CN105348170B - 1- (2- (carbohydrazide substituent group) -1H- indoles -5- base) -3- substituted urea derivative and preparation method - Google Patents
1- (2- (carbohydrazide substituent group) -1H- indoles -5- base) -3- substituted urea derivative and preparation method Download PDFInfo
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Abstract
1- (2- (carbohydrazide substituent group) -1H- indoles -5- base) -3- substituted urea derivative and preparation method, are related to urea derivative.Preparation method: synthesis ethyl pyruvate p-nitrophenyl hydrazone；Prepare 5- nitroindoline -2- carboxylic acid, ethyl ester；Prepare 5- amino -1H- indole -2-carboxylic ethyl ester；Prepare 5- isocyanate group -1H- indole -2-carboxylic ethyl ester；Prepare 5- (3- (4- methoxyl group -2- aminomethyl phenyl) urea groups) -1H- indole -2-carboxylic ethyl ester；Prepare 1- (2- (phosphinylidyne diazanyl) -1H- indoles -5- base) -3- (4- methoxyl group -2- aminomethyl phenyl) urea；Synthesize 1- (2- (carbohydrazide substituent group) -1H- indoles -5- base) -3- substituted urea derivative.1- (2- (carbohydrazide substituent group) -1H- indoles -5- base) -3- substituted urea derivative can be applied in the preparation of antitumor drugs.
Description
Technical field
The present invention relates to urea derivatives, more particularly, to a kind of 1- (2- (carbohydrazide substituent group) -1H- indoles -5- base) -
3- substituted urea derivative and preparation method.
Background technique
Cell maintains having for cell cycle by long-term evolution, the molecular regulation mechanism for developing and establishing a set of precision
Sequence carries out.The most basic feature of tumour cell then shows as cell cycle exception and cell infinite multiplication.With molecular biology
Deeply development, the molecular mechanism of cell cycle regulating are gradually recognized by people.Be in core status among these is referred to as thin
Born of the same parents' cycle dependent kinase family (cyclin-dependent kinases, CDKs), it is a kind of serine/threonine protein
Kinases.CDKs family is divided into two classes: the cell cycle regulation CDKs and CDKs for adjusting genetic transcription in function difference intracellular by it.
As the key factor in eukaryotic transcription regulation process, positive transcriptional elongation factors b (positive transcription
Elongation factor b, P-TEFb) it is mainly the heterodimer being made of CDK9 and its regulatory protein CycT1.It is adjusting
During saving genetic transcription, CDK9 can in phosphorylation RNA polymerase II Ser2 and negative transcription in the region CTD extend because
Son promotes the progress of transcription.Studies have shown that CDK9 Active Regulation is current disease such as tumour in transcriptional control especially P-TEFb
The important target spot of equal treatments.Therefore design synthesis has that bioavilability is high, anticancer activity is obvious and low toxin
CDKs inhibitor is the hot spot studied at present.
The applicant discloses 5- (replacing carbon acylamino) -1H- indoles -2- carbohydrazide in Chinese patent CN104860866A
Derivative and its preparation method and application.Preparation method: 1) synthetic intermediate ethyl pyruvate p-nitrophenyl hydrazone；2) preparation is intermediate
Body 5- nitroindoline -2- carboxylic acid, ethyl ester；3) intermediate 5- amino -1H- indole -2-carboxylic ethyl ester is prepared；4) intermediate 5- is prepared
(replacing carbon acylamino) -1H- indole -2-carboxylic ethyl ester；5) intermediate 5- (replacing carbon acylamino) -1H- indoles -2- phosphinylidyne is prepared
Hydrazine；6) N'- substituted methylene -5- (replacing carbon acylamino) -1H- indoles -2- carbohydrazide derivative is prepared.One kind N'- takes
For methylene -5- (replace carbon acylamino) -1H- indoles -2- carbohydrazide derivative can preparation prevention or treatment be related to CDK9 by
It is applied in body related disease drug.Reaction cost is low, and yield is high, and reaction process is simple and easy to control, has anticancer activity.
The applicant also discloses 1H- indoles -2- carbohydrazide derivative and its preparation in Chinese patent CN104829597A
Method and purposes.Preparation method: 1) synthetic intermediate ethyl pyruvate p-nitrophenyl hydrazone；2) intermediate 5- nitroindoline-is prepared
2- carboxylic acid, ethyl ester；3) intermediate 5- amino -1H- indole -2-carboxylic ethyl ester is prepared；4) 5- (4- (pyridin-3-yl) pyrimidine-is prepared
2- base amino) -1H- indole -2-carboxylic ethyl ester；5) 5- (4-- (pyridin-3-yl) pyrimidine -2-base) amino is prepared) -1H- indoles -
2- carbohydrazide；6) N'- substituent methyl subunit -5- ((4- (pyridin-3-yl) pyrimidine -2-base) amino) -1H- indoles -2- carbon is prepared
Hydrazide derivatives.It can be related to the purposes of CDK9 receptor associated diseases drug in preparation prevention or treatment.
Summary of the invention
The first object of the present invention is to provide a kind of 1- (2- (carbohydrazide substituent group) -1H- Yin with new construction
Diindyl -5- base) -3- substituted urea derivative and preparation method thereof.
The second object of the present invention is to provide one kind 1- (2- (carbohydrazide substituent group) -1H- indoles -5- base) -
3- substituted urea derivative application in preparation of anti-tumor drugs.
The structural formula of 1- (2- (carbohydrazide substituent group) -1H- indoles -5- the base) -3- substituted urea derivative are as follows:
Wherein, R1It is substituted or unsubstituted aryl, (C2-C8) alkyl；R2It is substituted or unsubstituted aryl, (C2-C8)
Alkyl.
The preparation method of 1- (2- (carbohydrazide substituent group) -1H- indoles -5- the base) -3- substituted urea derivative, including
Following steps:
1) synthesis of intermediate ethyl pyruvate p-nitrophenyl hydrazone
Paranitrophenylhydrazine and dehydrated alcohol are sequentially added in reaction flask, then pyruvic acid second is added in electromagnetic agitation state
Ester, heating are heated to back flow reaction, and reaction solution is cooled to room temperature, and filter, and collect filter cake, dry to obtain yellow intermediate pyruvic acid second
Ester p-nitrophenyl hydrazone；
2) preparation of intermediate 5- nitroindoline -2- carboxylic acid, ethyl ester
In reaction flask, ethyl pyruvate p-nitrophenyl hydrazone and polyphosphoric acids are sequentially added；Again under electromagnetic agitation state
80~100 DEG C are warming up to, insulation reaction, reaction solution is cooled to room temperature, water on the rocks, is filtered, and is collected filter cake, is dried to obtain green centre
Body 5- nitroindoline -2- carboxylic acid, ethyl ester；
3) preparation of intermediate 5- amino -1H- indole -2-carboxylic ethyl ester
In reaction flask, ethyl alcohol, water, acetic acid and iron powder are sequentially added；Again after stirring is warming up to 65~78 DEG C, add
Enter 5- nitroindoline -2- carboxylic acid, ethyl ester, insulation reaction, reaction solution heat filtering, filtrate decompression concentration removing solvent；Filtrate after concentration
In water is added, after ethyl acetate is added under stiring, finally with sodium bicarbonate tune pH to 7~8；Filtering, liquid separation, organic phase nothing
After aqueous sodium persulfate is dry, filtering, the crude product purified by silica gel column chromatography for separation that filtrate decompression is concentrated to get obtains red intermediate 5- ammonia
Base indole -2-carboxylic ethyl ester；
4) preparation of intermediate 5- isocyanate group -1H- indole -2-carboxylic ethyl ester
In reaction flask, methylene chloride is added；Solid phosgene is added under electromagnetic agitation state again to be dissolved in wherein；Then will
Reaction flask is placed under condition of ice bath, 5- amino -1H- indole -2-carboxylic ethyl ester reaction is added, then separated with silica gel column chromatography, is subtracted
Pressure concentration, obtains brown intermediate 5- isocyanate group -1H- indole -2-carboxylic ethyl ester；
5) preparation of intermediate 5- (3- (4- methoxyl group -2- aminomethyl phenyl) urea groups) -1H- indole -2-carboxylic ethyl ester
Under room temperature in reaction flask, toluene, 5- isocyanate group -1H- indole -2-carboxylic ethyl ester and 4- methoxy is added
Base -2-aminotoluene, outer temperature control system are condensed back reaction under the conditions of 85 DEG C, and reaction solution is cooling, filtering, again with toluene solution
Filter cake is washed, filter cake and by filtration cakes torrefaction is collected, obtains white intermediate 5- (3- (4- methoxyl group -2- aminomethyl phenyl) urea groups) -1H-
Indole -2-carboxylic ethyl ester；
6) preparation of intermediate 1- (2- (phosphinylidyne diazanyl) -1H- indoles -5- base) -3- (4- methoxyl group -2- aminomethyl phenyl) urea
In round-bottomed flask, 5- (3- (4- methoxyl group -2- aminomethyl phenyl) urea groups) -1H- indole-2-carboxylic acid second is sequentially added
Ester and ethyl alcohol, are added hydrazine hydrate after dissolution, outer temperature control system back flow reaction under the conditions of 80 DEG C filters reaction solution, and use ethyl alcohol
Solution washs filter cake, collects filter cake and obtains white intermediate 1- (2- (phosphinylidyne diazanyl) -1H- indoles -5- base) -3- (4- methoxyl group -2-
Aminomethyl phenyl) urea；
7) synthesis of 1- (2- (carbohydrazide substituent group) -1H- indoles -5- base) -3- substituted urea derivative
In round-bottomed flask, 1- (2- (phosphinylidyne diazanyl) -1H- indoles -5- base) -3- (4- methoxyl group -2- methyl is sequentially added
Phenyl) urea and P-methoxybenzal-dehyde, dehydrated alcohol is added as solvent, and 1 drop trifluoro is added dropwise after dissolution into reaction system
Acetic acid is stirred overnight at room temperature as catalyst, and reaction solution is filtered by vacuum, and takes filter cake, and ((carbohydrazide takes 2- dry white 1-
For group) -1H- indoles -5- base) -3- substituted urea derivative.
In step 1), the mol ratio of the nitrophenyl hydrazine, dehydrated alcohol and ethyl pyruvate can be 1: (5~15):
1.2；The time of the back flow reaction can be 1~2h, and yield is up to 89%~95%.
In step 2), the mol ratio of the ethyl pyruvate p-nitrophenyl hydrazone and polyphosphoric acids can be 1: (10~
15)；The time of the insulation reaction can be 1~2h, and yield is up to 88%~95%.
In step 3), the mol ratio of the 5- nitroindoline -2- carboxylic acid, ethyl ester, iron powder, ethyl alcohol, water, ethyl acetate
It can be 1: 4: 40: 133: 25；The time of the insulation reaction can be 1~2h；The amount that water is added can be isometric with ethyl alcohol, institute
The amount for stating addition ethyl acetate can be isometric with ethyl alcohol；The eluant, eluent of silica gel column chromatography separation can be petrol ether/ethyl acetate, stone
The volume ratio of oily ether and ethyl acetate can be 3: 1, and yield is up to 70%~85%.
In step 4), the 5- amino -1H- indole -2-carboxylic ethyl ester, methylene chloride, solid phosgene mol ratio
It can be 1: (10~20): 3；The time that 5- amino -1H- indole -2-carboxylic ethyl ester reaction is added can be 5h；It is described to use silica gel
The eluant, eluent of column chromatography for separation can be petrol ether/ethyl acetate, and the volume ratio of petroleum ether and ethyl acetate can be 10: 1 or 8: 1；
Yield is up to 70%~80%.
In step 5), the 5- isocyanate group -1H- indole -2-carboxylic ethyl ester, 4- methoxyl group -2-aminotoluene, toluene
Mol ratio can be 1: 2: (10~20)；The time for being condensed back reaction can be 2h；The condition of the drying can be 45
DEG C vacuum oven in dry 4~8h；Yield is up to 87%.
In step 6), 5- (3- (4- methoxyl group -2- aminomethyl phenyl) the urea groups) -1H- indole -2-carboxylic ethyl ester, second
Alcohol, hydrazine hydrate mol ratio can be 1: (20~30): 65；The time of the back flow reaction can be 5h；Yield is up to 70%.
In step 7), 1- (2- (phosphinylidyne diazanyl) -1H- indoles -5- the base) -3- (4- methoxyl group -2- aminomethyl phenyl)
Urea, P-methoxybenzal-dehyde, ethyl alcohol, trifluoroacetic acid mol ratio can be 1: 1.2: 20: 0.01；Yield is up to 71%.
1- (2- (carbohydrazide substituent group) -1H- indoles -5- the base) -3- substituted urea derivative can prepare it is antitumor
It is applied in drug.
Anti tumor activity in vitro test is carried out to compound using mtt assay: firstly, by each chemical combination under measurement a certain concentration
Object determines sensitive cells to the growth inhibition ratio of different tumour cells；9 pre-selection Compound cellular cytotoxic activities are measured again, are found
Under the concentration of 20uM/L, in addition to one of compound, the inhibiting rate of remaining compound on tumor cell is more than 60%；Most
Afterwards, measurement wherein higher three compounds of cytotoxic activity under various concentration to the inhibiting rate of tumour cell, calculate thin
IC of the born of the same parents to compound50It is worth (table 1), the tumour cell includes cervix cancer Hela cell, HepG2 cell, adenocarcinoma of lung H460
Cell.Cytotoxic activity test discovery, patents are in concentration dependent to the inhibition of growth of tumour cell, and are had certain
Selectivity (patents are to sub- cervical cancer Hela cells activity with higher), patents 1- (2- (2- carbohydrazide
Benzylidene) -1H- indoles -5- base) -3- normal-butyl urea, 1- normal-butyl -3- (2- (2- (4- is to ar-methoxy benzylidene) carbohydrazide
Base -1H- indoles -5- base) urea and 1- (2- (2- (4- is to ar-methoxy benzylidene) phosphinylidyne diazanyl) -1H- indoles -5- base) -3- phenylurea
To the IC of Hela cell50Value is 5.3uM/L, 6.6uM/L, 5.3uM/L respectively.
The present invention provides a kind of 1- (2- (carbohydrazide substituent group) -1H- indoles -5- base) -3- with new construction to take
For urea derivative, in addition new construction introduces work in addition to having and sharing N substituent group in the patent mentioned in background technique
The higher urea derivative group of property, novelty with higher in structure, while also having higher anti-tumor activity.
Preparation method provided by the present invention, reaction cost is low, and yield is high, and reaction process is simple and easy to control, is suitable for work
Industry metaplasia produces, and the analog derivative has certain anti-tumor activity, can be used for preparing anti-tumor drug and studies such chemical combination
The structure-activity relationship of object.
Specific embodiment
To facilitate the understanding of the present invention, now in conjunction with specific embodiment, the present invention is further described, further to annotate
The present invention, but the limitation to any mode of the invention is not constituted.
Embodiment 1:1- (2- (2- benzylidene phosphinylidyne diazanyl) -1H- indoles -5- base) -3- normal-butyl urea
In dry 25mL round-bottomed flask, 1- normal-butyl -3- (2- (phosphinylidyne diazanyl) -1H- indoles -5- base) is sequentially added
Urea (100mg, 0.35mmol), benzaldehyde (36.68mg, 0.35mmol), dehydrated alcohol (5mL) are used as solvent, and stirring fills it
Divide dissolution.Trifluoroacetic acid is dripped as catalyst then at being added dropwise 1 into reaction system at room temperature.It is stirred overnight at room temperature, TLC detection is anti-
After answering completely, reaction was completed.Reaction solution is filtered, filter cake, dry white solid 41.74mg, yield 32% are collected.
Spectral data:
1H NMR(600MHz,DMSO-d6):δ11.83(brs,1H),11.62(brs,1H),8.46(brs,1H),8.21
(s, 1H), 7.81 (brs, 1H), 7.76 (d, J=7.15Hz, 2H), 7.39~7.58 (m, 4H), 7.34 (d, J=8.62Hz,
1H), 7.21 (brs, 1H), 7.11 (dd, J=1.83,8.80Hz, 1H), 6.02 (t, J=5.59Hz, 1H), 3.10 (q, J=
6.72Hz, 2H), 1.38~1.49 (m, 2H), 1.26~1.38 (m, 2H), 0.91 (t, J=7.34Hz, 3H)；13C NMR
(151MHz,DMSO-d6):δ189.1,158.1,156.2,147.4,140.8,135.0,134.8,134.0,133.4,
130.7,130.4,129.8,129.3,129.1,127.5,118.2,112.8,110.1,103.7,62.2,56.5,20.0,
19.0,14.2,6.2；HRMS(+):m/z 378.1943([M+H]+,C21H23N5O2H+calcd:378.1933.
Embodiment 2:1- normal-butyl -3- (2- (2- propylidene phosphinylidyne diazanyl) -1H- indoles -5- base) urea
With the synthesis of embodiment 1, the reactant propionic aldehyde (20.1mg, 0.34mmol) finally put into finally divides reaction step
From obtaining white solid product 48.99mg, yield 46%.
Spectral data:
1H NMR(600MHz,DMSO-d6)δ11.60(brs,1H),11.43(brs,1H),9.71(s,1H),8.67(s,
1H), 8.63 (s, 1H), 7.83 (s, 1H), 7.72~7.81 (m, 2H), 7.65~7.72 (m, 2H), 7.58 (d, J=8.80Hz,
2H), 7.34 (d, J=8.80Hz, 1H), 7.36 (d, J=9.35Hz, 1H), 7.08~7.26 (m, 3H), 6.96~7.08 (m,
1H), 6.76~6.96 (m, 2H), 6.73 (dd, J=2.75,8.80Hz, 2H), 3.72 (s, 6H), 1.91~2.07 (m, 4H)；13C NMR(151MHz,DMSO-d6)δ161.7,157.8,155.7,155.6,154.0,148.1,133.4,133.3,133.1,
133.0,131.3,131.1,131.1,131.0,131.0,127.7,127.6,124.3,124.3,118.0,117.5,
115.9,112.9,112.8,111.7,110.4,103.3,102.2,55.6,18.8,18.5,14.8；HRMS(+):m/z
330.1928([M+H]+,C17H23N5O2H+calcd:330.1931.
Embodiment 3:1- normal-butyl -3- (2- (2- (4- is to ar-methoxy benzylidene) phosphinylidyne diazanyl) -1H- indoles -5- base) urea
Reaction step with the synthesis of embodiment 1, the reactant P-methoxybenzal-dehyde that finally puts into (37.5mg,
0.35mmol), white solid product 78.86g, yield 56% are finally separating to obtain.
Spectral data:
1H NMR(600MHz,DMSO-d6)δ11.58(brs,1H),11.42(brs,1H),8.70(brs,1H),7.83
(brs, 1H), 7.73 (brs, 2H), 7.57 (d, J=8.80Hz, 1H), 7.36 (d, J=8.44Hz, 1H), 7.10~7.20 (m,
2H), 6.78 (brs, 1H), 6.70~6.76 (m, 1H), 3.72 (s, 3H), 2.23 (s, 3H), 1.50 (brs, 2H), 1.36 (d, J
=6.42Hz, 2H), 1.23 (brs, 1H), 0.92 (t, J=6.97Hz, 3H)；13C NMR(151MHz,DMSO-d6)δ157.9,
155.7,154.0,152.1,133.4,133.3,131.2,131.0,130.1,127.6,124.3,118.0,115.9,
112.9,111.7,110.5,103.3,55.6,31.7,29.5,29.3,29.0,28.7,27.0,22.5,22.2,18.5,
14.4,14.2；HRMS(+):m/z 408.2020([M+H]+,C22H25N5O3H+calcd:408.1016.
Embodiment 4:1- (2- (2-2- benzylidene base phosphinylidyne diazanyl) -1H- indoles -5- base) -3- (4- methoxyl group -2- first
Base phenyl) urea
In dry 25mL round-bottomed flask, 1- (2- (phosphinylidyne diazanyl) -1H- indoles -5- base) -3- (4- first is sequentially added
Oxygroup -2- aminomethyl phenyl) urea (0.15g, 0.42mmol), benzaldehyde (0.014g, 0.138mmol), dehydrated alcohol (5mL) conduct
Solvent, stirring dissolve it sufficiently.Trifluoroacetic acid is dripped as catalyst then at being added dropwise 1 into reaction system at room temperature.Room temperature is stirred
It mixes overnight, after TLC detects fully reacting, reaction was completed.Reaction solution is filtered, filter cake, dry white solid are collected
117.18mg yield 67%.
Spectral data:
1H NMR(600MHz,DMSO-d6)δ11.70(brs,1H),11.58(brs,1H),8.40(brs,1H),8.20
(s, 1H), 7.79 (brs, 1H), 7.70 (d, J=8.25Hz, 2H), 7.33 (d, J=8.62Hz, 1H), 7.07~7.14 (m,
1H), 7.04 (d, J=7.70Hz, 2H), 6.01 (t, J=5.50Hz, 1H), 3.82 (s, 3H), 3.10 (q, J=6.79Hz,
2H), 1.43 (quin, J=7.20Hz, 2H), 1.27~1.38 (m, 2H), 0.91 (t, J=7.34Hz, 3H)；13C NMR
(151MHz,DMSO-d6)δ161.3,158.0,156.2,147.4,133.9,133.3,130.8,129.1,127.6,127.4,
118.1,114.8,112.8,110.0,103.5,55.8,20.0,14.2；HRMS(+):m/z 442.1839([M+H]+,
C25H23N5O3H+calcd:442.1841.
Embodiment 5:1- (4- methoxyl group -2- aminomethyl phenyl) -3- (2- (2- pentylidene phosphinylidyne diazanyl) -1H- indoles -5- base)
Urea
Reaction step is with the synthesis of embodiment 4, the reactant valeraldehyde (24.36mg, 0.283mmol) finally put into, most
Isolated white solid product 41.74mg afterwards, yield 35%.
Spectral data:
1H NMR(600MHz,DMSO-d6)δ8.18(s,1H),7.75(brs,2H),7.29(brs,1H),7.09(brs,
2H), 6.00 (s, 1H), 5.74~6.16 (m, 1H), 3.00~3.18 (m, 2H), 2.31 (brs, 2H), 1.37~1.54 (m,
2H), 1.23~1.37 (m, 2H), 1.09 (t, J=7.34Hz, 3H), 0.90 (t, J=7.34Hz, 3H)；13C NMR(151MHz,
DMSO-d6)δ157.9,156.2,152.8,133.8,130.8,127.6,117.9,112.7,110.0,103.2,32.4,
26.9,25.9,20.0,14.2,12.2,11.2；HRMS(+):m/z 422.2132([M+H]+,C24H21N5O3H+calcd:
422.2131).
Embodiment 6,1- (4- methoxyl group -2- aminomethyl phenyl) -3- (2- (2- (4- is to methoxybenzylidene) carbohydrazide) -
1H- indoles -5- base) urea
Reaction step with the synthesis of embodiment 4, the reactant P-methoxybenzal-dehyde that finally puts into (68.54mg,
0.504mmol), white solid product 144.1mg, yield 72% are finally separating to obtain.
Spectral data:
1H NMR(DMSO-d6):δ11.72(1H,brs),11.65(1H,brs),8.68(1H,brs),8.40(1H,
), brs 7.87 (1H, brs), 7.71 (3H, brs), 7.59 (1H, d, J=8.4Hz), 7.38 (1H, d, J=8.1Hz), 7.21
(1H, brs), 7.16 (1H, d, J=7.9Hz), 7.04 (2H, d, J=6.8Hz), 6.79 (1H, brs), 6.74 (1H, d, J=
8.3Hz),3.82(3H,s),3.72(3H,s),2.23(3H,s)；13C NMR(150MHz,DMSO-d6)δ161.3,157.9,
155.6,153.9,147.4,131.0,131.0,129.1,127.6,127.4,124.2,118.1,115.9,114.8,
112.9,111.6,110.5,110.4,103.6,55.8,55.6,18.6；HRMS:calcd for C26H25N5O4；[M+H]+
472.1979,found:472.1980
Embodiment 7,1- (2- (2- benzylidene phosphinylidyne diazanyl) -1H- indoles -5- base) -3- phenylurea
In dry 25mL round-bottomed flask, 1- (2- (carbon diazanyl) -1H- indoles -5- base) -3- phenylurea is sequentially added
(0.15g, 0.42mmol), P-methoxybenzal-dehyde (68.54mg, 0.504mmol), dehydrated alcohol (5mL) are used as reaction dissolvent,
It is dissolved sufficiently under the conditions of electromagnetic agitation.Trifluoroacetic acid is dripped as catalyst then at being added dropwise 1 into reaction system at room temperature.Room
Temperature is stirred overnight, and after TLC detects fully reacting, reaction was completed.Reaction solution is filtered, collects filter cake, and in thermostatic drying chamber
Dry white solid 91.86mg, yield 66%.
Spectral data:
1H-NMR(600MHz,DMSO-d6)δ11.86(brs,1H),11.70(brs,1H),8.59(brs,1H),8.51
(brs, 1H), 8.48 (brs, 1H), 7.88 (brs, 1H), 7.77 (brs, 2H), 7.48 (d, J=6.60Hz, 5H), 7.40 (d, J
=6.97Hz, 1H), 7.28 (brs, 3H), 7.18 (d, J=7.52Hz, 1H), 6.96 (brs, 1H)；13C-NMR(150MHz,
DMSO-d6)δ158.1,153.4,147.5,140.5,134.8,133.8,132.9,130.9,130.5,129.3,129.2,
127.5,122.0,118.5,113.0,111.0,103.9；HRMS:calcd for C23H19N5O2[M+H]+
398.1612found 398.1613
Embodiment 8,1- (2- (2- butylidene phosphinylidyne diazanyl) -1H- indoles -5- base) -3- phenylurea
Reaction step is with the synthesis of embodiment 7, the reactant butyraldehyde (36.288g, 0.504mmol) finally put into, finally
Isolated white solid product 27.20mg, yield 23%.
Spectral data:
1H-NMR(600MHz,DMSO-d6)δ11.61(brs,1H),11.42(brs,1H),8.58(s,1H),8.48(s,
1H), 7.83 (s, 1H), 7.76 (brs, 1H), 7.47 (d, J=7.70Hz, 2H), 7.37 (d, J=8.44Hz, 1H), 7.28 (t,
J=7.79Hz, 2H), 7.16 (d, J=9.54Hz, 2H), 6.96 (t, J=7.34Hz, 1H), 2.31 (br.s., 2H), 1.09
(t, J=6.97Hz, 3H)；13C-NMR(150MHz,DMSO-d6)δ157.9,153.4,152.9,140.5,133.6,132.8,
131.1,129.2,127.6,122.0,118.5,118.2,112.9,110.9,103.3,25.9,11.2；HRMS:calcd
for C19H19N5O2[M+H]+350.1612found 350.1610,
Embodiment 9,1- (2- (2- (4- is to ar-methoxy benzylidene) phosphinylidyne diazanyl) -1H- indoles -5- base) -3- phenylurea
Reaction step is with the synthesis of embodiment 7, the reactant benzaldehyde (53.424g, 0.504mmol) finally put into, most
Isolated white solid product 45.28mg afterwards, yield 35%.
Spectral data:
1H NMR(600MHz,DMSO-d6)δ11.74(brs,1H),11.67(brs,1H),8.59(s,1H),8.51(s,
1H), 8.41 (brs, 1H), 7.87 (brs, 1H), 7.71 (d, J=7.89Hz, 2H), 7.48 (d, J=7.89Hz, 2H), 7.40
(d, J=8.44Hz, 1H), 7.28 (t, J=7.79Hz, 2H), 7.23 (brs, 1H), 7.18 (d, J=8.62Hz, 1H), 7.04
(d, J=7.52Hz, 2H), 6.96 (t, J=7.24Hz, 1H), 3.82 (s, 3H)；13C NMR(151MHz,DMSO-d6)δ
161.3,157.9,153.4,147.5,140.5,133.7,132.9,131.1,129.2,129.1,127.6,127.4,
122.0,118.5,118.4,114.8,113.0,110.9,103.6,55.8,；HRMS(+):m/z 428.1643([M+H]+,
C20H21N5O2H+calcd:428.1643.
Table 1
Table 1 is 1- (2- (2- carbohydrazide benzylidene) -1H- indoles -5- base) -3- normal-butyl urea, 1- normal-butyl -3- (2-
(2- (4- is to ar-methoxy benzylidene) phosphinylidyne diazanyl -1H- indoles -5- base) urea and 1- (2- (2- (4- is to ar-methoxy benzylidene) phosphinylidyne
Diazanyl) -1H- indoles -5- base) -3- phenylurea is respectively to sub- cervical cancer Hela cells, hepatoma Hep G 2 cells, adenocarcinoma of lung H460 cell
IC50Value.
Claims (2)
1.1- (2- (carbohydrazide substituent group) -1H- indoles -5- base) -3- substituted urea derivative, it is characterised in that structural formula is
Wherein, R1Represent 4- methoxyl group -2- aminomethyl phenyl, phenyl, butyl；R2Represent phenyl, p-methoxyphenyl.
2. (2- (carbohydrazide substituent group) -1H- indoles -5- the base) -3- substituted urea derivative of 1- described in claim 1 is anti-in preparation
Application in tumour medicine.
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| WO2005030716A1 (en) * | 2003-09-25 | 2005-04-07 | Wyeth | Heterocyclic- or aryloxy, -thio or -amino substituted indoles-2-carboxylic acids or esters as pai-1 |
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| WO2005030716A1 (en) * | 2003-09-25 | 2005-04-07 | Wyeth | Heterocyclic- or aryloxy, -thio or -amino substituted indoles-2-carboxylic acids or esters as pai-1 |
| CN1950356A (en) * | 2004-01-30 | 2007-04-18 | 临床遗传公司 | Hydrazide type compounds and the use thereof in pharmaceutical compositions for the treatment of cardiovascular diseases |
| CN104829597A (en) * | 2015-05-25 | 2015-08-12 | 厦门大学 | 1H-indol-2-carbohydrazide derivative as well as preparation method and use of derivative |
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