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CN105198788A - Indole oxoacetyl (N-diaryl methyl) piperazine derivatives and preparation method and application thereof - Google Patents

Indole oxoacetyl (N-diaryl methyl) piperazine derivatives and preparation method and application thereof Download PDF

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Publication number
CN105198788A
CN105198788A CN201510639777.7A CN201510639777A CN105198788A CN 105198788 A CN105198788 A CN 105198788A CN 201510639777 A CN201510639777 A CN 201510639777A CN 105198788 A CN105198788 A CN 105198788A
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compound
indole
formula
piperazine derivatives
arylmethyl
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蒋军荣
徐峰
柯中炉
潘万贵
吴翰桂
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Taizhou Vocational and Technical College
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Taizhou Vocational and Technical College
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/18—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Indole Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
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Abstract

The invention relates to indole oxoacetyl (N-diaryl methyl) piperazine derivatives and a preparation method and application thereof, belongs to the technical field of pharmaceutical synthesis, and aims to provide new medicine with antitumor activity. The preparation method includes: in the presence of acid-binding agent, allowing indole oxoacetyl chloride to react with N-diaryl methyl piperazine so as to obtain the indole oxoacetyl (N-diaryl methyl) piperazine derivatives. The indole oxoacetyl (N-diaryl methyl) piperazine derivatives have the advantages that the indole oxoacetyl (N-diaryl methyl) piperazine derivatives have good tumor cell inhibiting activity, can be used as medicine and food for preventing or treating tumors, can be synthesized in one step, and are simple in process and easy to operate.

Description

A kind of indole oxo acetyl (N-bis-arylmethyl) bridged piperazine derivatives and its preparation method and application
Technical field
The present invention relates to a kind of indole oxo acetyl (N-bis-arylmethyl) bridged piperazine derivatives and its preparation method and application, belong to technical field of medicine synthesis.
Background technology
Indole oxo acetylpiperazine compounds has biological activity widely, and this compound is in advantage that is anticancer, anti-virus aspect especially in recent years, causes the extensive concern of a lot of scholar and investigator.As Wang, T. wait people at JournalofMedicinalChemical, 2003, a kind of biological activity of novel indole oxo acetylpiperazine derivative is reported in 46 (20): 4236-4239., then also carry out large quantifier elimination for this compounds researchist, indole oxo acetylpiperazine analog derivative after in succession having the bibliographical information of nearly more than 50 sections modified subsequently, what report in those references is do to modify research on indole ring or piperazine ring structure mostly, and the other end of piperazine without exception be all sweet-smelling formacyl, especially using benzoyl for as introducing group be many.As Chinese patent application (CN:1320037A) discloses a kind of antiviral indoleoxoacetyl piperazine derivatives; the process of the indoles-3-acetaldehyde acyl-oxygen 1-piperazinecarboxylic acid tert-butyl ester is obtained intermediate product, then by the Boc base of intermediate product with 20% TFA/CH 2cl 2deprotection, then, 1-(3-the dimethylamino-propyl)-3-ethylcarbodiimine on polymer support makes to obtain product indole oxo Acetylpiperazine derivative with carboxylic acid coupling under existing.Equally, it is by N at one end introduces sweet-smelling formacyl, and it mainly considers the effect of this compounds on antiviral activity.And on the other hand, two arylmethyl piperazines are class biological activity compounds widely, the biological activity of this kind of medicine mainly concentrates on the aspects such as antitumor, antihistamine.And do not have bibliographical information so far in the research that the other end of indole oxo acetylpiperazine introduces two arylmethyls, the corresponding derivative that the present invention wishes to realize introducing two arylmethyls on N by research and formed, make the corresponding derivative compound better with anti-tumor activity, for this compounds provides more selectivity as anti-tumor drug.
Summary of the invention
The present invention is directed to the defect existed in above prior art, propose a kind of indole oxo acetyl (N-bis-arylmethyl) bridged piperazine derivatives and its preparation method and application, the problem of solution how to realize the effect that a kind of new indole oxo acetyl (N-bis-arylmethyl) bridged piperazine derivatives makes to have anti-tumor activity.
An object of the present invention is achieved by the following technical programs, a kind of indole oxo acetyl (N-bis-arylmethyl) bridged piperazine derivatives, and the chemical structural formula of this derivative is as shown in the formula shown in I:
In formula I, described R 1and R 3independently be selected from H or halogen, described R separately 2be selected from H or C 1~ C 3alkyl.
Because indole oxo acetylpiperazine compounds has biological activity widely, this compound is in advantage that is anticancer, anti-virus aspect especially in recent years, causes the extensive concern of a lot of scholar and investigator.The present inventor wishes by the further research to this compounds, two arylmethyl class groups are incorporated on the N end on the piperazine ring of indole oxo acetylpiperazine compounds, realize a kind of indole oxo acetylpiperazine derivative compound of novelty, eventually through a large amount of experimental studies, the present inventor has found a class indole oxo acetyl (N-bis-arylmethyl) piperazine derivatives compound, and by carrying out large quantifier elimination to the activity performance of this compounds, find that it has higher restraining effect to tumour cell, universally recognizedly have compared with higher inhibiting cis-platinum to tumour with existing, the restraining effect of indole oxo acetyl (N-bis-arylmethyl) the piperazine derivatives compound on tumor of this class novelty of the present invention can reach in the suitable effect of cis-platinum, the restraining effect of some compound on tumor cell is even taller than the effect of cis-platinum.Therefore; indole oxo acetyl of the present invention (N-bis-arylmethyl) piperazine derivatives compound can be applied to food and the pharmaceutical preparation of prevention and therapy cancer aspect or be applied in other medically acceptable formulations; indole oxo acetyl of the present invention (N-bis-arylmethyl) piperazine derivatives compound can make corresponding medicinal composition to pharmaceutically acceptable auxiliary material equally; then make corresponding formulation, as the type processed that the medicines such as capsule, particle or injection are conventional.
In above-mentioned indole oxo acetylpiperazine compounds, as preferably, described R 1independently be selected from H or Br, described R 2be selected from H, CH 3or CH 3cH 2, described R 3be selected from H, F, Cl or Br.Adopt these group compounds not only to have the activity of higher inhibition tumor cell, meanwhile, these groups are sterically hindered relatively little, are easier to introduce, and are conducive to synthesis.As further preferred, indole oxo acetylpiperazine compounds described above is specifically selected from the compound of following structure:
The compound on tumor cell of structure above has better inhibition.
Two of object of the present invention is achieved by the following technical programs, a kind of preparation method of indole oxo acetylpiperazine compounds, under the method is included in acid binding agent existent condition, formula II compound indole oxo Acetyl Chloride 98Min. and formula III compound diarylmethylpiperazine are reacted, obtains type I compound indole oxo acetyl (N-bis-arylmethyl) piperazine derivatives compound;
Wherein, the R in formula II compound 1and R 2the R corresponding to type I compound 1and R 2one_to_one corresponding, the R in formula III compound 3the R corresponding to type I compound 3corresponding.
The preparation method of indole oxo acetylpiperazine compounds of the present invention, all raw materials all can buy from existing market or directly adopt existing method to synthesize, method of the present invention only needs to adopt single stage method can synthesize corresponding product, compared to polystep reaction process, save follow-up treating processes to a great extent, there is technological process simple, be conducive to the advantage of suitability for industrialized production, and due to processing step less, also provide certain guarantee for improving the yield of product.Certainly, raw material indole oxo Acetyl Chloride 98Min. of the present invention can with reference to existing method as Bioorganic & MedicinalChemistry, 2009, in 17 (16): 6073 – 6084, corresponding method is synthesized, and raw material diarylmethylpiperazine can with reference to existing method as MedicinalChemistryResearch, synthetic method in 2012,21 (4): 538 – 541 is synthesized.
In the preparation method of above-mentioned indole oxo acetylpiperazine compounds, described acid binding agent can be organic bases or mineral alkali, and described organic bases is as diethylamine, triethylamine, piperidines, pyridine, 4-(N, N-dimethyl) pyridine etc.; Described mineral alkali is as weakly alkaline reagent such as sodium carbonate, sodium bicarbonate, salt of wormwood.The acid HCl that acid binding agent can produce in neutralization reaction process, thus be more conducive to the carrying out that react; As preferably, described acid binding agent is selected from one or more in triethylamine, 4-(N, N-dimethyl) pyridine, pyridine and piperidines.Adopt these acid binding agents also to have reaction conditions gentleness, be more conducive to operation.As further preferred, the mol ratio of described acid binding agent and formula II compound is 1 ~ 3:1.
In the preparation method of above-mentioned indole oxo acetylpiperazine compounds, as preferably, described reaction is carried out in organic solvent, and described organic solvent can dissolution type II compound indole oxo Acetyl Chloride 98Min. and formula III compound diarylmethylpiperazine.By making material dissolution in organic solvent, reaction milder can be made, and organic solvent add the removal being conducive to follow-up impurity, the purity of product can be ensured and improve the effect of yield.As further preferred, described organic solvent is selected from one or more in tetrahydrofuran (THF), N, N-dimethyl formyl, chloroform and methylene dichloride.
In the preparation method of above-mentioned indole oxo acetylpiperazine compounds, as preferably, the temperature of described reaction is 20 DEG C ~ 35 DEG C.Substantially can the carrying out of realization response under normal temperature condition, there is the gentle and effect that security is high of reaction conditions.
In the preparation method of above-mentioned indole oxo acetylpiperazine compounds, in reaction process, the consumption of each raw material is according to the molar equivalent ratio of this area routine, not concrete restriction, for the requirement for solvent in the consumption reaction conveniently of solvent, equally there is no concrete restriction yet.As preferably, the mol ratio of described formula II compound and formula III compound is 1:1.0 ~ 1.2.Reaction can be made to have good effect, and also help and economize in raw materials, reduce the waste of raw material, reduce production cost.
In the preparation method of above-mentioned indole oxo acetylpiperazine compounds, as preferably, method of the present invention is specially:
Formula II compound indole oxo Acetyl Chloride 98Min. and formula III compound diarylmethylpiperazine are added in organic solvent, and control temperature adds acid binding agent under the condition of-10 DEG C ~ 10 DEG C, after adding, the condition of temperature to 20 DEG C ~ 35 DEG C is proceeded reaction, obtains type I compound indole oxo acetyl (N-bis-arylmethyl) piperazine derivatives compound.Mainly due to add acid binding agent process in easily cause local temperature in reaction system too high, and make other unnecessary impurity of generation, therefore, by adding acid binding agent under cryogenic, object is the generation in order to reduce impurity, improve yield and the purity of product, also can ensure the carrying out reacting milder.
Three of object of the present invention is achieved by the following technical programs, the application of a kind of indole oxo acetyl (N-bis-arylmethyl) bridged piperazine derivatives, and described type I compound is for the preparation of prevention or medicine and the food for the treatment of tumour.Because indole oxo acetyl of the present invention (N-bis-arylmethyl) bridged piperazine derivatives has the activity of good inhibition tumor cell, therefore, medicine and the food of prevention or treatment tumour can be used as, certainly, tumour mentioned here comprises cancer, visible, this kind of novel compound of the present invention has market application foreground widely.
In the application of above-mentioned indole oxo acetyl (N-bis-arylmethyl) bridged piperazine derivatives, as preferably, described medicine comprises activeconstituents type I compound and pharmaceutically acceptable auxiliary material.Described pharmaceutically acceptable auxiliary material can be conventional weighting agent, tackiness agent and softening agent and lubricant etc.As preferably, described weighting agent can be lactose, sucrose, Microcrystalline Cellulose, starch etc., and described tackiness agent can be ethyl cellulose, polyvinylpyrrolidone etc., and described lubricant can be calcium stearate, talcum powder etc.Certainly, medicine described above can be particle, liquid preparation or capsule etc.
The preparation method of indole oxo acetyl of the present invention (N-bis-arylmethyl) bridged piperazine derivatives, can adopt following reaction equation to represent:
In sum, the present invention compared with prior art, has the following advantages:
Indole oxo acetyl of the present invention (N-bis-arylmethyl) bridged piperazine derivatives is a class novelty, have comparatively high biological activity and have good restraining effect to tumour or cancer, compared with cis-platinum, can reach and the restraining effect effect of cis-platinum to tumour or cancer, some compound is even higher than the effect of cis-platinum.In the functional food that can be used in preparing prevention and therapy tumour or cancer etc. or medicine, there are good market outlook.And the compounds of this invention only needs to adopt single stage method to synthesize, have that technique is simple, the advantage of easy handling, be conducive to industrialization and produce.
Embodiment
Below by specific embodiment, technical scheme of the present invention is described in further detail, but the present invention is not limited to these embodiments.
Embodiment 1
A kind of N-(4-diphenyl-methyl)-N '-[(1H-indol-3-yl) oxoacetyl]-diethylenediamine compound, shown in the following I-a of structural formula of this compound:
Above-mentioned N-(4-diphenyl-methyl)-N '-[(1H-indol-3-yl) oxoacetyl]-diethylenediamine compound specifically adopts following methods to prepare:
R in the present embodiment Chinese style II compound 1and R 2be H, and the R in formula III compound 3for H;
Formula II compound indole oxo Acetyl Chloride 98Min. (10mmol) and formula III compound diarylmethylpiperazine (9.5mmol) are dissolved in 50mL anhydrous tetrahydro furan solvent, then, less than 5 DEG C are cooled under the condition of ice-water bath, and control to instill triethylamine 2mL under the condition of cooling bath, after dropwising, naturally reaction 10 ~ 20h is carried out under being warming up to the condition of 25 DEG C, allow to abundant reaction, stratographic analysis can be adopted in reaction process to carry out following the tracks of (elutriant that chromatogram tracking adopts is ethyl acetate: the volume ratio of ethanol is 9:1), after reacting completely, carry out the solvent in underpressure distillation removing system, wash-out is carried out again through column chromatography, be separated, collect the elutriant containing product, underpressure distillation removes desolventizing and obtains final light gray solid product formula I-a compound N-(4-diphenyl-methyl)-N '-[(1H-indol-3-yl) oxoacetyl]-piperazine again, molar yield is 55%.The elutriant that described column chromatography adopts is the mixed solution of ethyl acetate and methyl alcohol, and described ethyl acetate: the volume ratio of methyl alcohol is 9:1, certainly adopts other volume ratio also passable.
Analyzed by the product obtained, concrete analysis result is as follows:
Fusing point mp:225 DEG C ~ 227 DEG C.
IR：3157cm -1,3081cm -1,3062cm -1,2984cm -1,1652cm -1,1519cm -1,1436cm -1,1241cm -1,957cm -1,775cm -1。
1H-NMR(d 6-DMSO,500MHz)δ:12.30(s,1H,NH),8.13(s,1H,CH),8.08(d,1H,J＝7.6Hz,Ar),7.53(d,1H,J＝7.8Hz,Ar),7.42(d,4H,J＝7.8Hz,Ar),7.17-7.31(m,8H,Ar),4.37(s,1H,CH),3.66(t,2H,J＝4.6Hz,NCH 2),3.37(t,2H,J＝4.6Hz,NCH 2),2.43(t,2H,J＝4.6Hz,NCH 2),2.27(t,2H,J＝4.6Hz,NCH 2)。
ESI-MS,m/z(％)：423.5[(M+H) +,100]。
Anal.calcdforC 27H 25N 3O 2：C,76.57；H,5.95；N,9.92；O,7.56；Found：C,76.55；H,5.94；N,9.93；O,7.57。
Embodiment 2
A kind of N-[4-(4-chloro-phenyl-) (phenyl) methyl]-N '-[(1H-indol-3-yl) oxoacetyl]-diethylenediamine compound, shown in the following I-b of structural formula of this compound:
Above-mentioned N-[4-(4-chloro-phenyl-) (phenyl) methyl]-N '-[(1H-indol-3-yl) oxoacetyl]-diethylenediamine compound specifically adopts following methods to prepare:
R in the present embodiment Chinese style II compound 1and R 2be H, and the R in formula III compound 3for Cl;
Formula II compound indole oxo Acetyl Chloride 98Min. (10mmol) and formula III compound diarylmethylpiperazine (10mmol) are dissolved in 50mLN, in N-dimethyl formyl (DMF) solvent, then, about 0 DEG C is cooled under the condition of ice-water bath, and control to instill triethylamine 3mL under the condition of cooling bath, after dropwising, naturally reaction 10 ~ 20h is carried out under being warming up to the condition of 25 DEG C, allow to abundant reaction, stratographic analysis can be adopted in reaction process to carry out following the tracks of (elutriant that chromatogram tracking adopts is ethyl acetate: the volume ratio of ethanol is 9:1), after reacting completely, carry out the solvent in underpressure distillation removing system, wash-out is carried out again through column chromatography, be separated, collect the elutriant containing product, underpressure distillation removes desolventizing and obtains the shallow white solid product formula I of final product-b compound N-[4-(4-chloro-phenyl-) (phenyl) methyl]-N '-[(1H-indol-3-yl) oxoacetyl]-piperazine again, molar yield is 60%.The elutriant that described column chromatography adopts is the mixed solution of ethyl acetate and methyl alcohol, and described ethyl acetate: the volume ratio of methyl alcohol is 9:1.
Analyzed by the product obtained, concrete analysis result is as follows:
Fusing point mp:241 DEG C ~ 243 DEG C.
IR：3156cm -1,3099cm -1,3063cm -1,2983cm -1,1617cm -1,1523cm -1,1463cm -1,1242cm -1,1001cm -1,806cm -1。
1H-NMR(d 6-DMSO,500MHz)δ：12.29(s,1H,NH),8.13(s,1H,CH)，8.08(d,1H,J＝7.7Hz,Ar),7.53(d,1H,J＝7.8Hz,Ar),7.17-7.45(m,11H,Ar),4.43(s,1H,CH),3.46(t,2H,J＝4.6Hz,NCH 2),3.37(t,2H,J＝4.6Hz,NCH 2),2.42(t,2H,J＝4.6Hz,NCH 2),2.26(t,2H,J＝4.6Hz,NCH 2)。
ESI-MS,m/z(％)：458.4[(M+H) +,100]；
Anal.calcdforC 27H 24ClN 3O 2：C,70.81；H,5.28；N,9.18；O,6.99；Found：C,70.80；H,5.28；N,9.17；O,7.00。
Embodiment 3
A kind of N-[4-(4-fluorophenyl) (phenyl) methyl]-N '-[(1H-indol-3-yl) oxoacetyl]-diethylenediamine compound, shown in the following I-c of structural formula of this compound:
Above-mentioned N-[4-(4-fluorophenyl) (phenyl) methyl]-N '-[(1H-indol-3-yl) oxoacetyl]-diethylenediamine compound specifically adopts following methods to prepare:
R in the present embodiment Chinese style II compound 1and R 2be H, and the R in formula III compound 3for F;
Formula II compound indole oxo Acetyl Chloride 98Min. (10mmol) and formula III compound diarylmethylpiperazine (11mmol) are dissolved in 100mLN, in N-dimethyl formyl (DMF) solvent, then, about 0 DEG C is cooled under the condition of ice-water bath, and control to instill piperidines 4mL under the condition of cooling bath, after dropwising, reaction 18h is carried out under being slowly warming up to the condition of 25 DEG C, allow to abundant reaction, stratographic analysis can be adopted in reaction process to carry out following the tracks of (elutriant that chromatogram tracking adopts is ethyl acetate: the volume ratio of ethanol is 9:1), if reaction is not completely, reaction can be proceeded, until after reacting completely, carry out the solvent in underpressure distillation removing system, wash-out is carried out again through column chromatography, be separated, collect the elutriant containing product, underpressure distillation removes desolventizing and obtains final product white solid product formula I-c compound N-[4-(4-fluorophenyl) (phenyl) methyl]-N '-[(1H-indol-3-yl) oxoacetyl]-piperazine again, molar yield is 59%.The elutriant that described column chromatography adopts is the mixed solution of ethyl acetate and methyl alcohol, and described ethyl acetate: the volume ratio of methyl alcohol is 10:1.
Analyzed by the product obtained, concrete analysis result is as follows:
Fusing point mp:246 DEG C ~ 248 DEG C;
IR：3159cm -1,3099cm -1,3063cm -1,2982cm -1,1610cm -1,1506cm -1,1446cm -1,1244cm -1,999cm -1,800cm -1。
1H-NMR(d 6-DMSO,500MHz)δ：12.28(s,1H,NH),8.13(s,1H,CH),8.08(d,1H,J＝7.5Hz,Ar),7.53(d,1H,J＝7.9Hz,Ar),7.10-7.46(m,11H,Ar),4.42(s,1H,CH),3.65(s,2H,NCH 2),3.37(s,2H,NCH 2),2.42(s,2H,NCH 2),2.26(s,2H,NCH 2)。
ESI-MS,m/z(％)：442.4[(M+H) +,100]。
Anal.calcdforC27H24FN3O2：C,73.45；H,5.48；N,9.52；O,7.25；Found：C,73.48；H,5.47；N,9.53；O,7.24。
Embodiment 4
A kind of N-[4-(4-bromophenyl) (phenyl) methyl]-N '-[(1H-indol-3-yl) oxoacetyl]-diethylenediamine compound, shown in the following I-d of structural formula of this compound:
Above-mentioned N-[4-(4-bromophenyl) (phenyl) methyl]-N '-[(1H-indol-3-yl) oxoacetyl]-diethylenediamine compound specifically adopts following methods to prepare:
R in the present embodiment Chinese style II compound 1and R 2be H, and the R in formula III compound 3for Br;
Formula II compound indole oxo Acetyl Chloride 98Min. (10mmol) and formula III compound diarylmethylpiperazine (11.5mmol) are dissolved in 70mL dichloromethane solvent, then, about 0 DEG C is cooled under the condition of ice-water bath, and control to instill pyridine 2mL under the condition of cooling bath, after dropwising, after carrying out reaction 10h under being slowly warming up to the condition of 30 DEG C, stratographic analysis is adopted to carry out following the tracks of (elutriant that chromatogram tracking adopts is ethyl acetate: the volume ratio of ethanol is 9:1), if react incomplete, proceed reaction, after making fully to react completely, carry out the solvent in underpressure distillation removing system, wash-out is carried out again through column chromatography, be separated, collect the elutriant containing product, underpressure distillation removes desolventizing and obtains the shallow white solid product formula I of final product-d compound N-[4-(4-bromophenyl) (phenyl) methyl]-N '-[(1H-indol-3-yl) oxoacetyl]-piperazine again, molar yield is 62%.The elutriant that described column chromatography adopts is the mixed solution of ethyl acetate and methyl alcohol, and described ethyl acetate: the volume ratio of methyl alcohol is 9:1.
Analyzed by the product obtained, concrete analysis result is as follows:
Fusing point mp:227 DEG C ~ 229 DEG C;
IR：3225cm -1,3060cm -1,2980cm -1,1617cm -1,1491cm -1,1444cm -1,1244cm -1,997cm -1,775cm -1；
1H-NMR(d 6-DMSO,500MHz)δ:12.28(s,1H,NH),8.13(s,1H,CH),8.10(d,1H,J＝7.7Hz,Ar),7.53(d,1H,J＝7.8Hz,Ar),7.17-7.50(m,11H,Ar),4.41(s,1H,CH),3.66(s,2H,NCH 2),3.36(t,2H,J＝4.5Hz,NCH 2),2.43(t,2H,J＝4.7Hz,NCH 2),2.26(s,2H,NCH 2)；
ESI-MS,m/z(％)：524.4[(M+Na) +,25],502.4[(M+H) +,100]；
Anal.calcdforC 27H 24BrN 3O 2：C,64.55；H,4.81；N,8.36；O,6.37；Found：C,64.53；H,4.82；N,8.35；O,6.38。
Embodiment 5
A kind of N-(4-diphenyl-methyl)-N '-[(the bromo-1H-indol-3-yl of 5-) oxoacetyl]-diethylenediamine compound, shown in the following I-e of structural formula of this compound:
Above-mentioned N-(4-diphenyl-methyl)-N '-[(the bromo-1H-indol-3-yl of 5-) oxoacetyl]-diethylenediamine compound specifically adopts following methods to prepare:
R in the present embodiment Chinese style II compound 1for Br, R 2for H, and the R in formula III compound 3for H;
Formula II compound indole oxo Acetyl Chloride 98Min. (10mmol) and formula III compound diarylmethylpiperazine (9.5mmol) are dissolved in 100mL chloroform solvent, then, about 0 DEG C is cooled under the condition of ice-water bath, and control to instill 4-(N under the condition of cooling bath, N-dimethyl) pyridine 3mL, after dropwising, after carrying out reaction 12h under being slowly warming up to the condition of 35 DEG C, stratographic analysis can be adopted to carry out following the tracks of (elutriant that chromatogram tracking adopts is ethyl acetate: the volume ratio of ethanol is 9:1), if reaction not exclusively, proceed after reaction makes fully to react completely, carry out the solvent in underpressure distillation removing system, wash-out is carried out again through column chromatography, be separated, collect the elutriant containing product, underpressure distillation removes desolventizing and obtains final product shallow white solid product formula I-e compound N-(4-diphenyl-methyl)-N '-[(the bromo-1H-indol-3-yl of 5-) oxoacetyl]-piperazine again, molar yield is 53%.The elutriant that described column chromatography adopts is the mixed solution of ethyl acetate and methyl alcohol, and described ethyl acetate: the volume ratio of methyl alcohol is 9:1.
Analyzed by the product obtained, concrete analysis result is as follows:
Fusing point mp:238 DEG C ~ 240 DEG C;
IR：3154cm -1,3083cm -1,3061cm -1,2970cm -1,1617cm -1,1477cm -1,1438cm -1,1232cm -1,998cm -1,807cm -1。
1H-NMR(d 6-DMSO,500MHz)δ:12.46(s,1H,NH),8.19-8.21(m,2H,Ar+CH),7.50(d,1H,J＝8.6Hz,Ar),7.18-7.43(m,11H,Ar),4.38(s,1H,CH),3.65(s,2H,NCH 2),3.37(t,2H,J＝4.7Hz,NCH 2),2.43(t,2H,J＝4.7Hz,NCH 2),2.27(s,2H,NCH 2)。
ESI-MS,m/z(％):502.4[(M+H) +,100]。
Anal.calcdforC 27H 24BrN 3O 2：C,64.55；H,4.81；N,8.36；O,6.37；Found：C,64.57；H,4.80；N,8.34；O,6.38。
Embodiment 6
A kind of N-[4-(4-chloro-phenyl-) (phenyl) methyl]-N '-[(the bromo-1H-indol-3-yl of 5-) oxoacetyl]-diethylenediamine compound, shown in the following I-f of structural formula of this compound:
Above-mentioned N-[4-(4-chloro-phenyl-) (phenyl) methyl]-N '-[(the bromo-1H-indol-3-yl of 5-) oxoacetyl]-diethylenediamine compound specifically adopts following methods to prepare:
R in the present embodiment Chinese style II compound 1for Br, R 2for H, and the R in formula III compound 3for Cl;
Formula II compound indole oxo Acetyl Chloride 98Min. (10mmol) and formula III compound diarylmethylpiperazine (12mmol) are dissolved in 100mL anhydrous tetrahydro furan solvent, then, about 0 DEG C is cooled under the condition of ice-water bath, and control to instill triethylamine 3mL under the condition of cooling bath, after dropwising, after carrying out reaction 13h under being slowly warming up to the condition of 20 DEG C, stratographic analysis is adopted to carry out following the tracks of (elutriant that chromatogram tracking adopts is ethyl acetate: the volume ratio of ethanol is 9:1), if reaction not exclusively, proceed after reaction makes to react completely, carry out the solvent in underpressure distillation removing system, wash-out is carried out again through column chromatography, be separated, collect the elutriant containing product, underpressure distillation removes desolventizing and obtains final product white solid product formula I-f compound N-[4-(4-chloro-phenyl-) (phenyl) methyl]-N '-[(the bromo-1H-indol-3-yl of 5-) oxoacetyl]-piperazine again, molar yield is 81%.The elutriant that described column chromatography adopts is the mixed solution of ethyl acetate and methyl alcohol, and described ethyl acetate: the volume ratio of methyl alcohol is 9:1.
Analyzed by the product obtained, concrete analysis result is as follows:
Fusing point mp:240 DEG C ~ 242 DEG C.
IR：3164cm -1,3061cm -1,3028cm -1,2922cm -1,1620cm -1,1489cm -1,1447cm -1,1234cm -1,954cm -1,804cm -1。
1H-NMR(DMSO,500MHz)δ：12.46(s,1H,NH),8.19-8.21(m,2H,Ar+CH),7.50(d,1H,J＝8.6Hz,Ar),7.19-7.46(m,11H,Ar),4.43(s,1H,CH),3.65(s,2H,NCH 2),3.37(s,2H,NCH 2),2.42(s,2H,NCH 2),2.26(s,2H,NCH 2)。
ESI-MS,m/z(％)：536.1[(M+H) +,100]。
Anal.calcdforC 27H 23BrClN 3O 2：C,60.41；H,4.32；N,7.83；O,5.96；Found：C,60.44；H,4.31；N,7.84；O,5.95。
Embodiment 7
A kind of N-[4-(4-fluorophenyl) (phenyl) methyl]-N '-[(the bromo-1H-indol-3-yl of 5-) oxoacetyl]-diethylenediamine compound, shown in the following I-g of structural formula of this compound:
Above-mentioned N-[4-(4-fluorophenyl) (phenyl) methyl]-N '-[(the bromo-1H-indol-3-yl of 5-) oxoacetyl]-diethylenediamine compound specifically adopts following methods to prepare:
R in the present embodiment Chinese style II compound 1for Br, R 2for H, and the R in formula III compound 3for F;
Formula II compound indole oxo Acetyl Chloride 98Min. (10mmol) and formula III compound diarylmethylpiperazine (10mmol) are dissolved in 80mL anhydrous tetrahydro furan solvent, then, about 10 DEG C are cooled under the condition of ice-water bath, and control to instill triethylamine 2mL under the condition of 5 DEG C ~ 10 DEG C, after dropwising, after carrying out reaction 15h under being slowly warming up to the condition of 25 DEG C, stratographic analysis is adopted to carry out following the tracks of (elutriant that chromatogram tracking adopts is ethyl acetate: the volume ratio of ethanol is 9:1), if reaction not exclusively, proceed reaction until after reacting completely, carry out the solvent in underpressure distillation removing system, wash-out is carried out again through column chromatography, be separated, collect the elutriant containing product, underpressure distillation removes desolventizing and obtains final product white solid product formula I-g compound N-[4-(4-fluorophenyl) (phenyl) methyl]-N '-[(the bromo-1H-indol-3-yl of 5-) oxoacetyl]-piperazine again, molar yield is 82%.The elutriant that described pillar layer separation adopts is the mixed solution of ethyl acetate and methyl alcohol, and described ethyl acetate: the volume ratio of methyl alcohol is 9:1.
Analyzed by the product obtained, concrete analysis result is as follows:
Fusing point mp:251 DEG C ~ 253 DEG C.
IR：3156cm -1,3064cm -1,3031cm -1,2964cm -1,1624cm -1,1478cm -1,1437cm -1,1232cm -1,999cm -1,806cm -1。
1H-NMR(DMSO,500MHz)δ：12.46(s,1H),8.20-8.21(m,2H,Ar+CH),7.50(d,1H,J＝8.6Hz,Ar),7.11-7.47(m,11H,Ar),4.42(s,1H,CH),3.65(s,2H,NCH 2),3.36(s,2H,NCH 2),2.42(s,2H,NCH 2),2.26(s,2H,NCH 2)。
ESI-MS,m/z(％)：520.4[(M+H) +,100]。
Anal.calcdforC 27H 23BrFN 3O 2：C,62.32；H,4.45；N,8.07；O,6.15；Found：C,62.33；H,4.45；N,8.08；O,6.14。
Embodiment 8
A kind of N-[4-(4-bromophenyl) (phenyl) methyl]-N '-[(the bromo-1H-indol-3-yl of 5-) oxoacetyl]-diethylenediamine compound, shown in the following I-h of structural formula of this compound:
Above-mentioned N-[4-(4-fluorophenyl) (phenyl) methyl]-N '-[(the bromo-1H-indol-3-yl of 5-) oxoacetyl]-diethylenediamine compound specifically adopts following methods to prepare:
R in the present embodiment Chinese style II compound 1for Br, R 2for H, and the R in formula III compound 3for Br;
Formula II compound indole oxo Acetyl Chloride 98Min. (10mmol) and formula III compound diarylmethylpiperazine (11.5mmol) are dissolved in 60mL dichloromethane solvent, then, cooling down is to about-10 DEG C, and control under the condition of-10 DEG C ~-5 DEG C, instill piperidines 3mL, after dropwising, after carrying out reaction 18h under being slowly warming up to the condition of 30 DEG C, stratographic analysis is adopted to carry out following the tracks of (elutriant that chromatogram tracking adopts is ethyl acetate: the volume ratio of ethanol is 9:1), after reacting completely, carry out the solvent in underpressure distillation removing system, wash-out is carried out again through column chromatography, be separated, collect the elutriant containing product, underpressure distillation removes desolventizing and obtains final product white solid product formula I-h compound N-[4-(4-bromophenyl) (phenyl) methyl]-N '-[(the bromo-1H-indol-3-yl of 5-) oxoacetyl]-piperazine again, molar yield is 78%.The elutriant that described column chromatography adopts is the mixed solution of ethyl acetate and methyl alcohol, and described ethyl acetate: the volume ratio of methyl alcohol is 9:1.
Analyzed by the product obtained, concrete analysis result is as follows:
Fusing point mp:227 DEG C ~ 229 DEG C.
IR：3158cm -1,3082cm -1,3060cm -1,2970cm -1,1617cm -1,1477cm -1,1437cm -1,1233cm -1,998cm -1,807cm -1。
1H-NMR(d 6-DMSO,500MHz)δ：12.46(s,1H,NH),8.20-8.21(m,2H,Ar),7.51(d,1H,J＝8.6Hz,Ar),7.18-7.49(m,11H,Ar),4.41(s,1H,CH),3.65(s,2H,NCH 2),3.37(t,2H,J＝4.5Hz,NCH 2),2.42(t,2H,J＝4.6Hz,NCH 2),2.27(s,2H,NCH 2)。
ESI-MS,m/z(％)：580.4[(M+H) +,10],500.4[(M-Br) +,100]。
Anal.calcdforC 27H 23Br 2N 3O 2：C,55.79；H,3.99；N,7.23；O,5.50；Found：C,55.81；H,4.00；N,7.22；O,5.51。
Embodiment 9
A kind of N-(4-diphenyl-methyl)-N '-[(2-Methyl-1H-indole-3-base) oxoacetyl]-diethylenediamine compound, shown in the following I-i of structural formula of this compound:
Above-mentioned N-(4-diphenyl-methyl)-N '-[(2-Methyl-1H-indole-3-base) oxoacetyl]-diethylenediamine compound specifically adopts following methods to prepare:
R in the present embodiment Chinese style II compound 1for H, R 2for CH 3, and the R in formula III compound 3for H;
Formula II compound indole oxo Acetyl Chloride 98Min. (10mmol) and formula III compound diarylmethylpiperazine (10.5mmol) are dissolved in 100mLN, in N-dimethyl formyl (DMF) solvent, then, about 0 DEG C is cooled under the condition of ice-water bath, and control to instill piperidines 2mL under the condition of cooling bath, after dropwising, after carrying out reaction 12h under being slowly warming up to the condition of 25 DEG C, stratographic analysis can be adopted to carry out following the tracks of (elutriant that chromatogram tracking adopts is ethyl acetate: the volume ratio of ethanol is 8:1), if reaction not exclusively, then proceed reaction until after reacting completely, carry out the solvent in underpressure distillation removing system, wash-out is carried out again through column chromatography, be separated, collect the elutriant containing product, underpressure distillation removes desolventizing and obtains final product product as off-white solid formula I-i compound N-(4-diphenyl-methyl)-N '-[(2-Methyl-1H-indole-3-base) oxoacetyl]-piperazine again, molar yield is 78%.The elutriant that described column chromatography adopts is the mixed solution of ethyl acetate and methyl alcohol, and described ethyl acetate: the volume ratio of methyl alcohol is 9:1.
Analyzed by the product obtained, concrete analysis result is as follows:
Fusing point mp:199 DEG C ~ 201 DEG C.
IR：3180cm -1,3103cm -1,3058cm -1,2974cm -1,1610cm -1,1492cm -1,1457cm -1,1246cm -1,986cm -1,790cm -1。
1H-NMR(d 6-DMSO，500MHz)δ：12.22(s,1H,NH),7.88(s,1H,Ar),7.15-7.44(m,13H,Ar),4.38(s,1H,CH),3.66(s,2H,NCH 2),3.33(s,2H,NCH 2),2.59(s,3H,CH 3),2.41(s,2H,NCH 2),2.22(s,2H,NCH 2)。
ESI-MS,m/z(％)：438.2[(M+H) +,100]。
Anal.calcdforC 28H 27N 3O 2：C,76.86；H,6.22；N,9.60；O,7.31；Found：C,76.89；H,6.21；N,9.62；O,7.30。
Embodiment 10
A kind of N-[4-(4-chloro-phenyl-) (phenyl) methyl]-N '-[(2-Methyl-1H-indole-3-base) oxoacetyl]-diethylenediamine compound, shown in the following I-j of structural formula of this compound:
Above-mentioned N-[4-(4-chloro-phenyl-) (phenyl) methyl]-N '-[(2-Methyl-1H-indole-3-base) oxoacetyl]-diethylenediamine compound specifically adopts following methods to prepare:
R in the present embodiment Chinese style II compound 1for H, R 2for CH 3, and the R in formula III compound 3for Cl;
Formula II compound indole oxo Acetyl Chloride 98Min. (10mmol) and formula III compound diarylmethylpiperazine (11mmol) are dissolved in 50mLN, in N-dimethyl formyl (DMF) solvent, then, about 0 DEG C is cooled under the condition of ice-water bath, and control to instill piperidines 2mL under the condition of cooling bath, after dropwising, naturally after carrying out reaction 10h under being warming up to the condition of 25 DEG C, stratographic analysis is adopted to carry out following the tracks of (elutriant that chromatogram tracking adopts is ethyl acetate: the volume ratio of ethanol is 9:1), if reaction not exclusively, proceed reaction until after reacting completely, carry out the solvent in underpressure distillation removing system, wash-out is carried out again through column chromatography, be separated, collect the elutriant containing product, underpressure distillation removes desolventizing and obtains final product light gray solid product formula I-j compound N-[4-(4-chloro-phenyl-) (phenyl) methyl]-N '-[(2-Methyl-1H-indole-3-base) oxoacetyl]-piperazine again, molar yield is 85%.The elutriant that described column chromatography adopts is the mixed solution of ethyl acetate and methyl alcohol, and described ethyl acetate: the volume ratio of methyl alcohol is 9:1.
Analyzed by the product obtained, concrete analysis result is as follows:
Fusing point mp:180 DEG C ~ 182 DEG C.
IR：3180cm -1,3103cm -1,3058cm -1,2974cm -1,1610cm -1,1492cm -1,1457cm -1,1247cm -1,986cm -1,790cm -1。
1H-NMR(d 6-DMSO，500MHz)δ：12.22(s,1H,NH),7.87(s,1H,Ar),7.14-7.44(m,12H,Ar),4.43(s,1H,CH),3.66(s,2H,NCH 2),3.33(s,2H,NCH 2),2.59(s,3H,NCH 2),2.42(s,2H,NCH 2),2.24(s,2H,NCH 2)。
ESI-MS,m/z(％)：472.2[(M+H) +,100]。
Anal.calcdforC 28H 26ClN 3O 2：C,71.25；H,5.55；N,8.90；O,6.78；Found：C,71.26；H,5.54；N,8.89；O,6.79。
Embodiment 11
A kind of N-[4-(4-fluorophenyl) (phenyl) methyl]-N '-[(2-Methyl-1H-indole-3-base) oxoacetyl]-diethylenediamine compound, shown in the following I-k of structural formula of this compound:
Above-mentioned N-[4-(4-fluorophenyl) (phenyl) methyl]-N '-[(2-Methyl-1H-indole-3-base) oxoacetyl]-diethylenediamine compound specifically adopts following methods to prepare:
R in the present embodiment Chinese style II compound 1for H, R 2for CH 3, and the R in formula III compound 3for F;
Formula II compound indole oxo Acetyl Chloride 98Min. (10mmol) and formula III compound diarylmethylpiperazine (12mmol) are dissolved in 50mLN, in N-dimethyl formyl (DMF) solvent, then, about 0 DEG C is cooled under the condition of ice-water bath, and control to instill triethylamine 2mL under the condition of cooling bath, after dropwising, reaction 10 ~ 20h is carried out under being slowly warming up to the condition of 25 DEG C, allow to abundant reaction, stratographic analysis can be adopted in reaction process to carry out following the tracks of (elutriant that chromatogram tracking adopts is ethyl acetate: the volume ratio of ethanol is 9:1), after reacting completely, carry out the solvent in underpressure distillation removing system, wash-out is carried out again through column chromatography, be separated, collect the elutriant containing product, underpressure distillation removes desolventizing and obtains final product light gray solid product formula I-k compound N-[4-(4-fluorophenyl) (phenyl) methyl]-N '-[(2-Methyl-1H-indole-3-base) oxoacetyl]-piperazine again, molar yield is 79%.The elutriant that described column chromatography adopts is the mixed solution of ethyl acetate and methyl alcohol, and described ethyl acetate: the volume ratio of methyl alcohol is 9:1.
Analyzed by the product obtained, concrete analysis result is as follows:
Fusing point mp:>300 DEG C.
IR：3185cm -1,3085cm -1,3057cm -1,2973cm -1,1616cm -1,1508cm -1,1437cm -1,1245cm -1,986cm -1,800cm -1。
1H-NMR(d 6-DMSO，500MHz)δ：12.22(s,1H,NH),7.88(s,1H,Ar),7.11-7.46(m,12H,Ar),4.39(s,1H,CH),3.66(s,2H,NCH 2),3.33(s,2H,NCH 2),2.59(s,3H,CH 3),2.41(s,2H,NCH 2),2.22(s,2H,NCH 2)。
ESI-MS,m/z(％)：456.5[(M+2) +,60],457.4[(M+2) +,100]。
Anal.calcdforC 28H 26FN 3O 2：C,73.83；H,5.75；N,9.22；O,7.02；Found：C,73.81；H,5.75；N,9.21；O,7.03。
Embodiment 12
A kind of N-[4-(4-bromophenyl) (phenyl) methyl]-N '-[(2-Methyl-1H-indole-3-base) oxoacetyl]-diethylenediamine compound, shown in the following I-m of structural formula of this compound:
Above-mentioned N-[4-(4-bromophenyl) (phenyl) methyl]-N '-[(2-Methyl-1H-indole-3-base) oxoacetyl]-diethylenediamine compound specifically adopts following methods to prepare:
R in the present embodiment Chinese style II compound 1for H, R 2for CH 3, and the R in formula III compound 3for F;
Formula II compound indole oxo Acetyl Chloride 98Min. (10mmol) and formula III compound diarylmethylpiperazine (10mmol) are dissolved in 50mLN, in N-dimethyl formyl (DMF) solvent, then, about 0 DEG C is cooled under the condition of ice-water bath, and control to instill triethylamine 2mL under the condition of cooling bath, after dropwising, reaction 10 ~ 20h is carried out under being slowly warming up to the condition of 25 DEG C, allow to abundant reaction, stratographic analysis can be adopted in reaction process to carry out following the tracks of (elutriant that chromatogram tracking adopts is ethyl acetate: the volume ratio of ethanol is 9:1), after reacting completely, carry out the solvent in underpressure distillation removing system, wash-out is carried out again through column chromatography, be separated, collect the elutriant containing product, underpressure distillation removes desolventizing and obtains final product light gray solid product formula I-m compound N-[4-(4-bromophenyl) (phenyl) methyl]-N '-[(2-Methyl-1H-indole-3-base) oxoacetyl]-piperazine again, molar yield is 79%.The elutriant that described pillar layer separation adopts is the mixed solution of ethyl acetate and methyl alcohol, and described ethyl acetate: the volume ratio of methyl alcohol is 9:1.
Analyzed by the product obtained, concrete analysis result is as follows:
Fusing point mp:mp181 DEG C ~ 183 DEG C.
IR：3182cm -1,3085cm -1,3057cm -1,2970cm -1,1612cm -1,1491cm -1,1453cm -1,1246cm -1,986cm -1,789cm -1。
1H-NMR(d 6-DMSO,500MHz)δ：12.22(s,1H,NH),7.87(s,1H,Ar),7.15-7.49(m,12H,Ar),4.39(s,1H,CH),3.66(s,2H,NCH 2),3.38(s,2H,NCH 2),2.58(s,3H,CH 3),2.42(s,2H,NCH 2),2.24(s,2H,NCH 2)。
ESI-MS,m/z(％)：516.1[(M+H) +,100]。
Anal.calcdforC 28H 26BrN 3O 2：C,65.12；H,5.07；N,8.14；O,6.20；Found：C,65.15；H,5.06；N,8.15；O,6.19。
Certainly, the column chromatography adopted in above-described embodiment 1-12 also can adopt the mode of recrystallization to carry out purifying, carrying out recrystallization, can realize the effect of purifying equally as added in ethyl acetate solvent by the product obtained in embodiment 1-12.
The acid binding agent adopted in above-described embodiment 1-12 can adopt mineral alkali such as sodium bicarbonate, saleratus or sodium carbonate to replace, and can realize equally carrying out neutralizing effect to the HCl that reaction process produces, reaction is carried out to positive dirction.
Corresponding indole oxo acetyl (N-bis-arylmethyl) the piperazine derivatives compound obtained in random selecting above-described embodiment 1-12, carries out vitro detection display and whether has obvious anti-tumor activity.
Concrete testing method adopts tetrazolium reduction method (mtt assay);
Select human cervical carcinoma cell strain Hela, people lung cancer A549, human stomach cancer cell line ECA-109, action time is 48h.
With cis-platinum (Cisplatin) to the restraining effect of corresponding tumor cell line for check analysis.
Concrete test result is as shown in table 1 below.
With the data in following table 1 be the compound that obtains using corresponding embodiment 1-12 as medicine, to the restraining effect of the corresponding tumor cell in vitro strain of the above-mentioned cell strain selected.
Data results in above-mentioned table 1 is the average of three parallel test results.
Table 1:
Data as can be seen from above-mentioned table 1, the cell of cis-platinum to Hela, A-549, ECA-109 has stronger resistancing action, its IC 50be respectively 17.50 μMs, 9.27 μMs, 12.73 μMs, suitable with bibliographical information, and relative to the restraining effect of cis-platinum to above-mentioned tumour cell, respective compound of the present invention has good restraining effect equally to above-mentioned tumour cell, and some compound of the present invention has stronger restraining effect to some tumour cell, biological activity is higher, if I-a, I-b, I-e, I-h are to the restraining effect IC of Hela 50be respectively 6.75 μMs, 4.06 μMs, 4.78 μMs and 5.21 μMs, be also eager to excel than the restraining effect of cis-platinum to corresponding tumour cell; And I-e, I-h are to the restraining effect IC of ECA-109 50be respectively 2.13 μMs and 2.60 μMs, restraining effect is better than cis-platinum 5-6 far away doubly.Visible, indole oxo acetyl of the present invention (N-bis-arylmethyl) piperazine compounds has stronger restraining effect to tumour cell, is expected to be applied in the medicine and food preparing prevention and therapy tumor disease, is with a wide range of applications.
Specific embodiment described in the present invention is only to the explanation for example of the present invention's spirit.Those skilled in the art can make various amendment or supplement or adopt similar mode to substitute to described specific embodiment, but can't depart from spirit of the present invention or surmount the scope that appended claims defines.
Although made a detailed description the present invention and quoted some specific embodiments as proof, to those skilled in the art, only otherwise it is obvious for leaving that the spirit and scope of the present invention can make various changes or revise.

Claims (10)

1. indole oxo acetyl (N-bis-arylmethyl) bridged piperazine derivatives, is characterized in that, the chemical structural formula of this derivative is as shown in the formula shown in I:
In formula I, described R 1and R 3independently be selected from H or halogen, described R separately 2be selected from H or C 1~ C 3alkyl.
2. indole oxo acetyl (N-bis-arylmethyl) bridged piperazine derivatives according to claim 1, is characterized in that, described R 1be selected from H or Br, described R 2be selected from H or CH 3, described R 3be selected from H, F, Cl or Br.
3. a preparation method for indole oxo acetyl (N-bis-arylmethyl) bridged piperazine derivatives, is characterized in that, the chemical structural formula of this derivative is as shown in the formula shown in I:
In formula I, described R 1and R 3independently be selected from H or halogen, described R separately 2be selected from H or C 1~ C 3alkyl; The preparation method of this derivative comprises the following steps:
Under acid binding agent existent condition, formula II compound indole oxo Acetyl Chloride 98Min. and formula III compound diarylmethylpiperazine are reacted, obtains type I compound indole oxo acetyl (N-bis-arylmethyl) piperazine derivatives compound;
Wherein, the R in formula II compound 1and R 2the R corresponding to type I compound 1and R 2one_to_one corresponding, the R in formula III compound 3the R corresponding to type I compound 3corresponding.
4. the preparation method of indole oxo acetyl (N-bis-arylmethyl) bridged piperazine derivatives according to claim 3, it is characterized in that, described acid binding agent is selected from one or more in triethylamine, 4-(N, N-dimethyl) pyridine, pyridine and piperidines.
5. the preparation method of indole oxo acetyl (N-bis-arylmethyl) bridged piperazine derivatives according to claim 3 or 4, it is characterized in that, described reaction is carried out in organic solvent, and described organic solvent can dissolution type II compound indole oxo Acetyl Chloride 98Min. and formula III compound diarylmethylpiperazine.
6. the preparation method of indole oxo acetyl (N-bis-arylmethyl) bridged piperazine derivatives according to claim 5, it is characterized in that, described organic solvent is selected from one or more in tetrahydrofuran (THF), N, N-dimethyl formyl, chloroform and methylene dichloride.
7. the preparation method of indole oxo acetyl (N-bis-arylmethyl) bridged piperazine derivatives according to claim 3, it is characterized in that, the temperature of described reaction is 20 DEG C ~ 35 DEG C.
8. the preparation method of indole oxo acetyl (N-bis-arylmethyl) bridged piperazine derivatives according to claim 3, it is characterized in that, the mol ratio of described formula II compound and formula III compound is 1:1.0 ~ 1.2.
9. the preparation method of indole oxo acetyl (N-bis-arylmethyl) bridged piperazine derivatives according to claim 3, it is characterized in that, the method is specially:
Formula II compound indole oxo Acetyl Chloride 98Min. and formula III compound diarylmethylpiperazine are added in organic solvent, and control temperature adds acid binding agent under the condition of-10 DEG C ~ 10 DEG C, after adding, the condition of temperature to 20 DEG C ~ 35 DEG C is proceeded reaction, obtains type I compound indole oxo acetyl (N-bis-arylmethyl) piperazine derivatives compound.
10. an application for indole oxo acetyl (N-bis-arylmethyl) bridged piperazine derivatives as claimed in claim 1 or 2, is characterized in that, described type I compound is for the preparation of the medicine of prevention or treatment tumour or food.
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Application publication date: 20151230