CN106957242A - A kind of schiff base compounds and preparation method thereof and pharmaceutical applications - Google Patents

A kind of schiff base compounds and preparation method thereof and pharmaceutical applications Download PDF

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CN106957242A
CN106957242A CN201710269487.7A CN201710269487A CN106957242A CN 106957242 A CN106957242 A CN 106957242A CN 201710269487 A CN201710269487 A CN 201710269487A CN 106957242 A CN106957242 A CN 106957242A
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alkyl
phenyl
base
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radicals
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师健友
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Sichuan Provincial Peoples Hospital
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Sichuan Provincial Peoples Hospital
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C249/00—Preparation of compounds containing nitrogen atoms doubly-bound to a carbon skeleton
    • C07C249/02—Preparation of compounds containing nitrogen atoms doubly-bound to a carbon skeleton of compounds containing imino groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C241/00—Preparation of compounds containing chains of nitrogen atoms singly-bound to each other, e.g. hydrazines, triazanes
    • C07C241/04—Preparation of hydrazides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
    • C07C303/36—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of amides of sulfonic acids
    • C07C303/38—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of amides of sulfonic acids by reaction of ammonia or amines with sulfonic acids, or with esters, anhydrides, or halides thereof
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
    • C07C303/36—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of amides of sulfonic acids
    • C07C303/40—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of amides of sulfonic acids by reactions not involving the formation of sulfonamide groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C67/00—Preparation of carboxylic acid esters
    • C07C67/08—Preparation of carboxylic acid esters by reacting carboxylic acids or symmetrical anhydrides with the hydroxy or O-metal group of organic compounds

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Abstract

The invention discloses a kind of schiff base compounds and preparation method with structural formula shown in Formulas I, and compound of formula I or the acceptable salt of its biology are prepared to the application of medicine as active component.The schiff base compound of the present invention is applied in the medicine for the treatment of tumor disease, good for the growth of suppression tumour cell.

Description

A kind of schiff base compounds and preparation method thereof and pharmaceutical applications
Technical field
The present invention relates to a kind of schiff base compounds and its preparation method and application, the compound can apply to prepare The medicine of tumor disease is treated, more particularly to a kind of schiff base compounds are as active component for treating tumor disease Medicine, belongs to biomedicine technical field.Schiff bases, also referred to as schiff bases, schiff base, Schiff 's base, are primarily referred to as containing imines Or a class organic compound of azomethine characteristic group.
Background technology
Modern society's life rhythm is fast, and people's routine work pressure is big, is chronically at sub-health state.Autoimmunity Deficiency, causes various exogenous germ invasions and endogenic abnormal growth of cells ratio persistently to increase, seriously threatens the mankind Life.
The mankind are increasingly turned to organic chemical synthesis for the research of medicine since 20th century, and wherein micromolecular compound is with it The features such as unique stereoeffect, electronics distribution, spatial arrangement of active group, given play in various disease treatments Prominent effect.
Schiff base compounds it can be related with tumor disease in organism by the polar bond and atom in structure Enzyme and acceptor occur hydrogen bond action.On the other hand, aromatic rings in the structure enzyme related to tumor disease and acceptor form virtue Ring stacking is acted on.So as to reach the purpose for the treatment of tumor disease.
The content of the invention
Object of the present invention is to provide a kind of schiff base compounds with Formulas I structure, while the present invention is also carried The method for having supplied to prepare the compound.
In order to realize foregoing invention purpose, the invention provides following technical scheme：
A kind of schiff base compounds with Formulas I structure,
Wherein, R1, R2It is independently selected from：Hydrogen, hydroxyl, halogen, phenyl, benzyl, aryl alkyl, C3-C7 cycloalkyl, Cycloheteroalkylalkyl, oxazolyl, thiazolyl, substituted thiazolyl, piperidyl, hexahydro piperidyl, pyridine radicals, dihydropyridine base, tetrahydrochysene Pyridine radicals, thiazinyl, pyrrole radicals, imidazole radicals, pyrazolyl, pyrimidine radicals, pyrazinyl, piperazinyl, morpholinyl, furyl, pyranose, Pyridine radicals, triazol radical, naphthyl, quinolyl, isoquinolyl, purine radicals, 2H purine radicals and optional by M1Substituent group Above-mentioned group, the M1It is monosubstituted or polysubstituted when substituent group above-mentioned group, you can thinking monosubstituted can also be It is polysubstituted.Particularly, M is worked as1It is same by M when the above-mentioned group of substituent group is disubstituted1Connected on the group of substituent group Two M1Group is separate or is interconnected to form loop configuration.When by M1The above-mentioned group of substituent group has ring When structure, the disubstituted loop configuration further formed and by M1Original ring structure of substituent group constitutes condensed ring.
The aryl alkyl is：The C1-C4 of aryl substitution alkylidene, such as phenyl-ethylene, phenylpropylene, phenyl (methyl) ethylidene, phenyl (ethyl) ethylidene.
In the cycloheteroalkylalkyl heterocyclic radical be furyl, it is pyrrole radicals, thienyl, oxazolyls, imidazole radicals, pyrazolyl, phonetic One in piperidinyl, pyrazinyl, piperazinyl, morpholinyl, pyranose, the alkyl in the cycloheteroalkylalkyl is C1-C4 alkyl, Such as methyl, ethyl, propyl group, isopropyl, butyl, isobutyl group.
The M1Group is selected from：Hydrogen, fluorine, chlorine, bromine, iodine, nitro, amino, hydroxyl, C1-C12 alkyl, C1-C12 alkoxies, Halo C1-C12 alkyl, C2-C12 alkenyls, the C1-C12 alkyl of hydroxyl substitution, (two-C1-C12 alkyl aminos)-C1-C12 alkane Base, C1-C12 alkyl aminos, C3-C7 cycloalkyl aminos, two (C1-C12 alkyl) amino, amino C1-C12 alkyl, amino C1- C12 alkoxies, C1-C12 alkoxy carbonyls, C1-C12 alkyl aminos, two (C1-C12 alkoxy -C 1-C12 alkyl) amino, ammonia Base carbonyl, C1-C12 alkyl amino-carbonyls, two (C1-C12 alkyl) amino carbonyls, C3-C12 cycloalkyl amino carbonyls, C3-C12 Cycloalkyloxy, hydroxyl C1-C12 alkoxies, halo C1-C12 alkoxies, C1-C12 alkyl sulfone, C2-12 alkenyls sulfone, C3-C7 cycloalkanes Base sulfone, C3-C7 cycloalkyl, halo C3-C7 cycloalkyl, heterocyclic oxy group, piperidyl amino, N- methyl piperidine -4- carbonyls, piperazine - C1-C12 alkyl, pyrrolylcarbonyl amido, N- methyl piperidines formamido or heterocycle C1-C12 alkyl oxies etc..It is multiple when existing M1When group replaces to above-mentioned R1 and R2, each M1It is separate between group.
M=0 or 1,
X is imino group, substituted imido, carbonyl, thiocarbonyl, sulfonyl, sulfinyl, alkyl, alkoxy, carbonyl ammonia Base, amino carbonyl etc..
N=0 or 1,
Y is carbonyl, thiocarbonyl, sulfonyl, sulfinyl, C1-12 alkyl, C1-12 substituted hydrocarbon radicals, carbonylamino, ammonia Base carbonyl etc..
P=0 or 1,
Z is oxygen, sulphur, C1-12 alkyl, C1-12 substitutions alkyl, C1-C12 alkoxies, C3-C7 cycloalkyl, C3-C7 substitution rings Alkyl, C2-12 alkenyls, C2-12 substituted alkenyls, C2-12 alkynyls, imino group, substituted imido, C1-C12 alkoxy carbonyls, C1- C12 alkyl-carbonyls, amino carbonyl.
Further, R1, R2It is independently selected from：Hydrogen, hydroxyl, fluorine, chlorine, bromine, iodine, phenyl, aminomethyl phenyl, ethylphenyl, Propyl group phenyl, isopropyl phenyl, halogen substituted-phenyl, 3,5-dimethylphenyl, Methylethyl phenyl, diethyl phenyl, trimethylphenyl, Triethyl group phenyl, benzyl, phenylmethylene, phenyl-ethylene, phenylpropylene, phenyl butylidene, cyclohexyl, hydroxy cyclohexylphenyl Base, dihydroxy butylcyclohexyl, methylcyclohexyl, phenyl methyl, phenylethyl, hydroxyphenylmethyl, hydroxypropiophenone, oxazole Base, thiazolyl, piperidyl, hexahydro piperidyl, pyridine radicals, hydroxy-pyridyl, picolyl, dihydropyridine base, tetrahydropyridine Base, thiazinyl, pyrrole radicals, imidazole radicals, pyrazolyl, pyrimidine radicals, pyrazinyl, piperazinyl, morpholinyl, furyl, pyranose, pyridine Base, triazol radical, naphthyl, quinolyl, isoquinolyl, purine radicals, 2H purine radicals, C1-C10 low alkyl group, cyclopropyl, methoxy Base, ethyoxyl, propoxyl group, isobutyl group epoxide, vinyl, acrylic.
Further, R1, R2It is independently selected from：Substituent M2Substituted aromatic ring yl or heterocyclic radical, substituent M2There is one Or it is multiple；Substituent M2Selected from hydrogen, hydroxyl, carboxyl, fluorine, chlorine, bromine, iodine, methyl, ethyl, propyl group, isopropyl, butyl, isobutyl Base, new butyl, halogen substitution C1-C4 alkyl, cyano group, C1-C4 alkoxy carbonyls；Aromatic ring be selected from phenyl ring, naphthalene nucleus, anthracene nucleus, pyrrole ring, Piperidine ring, thiphene ring, pyridine ring, oxazole ring, thiazole ring, pyrimidine ring, pyrazine ring.
Further, R1, R2 are independently selected from：Phenyl, hydroxy phenyl, dihydroxy phenyl, hydroxy pyrimidine base, dihydroxy Pyrimidine radicals, pyridine radicals, hydroxy-pyridyl, dihydroxy-pyridine base, thiazolyl, hydroxyl thiazolyl, dihydroxy thiazole, cyclohexyl, hydroxyl Butylcyclohexyl, dihydroxy butylcyclohexyl, piperazinyl, hydroxyl piperazinyl, dihydroxy piperazinyl, pyrrole radicals, hydroxypyrrolyl, dihydroxy Pyrrole radicals, oxazolyls, dihydroxy oxazolyl, aminomethyl phenyl, hydroxyl (methyl) phenyl, anthryl, tetrahydrochysene piperazinyl, hydroxyl (methyl) Cyclohexyl.
Further, during m=1, X is imino group, substituted imido, carbonyl, thiocarbonyl, sulfonyl, sulfinyl, hydrocarbon Base, alkoxy, carbonylamino, amino carbonyl etc., X preferably is imino group.
Further, during n=1, Y is carbonyl, thiocarbonyl, sulfonyl, sulfinyl, C1-12 alkyl, C1-12 substitution hydrocarbon Base, carbonylamino, amino carbonyl etc., Y preferably is carbonyl.
Further, during p=1, Z is oxygen, sulphur, C1-12 alkyl, C1-12 substitutions alkyl, C1-C12 alkoxies, C3-C7 cycloalkanes Base, C3-C7 substituted cycloalkyls, C2-12 alkenyls, C2-12 substituted alkenyls, C2-12 alkynyls, imino group, substituted imido, C1-C12 Alkoxy carbonyl, C1-C12 alkyl-carbonyls, amino carbonyl.It is preferred that, p=0.
Wherein represent that corresponding X, Y, Z group are not present when m, n, p are 0, adjacent group is connected directly between Together.
Further, R1It is selected from
2- hydroxy phenyls, 2,4- dihydroxy phenyls, p-hydroxybenzene, 3,4- dihydroxy phenyls, 3,5- dihydroxy phenyls, 5- Hydroxyl -3- pyridine radicals, 5,6- dihydroxy -3- pyridine radicals, 2,5- dihydroxy -3- pyridine radicals, 4,5- dihydroxy -3- pyridine radicals, 2- Hydroxyl -4- thiazolyls, 2,5- dihydroxy -4- thiazolyls, phenyl, cyclohexyl, 3,5- dihydroxy-cyclohexyl, 3- hydroxy-cyclohexans One in base, 1- piperazinyls, 3- pyrrole radicals, 2- naphthyls, 4- morpholinyls, 4- isoxazolyls.
Further, R2It is selected from
2- fluoro-phenyls, 4- tert-butyl-phenyls, 4- isopropyl-phenyls, phenyl, 2- pyridine radicals, m- (trifluoromethyl) phenyl, 4- cvano-phenyls, 2- hydroxyls -3- (methoxycarbonyl)-phenyl, the trifluoromethyl-phenyls of 3,5- bis-, 2- hydroxyl -4- carboxyl phenyls, P-methylphenyl, 4- fluoro-phenyls, the chloro- phenyl of 4-, 2,6- dibromo phenyls, 3- aminomethyl phenyls, 1- piperazinyls, cyclohexyl, 3- pyrroles One in base, 2- naphthyls, 4- morpholinyls, 4- isoxazolyls, phenyl, cyclohexyl.
Further, for more specifically, schiff base compounds of the present invention are one of following compounds：
The present invention additionally provides the method for preparing above-mentioned Formulas I schiff base compounds simultaneously.
A kind of method for synthesizing above-mentioned schiff base compounds, comprises the following steps：
Compound formula I (wherein m=0, n=0, p=0) can the route shown in flow 1 synthesize, with commercially available substituted benzene Amine and substituted benzaldehyde are raw material, using methanol as reaction dissolvent, add a small amount of dilute HCl and are stirred at reflux reaction generation.
Flow 1
R2In addition to being chosen as both the above substituent, 3,5-OH, 2,4,6-OH are further selected from.For the specific of R1 and R2 Group includes above-mentioned 1a, 1b, 1c, 1d, 1e, but is not limited to these group/compounds, can also be other people in the art Member is readily appreciated that the compound for expecting being synthesized using the flow 1.Special compound and R1, R2 in scheme 2 below -4 Restriction is identical with above-mentioned situation, includes but is not limited to these specific chemical compositions.For the conjunction of the restriction in claims Situation into technique/flow should make same understanding, be not construed as limiting, can not be defined in flow specific compound.
Compound formula I (wherein m=1, n=1, p=0, X are-NH-, and Y is carbonyl) can be closed route as shown in flow 2 Into, by raw material of commercially available heterocyclic acids through esterification, hydrazinolysis, then generated with substituted benzoyl aldehyde reaction.
Flow 2
Compound formula I (wherein m=1, n=1, p=1, X are-NH-, and Y is carbonyl, and Z is methylene) can be by flow 3 Shown route synthesis, by raw material of commercially available heterocyclic acids through esterification, hydrazinolysis, then generated with substituted benzoyl aldehyde reaction.
Flow 3
Compound formula I (wherein m=1, n=1, p=0, X are-NH-, Y is sulfonyl) can as shown in flow 4 route Synthesis, passes through by raw material of commercially available heterocyclic sulfonyl chloride and is reacted generation sulfohydrazide with hydrazine hydrate, then with the life of substituted benzoyl aldehyde reaction Into.
Flow 4
It is a further object of the present invention to provide a kind of medicine for being used to treat tumor disease, the medicine contains Formulas I schiff bases Class compound or the acceptable salt of its biology, as active component.Can be the Schiff bases chemical combination of above method synthesis Any one in the case of thing, can the only situation containing one of which or containing many of Application of composite.
Said medicine can be made compound preparation with other drug regimens and be applied.
Further, pharmaceutical salts refer to type I compound and acetic acid, dihydrokainic acid, benzoic acid, citric acid, sorbic acid, propionic acid, Oxalic acid, fumaric acid, maleic acid, hydrochloric acid, malic acid, phosphoric acid, sulfurous acid, sulfuric acid, vanillic acid, tartaric acid, ascorbic acid, boric acid, The salt of at least one formation in lactic acid and ethylenediamine tetra-acetic acid.
Compared with prior art, beneficial effects of the present invention：
The invention provides a kind of novel compounds with structure shown in formula I, it can effectively suppress the growth of tumour cell, Treatment and prevention applied to tumor disease caused by a variety of human body own cells misgrowths.
Brand-new schiff base compounds in the present invention, are expected to " weight pound a formula as antineoplaston drug field Bomb ", becomes the first-line drug for treating certain tumour, and a kind of brand-new efficient treatment is provided for treatment human cancerous disease Medicine/active component.
Brief description of the drawings：
Fig. 1 is compound 3b nuclear magnetic spectrums.
Fig. 2 is compound 3g nuclear magnetic spectrums.
Embodiment
With reference to test example and embodiment, the present invention is described in further detail.But this should not be understood Following embodiment is only limitted to for the scope of above-mentioned theme of the invention, it is all that this is belonged to based on the technology that present invention is realized The scope of invention.
Embodiment 1
Compound 1a-1e synthesis
Using commercially available substituted aniline and substituted benzaldehyde as raw material, using methanol as reaction dissolvent, a small amount of dilute HCl stirrings are added Backflow, thin-layer chromatography (TLC) tracking reaction process.After reaction terminates, solvent is removed, a small amount of NaHCO is added3Neutralization reaction liquid, A certain amount of water is added, is stood, yellow mercury oxide, suction filtration is separated out, then use CH3OH, which is washed and purified, obtains Skeleton A classes Compound, gross production rate is in 62%-85%.NMR and MS spectral datas are correct.
Specific synthetic method, by taking compound 1a as an example：Aniline 2mmol (about 182 μ l), Benzaldehyde,2-hydroxy are taken respectively 2mmol (about 208 μ l) adds 3-4ml methanol into bottle as reaction dissolvent, adds a small amount of (about 100 in pyriform reaction bulb μ l) dilute HCl, reaction bulb, which is put into oil bath pan, is stirred at reflux it.Thin-layer chromatography (TLC) tracks reaction process.Reaction terminates Afterwards, solvent is removed, a small amount of NaHCO is added3Neutralization reaction liquid, adds a certain amount of water, stands, precipitation yellow mercury oxide, suction filtration, CH is used again3OH, which is washed and purified, obtains compound 1a (314.9mg), yield about 80%.NMR and MS spectral datas are correct.
Compound 1a-1e nuclear magnetic data：
(E)-2-((phenylimino)methyl)phenol(1a)
1H NMR(400MHz,DMSO-d6) δ 13.10 (s, 1H), 8.97 (s, 1H), 7.67 (dd, J=7.6,1.7Hz, 1H), 7.60-7.29 (m, 6H), 6.99 (ddd, J=9.5,7.8,1.6Hz, 2H) .HRMS calcd for C13g11NO-[M- H]-：196.24,found 196.6.
(E)-4-(((3-(trifluoromethyl)phenyl)imino)methyl)benzene-1,3-diol(1b)
1H NMR(400MHz,DMSO-d6)δ13.10(s,1H),10.39(s,1H),8.88(s,1H),8.11–7.14(m, 5H),7.04–6.04(m,2H).HRMS calcd for C14H10F3NO2 -[M-H]-：280.23,found 280.1.
methyl(E)-3-((2,4-dihydroxybenzylidene)amino)-2-hydroxybenzoate(1c)
1H NMR(400MHz,DMSO-d6)δ10.91(s,1H),10.62–10.02(m,1H),8.85(s,1H),8.01– 5.83 (m, 7H), 3.91 (d, J=19.9Hz, 3H) .HRMS calcd for C15H13NO5 -[M-H]-:286.27,found 286.4.
(E)-4-(((3,5-bis(trifluoromethyl)phenyl)imino)methyl)benzene-1,3-diol (1d)
1H NMR(400MHz,DMSO-d6)δ12.73(s,1H),10.48(s,1H),8.96(s,1H),8.18–7.46(m, 4H),6.67–6.24(m,2H).HRMS calcd for C15H9F6NO2 -[M-H]-:348.23,found 348.1.
(E)-4-((2,4-dihydroxybenzylidene)amino)-3-hydroxybenzoic acid(1e)
1H NMR(400MHz,DMSO-d6)δ13.98(s,1H),12.74(s,1H),10.27(s,1H),10.01(s, 1H),8.83(s,1H),8.04–6.91(m,4H),6.60–5.79(m,2H).HRMS calcd for C14H11NO5 -[M-H]-: 272.24,found 272.2.
Embodiment 2
Compound 2a-2b synthesis
(1) using commercially available substituted phenylsulfonyl chloride and hydrazine hydrate as raw material, using distilled water as reaction dissolvent, under room temperature condition Reaction solution is poured into a certain amount of cold water, crosses filter solid, wash by stirring, thin-layer chromatography (TLC) tracking reaction process, reaction after terminating Wash, obtain intermediate (2-1).
(2) product and substituted benzaldehyde using step one is raw materials, and methanol is reaction dissolvent, add a small amount of dilute HCl stirrings Backflow, thin-layer chromatography (TLC) tracking reaction process.After reaction terminates, solvent is removed, a small amount of NaHCO is added3Neutralization reaction liquid, A certain amount of water is added, is stood, pale yellow precipitate, suction filtration is separated out, then use CH3OH, which is washed and purified, obtains Skeleton B classes Compound (2), gross production rate is in 60%-80%.NMR and MS spectral datas are correct.
Specific synthetic method, by taking compound 2a as an example：
(1) 4- toluene sulfonyl chlorides 1mmol (about 190mg) is taken respectively, and hydrazine hydrate 1mmol (about 50 μ l) is in pyriform reaction bulb In, using distilled water as reaction dissolvent, in being stirred under room temperature condition, thin-layer chromatography (TLC) tracking reaction process, reaction will after terminating Reaction solution is poured into a certain amount of cold water, crosses filter solid, and washing obtains intermediate (2-1) about 158mg.
(2) the product 0.8mmol (about 148mg) and Benzaldehyde,2-hydroxy 0.8mmol (about 83 μ l) of step one are taken in pyriform In reaction bulb, 2-3ml methanol is added into bottle as reaction dissolvent, a small amount of (about 50 μ l) dilute HCl is added, reaction bulb is put into It is stirred at reflux it in oil bath pan.Thin-layer chromatography (TLC) tracks reaction process.After reaction terminates, solvent is removed, is added a small amount of NaHCO3Neutralization reaction liquid, adds a certain amount of water, stands, and separates out yellow mercury oxide, suction filtration, then use CH3OH is washed and purified To compound 2a (174.8mg), yield about 75%.NMR and MS spectral datas are correct.
Compound 2a-2b nuclear magnetic data：
(Z)-N'-(2-hydroxybenzylidene)-4-methylbenzenesulfonohydrazide(2a)
1H NMR(400MHz,Chloroform-d)δ10.21(s,1H),8.53(s,1H),8.27–7.64(m,3H), 7.55–6.54(m,7H),4.26–3.29(m,2H).HRMS calcd for C14H11NO5 -[M-H]-:289.34,found 289.4.
(Z)-N'-(2,4-dihydroxybenzylidene)-4-methylbenzenesulfonohydrazide(2b)
1H NMR(400MHz,DMSO-d6)δ11.17(s,1H),10.27(s,1H),9.89(s,1H),8.05(s,1H), 7.72 (d, J=8.2Hz, 2H), 7.41 (d, J=8.1Hz, 2H), 7.24 (d, J=8.4Hz, 1H), 6.57-5.98 (m, 2H), 2.36(s,3H).HRMS calcd for C14H11NO5 -[M-H]-:305.34,found 305.2.
Embodiment 3
Compound 3a-3l synthesis
(1) using substituted benzoic acid as raw material, methanol is reaction dissolvent, a small amount of sulphuric acid catalysis, in stirring under heating condition Backflow, thin-layer chromatography (TLC) tracking reaction process, reaction adds a certain amount of NaHCO after terminating3Solution neutralization reaction liquid, obtains ester Class intermediate (3-1), the hydrazine hydrate for continuing to add corresponding proportion in the reaction solution more than carries out hydrazinolysis reaction, and heating stirring is returned Stream, thin-layer chromatography (TLC) tracking reaction process, reaction terminates to add a certain amount of water in backward reaction solution, produces immediately a large amount of White is sunk to the bottom, suction filtration, obtains hydrazides class intermediate (3-2).
(2) using hydrazides class intermediate (3-2) and substituted benzaldehyde as raw material, methanol is reaction dissolvent, under heating condition Stirring, thin-layer chromatography (TLC), which is tracked, has precipitation to produce in reaction process, course of reaction, filter solid removing is crossed in reaction after terminating molten Agent, and recrystallization purifying obtains Skeleton C classes compounds (3), gross production rate is in 60%-86%.NMR and MS spectral datas are correct.
Specific synthetic method, by taking compound 3a as an example：
(1) 4- fluobenzoic acids 2mmol (about 280mg) is taken in pyriform reaction bulb, adds 3-4ml methanol molten as reaction Agent, a small amount of concentrated sulfuric acid (about 30 μ l) is stirred at reflux as catalyst under heating condition, thin-layer chromatography (TLC) tracking react into Journey, reaction adds a certain amount of NaHCO after terminating3Solution neutralization reaction liquid, obtains ester intermediate (3-1), continues anti-more than Answer in liquid add corresponding proportion hydrazine hydrate carry out hydrazinolysis reaction, heating stirring backflow, thin-layer chromatography (TLC) tracking react into Journey, reaction terminates to add a certain amount of water in backward reaction solution, and a large amount of whites are produced immediately and are sunk to the bottom, suction filtration is obtained in the middle of hydrazides class Body (3-2) (about 280mg).
(2) hydrazides class intermediate (3-2) 1mmol (about 154mg) and 2,4- 4-dihydroxy benzaldehydes 1mmol (about 138mg) are taken In reaction bulb, using methanol as reaction dissolvent, in being stirred under heating condition, thin-layer chromatography (TLC) tracking reaction process reacted Cheng Zhongyou precipitations are produced, and reaction crosses filter solid after terminating and removes solvent, and recrystallization purifying obtains compound 3a (224mg), always Yield is 82%.NMR and MS spectral datas are correct.
Compound 3a-3l nuclear magnetic data：
(Z)-N'-(2,4-dihydroxybenzylidene)-4-fluorobenzohydrazide(3a)
1H NMR(400MHz,DMSO-d6)δ11.94(s,1H),11.43(s,1H),8.50(s,1H),8.26–7.63(m, 2H),7.67–6.88(m,3H),6.69–5.82(m,2H).HRMS calcd for C14H11FN2O3 -[M-H]-:273.25, found 273.1.
(Z)-3-chloro-N'-(2,4-dihydroxybenzylidene)benzohydrazide(3b)
1H NMR(400MHz,DMSO-d6)δ11.98(s,1H),11.26(s,2H),10.13(s,1H),8.52(s,1H), 8.26–7.26(m,5H),6.33(s,1H).HRMS calcd for C14H11ClN2O3 -[M-H]-:289.70,found 289.1.
(Z)-4-dichloro-N'-(2,4-dihydroxybenzylidene)benzohydrazide(3c)
1H NMR(400MHz,DMSO-d6)δ11.98(s,1H),11.40(s,1H),9.98(s,1H),8.51(s,1H), (m, the 2H) .HRMS of 8.20-7.76 (m, 2H), 7.62 (d, J=8.5Hz, 2H), 7.33 (d, J=8.4Hz, 1H), 6.70-5.94 calcd for C14H11ClN2O3 -[M-H]-:289.70,found 289.2.
(Z)-2,6-dibromo-N'-(2,4-dihydroxybenzylidene)benzohydrazide(3d)
1H NMR(400MHz,DMSO-d6)δ12.01(s,1H),11.22(s,1H),9.98(s,1H),8.51(s,1H), (m, 2H) .HRMS calcd for of 8.10 (s, 3H), 7.35 (d, J=8.5Hz, 1H), 6.63-6.06 C14H10Br2N2O3 -[M- H]-:413.05,found 413.1.
(Z)-4-cyano-N'-(2,4-dihydroxybenzylidene)benzohydrazide(3e)
1H NMR(400MHz,DMSO-d6)δ12.10(s,1H),11.30(s,1H),9.99(s,1H),8.52(s,1H), (m, 2H) the .HRMS calcd of 8.05 (q, J=8.3Hz, 4H), 7.35 (d, J=8.5Hz, 1H), 6.91-6.19 for C15H11N3O3 -[M-H]-:280.27,found 280.3.
(Z)-N'-(2,4-dihydroxybenzylidene)-2-fluorobenzohydrazide(3f)
1H NMR(400MHz,DMSO-d6)δ11.86(s,1H),11.27(s,1H),9.97(s,1H),8.40(s,1H), 7.82–7.48(m,1H),7.51–7.20(m,4H),6.44–6.28(m,2H).HRMS calcd for C14H11FN2O3 -[M- H]-:273.25,found 273.1.
(Z)-N'-(2,4-dihydroxybenzylidene)-3-(trifluoromethyl)benzohydrazide (3g)
1H NMR(400MHz,DMSO-d6)δ12.09(s,1H),11.32(s,1H),9.98(s,1H),8.54(s,1H), 8.42-8.11 (m, 2H), 7.98 (d, J=7.8Hz, 1H), 7.79 (t, J=7.8Hz, 1H), 7.36 (d, J=8.4Hz, 1H), 6.54–6.01(m,2H).HRMS calcd for C15H11F3N2O3 -[M-H]-:323.26,found 323.1.
(Z)-N'-(2,4-dihydroxybenzylidene)-3-methylbenzohydrazide(3h)
1H NMR(400MHz,DMSO-d6)δ11.87(s,1H),11.47(s,1H),10.58–9.67(m,1H),8.51 (s,1H),7.98–7.63(m,2H),7.60–7.04(m,3H),6.57–6.10(m,2H),2.39(s,3H).HRMS calcd for C15H14N2O3 -[M-H]-:269.29,found 269.2.
(E)-4-(tert-butyl)-N'-(2,4-dihydroxybenzylidene)benzohydrazide(3i)
1H NMR(400MHz,DMSO-d6)δ11.85(s,1H),11.51(s,1H),9.96(s,1H),8.49(s,1H), 8.10-7.73 (m, 2H), 7.73-7.48 (m, 2H), 7.30 (d, J=8.4Hz, 1H), 6.50-5.97 (m, 2H), 1.32 (s, 9H).HRMS calcd for C16H16N2O3 -[M-H]-:283.32,found 283.4.
(E)-N'-(2,4-dihydroxybenzylidene)-4-isopropylbenzohydrazide(3j)
1H NMR(400MHz,DMSO-d6)δ11.85(s,1H),11.50(s,1H),9.96(s,1H),8.49(s,1H), 8.04-7.63 (m, 2H), 7.35 (dd, J=43.7,8.4Hz, 3H), 6.57-6.16 (m, 2H), 1.23 (d, J=6.9Hz, 6H).HRMS calcd for C17H18N2O-[M-H]-:297.13,found 297.2.
(E)-N'-(2,4-dihydroxybenzylidene)benzohydrazide(3k)
1H NMR(400MHz,DMSO-d6)δ11.92(s,1H),11.48(s,1H),9.97(s,1H),8.51(s,1H), (m, the 2H) .HRMS of 8.20-7.79 (m, 2H), 7.73-7.41 (m, 3H), 7.31 (d, J=8.4Hz, 1H), 6.60-6.01 calcd for C14H12N2O3 -[M-H]-:255.26,found 255.2.
Embodiment 4
Compound 4a-4b synthesis
(1) using commercially available heterocyclic acids as raw material, methanol is reaction dissolvent, a small amount of sulphuric acid catalysis, in stirring under heating condition Backflow, thin-layer chromatography (TLC) tracking reaction process, reaction adds a certain amount of NaHCO after terminating3Solution neutralization reaction liquid, obtains ester Class intermediate (4-1), the hydrazine hydrate for continuing to add corresponding proportion in the reaction solution more than carries out hydrazinolysis reaction, and heating stirring is returned Stream, thin-layer chromatography (TLC) tracking reaction process, reaction terminates to add a certain amount of water in backward reaction solution, produces immediately a large amount of White is sunk to the bottom, suction filtration, obtains hydrazides class intermediate (4-2).
(2) with hydrazides class intermediate (4-2) and 2,4- 4-dihydroxy benzaldehyde for raw material, methanol is reaction dissolvent, in heating Under the conditions of stir, thin-layer chromatography (TLC) tracking reaction process has in course of reaction precipitation to produce, reaction crosses filter solid after terminating Solvent is removed, and recrystallization purifying obtains Skeleton D classes compounds (4), gross production rate is in 62%-86%.NMR and MS wave spectrum numbers According to correct.
Specific synthetic method, by taking compound 4a as an example：
(1) 2- (4-chloropyridin-3-yl) acetic acid 2mmol (about 342mg) are taken in reaction bulb, with Methanol is reaction dissolvent, adds a small amount of concentrated sulfuric acid (about 50 μ l) as catalyst, is stirred at reflux under heating condition, thin layer color (TLC) tracking reaction process is composed, reaction adds a certain amount of NaHCO after terminating3Solution neutralization reaction liquid, obtains ester intermediate (4- 1) hydrazine hydrate for, continuing to add corresponding proportion in the reaction solution more than carries out hydrazinolysis reaction, heating stirring backflow, thin-layer chromatography (TLC) reaction process is tracked, reaction terminates to add a certain amount of water in backward reaction solution, a large amount of whites are produced immediately and are sunk to the bottom, are taken out Filter, obtains hydrazides class intermediate (4-2) (about 330mg).
(2) hydrazides class intermediate (4-2) 273mg (about 1.5mmol), 2,4- 4-dihydroxy benzaldehydes 1.5mmol are taken respectively (about 207mg) added for raw material in reaction bulb, using methanol as reaction dissolvent, in being stirred under heating condition, thin-layer chromatography (TLC) is tracked There is precipitation to produce in reaction process, course of reaction, reaction crosses filter solid after terminating and removes solvent, and recrystallization purifying obtains chemical combination Thing 4a (about 356mg), yield is 78%.NMR and MS spectral datas are correct.
Compound 4a-4b nuclear magnetic data：
(Z)-2-(4-chloropyridin-3-yl)-N'-(2,4-dihydroxybenzylidene) acetohydrazide(4a)
1H NMR(400MHz,DMSO-d6) δ 11.69 (s, 1H), 11.23 (d, J=29.9Hz, 1H), 10.36-9.45 (m, 1H), 8.64-8.04 (m, 2H), 7.78 (ddd, J=16.7,8.2,2.5Hz, 1H), 7.54-7.04 (m, 2H), 6.48-5.91 (m,2H),3.99(s,1H).HRMS calcd for C14H12ClN3O3 -[M-H]-:304.72,found 304.2.
(Z)-N'-(2,4-dihydroxybenzylidene)picolinohydrazide(4b)
1H NMR(400MHz,DMSO-d6)δ12.30(s,1H),11.60(s,1H),9.98(s,1H),8.95–8.57(m, 2H), 8.29-7.85 (m, 2H), 7.67 (ddd, J=7.5,4.7,1.4Hz, 1H), 7.24 (d, J=8.5Hz, 1H), 6.63- 5.85(m,2H).HRMS calcd for C13g11N3O3 -[M-H]-:256.25,found 256.2
Embodiment 5
The Anti-tumor angiogenesis of schiff base compounds
According to embodiment 1-4 processing step, multi-stage synthesis obtains compound in table (Coupounds) and uses it for phase The Anti-tumor angiogenesis experiment of pass.By the compound of above-mentioned synthesis using in vitro culture measurement of test method its for human brain Glioma cell (U87), human liver cancer cell (HEPG2), Human Prostate Cancer Cells (PC-3), human colon cancer cell (HCT116), Human breast cancer cell (MCF-7), mice colorectal cancer cell (CT26), the IC of mouse melanin tumor cell (B16)50Concentration (MIC), As a result it is as follows：
Using mtt assay：It is human glioma cell (U87), human liver cancer cell to adjust cell line with complete culture solution respectively (HEPG2), Human Prostate Cancer Cells (PC-3) human colon cancer cell (HCT116), human breast cancer cell (MCF-7), mouse large intestine Cancer cell (CT26), three kinds of cell concentrations of mouse melanin tumor cell (B16) are 2 × 104/ ml, is inoculated in 96 orifice plates, per hole 100 μ L, overnight incubation, next day respectively with the compound to be screened of various dose (final concentration is respectively 40,20,10,5,2.5, 1.25 μm of ol/L) processing cell, while isometric solvent control group, DMSO concentration is that 0.1% (0.1% DMSO is to cell Propagation does not influence).Each concentration sets 5 multiple holes, 37 DEG C, 5%CO2After culture 48 hours, 5mg/ml MTT examinations are added per hole The μ L of agent 20, continue to cultivate 2~4h, abandon supernatant, then add the μ L of DMSO 150, and vibration mixes 15min, with ELIASA (λ=570nm) Mensuration absorbance (A) value (A values are directly proportional to viable count), takes its average value.Relative cell proliferation inhibiting rate (%)=(control Group A 570- experimental groups A 570)/control group A 570 × 100%, inhibiting rate is the compound for 50% compound concentration IC50Value.Experiment is at least repeated 3 times.Positive control uses adriamycin.
Form 1

Claims (10)

1. a kind of schiff base compounds with Formulas I structure,
Wherein, R1, R2It is independently selected from：Hydrogen, hydroxyl, halogen, phenyl, benzyl, aryl alkyl, C3-C7 cycloalkyl, heterocycle Base alkyl, oxazolyl, thiazolyl, substituted thiazolyl, piperidyl, hexahydro piperidyl, pyridine radicals, dihydropyridine base, tetrahydropyridine Base, thiazinyl, pyrrole radicals, imidazole radicals, pyrazolyl, pyrimidine radicals, pyrazinyl, piperazinyl, morpholinyl, furyl, pyranose, pyridine Base, triazol radical, naphthyl, quinolyl, isoquinolyl, purine radicals, 2H purine radicals and optional by M1Substituent group it is above-mentioned Group；The M1It is monosubstituted or polysubstituted when substituent group above-mentioned group；Work as M1The above-mentioned group of substituent group is disubstituted When, it is same by M1Two M connected on the group of substituent group1Group is separate or is interconnected to form ring junction Structure；
The aryl alkyl is：The C1-C4 of aryl substitution alkylidene；
In the cycloheteroalkylalkyl heterocyclic radical be furyl, pyrrole radicals, thienyl, oxazolyls, imidazole radicals, pyrazolyl, pyrimidine radicals, One in pyrazinyl, piperazinyl, morpholinyl, pyranose, the alkyl in the cycloheteroalkylalkyl is C1-C4 alkyl；
The M1Group is selected from：Hydrogen, fluorine, chlorine, bromine, iodine, nitro, amino, hydroxyl, C1-C12 alkyl, C1-C12 alkoxies, halo C1-C12 alkyl, C2-C12 alkenyls, the C1-C12 alkyl of hydroxyl substitution, (two-C1-C12 alkyl aminos)-C1-C12 alkyl, C1- C12 alkyl aminos, C3-C7 cycloalkyl aminos, two (C1-C12 alkyl) amino, amino C1-C12 alkyl, amino C1-C12 alcoxyls Base, C1-C12 alkoxy carbonyls, C1-C12 alkyl aminos, two (C1-C12 alkoxy -C 1-C12 alkyl) amino, amino carbonyl, C1-C12 alkyl amino-carbonyls, two (C1-C12 alkyl) amino carbonyls, C3-C12 cycloalkyl amino carbonyls, C3-C12 cycloalkanes oxygen Base, hydroxyl C1-C12 alkoxies, halo C1-C12 alkoxies, C1-C12 alkyl sulfone, C2-12 alkenyls sulfone, C3-C7 cycloalkyl sulfone, C3-C7 cycloalkyl, halo C3-C7 cycloalkyl, heterocyclic oxy group, piperidyl amino, N- methyl piperidine -4- carbonyls, piperazine-C1-C12 Alkyl, pyrrolylcarbonyl amido, N- methyl piperidines formamido or heterocycle C1-C12 alkyl oxies；
When there are multiple M1When group replaces to above-mentioned R1 and R2, each M1It is separate between group；
M=0 or 1,
X be imino group, substituted imido, carbonyl, thiocarbonyl, sulfonyl, sulfinyl, alkyl, alkoxy, carbonylamino or Amino carbonyl；
N=0 or 1,
Y is carbonyl, thiocarbonyl, sulfonyl, sulfinyl, C1-12 alkyl, C1-12 substituted hydrocarbon radicals, carbonylamino or amino carbonyl Base；
P=0 or 1,
Z is oxygen, sulphur, C1-12 alkyl, C1-12 substitutions alkyl, C1-C12 alkoxies, C3-C7 cycloalkyl, C3-C7 substitution cycloalkanes Base, C2-12 alkenyls, C2-12 substituted alkenyls, C2-12 alkynyls, imino group, substituted imido, C1-C12 alkoxy carbonyls, C1- C12 alkyl-carbonyls or amino carbonyl.
It is further preferred that R1, R2It is independently selected from：Hydrogen, hydroxyl, fluorine, chlorine, bromine, iodine, phenyl, aminomethyl phenyl, ethylo benzene Base, propyl group phenyl, isopropyl phenyl, halogen substituted-phenyl, 3,5-dimethylphenyl, Methylethyl phenyl, diethyl phenyl, trimethylbenzene Base, triethyl group phenyl, benzyl, phenylmethylene, phenyl-ethylene, phenylpropylene, phenyl butylidene, cyclohexyl, hydroxyl ring Hexyl, dihydroxy butylcyclohexyl, methylcyclohexyl, phenyl methyl, phenylethyl, hydroxyphenylmethyl, hydroxypropiophenone, oxazole Base, thiazolyl, piperidyl, hexahydro piperidyl, pyridine radicals, hydroxy-pyridyl, picolyl, dihydropyridine base, tetrahydropyridine Base, thiazinyl, pyrrole radicals, imidazole radicals, pyrazolyl, pyrimidine radicals, pyrazinyl, piperazinyl, morpholinyl, furyl, pyranose, pyridine Base, triazol radical, naphthyl, quinolyl, isoquinolyl, purine radicals, 2H purine radicals, C1-C10 low alkyl group, cyclopropyl, methoxy Base, ethyoxyl, propoxyl group, isobutyl group epoxide, vinyl, acrylic.
It is further preferred that R1, R2It is independently selected from：Substituent M2Substituted aromatic ring yl or heterocyclic radical, substituent M2Have one It is individual or multiple；Substituent M2Selected from hydrogen, hydroxyl, carboxyl, fluorine, chlorine, bromine, iodine, methyl, ethyl, propyl group, isopropyl, butyl, isobutyl Base, new butyl, halogen substitution C1-C4 alkyl, cyano group, C1-C4 alkoxy carbonyls；Aromatic ring be selected from phenyl ring, naphthalene nucleus, anthracene nucleus, pyrrole ring, Piperidine ring, thiphene ring, pyridine ring, oxazole ring, thiazole ring, pyrimidine ring, pyrazine ring.
It is further preferred that R1, R2 are independently selected from：Phenyl, hydroxy phenyl, dihydroxy phenyl, hydroxy pyrimidine base, dihydroxy Yl pyrimidines base, pyridine radicals, hydroxy-pyridyl, dihydroxy-pyridine base, thiazolyl, hydroxyl thiazolyl, dihydroxy thiazole, cyclohexyl, Hydroxy-cyclohexyl, dihydroxy butylcyclohexyl, piperazinyl, hydroxyl piperazinyl, dihydroxy piperazinyl, pyrrole radicals, hydroxypyrrolyl, dihydroxy Base pyrrole radicals, oxazolyls, dihydroxy oxazolyl, aminomethyl phenyl, hydroxyl (methyl) phenyl, anthryl, tetrahydrochysene piperazinyl, hydroxyl (first Base) cyclohexyl.
It is further preferred that during m=1, X is imino group, substituted imido, carbonyl, thiocarbonyl, sulfonyl, sulfinyl, hydrocarbon Base, alkoxy, carbonylamino or amino carbonyl.
2. the medicine according to claim 1 for being used to treat tumor disease, it is characterised in that during n=1, Y is carbonyl, sulphur For carbonyl, sulfonyl, sulfinyl, C1-12 alkyl, C1-12 substituted hydrocarbon radicals, carbonylamino or amino carbonyl.
3. according to claim 1 be used to treat the medicine of tumor disease, it is characterised in that during p=1, Z be oxygen, sulphur, C1-12 alkyl, C1-12 substitution alkyl, C1-C12 alkoxies, C3-C7 cycloalkyl, C3-C7 substituted cycloalkyls, C2-12 alkenyls, C2-12 substituted alkenyls, C2-12 alkynyls, imino group, substituted imido, C1-C12 alkoxy carbonyls, C1-C12 alkyl-carbonyls, ammonia Base carbonyl.
4. the medicine according to claim 1 for being used to treat tumor disease, it is characterised in that p=0.
5. the medicine according to claim 1 for being used to treat tumor disease, it is characterised in that R1It is selected from
2- hydroxy phenyls, 2,4- dihydroxy phenyls, p-hydroxybenzene, 3,4- dihydroxy phenyls, 3,5- dihydroxy phenyls, 5- hydroxyls Base -3- pyridine radicals, 5,6- dihydroxy -3- pyridine radicals, 2,5- dihydroxy -3- pyridine radicals, 4,5- dihydroxy -3- pyridine radicals, 2- hydroxyls Base -4- thiazolyls, 2,5- dihydroxy -4- thiazolyls, phenyl, cyclohexyl, 3,5- dihydroxy-cyclohexyl, 3- hydroxy-cyciohexyls, One in 1- piperazinyls, 3- pyrrole radicals, 2- naphthyls, 4- morpholinyls, 4- isoxazolyls.
6. the medicine according to claim 1 for being used to treat tumor disease, it is characterised in that R2It is selected from
2- fluoro-phenyls, 4- tert-butyl-phenyls, 4- isopropyl-phenyls, phenyl, 2- pyridine radicals, m- (trifluoromethyl) phenyl, 4- cyanogen Base-phenyl, 2- hydroxyls -3- (methoxycarbonyl)-phenyl, the trifluoromethyl-phenyls of 3,5- bis-, 2- hydroxyl -4- carboxyl phenyls, to first Phenyl, 4- fluoro-phenyls, the chloro- phenyl of 4-, 2,6- dibromo phenyls, 3- aminomethyl phenyls, 1- piperazinyls, cyclohexyl, 3- pyrrole radicals, 2- One in naphthyl, 4- morpholinyls, 4- isoxazolyls, phenyl, cyclohexyl.
7. the medicine according to claim 1 for being used to treat tumor disease, it is characterised in that described Schiff bases chemical combination Thing is one of following compound：
8. a kind of method for synthesizing above-mentioned schiff base compounds, comprises the following steps：
Compound formula I, wherein m=0, n=0, p=0, the route shown in flow 1 are synthesized, with commercially available substituted aniline and substitution Benzaldehyde is raw material, using methanol as reaction dissolvent, adds a small amount of dilute HCl and is stirred at reflux reaction generation；
Flow 1
Compound formula I, wherein m=1, n=1, p=0, X is-NH-, and Y is carbonyl, and the route shown in flow 2 is synthesized, with commercially available Heterocyclic acids be raw material through esterification, hydrazinolysis, then with substituted benzoyl aldehyde reaction generate；
Flow 2
Compound formula I, wherein m=1, n=1, p=1, X is-NH-, and Y is carbonyl, and Z is methylene, the route as shown in flow 3 Synthesis, by raw material of commercially available heterocyclic acids through esterification, hydrazinolysis, then generated with substituted benzoyl aldehyde reaction；
Flow 3
Compound formula I, wherein m=1, n=1, p=0, X is-NH-, and Y is sulfonyl, and the route shown in flow 4 is synthesized, with city Sell heterocyclic sulfonyl chloride and passed through for raw material and reacted generation sulfohydrazide with hydrazine hydrate, then generated with substituted benzoyl aldehyde reaction；
Flow 4
9. a kind of medicine for being used to treat tumor disease, the medicine contains Formulas I schiff base compounds or its biology is acceptable Salt, as active component.
10. it is used for the medicine for treating tumor disease according to claim 13, it is characterised in that pharmaceutical salts refer to the chemical combination of formula I Thing and acetic acid, dihydrokainic acid, benzoic acid, citric acid, sorbic acid, propionic acid, oxalic acid, fumaric acid, maleic acid, hydrochloric acid, malic acid, phosphorus At least one formation in acid, sulfurous acid, sulfuric acid, vanillic acid, tartaric acid, ascorbic acid, boric acid, lactic acid and ethylenediamine tetra-acetic acid Salt.
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Application publication date: 20170718