of first aspect present invention, wherein said aromatic heterocycle is selected from: pyridine, pyrroles, furans, thiophene, pyrazoles, imidazoles, thiazole 、 oxazole 、 isoxazole, indoles, cumarone, benzoglyoxaline, carbazole, pyridazine, pyrimidine, pyrazine, quinoline, isoquinoline 99.9, purine, thiodiphenylamine 、 phenoxazine.
According to first aspect present invention compound, it is selected from:
(E)-N '-(3-allyl group-2-phenol methylene)-2-(N-(2-(N-benzyl-N-methylamino) ethyl) N-methylamino) acethydrazide;
(E)-N '-(3,5-di-t-butyl-2-phenol methylene)-2-(N-(2-(N-benzyl-N-methylamino) ethyl) N-methylamino) acethydrazide;
(E)-and N '-(4-N, N '-diethylamino-2-phenol methylene)-2-(N-(2-benzyl-N-methylamino) ethyl) N-methylamino) acethydrazide;
(E)-N '-(2-phenol methylene)-2-(N-(2-(N-benzyl-N-methylamino) ethyl) N-methylamino) acethydrazide;
(E)-N '-(3-allyl group-2-phenol methylene)-2-(N-(2-(N-(4-tertiary butyl benzyl)-N-methylamino) ethyl) N-methylamino) acethydrazide;
(E)-N '-(3,5-di-t-butyl-2-phenol methylene)-2-(N-(2-(N-(4-tertiary butyl benzyl)-N-methylamino) ethyl) N-methylamino) acethydrazide;
(E)-N '-(4-N, N '-diethylamino-2-phenol methylene)-2-(N-(2-(N-(4-tertiary butyl benzyl)-N-methylamino) ethyl) N-methylamino) acethydrazide;
(E)-N '-(2-hydroxyl-1-naphthyl methylene)-2-(N-(2-(N-(4-tertiary butyl benzyl)-N-methylamino) ethyl) N-methylamino) acethydrazide;
(E)-N '-(3,5-di-t-butyl-2-phenol methylene)-2-(N-(2-(N-(4-methoxy-benzyl)-N-methylamino) ethyl) N-methylamino) acethydrazide;
(E)-N '-(4-N, N '-diethylamino-2-phenol methylene)-2-(N-(2-(N-(4-methoxy-benzyl)-N-methylamino) ethyl) N-methylamino) acethydrazide;
(E)-N '-(2-hydroxyl-1-naphthyl methylene)-2-(N-(2-(N-(4-methoxy-benzyl)-N-methylamino) ethyl) N-methylamino) acethydrazide;
(E)-N '-(3,5-di-t-butyl-2-phenol methylene)-2-(N-(2-(N-(4-benzyloxy benzyl)-N-methylamino) ethyl) N-methylamino) acethydrazide;
(E)-N '-(4-N, N '-diethylamino-2-phenol methylene)-2-(N-(2-(N-(4-benzyloxy benzyl)-N-methylamino) ethyl) N-methylamino) acethydrazide;
(E)-N '-(3-allyl group-2-phenol methylene)-2-(N-(2-(N-(4-benzyloxy benzyl)-N-methylamino) ethyl) N-methylamino) acethydrazide;
(E)-N '-(2-hydroxyl-1-naphthyl methylene)-2-(N-(2-(N-(4-benzyloxy benzyl)-N-methylamino) ethyl) N-methylamino) acethydrazide;
(E)-N '-(3-allyl group-2-phenol methylene)-2-(N-(3-(N-benzyl-N-methylamino) propyl group) N-methylamino) acethydrazide;
(E)-N '-(3,5-di-t-butyl-2-phenol methylene)-2-(N-(3-(N-benzyl-N-methylamino) propyl group) N-methylamino) acethydrazide;
(E)-N '-(4-N, N '-diethylamino-2-phenol methylene)-2-(N-(3-(N-benzyl-N-methylamino) propyl group) N-methylamino) acethydrazide;
(E)-N '-(2-hydroxyl-1-naphthyl methylene)-2-(N-(3-(N-benzyl-N-methylamino) propyl group) N-methylamino) acethydrazide;
(E)-N '-(3-allyl group-2-phenol methylene)-2-(N-(3-(N-(4-tertiary butyl benzyl)-N-methylamino) propyl group) N-methylamino) acethydrazide;
(E)-N '-(3,5-di-t-butyl-2-phenol methylene)-2-(N-(3-(N-(4-tertiary butyl benzyl)-N-methylamino) propyl group) N-methylamino) acethydrazide;
(E)-N '-(4-N, N '-diethylamino-2-phenol methylene)-2-(N-(3-(N-(4-tertiary butyl benzyl)-N-methylamino) propyl group) N-methylamino) acethydrazide;
(E)-N '-(2-hydroxyl-1-naphthyl methylene)-2-(N-(3-(N-(4-tertiary butyl benzyl)-N-methylamino) propyl group) N-methylamino) acethydrazide;
(E)-N '-(3-allyl group-2-phenol methylene)-2-(N-(3-(N-(4-methoxy-benzyl)-N-methylamino) propyl group) N-methylamino) acethydrazide;
(E)-N '-(3,5-di-t-butyl-2-phenol methylene)-2-(N-(3-(N-(4-methoxy-benzyl)-N-methylamino) propyl group) N-methylamino) acethydrazide;
(E)-N '-(4-N, N '-diethylamino-2-hydroxyl-1-Ben Yajiaji)-2-(N-(3-(N-(4-methoxy-benzyl)-N-methylamino) propyl group) N-methylamino) acethydrazide;
(E)-N '-(2-hydroxyl-1-naphthyl methylene)-2-(N-(3-(N-(4-methoxy-benzyl)-N-methylamino) propyl group) N-methylamino) acethydrazide;
(E)-N '-(3-phenol methylene)-2-(N-(2-(N-benzyl-N-methylamino) ethyl) N-methylamino) acethydrazide;
(E)-N '-(2-phenol methylene)-2-(N-(2-(N-(4-tertiary butyl benzyl)-N-methylamino) ethyl) N-methylamino) acethydrazide;
(E)-N '-(3-phenol methylene)-2-(N-(2-(N-(4-tertiary butyl benzyl)-N-methylamino) ethyl) N-methylamino) acethydrazide;
N, N '-two (4-(benzyloxy) benzyl)-N, N '-dimethyl-ethylenediamine;
(E)-N '-(3,5-di-t-butyl Ben Yajiaji)-2-(4-benzyl-3-ketone-piperazinyl) acethydrazide; With
(E)-N '-(2-hydroxyl-1-naphthyl methylene)-2-(4-benzyl-3-ketone-piperazinyl) acethydrazide,
And pharmacologically acceptable salt and solvate.
Second aspect present invention provides the compound of formula a, b or c,
And pharmacologically acceptable salt and solvate.
Third aspect present invention provides the preparation method of the said compound of first aspect present invention, and this method may further comprise the steps:
1) make N, N '-dimethyl-ethylenediamine or N, N '-dimethylated propyl diethylenetriamine with have an Ar
1The compound of group part (such as but not limited to: reaction benzyl chloride), obtain formula 1 compound,
[the Ar in its Chinese style 1
1With the definition of n with the described general formula I of claim 1, this formula 1 compound preference is as being expressed as the compound of formula 1 ':
Wherein R group (down together) is optional suitable substituting group]
2) make formula 1 compound and halogenated acetic acids methyl esters or halo ethyl sulfonic acid methyl esters (such as but not limited to methyl chloroacetate or chloroethene methylmesylate) reaction, obtain formula 2 compounds,
[the Ar in its Chinese style 2
1, A and n definition with the described general formula I of claim 1, these formula 2 compound preferences are as being expressed as the compound of formula 2 ':
2 ']
3) make Hydrazine Hydrate 80 or replace hydrazine accordingly and formula 2 compounds carry out hydrazinolysis reaction, obtain formula 3 compounds,
[the Ar in its Chinese style 3
1, A and n definition with the described general formula I of claim 1, these formula 2 compound preferences are as being expressed as the compound of formula 3 ':
4) make formula 3 compounds and have Ar
2The compound of group part (such as but not limited to: corresponding bigcatkin willow aldehydes or aromatic ketone compounds) reaction, obtain compound of Formula I,
[each substituent definition is with the described general formula I of claim 1 in the formula, and this formula I compound preference is as being expressed as the compound of formula I ':
Fourth aspect present invention provides the preparation method of the said formula a compound of second aspect present invention, and this method may further comprise the steps:
1) makes 4-benzyloxy benzylalcohol and SOCl
2Reaction obtains formula 1a compound,
2) make N, N '-dimethyl-ethylenediamine and the reaction of formula 1a compound obtain formula a compound,
Fourth aspect present invention also provides the preparation method of said formula b of second aspect present invention and c compound, and this method may further comprise the steps:
1) make the reaction of quadrol and benzyl chloride obtain formula 1bc compound.
2) make formula 1 compound and formaldehyde carry out condensation reaction, obtain formula 2bc compound,
3) make the reaction of formula 2 compounds and methyl chloroacetate, obtain formula 3bc compound,
4) make Hydrazine Hydrate 80 or replace hydrazine accordingly and in solvent, reflux, add formula 3bc compound and carry out the hydrazinolysis reaction, obtain formula 4bc compound,
5) make formula 4 compounds and corresponding aldehydes or ketone compounds reaction, obtain the compound of formula b or c,
Fifth aspect present invention provides a kind of medicinal compsns, and it comprises each compound of first aspect present invention and second aspect, or its pharmacologically acceptable salt or solvate, and at least a pharmaceutically acceptable carrier, thinner or vehicle.
Sixth aspect present invention provide each compound of first aspect present invention and second aspect in preparation as the purposes in the medicine of tumour cell suppressor factor.
Seventh aspect present invention provides treatment or the prevention disease relevant with tumour or the method for illness, and this comprises each the compound of first aspect present invention and second aspect of object treatment that these needs are arranged or prevention significant quantity.
Detailed Description Of The Invention:
As be used for this paper's; Term " aromatic carbocyclic " has its general sense well known in the art; It forms the group part in compound of Formula I, and it generally includes but is not limited to: benzene, naphthalene, anthracene, phenanthrene, indenes, fluorenes, acenaphthene, it can be chosen wantonly by single and replace or repeatedly replace.
As be used for this paper's; Term " aromatic heterocycle " has its general sense well known in the art; It forms the group part in compound of Formula I; And it generally includes but is not limited to: pyridine, pyrroles, furans, thiophene, pyrazoles, imidazoles, thiazole, oxazole, isoxazole, indoles, cumarone, benzoglyoxaline, carbazole, pyridazine, pyrimidine, pyrazine, quinoline, isoquinoline 99.9, purine, thiodiphenylamine, phenoxazine, it can be chosen wantonly by single and replace or repeatedly replace.
As being used for this paper, term " alkyl group " has its general sense well known in the art, and generally include straight line or ramose chain-like alkyl, for example methyl, ethyl, propyl group, sec.-propyl, normal-butyl, sec.-butyl, the tertiary butyl etc.
As being used for this paper, the group of following term representative has general sense well known in the art: halogen, itrile group, trifluoromethyl, trifluoromethoxy, hydroxyl, nitro, carboxyalkyl, alkoxyl group, carbalkoxy, alkoxycarbonyl alkyl, alkoxy aromatic yl, carboxamide, carboxamido alkyl, alkyl, naphthenic base, alkylthio, alkyl sulphinyl, alkyl sulphonyl, sulfamyl, amidino groups, cyanic acid, amino, amido, alkylamino, dialkylamino, alkyl amino alkyl, allyl group, alkynyl.
According to the present invention; Above-mentioned compound of Formula I or its pharmacologically acceptable salt or solvate exemplary method below can using prepares; Wherein used midbody is exemplary; Other feasible midbody that is used for this reaction that the present invention does not enumerate also is fit to certainly, and this exemplary method may further comprise the steps:
1) with N, N '-dimethyl-ethylenediamine or N, N '-dimethylated propyl diethylenetriamine is dissolved in the THF, is heated to backflow, slowly drips benzyl chloride again, and wherein the mol ratio of benzyl chloride and amine is 1:6.The adularescent deposition generates gradually, uses the TLC monitoring reaction.After treating that benzyl chloride reacts completely, stop heating, the cooling back screws out solvent, uses the NaOH solution washing, CH
2Cl
2Extraction will guarantee pH>=12 in the extraction process.Merge organic layer, column chromatography for separation obtains formula 1 compound:
2) formula 1 compound, the NaHCO that step 1) are obtained
3Join in the acetone, reflux, drip methyl chloroacetate or chloroethene methylmesylate again.Reaction is used column chromatography purification after finishing, and obtains formula 2 compounds:
3) with ethanol as solvent; Add Hydrazine Hydrate 80 or replace hydrazine accordingly; Splash into formula 2 compounds that step 2 obtains after the backflow; The reaction of generation hydrazinolysis, production 3 compounds:
preference such as compound:
be the same general formula I of the definition of each group wherein.
4) with formula 3 compounds and corresponding bigcatkin willow aldehydes or aromatic ketone compounds reaction, obtain compound of Formula I:
Preference such as compound:
be the same general formula I of the definition of each group wherein.
According to the present invention, said structure formula a or its pharmacologically acceptable salt or solvate exemplary method below can using prepares, and this exemplary method may further comprise the steps:
1) 4-benzyloxy benzylalcohol is dissolved among the THF, places dry three-necked bottle, the entire reaction device is a sealed state, is vented on the stink cupboard with direct-cooled pipe in addition, adds SOCl again
2Stirring at room when raw material point disappears, adds water and finishes reaction.Ethyl acetate extraction merges organic layer, dried overnight.Concentrate and obtain formula 1a compound.
2) with N, N '-dimethyl-ethylenediamine is dissolved in the THF, is heated to backflow, drips 4-benzyloxy benzyl chloride again, wherein benzyl chloride and N, and the mol ratio of N '-dimethyl-ethylenediamine is 2:1.The adularescent deposition generates gradually, uses the TLC monitoring reaction.After treating that 4-benzyloxy benzyl chloride reacts completely, stop heating, the cooling back screws out solvent, uses the NaOH solution washing, CH
2Cl
2Extraction will guarantee pH>=12 in the extraction process.Merge organic layer, column chromatography for separation obtains formula a compound.
According to the present invention, said structure formula b and c or its pharmacologically acceptable salt or solvate exemplary method below can using prepares, and this exemplary method may further comprise the steps:
1) quadrol is dissolved among the THF, after mixing, is heated to little boiling, slowly splash into benzyl chloride, use the TLC monitoring reaction.After treating that benzyl chloride reacts completely, stop heating, the cooling back screws out solvent, uses the NaOH solution washing, CH
2Cl
2Extraction will guarantee pH>=12 in the extraction process.Merge organic layer, column chromatography for separation obtains formula 1bc compound.
2) formula 1 compound is dissolved in methyl alcohol,, obtains formula 2bc compound, can directly cast single step reaction with formaldehyde generation condensation reaction.
3) with step 2) the formula 2bc compound, the NaHCO that obtain
3Join in the acetone, reflux, drip methyl chloroacetate again.Reaction is used column chromatography purification after finishing, and obtains formula 3bc compound.
4) with ethanol as solvent, add Hydrazine Hydrate 80 or replace hydrazine accordingly, splash into the formula 3bc compound that step 3) obtains after the backflow, the hydrazinolysis reaction takes place, production 4bc compound.
5), obtain the compound of structural formula b or c with formula 4bc compound and corresponding aldehydes or ketone compounds reaction.
It will be appreciated by those skilled in the art that The compounds of this invention also can use with the form of its pharmacologically acceptable salt or solvate.Acceptable salt comprises the salt of the routine that is formed by pharmaceutically acceptable mineral acid or organic acid or mineral alkali or organic bases and the acid salt of quaternary ammonium on the physiology of the compound of compound of Formula I and structural formula a-c.The example more specifically of suitable hydrochlorate comprises hydrochloric acid, Hydrogen bromide, sulfuric acid, phosphoric acid, nitric acid, perchloric acid, fumaric acid, acetate, propionic acid, succsinic acid, oxyacetic acid, formic acid, lactic acid, toxilic acid, tartrate, Hydrocerol A, pounces on the salt of acid, propanedioic acid, hydroxymaleic acid, toluylic acid, L-glutamic acid, phenylformic acid, Whitfield's ointment, fumaric acid, toluenesulphonic acids, methylsulfonic acid, naphthalene-2-sulfonic acid, Phenylsulfonic acid, hydroxynaphthoic acid, hydroiodic acid HI, oxysuccinic acid, steroic, tannic acid etc.Other acid like oxalic acid, though itself be not pharmaceutically acceptable, can be used to prepare the salt as midbody, to obtain The compounds of this invention and pharmacologically acceptable salt thereof.The example more specifically of suitable alkali salt comprises sodium, lithium, potassium, magnesium, aluminium, calcium, zinc, N, N '-dibenzyl-ethylenediamin, chloro PROCAINE HCL, PHARMA GRADE, choline, diethylolamine, quadrol, N-NMG and procaine salt.When after this relating to compound of the present invention, comprise compound and pharmacologically acceptable salt and the solvate of compound of Formula I and structural formula a-c.
The present invention also comprises the prodrug of The compounds of this invention, and this prodrug promptly carries out chemical conversion through metabolic process once administration, becomes afterwards to have active medicine.Usually, this type prodrug is the functional derivatives of The compounds of this invention, and it changes into required formula I compound and the compound of structural formula a-c in vivo easily.For example, at " Design Of Prodrugs ", H Bund Saard, Elsevier edits, and has described in 1985 and has selected and the ordinary method of the suitable prodrug derivant of preparation.
The present invention also comprises the active metabolite of The compounds of this invention.
Another aspect of the present invention relates to pharmaceutical composition, and it contains raceme or the optically active isomer and at least a pharmaceutically acceptable carrier of The compounds of this invention, and it can be used for interior therapeutic and has biocompatibility.Said pharmaceutical composition can be prepared into various forms according to different way of administration.The mentioned compound of the present invention also can be prepared to various pharmacologically acceptable salts.
Pharmaceutical composition of the present invention comprises the compound of Formula I of the present invention of effective dose and compound or pharmaceutically acceptable salt thereof or the hydrate and one or more suitable pharmaceutically acceptable carrier of structural formula a-c.The pharmaceutical carrier here includes but not limited to: ionite, aluminum oxide, StAl, Yelkin TTS, serum proteins such as rHSA, buffer substance such as phosphoric acid salt; Glycerine, Sorbic Acid, POTASSIUM SORBATE GRANULAR WHITE, the partial glycerol ester mixture of saturated vegetable fatty acid, water; Salt or ionogen, like protamine sulfate, Sodium phosphate, dibasic, potassium hydrogen phosphate, sodium-chlor; Zinc salt, colloidal silica, Magnesium Trisilicate, Vinylpyrrolidone polymer, cellulosic material; Polyoxyethylene glycol, Xylo-Mucine, polyacrylic ester, beeswax, yolk.
The pharmaceutical composition of The compounds of this invention can be used with following any-mode: oral, spraying sucks, rectal application; Nasal cavity applied medicine; The cheek medication, local application, non-enterally administer; As in subcutaneous, vein, intramuscular, intraperitoneal, the sheath, in the ventricle, in the breastbone and intracranial injection or input, or by the medication of a kind of outer planting reservoir.Wherein preferred oral, intraperitoneal or intravenous administration mode.
When medicine for oral use, The compounds of this invention can be made into oral acceptable dosage form arbitrarily, includes but not limited to tablet, capsule, the aqueous solution or aqeous suspension.Wherein, the carrier that tablet uses generally comprises lactose and W-Gum, also can add lubricant such as Magnesium Stearate in addition.The thinner that capsule preparations uses generally comprises lactose and dried corn starch.Aqueous suspension preparation then normally mixes use with activeconstituents with examples of suitable emulsifiers and suspension agent.If desired, also can add some sweeting agents, perfume compound or tinting material in the above oral prepns form.
During the Where topical medication; Particularly treat local external application easy to reach and suffer from face or organ; During like eyes, skin or lower intestinal tract nervous system disease, can The compounds of this invention be processed different local application's dosage forms, specify as follows according to different trouble faces or organ:
When the eye topical application, The compounds of this invention can be mixed with the dosage form of a kind of micronization suspension-s or solution, and the carrier that uses is the Sterile Saline of isoosmotic certain pH, wherein can add also not adding preservative agent such as zephiran chloride alkoxide.For eye usefulness, also can compound be processed paste form such as vaseline paste.
When topical application, The compounds of this invention can be made into suitable ointment, lotion or creme dosage form, wherein activeconstituents is suspended or is dissolved in one or more carriers.The spendable carrier of ointment formulation includes but not limited to: MO, Albolene, white vaseline, Ucar 35, polyoxyethylene, polyoxytrimethylene, emulsifying wax and water; The spendable carrier of lotion or creme includes but not limited to: MO, and sorbitan monostearate, polysorbate60, the n-Hexadecane ester type waxes, cetene is fragrant and mellow, 2-Standamul G, benzyl alcohol and water.
The all right aseptic injection preparation form medication of The compounds of this invention comprises aseptic injection water or oil suspension or aseptic injectable solution.Wherein, spendable carrier and solvent comprise water, Ringer's solution and isotonic sodium chlorrde solution.In addition, the fixed oil of sterilization also can be used as solvent or suspension medium, like direactive glyceride or two glyceryl ester.
It may be noted that in addition; The using dosage of The compounds of this invention and method of use depend on many factors, comprise activity intensity, Time of Administration, metabolic rate, the severity of illness and diagnosis and treatment doctor's the subjective judgement of patient's age, body weight, sex, natural health situation, nutritional status, compound.Preferred using dosage is between 0.01~100mg/kg body weight/day, and wherein optimal dosage is in the 5mg/kg-10mg/kg body weight/day.
Embodiment
The present invention further specifies with following midbody and embodiment, and these midbodys and embodiment are not construed as limiting the invention.
Melting point compound is measured by YRT-3 type fusing point appearance, and temperature is not calibrated.
1H-NMR spectrum is measured by Bruker ARX 400 type nuclear magnetic resonance spectrometers.The FAB mass spectrum is measured by Zabspect high resolution magnetic mass spectrometer.
The preparation of midbody
Midbody 1
Be equipped with in the 250mL three-necked bottle of TM, constant pressure funnel, reflux condensation mode one, add THF100mL, N; N '-dimethyl-ethylenediamine 16mL (0.6mol) after mixing, is heated to little boiling; Begin 10g benzyl chloride (0.1mol) is slowly splashed into; The control rate of addition, the adularescent deposition generates gradually, uses the TLC monitoring reaction.After treating that benzyl chloride reacts completely, stop heating, the cooling back screws out solvent, uses the NaOH solution washing, CH
2Cl
2Extraction will guarantee pH>=12 in the extraction process.Merge organic layer, column chromatography for separation obtains the weak yellow liquid of midbody 1, yield 90%.
1H-NMR(400MHz,CDCl
3)δ?ppm:7.31(1H,m),7.30(2H,m),7.30(2H,m),3.49(2H,s),2.67(2H,t,J=5.60,6.16Hz),2.53(2H,t,J=6.16,5.60Hz),2.40(3H,s),2.18(3H,s);MS[M]
+=179.5m/e。
Midbody 2
In the 100mL flask, add 3.56g midbody 1 (0.02mol) and 2.1g NaHCO
3(0.025mol) join in the 40mL acetone, reflux, drip 2.367g methyl chloroacetate (0.022mol) again.After reaction finishes,, get the weak yellow liquid of midbody 2, yield 85% with column chromatography purification (eluent system is an ethyl acetate/petroleum ether).
1H-NMR(400MHz,CDCl
3)δ?ppm:7.31(1H,m),7.27(2H,m),7.30(2H,m),3.69(3H,s),3.51(2H,s),3.32(2H,s),2.68(2H,t,J=5.60,6.16Hz),2.54(2H,t,J=6.16,5.60Hz),2.36(3H,s),2.22(3H,s);MS[M]
+=250.2m/e。
Midbody 3
In the 250mL three-necked bottle, add the Hydrazine Hydrate 80 (0.06mol) of 2.1g85%, the 50mL absolute ethyl alcohol is heated to backflow, slow then Dropwise 5 .0g midbody 2 (0.02mol).After reaction finishes, reaction solution is concentrated rear pillar separate (eluent: CH
2Cl
2/ methyl alcohol/ammoniacal liquor system), get white solid product 4.35g, yield 86.7%.MS[M]
+=250.1m/e。
Midbody 4
With the 4 tert butylbenzyl chloride is raw material, and operation is with midbody 1.Get the weak yellow liquid product.MS[M]
+=234.2m/e。
Midbody 5
With midbody 4 is raw material, and operation is with midbody 2.Get the weak yellow liquid product.MS[M]
+=306.2m/e。
Midbody 6
With midbody 5 is raw material, and operation is with midbody 3.Get the weak yellow liquid product.MS[M]
+=306.2m/e。
Midbody 7
To be raw material to the methoxyl group benzyl chloride, operation is with midbody 1.Get the weak yellow liquid product.MS[M]
+=208.2m/e。
Midbody 8
With midbody 7 is raw material, and operation is with midbody 2.Get the weak yellow liquid product.MS[M]
+=280.1m/e。
Midbody 9
With midbody 8 is raw material, and operation is with midbody 3.Get the weak yellow liquid product.MS[M]
+=280.1m/e。
Midbody 10
The 4-benzyloxy benzylalcohol of 500mg is dissolved among the 6mL THF, places the dry three-necked bottle of 50mL, the entire reaction device is a sealed state, is vented on the stink cupboard with direct-cooled pipe in addition, adds 0.5mL SOCl again
2Stirring at room when raw material point disappears, adds water and finishes reaction.The 5mL*3 ethyl acetate extraction merges organic layer, uses anhydrous Na
2SO
4Dried overnight.Concentrate and obtain 450mg white solid product midbody 10.
1H-NMR(400MHz,CDCl
3)δ?ppm:7.38(H,m),7.19(2H,m),6.91(2H,m),5.20(2H,s),3.45(2H,s);MS[M]
+=232.0m/e。
Midbody 11
With midbody 10 is raw material, and operation is with midbody 1.Get the weak yellow liquid product.MS[M]
+=284.2m/e。
Midbody 12
With midbody 11 is raw material, and operation is with midbody 2.Get the weak yellow liquid product.MS[M]
+=356.2m/e。
Midbody 13
With midbody 12 is raw material, and operation is with midbody 3.Get the yellow liquid product.MS[M]
+=356.2m/e。
Midbody 14
With benzyl chloride and N, N '-dimethylated propyl diethylenetriamine is a raw material, and operation is with midbody 1.Get the weak yellow liquid product.MS[M]
+=192.1m/e。
Midbody 15
With midbody 14 is raw material, and operation is with midbody 2.Get the yellow liquid product.MS[M]
+=264.2m/e。
Midbody 16
With midbody 15 is raw material, and operation is with midbody 3.Get the yellow liquid product.MS[M]
+=264.2m/e。
Midbody 17
With 4 tert butylbenzyl chloride and N, N '-dimethylated propyl diethylenetriamine is a raw material, and operation is with midbody 1.Get the weak yellow liquid product.MS[M]
+=248.2m/e。
Midbody 18
With midbody 17 is raw material, and operation is with midbody 2.Get the weak yellow liquid product.MS[M]
+=320.2m/e。
Midbody 19
With midbody 18 is raw material, and operation is with midbody 3.Get the weak yellow liquid product.MS[M]
+=320.2m/e
Midbody 20
With to methoxyl group benzyl chloride and N, N '-dimethylated propyl diethylenetriamine is a raw material, and operation is with midbody 1.Get the weak yellow liquid product.MS[M]
+=208.2m/e。
Midbody 21
With midbody 20 is raw material, and operation is with midbody 2.Get the weak yellow liquid product.MS[M]
+=294.2m/e。
Midbody 22
With midbody 21 is raw material, and operation is with midbody 3.Get the weak yellow liquid product.MS[M]
+=294.2m/e。
Midbody 23
Be equipped with in the 250mL three-necked bottle of TM, constant pressure funnel, reflux condensation mode one, add THF100mL, quadrol 32mL (0.6mol); After mixing, be heated to little boiling, begin 10g benzyl chloride (0.1mol) is slowly splashed into; Control rate of addition, reaction solution become muddy gradually, use the TLC monitoring reaction.After treating that benzyl chloride reacts completely, stop heating, the cooling back screws out solvent, uses the NaOH solution washing, CH
2Cl
2Extraction will guarantee pH>=12 in the extraction process.Merge organic layer, column chromatography for separation obtains weak yellow liquid.
Midbody 24
In the dry flask of 200mL, add 4.5g (0.03mol) midbody 1,100mL methyl alcohol, stirring at room, adding specification again is the formaldehyde 2.5g (0.03mol) of 35-40%, still room temperature reaction is used the TLC monitoring reaction.Raw material reaction is complete, stopped reaction.Screw out solvent, obtain the 4.8g weak yellow liquid, yield almost 100% can directly be cast single step reaction.
1H-NMR(400MHz,CDCl
3)δ?ppm:7.33(5H,m),3.65(2H,d),3.50(2H,d),3.10(1H,t),2.91(1H,t),2.76(1H,t),2.67(1H,t),2.28(1H,s).
Midbody 25
In the 100mL three-necked bottle, add 3.24g midbody 2 (0.02mol) and 2.1gNaHCO
3(0.025mol) join in the 40mL methyl alcohol, reflux, drip 2.36g methyl chloroacetate (0.022mol) again.After reaction finishes,, get weak yellow liquid, yield 34% with column chromatography purification (eluent system is an ethyl acetate/petroleum ether).
1H-NMR(400MHz,CDCl
3)δ?ppm:7.32(5H,m),3.74(3H,s),3.72(2H,s),3.54(2H,s),3.45(2H,s),2.99(2H,t,J=6.44,13.2Hz),2.54(2H,brm);MS[M]
+:234.14m/e。
Midbody 26
The Hydrazine Hydrate 80 (6mmol) that in the 100mL three-necked bottle, adds 210mg85%, the 10mL absolute ethyl alcohol, temperature of reaction is reduced to below-0 ℃, slow then Dropwise 5 00mg midbody 3 (2mmol), rate of addition is slow as far as possible.After reaction finishes, reaction solution is concentrated rear pillar separate (eluent: CH
2Cl
2/ methyl alcohol/ammoniacal liquor system), obtain weak yellow liquid, yield is 27%.MS[M]
+:263.1m/e。
Embodiment
Embodiment 1: (E)-N '-(3-allyl group-2-phenol methylene)-2-(N-(2-(N-benzyl-N-methylamino) ethyl) N-methylamino) acethydrazide;
500mg (0.2mmol) midbody 3 is dissolved in the 10mL absolute ethyl alcohol, adds 3-allyl group salicylic aldehyde 380mg (0.24mmol), 2 hours rear center bodies 3 of refluxing and stirring react completely stopped reaction.The concentration of reaction solution rear pillar separates (eluent: methylene chloride/ammoniacal liquor system), get white solid, use ethyl alcohol recrystallization again, obtain white crystal.
1H-NMR(400MHz,CDCl
3)δ?ppm:11.68(1H,s),11.62(1H,s),7.90(1H,s),7.31(1H,m),7.27(2H,m),7.30(2H,m),6.01(1H,m),5.04(2H,m),3.47(2H,m),3.69(3H,s),3.51(2H,s),3.32(2H,s),2.68(2H,t,J=5.60,6.16Hz),2.54(2H,t,J=6.16,5.60Hz),2.36(3H,s),2.22(3H,s);FAB-MS(m/z):395.2[M+H]
+。
Embodiment 2: (E)-N '-(3,5-di-t-butyl-2-phenol methylene)-2-(N-(2-(N-benzyl-N-methylamino) ethyl) N-methylamino) acethydrazide;
With midbody 3 and 3, the 5-di-tert-butyl salicylaldehyde is a raw material, and operation is with embodiment 1.Get the white solid product.
1H-NMR(400MHz,CDCl
3)δ?ppm:11.68(1H,s),11.62(1H,s),7.90(1H,s),7.31(1H,m),7.27(2H,m),7.30(2H,m),7.31(1H,m),6.74(1H,m),3.58(2H,s),3.21(2H,s),2.59(2H,t,J=5.50,6.16Hz),2.47(2H,t,J=5.50,6.16Hz),2.57(3H,s),2.31(3H,s),1.27(9H,s),1.25(9H,s);FAB-MS(m/z):523.3[M+H]
+。
Embodiment 3: (E)-N '-(4-N, N '-diethylamino-2-phenol methylene)-2-(N-(2-(N-benzyl-N-methylamino) ethyl) N-methylamino) acethydrazide;
With midbody 3 and 4-N, N '-diethylamino salicylic aldehyde is a raw material, and operation is with embodiment 1.Get the white solid product.
1H-NMR(400MHz,CDCl
3)δ?ppm:11.30(1H,s),11.24(1H,s),7.38(1H,s),7.37(1H,m),7.33(4H,m),6.57(1H,m),6.12(1H,m),6.19(1H,m),3.34(4H,m),3.35(2H,s),3.23(2H,s),2.59(2H,t,J=5.50,6.16Hz),2.49(2H,t,J=5.50,6.16Hz),2.34(3H,s),2.19(3H,s),1.16(6H,m);FAB-MS(m/z):426.3[M+H]
+。
Embodiment 4: (E)-N '-(2-phenol methylene)-2-(N-(2-(N-benzyl-N-methylamino) ethyl) N-methylamino) acethydrazide;
Is raw material with midbody 3 with salicylic aldehyde, and operation is with embodiment 1.Get the white solid product.
1H-NMR(400MHz,CDCl
3)δ?ppm:11.68(1H,s),11.23(1H,s),7.64(1H,s),7.38(5H,m),7.24(1H,m),6.95(1H,m),6.80(1H,m),6.72(1H,m),3.59(2H,s),3.27(2H,s),2.62(2H,brm),2.52(2H,brm),2.39(3H,s),2.20(3H,s);MS(m/z):354.0[M]
+。
Embodiment 5: (E)-N '-(2-hydroxyl-1-naphthyl methylene)-2-(N-(2-(N-(4-tertiary butyl benzyl)-N-methylamino) ethyl) N-methylamino) acethydrazide;
Is raw material with midbody 3 with 2-hydroxyl-1 naphthaldehyde, and operation is with embodiment 1.Get the faint yellow solid product.
1H-NMR(400MHz,CDCl
3)δ?ppm:12.65(1H,s),12.12(1H,s),8.81(1H,s),7.37(2H,m),7.73(2H,m),7.35(1H,m),7.28(4H,m),7.21(1H,m),3.62(2H,s),3.33(2H,s),2.68(2H,t,J=5.50,6.16Hz),2.54(2H,t,J=5.50,6.16Hz),2.41(3H,s),1.14(3H,s);FAB-MS(m/z):460.3[M+H]
+。
Embodiment 6: (E)-N '-(3-allyl group-2-phenol methylene)-2-(N-(2-(N-(4-tertiary butyl benzyl)-N-methylamino) ethyl) N-methylamino) acethydrazide;
Is raw material with midbody 6 with 3-allyl group salicylic aldehyde, and operation is with embodiment 1.Get white solid phase prod.
1H-NMR(400MHz,CDCl
3)δ?ppm:11.84(1H,s),11.50(1H,s),7.56(1H,s),7.39(2H,m),7.33(2H,m),7.12(1H,m),6.71(1H,m),6.49(1H,m),6.01(1H,m),5.04(2H,m),3.47(2H,m),3.54(2H,s),3.28(2H,s),2.64(2H,t,J=5.50,6.16Hz),2.52(2H,t,J=5.50,6.16Hz),2.41(3H,s),2.16(3H,s),1.31(9H,s);FAB-MS(m/z):451.3[M+H]
+。
Embodiment 7: (E)-N '-(3,5-di-t-butyl-2-phenol methylene)-2-(N-(2-(N-(4-tertiary butyl benzyl)-N-methylamino) ethyl) N-methylamino) acethydrazide;
With midbody 6 and 3, the 5-di-tert-butyl salicylaldehyde is a raw material, and operation is with embodiment 1.Get the white solid product.
1H-NMR(400MHz,CDCl
3)δ?ppm:11.68(1H,s),11.62(1H,s),7.90(1H,s),7.38(1H,m),7.36(1H,m),7.33(2H,m),7.31(1H,m),6.74(1H,m),3.58(2H,s),3.21(2H,s),2.59(2H,t,J=5.50,6.16Hz),2.47(2H,t,J=5.50,6.16Hz),2.57(3H,s),2.31(3H,s),1.43(9H,s),1.27(9H,s),1.25(9H,s);FAB-MS(m/z):523.3[M+H]
+。
Embodiment 8: (E)-N '-(4-N, N '-diethylamino-2-phenol methylene)-2-(N-(2-(N-(4-tertiary butyl benzyl)-N-methylamino) ethyl) N-methylamino) acethydrazide;
With midbody 6 and 4-N, N '-diethylamino salicylic aldehyde is a raw material, and operation is with embodiment 1.Get the white solid product.
1H-NMR(400MHz,CDCl
3)δ?ppm:11.44(1H,s),11.23(1H,s),7.59(1H,s),7.35(4H,m),6.52(1H,m),6.19(1H,m),6.07(1H,m),3.54(2H,s),3.24(2H,s),3.34(4H,m),2.58(2H,t,J=5.50,6.16Hz),2.48(2H,t,J=5.50,6.16Hz),2.36(3H,s),2.17(3H,s),1.31(9H,s),1.15(6H,m);FAB-MS(m/z):482.3[M+H]
+。
Embodiment 9: (E)-N '-(3,5-di-t-butyl-2-phenol methylene)-2-(N-(2-(N-(4-methoxy-benzyl)-N-methylamino) ethyl) N-methylamino) acethydrazide;
With midbody 9 and 3, the 5-di-tert-butyl salicylaldehyde is a raw material, and operation is with embodiment 1.Get the white solid product.
1H-NMR(400MHz,CDCl
3)δ?ppm:11.72(1H,s),11.62(1H,s),7.59(1H,s),7.32(1H,m),7.31(1H,m),7.29(1H,m),6.90(2H,m),6.55(1H,m),3.70(3H,s)3.51(2H,s),3.27(2H,s),2.64(2H,t,J=5.50,6.16Hz),2.51(2H,t,J=5.50,6.16Hz),2.42(3H,s),2.18(3H,s),1.42(9H,s),1.29(9H,s);FAB-MS(m/z):497.3[M+H]
+。
Embodiment 10: (E)-N '-(4-N, N '-diethylamino-2-phenol methylene)-2-(N-(2-(N-(4-methoxy-benzyl)-N-methylamino) ethyl) N-methylamino) acethydrazide;
With midbody 9 and 4-N, N '-diethylamino salicylic aldehyde is a raw material, and operation is with embodiment 1.Get the light yellow crystal product.
1H-NMR(400MHz,CDCl
3)δ?ppm:11.34(1H,s),11.25(1H,s),7.59(1H,s),7.29(2H,m),7.26(1H,m),6.89(1H,m),6.59(1H,m),6.19(1H,m),6.14(1H,m),3.51(2H,s),3.22(2H,s),3.37(3H,s),3.34(4H,m),2.58(2H,t,J=5.50,6.16Hz),2.48(2H,t,J=5.50,6.16Hz),2.35(3H,s),2.18(3H,s),1.15(6H,m);FAB-MS(m/z):456.2[M+H]
+。
Embodiment 11: (E)-N '-(2-hydroxyl-1-naphthyl methylene)-2-(N-(2-(N-(4-methoxy-benzyl)-N-methylamino) ethyl) N-methylamino) acethydrazide;
Is raw material with midbody 9 with 2-hydroxyl-1 naphthaldehyde, and operation is with embodiment 1.Get the white solid product.
1H-NMR(400MHz,CDCl
3)δ?ppm:12.73(1H,s),12.17(1H,s),8.69(1H,s),7.35(4H,m),7.73(1H,m),7.21(1H,m),7.18(1H,m),7.14(1H,m),6.83(2H,m),3.61(3H,s),3.56(2H,s),3.33(2H,s),2.69(2H,t,J=5.50,6.16Hz),2.53(2H,t,J=5.50,6.16Hz),2.47(3H,s),2.24(3H,s);FAB-MS(m/z):460.3[M+H]
+。
Embodiment 12: (E)-N '-(3,5-di-t-butyl-2-phenol methylene)-2-(N-(2-(N-(4-benzyloxy benzyl)-N-methylamino) ethyl) N-methylamino) acethydrazide;
With midbody 13 and 3, the 5-di-tert-butyl salicylaldehyde is a raw material, and operation is with embodiment 1.Get the white solid product.
1H-NMR(400MHz,CDCl
3)δ?ppm:11.72(1H,s),11.61(1H,s),7.65(1H,s),7.34(4H,m),7.31(3H,m),6.97(1H,m),6.95(2H,m),6.60(1H,m),4.95(2H,s)3.51(2H,s),3.27(2H,s),2.62(2H,t,J=5.50,6.16Hz),2.51(2H,t,J=5.50,6.16Hz),2.39(3H,s),2.20(3H,s),1.42(9H,s),1.25(9H,s);FAB-MS(m/z):573.3[M+H]
+。
Embodiment 13: (E)-N '-(3-allyl group-2-phenol methylene)-2-(N-(2-(N-(4-benzyloxy benzyl)-N-methylamino) ethyl) N-methylamino) acethydrazide;
Is raw material with midbody 13 with 3-allyl group salicylic aldehyde, and operation is with embodiment 1.Get the white crystal product.
1H-NMR(400MHz,CDCl
3)δ?ppm:11.71(1H,s),11.52(1H,s),7.60(1H,s),7.32(4H,m),7.21(4H,m),7.15(1H,m),6.96(1H,m),6.94(1H,m),6.75(1H,m),6.10(1H,m),5.05(2H,m),4.97(2H,s),3.51(2H,s),3.47(2H,m),3.26(2H,s),2.60(2H,t,J=5.50,6.16Hz),2.51(2H,t,J=5.50,6.16Hz),2.38(3H,s),2.18(3H,s);FAB-MS(m/z):501.2[M+H]
+。
Embodiment 14: (E)-N '-(2-hydroxyl-1-naphthyl methylene)-2-(N-(2-(N-(4-benzyloxy benzyl)-N-methylamino) ethyl) N-methylamino) acethydrazide;
Is raw material with midbody 13 with 2-hydroxyl-1-naphthalene first, and operation is with embodiment 1.Get the white solid product.
1H-NMR(400MHz,CDCl
3)δ?ppm:12.74(1H,s),12.20(1H,s),8.68(1H,s),7.32(4H,m),7.30(1H,m),7.21(6H,m),7.19(2H,m),6.97(2H,m),3.56(2H,s),3.33(2H,s),2.72(2H,t,J=5.50,6.16Hz),2.54(2H,t,J=5.50,6.16Hz),2.46(3H,s),2.26(3H,s);FAB-MS(m/z):510.1[M+H]
+。
Embodiment 15: N, N '-two (4-(benzyloxy) benzyl)-N, N '-dimethyl-ethylenediamine;
Be equipped with in the 150mL three-necked bottle of TM, constant pressure funnel, reflux condensation mode one, add THF 100mL, N; N '-dimethyl-ethylenediamine 2.4mL (0.02mol) after mixing, is heated to little boiling; Begin 10g midbody 10 (0.04mol) is slowly splashed into; The control rate of addition, the adularescent deposition generates gradually, uses the TLC monitoring reaction.After treating that benzyl chloride reacts completely, stop heating, the cooling back screws out solvent, uses the NaOH solution washing, CH
2Cl
2Extraction will guarantee pH>=12 in the extraction process.Merge organic layer, crystallization obtains white crystal, yield 90%.
1H-NMR(400MHz,CDCl
3)δ?ppm:7.37(10H,m),7.20(4H,m),6.91(4H,m),5.04(4H,s),3.44(4H,s),2.53(4H,s),2.19(6H,s);FAB-MS(m/z):481.1[M+H]
+。
Embodiment 16: (E)-N '-(3,5-di-t-butyl-2-phenol methylene)-3-(N-(2-(N-benzyl-N-methylamino) propyl group) N-methylamino) acethydrazide;
With midbody 16 and 3, the 5-di-tert-butyl salicylaldehyde is a raw material, and operation is with embodiment 1.Get the white solid product.
1H-NMR(400MHz,CDCl
3)δ?ppm:11.41(1H,s),10.29(1H,s),8.22(1H,s),7.35(2H,m),7.32(2H,m),7.30(1H,m)7.24(1H,m),6.92(1H,s),3.57(2H,s),3.21(2H,s),2.56(2H,t,J=6.72,6.76Hz),2.56(2H,t,J=6.72,6.76Hz),2.33(3H,s),2.27(3H,s),1.74(2H,m),1.43(9H,s),1.29(9H,s);MS(m/z):480.3[M]
+。
Embodiment 17: (E)-N '-(4-N, N '-diethylamino-2-phenol methylene)-3-(N-(2-(N-benzyl-N-methylamino) propyl group) N-methylamino) acethydrazide;
With midbody 16 and 4-N, N '-diethylamino salicylic aldehyde is a raw material, and operation is with embodiment 1.Get the faint yellow solid product.
1H-NMR(400MHz,CDCl
3)δppm:11.15(1H,s),10.20(1H,s),8.15(1H,s),7.32(4H,m),6.93(1H,d),6.18(2H,m),3.57(2H,br),3.37(4H,J=7.00,7.28,21.28Hz,dd),3.18(2H,s),2.54(2H,t,J=6.72,6.76Hz),2.51(2H,br),2.32(3H,s),2.27(3H,s),1.73(2H,m),1.18(6H,t,J=7.04,7.00Hz);FAB-MS(m/z):440.1[M+H]
+。
Embodiment 18: (E)-N '-(3-allyl group-2-phenol methylene)-3-(N-(2-(N-benzyl-N-methylamino) propyl group) N-methylamino) acethydrazide;
Is raw material with midbody 16 with 3-allyl group salicylic aldehyde, and operation is with embodiment 1.Get the weak yellow liquid product.
1H-NMR(400MHz,CDCl
3)δ?ppm:11.35(1H,s),10.41(1H,s),8.24(1H,s),7.30(7H,m),6.98(1H,m),6.82(1H,m),6.04(1H,m),5.07(2H,m),3.54(2H,br),3.46(2H,m),3.20(2H,s),2.51(2H,m),2.49(2H,brm),2.32(3H,s),2.26(3H,s),1.73(2H,m);FAB-MS(m/z):409.1[M+H]
+。
Embodiment 19: (E)-N '-(2-hydroxyl-1-naphthyl methylene)-3-(N-(2-(N-benzyl-N-methylamino) propyl group) N-methylamino) acethydrazide;
Is raw material with midbody 22 with 3-isopropoxy propylamine, and operation is with embodiment 1.Get the faint yellow solid product.
1H-NMR(400MHz,CDCl
3)δ?ppm:12.50(1H,s),10.73(1H,s),9.28(1H,s),7.77(3H,m),7.45(1H,m),7.40(5H,m),7.21(2H,m),3.60(2H,s),3.27(2H,s),2.58(2H,t,J=6.72,6.76Hz),2.54(2H,br),2.37(3H,s),2.29(3H,s),1.78(2H,m);MS(m/z):418.0[M]
+。
Embodiment 20: (E)-N '-(3,5-di-t-butyl-2-phenol methylene)-3-(N-(2-(N-(4-tertiary butyl benzyl)-N-methylamino) propyl group) N-methylamino) acethydrazide;
With midbody 19 and 3, the 5-di-tert-butyl salicylaldehyde is a raw material, and operation is with embodiment 1.Get the faint yellow solid product.
1H-NMR(400MHz,CDCl
3)δ?ppm:11.43(1H,s),10.36(1H,s),8.26(1H,s),7.35(2H,m),7.34(2H,m),7.30(1H,m),6.95(1H,s),3.50(2H,s),3.22(2H,s),2.56(2H,t,J=6.72,6.76Hz),2.56(2H,t,J=6.72,6.76Hz),2.34(3H,s),2.26(3H,s),1.75(2H,br),1.43(9H,s),1.43(9H,s),1.29(9H,s);FAB-MS(m/z):537.4[M+H]
+。
Embodiment 21: (E)-N '-(3-allyl group-2-phenol methylene)-3-(N-(2-(N-(4-tertiary butyl benzyl)-N-methylamino) propyl group) N-methylamino) acethydrazide;
Is raw material with midbody 19 with 3-allyl group salicylic aldehyde, and operation is with embodiment 1.Get faint yellow oily product.
1H-NMR(400MHz,CDCl
3)δ?ppm:11.43(1H,s),8.29(1H,s),7.33(2H,m),7.27(2H,m),7.14(1H,m),6.97(1H,m),6.81(1H,m),6.02(1H,m),5.06(2H,m),3.58(2H,br),3.45(2H,m),3.27(2H,s),2.56(4H,m),2.34(3H,s),2.31(3H,s),1.78(2H,brm),1.26(9H,s);FAB-MS(m/z):465.1[M+H]
+。
Embodiment 22: (E)-N '-(2-hydroxyl-1-naphthyl methylene)-3-(N-(2-(N-(4-tertiary butyl benzyl)-N-methylamino) propyl group) N-methylamino) acethydrazide;
Is raw material with midbody 19 with 2-hydroxyl-1-naphthaldehyde, and operation is with embodiment 1.Get the faint yellow solid product.
1H-NMR(400MHz,CDCl
3)δ?ppm:12.52(1H,s),9.23(1H,s),7.75(3H,m),7.32(3H,m),7.30(2H,m),7.28(2H,m),3.53(2H,s),3.27(2H,s),2.58(2H,t,J=6.72,6.76Hz),2.54(2H,br),2.38(3H,s),2.26(3H,s),1.78(2H,m),1.18(9H,s);FAB-MS(m/z):475.0[M+H]
+。
Embodiment 23: (E)-N '-(4-N, N '-diethylamino-2-phenol methylene)-3-(N-(2-(N-(4-tertiary butyl benzyl)-N-methylamino) propyl group) N-methylamino) acethydrazide;
With midbody 19 and 4-N, N '-diethylamino salicylic aldehyde is a raw material, and operation is with embodiment 1.Getting faint yellow solid produces.
1H-NMR(400MHz,CDCl
3)δ?ppm:11.14(1H,s),10.20(1H,s),8.11(1H,s),7.30(2H,m),7.24(2H,m),6.88(1H,m),6.19(2H,m),3.49(2H,s),3.34(4H,m),3.17(2H,s),2.53(2H,t,J=6.72,6.76Hz),2.46(2H,br),2.33(3H,s),2.22(3H,s),1.75(2H,m),1.27(9H,s),1.17(6H,t,J=7.04,7.00Hz);FAB-MS(m/z):496.2[M+H]
+。
Embodiment 24: (E)-N '-(4-N, N '-diethylamino-2-phenol methylene)-3-(N-(2-(N-(4-methoxy-benzyl)-N-methylamino) propyl group) N-methylamino) acethydrazide;
With midbody 22 and 4-N, N '-diethylamino salicylic aldehyde is a raw material, and operation is with embodiment 1.Get the faint yellow solid product.
1H-NMR(400MHz,CDCl
3)δ?ppm:11.15(1H,s),10.25(1H,s),8.13(1H,s),7.22(2H,m),6.90(1H,d),6.83(1H,s),6.81(1H,s),6.18(3H,m),3.74(3H,s),3.47(2H,s),3.36(4H,J=7.00,7.28,21.28Hz,dd),3.17(2H,s),2.53(2H,t,J=6.72,6.76Hz),2.46(2H,br),2.32(3H,s),2.23(3H,s),1.72(2H,m),1.18(6H,t,J=7.04,7.00Hz);FAB-MS(m/z):470.1[M+H]
+。
Embodiment 25: (E)-N '-(2-hydroxyl-1-naphthyl methylene)-3-(N-(2-(N-(4-methoxy-benzyl)-N-methylamino) propyl group) N-methylamino) acethydrazide;
Is raw material with midbody 22 with 2-hydroxyl-1-naphthaldehyde, and operation is with embodiment 1.Get the faint yellow solid product.
1H-NMR(400MHz,CDCl
3)δ?ppm:12.48(1H,s),9.25(1H,s),7.78(3H,m),7.45(1H,m),7.33(1H,m),7.22(3H,m),6.80(1H,m),6.77(1H,m)3.65(3H,s),3.48(2H,s),3.25(2H,s),2.57(2H,t,J=6.72,6.76Hz),2.48(2H,brm),2.37(3H,s),2.25(3H,s),1.78(2H,m);FAB-MS(m/z):449.0[M+H]
+。
Embodiment 26: (E)-N '-(3,5-di-t-butyl-2-phenol methylene)-3-(N-(2-(N-(4-methoxy-benzyl)-N-methylamino) propyl group) N-methylamino) acethydrazide;
With midbody 22 and 3, the 5-di-tert-butyl salicylaldehyde is a raw material, and operation is with embodiment 1.Get the faint yellow solid product.
1H-NMR(400MHz,CDCl
3)δ?ppm:11.44(1H,s),10.39(1H,s),8.20(1H,s),7.35(1H,m),7.23(1H,br),7.21(1H,br),6.90(1H,br),6.82(1H,br),6.80(1H,br),3.68(3H,s),3.46(2H,s),3.21(2H,s),2.54(2H,t,J=6.72,6.76Hz),2.45(2H,brm),2.33(3H,s),2.23(3H,s),1.73(2H,m),1.43(9H,s),1.25(9H,s);FAB-MS(m/z):511.1[M+H]
+。
Embodiment 27: (E)-N '-(3-allyl group-2-phenol methylene)-3-(N-(2-(N-(4-methoxy-benzyl)-N-methylamino) propyl group) N-methylamino) acethydrazide;
Is raw material with midbody 22 with 3-allyl group salicylic aldehyde, and operation is with embodiment 1.Get faint yellow oily product.
1H-NMR(400MHz,CDCl
3)δ?ppm:11.37(1H,s),11.50(1H,s),8.21(1H,s),7.21(3H,m),6.95(1H,m),6.80(3H,m),6.03(1H,m),5.07(2H,m),3.69(3H,s),3.45(4H,m),3.20(3H,s),2.53(2H,t),2.46(2H,brm),2.32(3H,s),2.23(3H,s),1.73(2H,m);FAB-MS(m/z):439.2[M+H]
+。
Embodiment 28: (E)-N '-(2-phenol methylene)-2-(N-(2-(N-(4-tertiary butyl benzyl)-N-methylamino) ethyl) N-methylamino) acethydrazide;
Is raw material with midbody 6 with the 2-hydroxy benzaldehyde, and operation is with embodiment 1.Get the faint yellow solid product.
1H-NMR(400MHz,CDCl
3)δ?ppm:12.31(1H,s),11.63(1H,s),9.12(1H,s),7.54(2H,m),7.45(2H,m),7.33(1H,m),7.27(2H,m),6.95(1H,brm),6.88(1H,brm),4.30(2H,s),3.31(2H,s),3.07(2H,m),2.79(2H,m),2.87(3H,s),2.28(3H,s),1.28(9H,s);MS(m/z):410.0[M]
+。
Embodiment 29: (E)-N '-(3,5-di-t-butyl Ben Yajiaji)-2-(4-benzyl-3-ketone-piperazinyl) acethydrazide
147mg (0.5mmol) midbody 26 is dissolved in the 10mL absolute ethyl alcohol, adds 3,5-di-tert-butyl salicylaldehyde 176mg (0.75mmol), refluxing and stirring, midbody 26 reacts completely, stopped reaction.The evaporating column chromatographic separation (eluent: methylene chloride/ammoniacal liquor system), gray solid, use ethyl alcohol recrystallization, obtain white crystal 140, yield is 58%, m.p.229~232 ℃.
1H-NMR(400MHz,CDCl
3)δ?ppm:12.10(1H,s),11.62(1H,s),8.45(1H,s),7.35(2H,m),7.28(3H,m),7.17(2H,m),4.53(2H,s),3.28(4H,s),3.26(2H,m),2.78(2H,t,J=4.76,9.08Hz),1.38(3H,s),1.26(3H,s);FAB-MS(m/z):478.1[M+H]
+。
Embodiment 30: (E)-N '-(2-hydroxyl-1-naphthyl methylene)-2-(4-benzyl-3-ketone-piperazinyl) acethydrazide
Is raw material with midbody 26 with 2 hydroxy naphthalene formaldehyde, and operation is with embodiment 31.Obtain yellow crystals, yield is 75%, m.p.186~188 ℃.
1H-NMR(400MHz,CDCl
3)δ?ppm:12.67(1H,s),11.62(1H,s),9.41(1H,s),8.19(1H,m),7.90(2H,m),7.48(1H,m),7.36(4H,m),7.29(2H,m),7.19(2H,m),4.55(2H,s),3.32(2H,s),3.29(2H,m),2.82(2H,m);MS(m/z):416.0[M+H]
+。
The active available mtt assay that the present invention relates to the antitumor cell of compound detects, and is specific as follows:
Embodiment 31: the activity rating of compound antitumor cell of the present invention
1, get the HL60 cell of exponential phase of growth, counting, inoculating cell is in 96 well culture plates, and inoculum density is 3 * 10
3Individual/hole, 100 μ L/ holes, parallel 3 holes of each compound concentration.
2, behind the cell cultures 24h, give certain density compound, the compound effects time is 72h.
3, behind the 72h, every hole adds tetrazolium bromide (MTT) solution of 5mg/mL, and 37 ℃ are continued to hatch 4h.
4, every then hole adds the SDS of 100 μ L10%, hatches 24h for 37 ℃, and the bluish voilet crystallisate is fully dissolved.
5, select the wavelength of 570nm, on enzyme-linked immunosorbent assay instrument, measure each hole absorbance value, calculate and suppress percentage.Try to achieve the IC50 value of each compound according to suppressing percentage.
Active (the IC of the inhibition of part embodiment compound
50)
Embodiment number | IC 50(μM) | Embodiment number | IC 50(μM) |
3 | 0.27 | 17 | 0.64 |
5 | 0.28 | 19 | 0.84 |
6 | 0.73 | 20 | 1.23 |
7 | 0.82 | 21 | 0.99 |
8 | 0.25 | 22 | 0.28 |
9 | 0.91 | 23 | 0.26 |
10 | 0.30 | 24 | 0.46 |
11 | 0.56 | 25 | 0.71 |
12 | 1.11 | 26 | 0.54 |
13 | 0.73 | 28 | 0.38 |
14 | 0.26 | 29 | 2.08 |
15 | 1.66 | 30 | 1.09 |
16 | 0.85 |
Claims (5)
1. compound of Formula I,
Wherein:
N is 1 or 2;
Ar
1Be aromatic carbocyclic, it is chosen wantonly and is selected from following substituting group list-replacement: the tertiary butyl and alkoxyl group;
Ar
2Be quilt-OR at the ortho position of its tie point
2The substituted aromatic carbocyclic of group, wherein said aromatic carbocyclic is optional to be selected from following substituting group list-or many-replacement: the tertiary butyl, allyl group and dialkylamino;
A is O or S;
R
2And R
3Be selected from hydrogen independently of one another;
Described aromatic carbocyclic is selected from: benzene, naphthalene, anthracene, phenanthrene, indenes, fluorenes and acenaphthene;
And pharmacologically acceptable salt.
2. following compound or pharmaceutically acceptable salt thereof:
(E)-N '-(4-N, N '-diethylamino-2-phenol methylene)-2-(N-(2-(N-benzyl-N-methylamino) ethyl) N-methylamino) acethydrazide;
(E)-N '-(3-allyl group-2-phenol methylene)-2-(N-(2-(N-(4-tertiary butyl benzyl)-N-methylamino) ethyl) N-methylamino) acethydrazide;
(E)-N '-(3,5-di-t-butyl-2-phenol methylene)-2-(N-(2-(N-(4-tertiary butyl benzyl)-N-methylamino) ethyl) N-methylamino) acethydrazide;
(E)-N '-(4-N, N '-diethylamino-2-phenol methylene)-2-(N-(2-(N-(4-tertiary butyl benzyl)-N-methylamino) ethyl) N-methylamino) acethydrazide;
(E)-N '-(2-hydroxyl-1-naphthyl methylene)-2-(N-(2-(N-(4-tertiary butyl benzyl)-N-methylamino) ethyl) N-methylamino) acethydrazide;
(E)-N '-(3,5-di-t-butyl-2-phenol methylene)-2-(N-(2-(N-(4-methoxy-benzyl)-N-methylamino) ethyl) N-methylamino) acethydrazide;
(E)-N '-(4-N, N '-diethylamino-2-phenol methylene)-2-(N-(2-(N-(4-methoxy-benzyl)-N-methylamino) ethyl) N-methylamino) acethydrazide;
(E)-N '-(2-hydroxyl-1-naphthyl methylene)-2-(N-(2-(N-(4-methoxy-benzyl)-N-methylamino) ethyl) N-methylamino) acethydrazide;
(E)-N '-(3,5-di-t-butyl-2-phenol methylene)-2-(N-(2-(N-(4-benzyloxy benzyl)-N-methylamino) ethyl) N-methylamino) acethydrazide;
(E)-N '-(3-allyl group-2-phenol methylene)-2-(N-(2-(N-(4-benzyloxy benzyl)-N-methylamino) ethyl) N-methylamino) acethydrazide;
(E)-N '-(2-hydroxyl-1-naphthyl methylene)-2-(N-(2-(N-(4-benzyloxy benzyl)-N-methylamino) ethyl) N-methylamino) acethydrazide;
(E)-N '-(3,5-di-t-butyl-2-phenol methylene)-2-(N-(3-(N-benzyl-N-methylamino) propyl group) N-methylamino) acethydrazide;
(E)-N '-(4-N, N '-diethylamino-2-phenol methylene)-2-(N-(3-(N-benzyl-N-methylamino) propyl group) N-methylamino) acethydrazide;
(E)-N '-(2-hydroxyl-1-naphthyl methylene)-2-(N-(3-(N-benzyl-N-methylamino) propyl group) N-methylamino) acethydrazide;
(E)-N '-(3-allyl group-2-phenol methylene)-2-(N-(3-(N-(4-tertiary butyl benzyl)-N-methylamino) propyl group) N-methylamino) acethydrazide;
(E)-N '-(3,5-di-t-butyl-2-phenol methylene)-2-(N-(3-(N-(4-tertiary butyl benzyl)-N-methylamino) propyl group) N-methylamino) acethydrazide;
(E)-N '-(4-N, N '-diethylamino-2-phenol methylene)-2-(N-(3-(N-(4-tertiary butyl benzyl)-N-methylamino) propyl group) N-methylamino) acethydrazide;
(E)-N '-(2-hydroxyl-1-naphthyl methylene)-2-(N-(3-(N-(4-tertiary butyl benzyl)-N-methylamino) propyl group) N-methylamino) acethydrazide;
(E)-N '-(3,5-di-t-butyl-2-phenol methylene)-2-(N-(3-(N-(4-methoxy-benzyl)-N-methylamino) propyl group) N-methylamino) acethydrazide;
(E)-N '-(4-N, N '-diethylamino-2-hydroxyl-1-Ben Yajiaji)-2-(N-(3-(N-(4-methoxy-benzyl)-N-methylamino) propyl group) N-methylamino) acethydrazide;
(E)-N '-(2-hydroxyl-1-naphthyl methylene)-2-(N-(3-(N-(4-methoxy-benzyl)-N-methylamino) propyl group) N-methylamino) acethydrazide; With
(E)-N '-(2-phenol methylene)-2-(N-(2-(N-(4-tertiary butyl benzyl)-N-methylamino) ethyl) N-methylamino) acethydrazide.
3. the preparation method of each said compound of claim 1 to 2, this method may further comprise the steps:
1) make N, N '-dimethyl-ethylenediamine or N, N '-dimethylated propyl diethylenetriamine with have an Ar
1The compound reaction of group part obtains formula 1 compound,
Ar in its Chinese style 1
1With the definition of n with the described general formula I of claim 1, perhaps with each compound in the claim 2;
2) make the reaction of formula 1 compound and halogenated acetic acids methyl esters or halo ethyl sulfonic acid methyl esters, obtain formula 2 compounds,
Ar in its Chinese style 2
1, A and n definition with the described general formula I of claim 1, perhaps with each compound in the claim 2;
3) make Hydrazine Hydrate 80 or replace hydrazine accordingly and formula 2 compounds carry out hydrazinolysis reaction, obtain formula 3 compounds,
Ar in its Chinese style 3
1, A and n definition with the described general formula I of claim 1, perhaps with each compound in the claim 2;
4) make formula 3 compounds and have Ar
2The compound reaction of group part obtains compound of Formula I,
Each substituent definition is with the described general formula I of claim 1, perhaps with each compound in the claim 2 in the formula.
4. medicinal compsns, it comprises each compound of claim 1 to 2, or its pharmacologically acceptable salt, and at least a pharmaceutically acceptable carrier, thinner or vehicle.
Claim 1 to 2 each compound the preparation as the purposes in the medicine of tumour cell suppressor factor.
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US4239526A (en) * | 1979-09-04 | 1980-12-16 | W. R. Grace & Co. | Substituted ureas as sugarcane ripeners |
CN1145075A (en) * | 1994-03-28 | 1997-03-12 | 贾帕特有限公司 | Antagonist's of endothelin receptors |
CN1863764A (en) * | 2003-10-09 | 2006-11-15 | 默克专利股份公司 | Acylhydrazone derivatives and their use in the inhibition, regulation and/or modulation of the signal transduction of kinases |
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US4239526A (en) * | 1979-09-04 | 1980-12-16 | W. R. Grace & Co. | Substituted ureas as sugarcane ripeners |
CN1145075A (en) * | 1994-03-28 | 1997-03-12 | 贾帕特有限公司 | Antagonist's of endothelin receptors |
CN1863764A (en) * | 2003-10-09 | 2006-11-15 | 默克专利股份公司 | Acylhydrazone derivatives and their use in the inhibition, regulation and/or modulation of the signal transduction of kinases |
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CN105218399B (en) * | 2014-05-30 | 2018-02-09 | 中国人民解放军军事医学科学院毒物药物研究所 | A kind of substituted acethydrazide derivatives, preparation method and the usage |
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