CN107915726A - New 3,5 2 substitution 1H indole derivativeses and its synthesis and application - Google Patents

New 3,5 2 substitution 1H indole derivativeses and its synthesis and application Download PDF

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CN107915726A
CN107915726A CN201711277059.5A CN201711277059A CN107915726A CN 107915726 A CN107915726 A CN 107915726A CN 201711277059 A CN201711277059 A CN 201711277059A CN 107915726 A CN107915726 A CN 107915726A
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CN107915726B (en
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杨羚羚
晏婕
苏荟琳
王周玉
钱珊
王丽姣
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Xihua University
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

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Abstract

The invention discloses a kind of new 3,5 two substitution 1H indole derivativeses and its synthesis and application, its structural formula is as shown in Equation 11, and in formula, R is selected from halogen, C1~C6Methyl, C1~C6Methoxyl group, OH, COOH, SO3H or SO2NH2.Present invention also offers the method for preparing the compound, this method totally eight step, often walks reaction yield and is above 60%, and wherein four-step reaction yield is all higher than 90%, all compound purities of the present invention are all higher than 95%, meet purity needed for the test of later stage Anti-tumor angiogenesis.The compound 11a 11h that the present invention is prepared are respectively provided with pancreas cancer cell strain BxPC 3 preferable inhibitory activity, and the activity of compound is best wherein shown in formula 11e, IC50Up to 2.28 μm of ol/L, and the compound is to the almost non-toxic side effect of human normal cell line.

Description

New bis- substituted 1 H-indole derivatives of 3,5- and its synthesis and application
Technical field
The present invention relates to a kind of new bis- substituted 1 H-indole derivatives of 3,5- and its synthesis and application.
Background technology
Cancer is the second largest cause of the death except angiocardiopathy, and for global range, nearly 1/6th death is by cancer Disease is caused.The morbidity and mortality of cancer are still constantly riseing in recent years, and it is pernicious swollen that China in 2015 there are about 429.2 Wan Xinfa Knurl case and 281.4 ten thousand deaths, account for the 27% of nearly 22% and death of global new cases respectively.
The common drug of clinical treatment malignant tumour mainly includes traditional cytotoxic drug at present, such as adriamycin, 5- Fluorouracil, endoxan etc., and targeted drug, such as Sorafenib, Gefitinib, gram azoles replace Buddhist nun.Although these medicines Play preferable clinical efficacy in kinds of tumors treatment, but cytotoxic drug because generally existing toxicity it is big, patient tolerability The shortcomings of poor, receives a definite limitation in Clinical practice；Targeted drug is generally also because individual difference is big, drug resistance phenomenon is serious etc. Deficiency cannot reach clinical efficacy of great satisfaction.
In consideration of it, it is still one of key task of global new drug development task to carry out new type antineoplastic medicine research.
The content of the invention
To solve the above-mentioned problems, the present invention provides a kind of new 3,5-, bis- substituted 1 H-indole derivatives and its synthesis With application.
The present invention provides the compound shown in a kind of formula 11 or its stereoisomer or its pharmaceutically acceptable salt, Or its solvate or its pro-drug or its metabolite：
In formula, R is selected from halogen, C1~C6Methyl, C1~C6Methoxyl group ,-OH ,-COOH ,-SO3H or-SO2NH2。
Preferably, the position of the R substituent substitutes for 3 substitutions of compound shown in formula 11 or 4.
Preferably, the R is selected from halogen, C1~C4Methyl or C1~C4Methoxyl group.
It is further preferred that the structure of the compound is：
The present invention provides a kind of method for preparing aforesaid compound, it comprises the following steps：
(1) by POCl3Add in DMF, stir 0.5h, add compound shown in formula 1, compound shown in formula 2 is made；
(2) compound, di-tert-butyl dicarbonate, 4-dimethylaminopyridine shown in formula 2 are added in tetrahydrofuran, are made Compound shown in formula 3；
(3) successively by compound, NaBH shown in formula 34Add in methanol, be quenched, compound shown in formula 4 is made；
(4) compound, thionyl chloride shown in formula 4 are added in DCM successively, react 1.5h, be quenched, be made shown in formula 5 Compound；
(5) by compound, K shown in compound shown in formula 5, formula 62CO3Add in DMF, compound shown in formula 7 is made；
(6) by compound, iron powder, NH shown in formula 74Cl is added in absolute ethyl alcohol and water, and compound shown in formula 8 is made；
(7) compound shown in compound shown in formula 8, formula 9, HOBT, EDCI, DIEA are added in DCM successively, formula 10 is made Shown compound；
(8) compound shown in formula 10, trifluoroacetic acid are added in DCM, target compound 11 is made.
Preferably, in step (1), the POCl3Temperature when adding in DMF is 0 DEG C；Compound shown in the formula 1, POCl3, DMF molar ratio be 1:8:10；Compound shown in the formula 2 is by the way that reaction solution obtained by after reaction is adjusted pH successively For 7, extract, be concentrated to give；The adjusting pH is to adjust pH using 6N NaOH；The extraction is that profit is extracted with ethyl acetate 3 It is secondary；
In step (2), the reaction temperature is 25 ± 2 DEG C；The reaction time is 3h；Compound, two shown in the formula 2 Dimethyl dicarbonate butyl ester, 4-dimethylaminopyridine, the rate of charge of tetrahydrofuran are 18.9:20.8:1:76.9mmol/mmol/mmol/ ml；Formula shown in the formula 3 by concentrating the reaction solution after reaction, being recrystallized to give successively；
In step (3), the reaction temperature is 25 ± 2 DEG C；The reaction time is 0.5h；Compound shown in the formula 3, NaBH4, methanol rate of charge be 1:2.16:5.26mmol/mmol/ml；Described be quenched is that reaction is quenched using acetone；It is described Compound shown in formula 4 is that concentration, column chromatography obtain；The column chromatography is with PE:EA=3:1 is eluant, eluent；
In step (4), the reaction temperature is 25 ± 2 DEG C；Compound shown in the formula 4, thionyl chloride, DCM feed intake Than for 1:4:4.2mmol/mmol/ml；Described be quenched be plus water quenching is gone out reaction；Compound shown in the formula 5 is by extracting, doing Dry, concentration, column chromatography obtain；The extraction is extracted 3 times using DCM；The drying is dried using anhydrous magnesium sulfate；It is described Column chromatography is with PE:EA=4:1 is eluant, eluent；
In step (5), the reaction temperature is 25 ± 2 DEG C；The reaction time is 12h；Compound shown in the formula 5, K2CO3, compound shown in formula 6, the rate of charge of DMF be 1:2:1.23:3.85mmol/mmol/mmol/ml；7 shownization of formula Compound be by diluting, extracting, washing, drying, concentrating, column chromatography obtains；The dilution is plus 10 times of water dilute；The extraction It is that profit is extracted with ethyl acetate 3 times；The washing is to utilize saturated common salt water washing；The drying is done using anhydrous magnesium sulfate It is dry；The column chromatography is with PE:EA=4:1 is eluant, eluent；
In step (6), the reaction temperature is 80 ± 2 DEG C；The reaction time is 0.5h；Compound shown in the formula 7, Iron powder, NH4Cl, absolute ethyl alcohol, the rate of charge of water are 1:5:0.48:12.9:6.45mmol/mmol/mmol/ml/ml；The formula Compound shown in 8 be by filtering, concentrating, diluting, extracting, washing, dry, concentrating, column chromatography obtains；The dilution is to add water Dilution；The extraction is that profit is extracted with ethyl acetate 3 times；The washing is to utilize saturated common salt water washing；The drying is profit Dried with anhydrous magnesium sulfate；The column chromatography is with PE:EA=1:1 is eluant, eluent；
In step (7), the reaction temperature is 25 ± 2 DEG C；The reaction time is 12h；Compound shown in the formula 8, Compound shown in formula 9, the rate of charge of HOBT, EDCI, DIEA, DCM are 0.69:1:1:1:2.13:7.5mmol/mmol/mmol/ mmol/mmol/ml；Compound shown in the formula 10 be by concentrating, washing, extracting, washing, drying, concentrating, column chromatography obtains Arrive；The washing is washed using saturated sodium bicarbonate；The extraction is that profit is extracted with ethyl acetate 3 times；The washing is profit With saturated common salt water washing；The drying is dried using anhydrous magnesium sulfate；The column chromatography is with DCM:MeOH=60:1 is Eluant, eluent；
In step (8), the reaction temperature is 25 ± 2 DEG C；The reaction time is 12h；Compound shown in the formula 10, Trifluoroacetic acid, the rate of charge of DCM are 1:0.94:9.4mmol/ml/ml；The target compound 11 is by adjusting PH as 8, extraction Take, dry, concentrating, column chromatography obtains；The adjusting pH is adjusted using saturated sodium bicarbonate；The extraction is to utilize acetic acid second Ester extracts 3 times；The drying is dried using anhydrous magnesium sulfate；The column chromatography is with DCM:MeOH=20:1 is eluant, eluent.
Compound shown in previously described formula 11 or its stereoisomer or its pharmaceutically acceptable salt or its solvate, Or its pro-drug or its metabolite are preparing the purposes in treating pancreatic cancer drug.
The invention discloses a kind of drug regimen, it be with aforesaid compound or its stereoisomer or its pharmaceutically may be used The salt of receiving or its solvate or its pro-drug or its metabolite are active ingredient, plus pharmaceutically acceptable Auxiliary material or auxiliary element are prepared into pharmaceutically common preparation.
In the present invention：
DCM is dichloromethane.
DMF is dimethylformamide.
HOBT is I-hydroxybenzotriazole.
EDCI is 1- (3- dimethylamino-propyls) -3- ethyl-carbodiimide hydrochlorides.
DIEA is N, N- diisopropylethylamine.
" room temperature " of the present invention is 25 ± 2 DEG C.
It is of the present invention it is " overnight " be 12 ± 1h.
Term " pharmaceutically acceptable " refers to certain carrier, load, diluent, auxiliary material, and/or the salt formed is usual In chemistry or physically with forming the other compatible into split-phase of certain pharmaceutical dosage form, and physiologically mutually compatible with acceptor.
Term " salt " and " pharmaceutically useful salt " refer to above-claimed cpd or its stereoisomer, with inorganic and/or organic acid The acid and/or basic salt formed with alkali, also including amphion salt (inner salt), further includes quaternary ammonium salt, such as alkylammonium salt.This A little salt can be directly obtained in being finally separating and purify of compound.Can also be by by above-claimed cpd, or it is vertical Body isomers, is obtained by mixing with a certain number of acid or alkali appropriate (such as equivalent).These salt may be in the solution Form precipitation and collected with filter method, or recycle and obtain after the solvent evaporates, or be freeze-dried after being reacted in aqueous medium It is made.Heretofore described salt can be hydrochloride, sulfate, citrate, benzene sulfonate, hydrobromate, the hydrogen of compound Fluorate, phosphate, acetate, propionate, succinate, oxalates, malate, succinate, fumarate, maleic acid Salt, tartrate or trifluoroacetate.
The present invention provides a kind of new 3,5-, bis- substituted 1 H-indole derivatives, while provide and prepare the compound Method, is related to Wei Er David Smails-Haake reaction (Vilsmeier-Haack), tertbutyloxycarbonyl (Boc) protection of secondary amine, aldehyde altogether Reduction, eight steps such as condensation of carboxylic acid and amine react, often walk reaction yield and be above 60%, and wherein four-step reaction yield is all high In 90%, all compound purities of the present invention are all higher than 95%, meet purity needed for the test of later stage Anti-tumor angiogenesis.This hair The bright compound 11a-11h being prepared is respectively provided with pancreas cancer cell strain BxPC-3 preferable inhibitory activity, wherein formula 11e institutes Show that the activity of compound is best, IC50Up to 2.28 μm of ol/L, and the compound is to the almost non-toxic side effect of human normal cell line.
Obviously, the above according to the present invention, according to the ordinary technical knowledge and customary means of this area, is not departing from Under the premise of the above-mentioned basic fundamental thought of the present invention, the modification, replacement or change of other diversified forms can also be made.
The embodiment of form by the following examples, remakes further specifically the above of the present invention It is bright.But the scope that this should not be interpreted as to the above-mentioned theme of the present invention is only limitted to following example.It is all to be based on the above of the present invention The technology realized belongs to the scope of the present invention.
Embodiment
The raw material that is used in the specific embodiment of the invention, equipment are known product, are obtained by buying commercial product.
The synthesis of 1 target compound of embodiment
1st, the synthesis of intermediate 2
At 0 DEG C, by POCl3(9.2ml, 98.5mmol) is stirred with being added drop-wise in DMF (9.5ml, 123.1mmol) After 0.5h, 5- nitro -1H- indoles (compound 1,2.0g, 12.3mmol) is added into reaction solution, is then reacted at room temperature 1.5h.Then it is 7 to pour into a large amount of frozen water and adjust pH with 6N NaOH reaction solution, then (× 3) are extracted with ethyl acetate, dense Contracting, obtains 2.34g gray solids, yield 98%, purity 95.2%.LCMS m/z:191.0[M+H]+。
2nd, the synthesis of intermediate 3
Respectively by compound 2 (2.34g, 12.3mmol), di-tert-butyl dicarbonate (2.95g, 13.5mmol), 4- diformazan ammonia Yl pyridines (75.8mg, 0.62mmol) are added into 50ml tetrahydrofurans, and react 3h at room temperature, are then concentrated, acetic acid second Ester carries out recrystallizing to obtain faint yellow solid 3.3g, yield 92%, purity 97.0%.LCMS m/z:291.1[M+H]+。
3rd, the synthesis of intermediate 4
Under ice bath, compound 3 (3.3g, 11.4mmol) is added in 60ml methanol, then to add NaBH4 Room temperature reaction 0.5h is moved to after (0.93g, 24.6mmol).Finally reaction is quenched with acetone, is concentrated, silica gel post separation (PE:EA =3:1) 3.03g yellow-brown solids, yield 91%, purity 96.57% are obtained.LCMS m/z:293.0[M+H]+。
4th, the synthesis of intermediate 5
Compound 4 (2.78g, 9.5mmol) is added in 40ml DCM, then at 0 DEG C, by thionyl chloride (2.75ml, 37.8mmol) is added to above reaction solution, and reaction solution is moved to room temperature reaction 1.5h.Finally plus water quenching is gone out reaction Extracted (× 3) with DCM afterwards, anhydrous magnesium sulfate drying, is concentrated under reduced pressure, silica gel post separation (PE:EA=4:1) it is solid that 2.0g whites are obtained Body, yield 67%, purity 95.7%.LCMS m/z:311.1[M+H]+。
5th, the synthesis of intermediate 7
1) synthesis of intermediate 7e
Respectively by compound 5 (400mg, 1.3mmol), K2CO3(357mg, 2.6mmol) and to fluoro thiophenol (compound 6, 165 μ l, 1.6mmol) add into 5ml DMF, and in room temperature reaction overnight.Then plus 10 times of water dilutions, ethyl acetate extract (× 3), saturated common salt water washing, anhydrous magnesium sulfate drying, concentration, silica gel post separation (PE:EA=4:1) 476mg solids, production are obtained Rate 92%, purity 96.0%.LCMS m/z:403.1[M+H]+。
2) synthesis of intermediate 7a~7j
Synthetic intermediate 7a~7j methods are identical with the method for synthetic intermediate 7e, and wherein 6a~6j corresponds to 6e, such as table 1 It is shown, intermediate 7a~7j is finally made.
Yield, the purity of raw material and product used in 1 synthetic intermediate 7a~7f of table
6th, the synthesis of intermediate 8
1) synthesis of intermediate 8e
Respectively by compound 7e (250mg, 0.62mmol), iron powder (174mg, 3.1mmol) and NH4Cl(17mg, 0.3mmol) add into absolute ethyl alcohol (8ml) and water (4ml), and 0.5h is reacted in 80 DEG C.Question response finishes, and filters while hot, Concentration, after being diluted with water, adds ethyl acetate extraction (× 3), saturated common salt water washing, anhydrous magnesium sulfate drying, concentration, silica gel Post separation (PE:EA=1:1) 196mg clear viscous liquid, yield 85%, purity 95.3%, are obtained.LCMS m/z:373.1[M+ H]+。
2) synthesis of intermediate 8a~8j
Synthetic intermediate 8a~8j methods are identical with the method for synthetic intermediate 8e, and wherein 7a~7j corresponds to 7e, such as table 2 It is shown, intermediate 8a~8j is finally made.
Yield, the purity of raw material and product used in 2 synthetic intermediate 8a~8f of table
7th, the synthesis of intermediate 10
1) synthesis of intermediate 10e
By 1- methyl isophthalic acid H- pyrazoles -4- carboxylic acids (9,101mg, 0.8mmol), compound 8e (200mg, 0.55mmol), HOBT (117mg, 0.8mmol), EDCI (154mg, 0.8mmol) and DIEA (266 μ l, 1.7mmol) are added to 6ml under ice bath In DCM, reaction solution is then moved into reaction at room temperature overnight.Concentrate after question response, washed with saturated sodium bicarbonate, acetic acid Ethyl ester extracts (× 3), saturated common salt water washing, anhydrous magnesium sulfate drying, concentration, silica gel post separation (DCM:MeOH=60:1) 225mg white solids, yield 87%, purity 98.1%.LCMS m/z:463.2[M+H]+。
2) synthesis of intermediate 10a~10j
Synthetic intermediate 10a~10j methods are identical with the method for synthetic intermediate 10e, and wherein 8a~8j corresponds to 8e, such as Shown in table 3, intermediate 10a~10j is finally made.
The raw material of 3 synthetic intermediate 10a~10f of table and yield, the purity of product
8th, the synthesis of target compound 11
1) synthesis of target compound 11e
Compound 10e (154mg, 0.32mmol) and trifluoroacetic acid (300 μ l, 10%) are added into 3ml DCM, then Reaction is stayed overnight at room temperature.After completion of the reaction PH=8, ethyl acetate extraction (× 3), anhydrous slufuric acid are adjusted with saturated sodium bicarbonate Magnesium is dried, concentration, silica gel post separation (DCM:MeOH=20:1) 82mg white solids, yield 60%, purity 96.7% are obtained.
It characterize：
LCMS m/z:363.1[M+H]+。
1H NMR(400MHz,DMSO)δ10.91(s,1H),9.73(s,1H),8.30(s,1H),8.05(s,1H),7.97 (s, 1H), 7.48-7.36 (m, 3H), 7.32 (d, J=8.4Hz, 1H), 7.24 (d, J=2.0Hz, 1H), 7.16 (t, J= 8.8Hz,2H),4.37(s,2H),3.91(s,3H)ppm。
13C NMR(100MHz,DMSO)δ162.4,160.7,139.2,133.7,132.9,132.8,131.6,131.5, 131.4,126.8,125.7,119.4,116.8,116.5,116.3,111.8,111.0,109.7,39.3,30.0ppm。
96.7%HPLC purity.
2) synthesis of target compound 11a
Target compound 11a is identical with the synthetic method of target compound 11e, and wherein the dosage of 10a corresponds to 10e, silicon Rubber column gel column separates (DCM:MeOH=20:1) white solid, yield 63%, purity 97.6% are obtained.
It characterize：
LCMS m/z:363.1[M+H]+；
1H NMR(400MHz,DMSO)δ10.96(s,1H),9.73(s,1H),8.30(s,1H),8.04(s,1H),7.98 (s, 1H), 7.44 (d, J=8.8Hz, 1H), 7.34 (t, J=12.0Hz, 3H), 7.24 (d, J=10.0Hz, 1H), 7.19 (d, J =8.4Hz, 1H), 6.99 (td, J=8.8,2.4Hz, 1H), 4.46 (s, 2H), 3.91 (s, 3H) ppm；
13C NMR(100MHz,DMSO)δ164.0,160.7,140.7,139.2,133.7,132.8,131.4,131.1, 126.8,125.9,123.8,119.4,116.8,114.4,112.5,111.8,111.0,109.1,39.3,28.4ppm；
97.6%HPLC purity.
3) synthesis of target compound 11b
Target compound 11b is identical with the synthetic method of target compound 11e, and wherein the dosage of 10b corresponds to 10e, silicon Rubber column gel column separates (DCM:MeOH=20:1) white solid, yield 65%, purity 98.1% are obtained.
It characterize：
LCMS m/z:397.1[M+H]+；
1H NMR(400MHz,DMSO)δ10.95(s,1H),9.72(s,1H),8.30(s,1H),8.04(s,1H),7.98 (s, 1H), 7.44 (d, J=9.2Hz, 2H), 7.36-7.28 (m, 4H), 7.26-7.18 (m, 1H), 4.46 (s, 2H), 3.91 (s, 3H)ppm；
13C NMR(100MHz,DMSO)δ160.7,140.5,139.2,134.0,133.7,132.8,131.4,130.9, 127.1,126.8,126.6,125.9,125.6,119.4,116.9,111.8,111.0,109.1,39.3,31.2ppm；
98.1%HPLC purity.
4) synthesis of target compound 11c
Target compound 11c is identical with the synthetic method of target compound 11e, and wherein the dosage of 10c corresponds to 10e, silicon Rubber column gel column separates (DCM:MeOH=20:1) white solid, yield 65%, purity 97% are obtained.
It characterize：
LCMS m/z:377.1[M+H]+；
1H NMR(400MHz,DMSO)δ10.92(s,1H),9.73(s,1H),8.30(s,1H),8.04(s,1H),7.97 (s, 1H), 7.44 (d, J=8.8Hz, 1H), 7.33-7.30 (m, 2H), 7.22-7.16 (m, 3H), 6.98 (d, J=6.8Hz, 1H),4.39(s,2H),3.91(s,3H),2.29(s,3H)ppm；
13C NMR(100MHz,DMSO)δ160.7,139.2,138.7,137.6,133.7,132.8,131.4,129.2, 128.8,126.9,126.6,125.7,125.4,119.4,116.8,111.7,111.0,109.7,39.3,28.7, 21.4ppm；
97.3%HPLC purity.
5) synthesis of target compound 11d
Target compound 11d is identical with the synthetic method of target compound 11e, and wherein the dosage of 10d corresponds to 10e, silicon Rubber column gel column separates (DCM:MeOH=20:1) white solid, yield 60%, purity 97% are obtained.
It characterize：
LCMS m/z:393.1[M+H]+；
1H NMR(400MHz,DMSO)δ10.93(s,1H),9.72(s,1H),8.29(s,1H),8.04(s,1H),7.98 (s, 1H), 7.44 (d, J=8.8Hz, 1H), 7.32 (d, J=9.2Hz, 2H), 7.23 (t, J=8.0Hz, 1H), 6.94 (d, J= 7.6Hz, 1H), 6.90 (s, 1H), 6.74 (d, J=10.0Hz, 1H), 4.41 (s, 2H), 3.91 (s, 3H), 3.74 (s, 3H) ppm；
13C NMR(100MHz,DMSO)δ160.7,160.0,139.2,139.1,133.7,132.8,131.4,130.2, 126.9,125.7,120.3,119.4,116.8,113.4,111.7,111.0,109.6,55.5,39.3,31.2ppm；
97.0%HPLC purity.
6) synthesis of target compound 11f
Target compound 11f is identical with the synthetic method of target compound 11e, and wherein the dosage of 10f corresponds to 10e, silicon Rubber column gel column separates (DCM:MeOH=20:1) white solid, yield 65%, purity 97.8% are obtained.
It characterize：
LCMS m/z:397.1[M+H]+；
1H NMR(400MHz,DMSO)δ10.93(s,1H),9.71(s,1H),8.29(s,1H),8.02(s,1H),7.95 (s,1H),7.44-7.27(m,7H),4.40(s,2H),3.90(s,3H)ppm；
97.8%HPLC purity.
7) synthesis of target compound 11g
Target compound 11g is identical with the synthetic method of target compound 11e, and wherein the dosage of 10g corresponds to 10e, silicon Rubber column gel column separates (DCM:MeOH=20:1) white solid, yield 66%, purity 98.2% are obtained.
It characterize：
LCMS m/z:377.1[M+H]+；
1H NMR(400MHz,DMSO)δ10.93(s,1H),9.71(s,1H),8.29(s,1H),8.02(s,1H),7.95 (s, 1H), 7.51-7.45 (m, 2H), 7.42 (dd, J=8.8,1.6Hz, 1H), 7.35-7.27 (m, 4H), 4.40 (s, 2H), 3.90(s,3H),3.35(s,3H)ppm；
98.2%HPLC purity.
8) synthesis of target compound 11h
Target compound 11h is identical with the synthetic method of target compound 11e, and wherein the dosage of 10h corresponds to 10e, silicon Rubber column gel column separates (DCM:MeOH=20:1) white solid, yield 63%, purity 97.6% are obtained.
It characterize：
LCMS m/z:393.1[M+H]+；
1H NMR(400MHz,DMSO)δ10.87(s,1H),9.73(s,1H),8.31(s,1H),8.05(s,1H),7.96 (s, 1H), 7.44 (d, J=8.8Hz, 1H), 7.31 (d, J=8.8Hz, 3H), 7.16 (d, J=2.4Hz, 1H), 6.90 (d, J= 8.8Hz,2H),4.27(s,2H),3.91(s,3H),3.74(s,3H)ppm；
13C NMR(100MHz,DMSO)δ160.7,158.7,139.2,133.7,132.8,132.4,131.3,127.4, 126.8,125.6,119.5,116.8,115.1,111.7,111.1,110.3,55.6,39.3,31.1ppm；
97.6%HPLC purity.
9) synthesis of target compound 11i
Target compound 11i is identical with the synthetic method of target compound 11e, and wherein the dosage of 10i corresponds to 10e, silicon Rubber column gel column separates (DCM:MeOH=20:1) white solid, yield 62%, purity 97.5% are obtained.
It characterize：
LCMS m/z:441.1[M+H]+；
1H NMR(400MHz,DMSO)δ10.97(s,1H),9.74(s,1H),8.30(s,1H),8.05(s,1H),7.99 (s, 1H), 7.55 (s, 1H), 7.45 (d, J=8.8Hz, 1H), 7.40-7.30 (m, 4H), 7.26 (t, J=8.0Hz, 1H), 4.46(s,2H),3.91(s,3H)ppm；
13C NMR(100MHz,DMSO)δ160.7,140.8,139.2,133.7,132.8,131.4,131.2,130.0, 128.5,127.0,126.8,125.9,122.6,119.4,116.9,111.8,111.0,109.1,39.3,28.6ppm；
97.8%HPLC purity.
10) synthesis of target compound 11j
LCMS m/z:441.1[M+H]+；
1H NMR(400MHz,DMSO)δ10.89(s,1H),9.71(s,1H),8.29(s,1H),8.03(s,1H),7.94 (d, J=1.6Hz, 1H), 7.43 (dd, J=8.8,2.0Hz, 1H), 7.33-7.21 (m, 4H), 7.12 (d, J=8.0Hz, 2H), 4.33(s,2H),3.90(s,3H)ppm；
97.9%HPLC purity.
Illustrate beneficial effects of the present invention with the mode of experimental example below：
Experimental example 1
1st, experiment material
DMEM：DMEM culture mediums
10%FBS：Hyclone
DMSO：Dimethyl sulfoxide (DMSO)
Experimental tumor cell line：Cancer of pancreas BxPC-3 cell lines, Human normal hepatocyte HL-7702
2nd, the preparation and processing of cell
First, cell line is inoculated into 96 orifice plates containing DMEM+10%FBS culture mediums, in 37 DEG C, 5%CO2Bar Overnight incubation under part.Next day, adds into culture plate at testing compound and the blank control of the diluted gradient concentration of culture medium Manage 72 it is small when, then to every hole add concentration be 5mg/mL 20 μ l of MTT reagents, continue cultivate 2-4h.Until after first a ceremonial jade-ladle, used in libation is formed, inhale Supernatant is removed, then the DMSO of 150 μ L is added into every hole, vibration makes the first a ceremonial jade-ladle, used in libation to be formed fully dissolve, and is measured using microplate reader Absorbance (OD570) under 570nm wavelength.
Finally, according to inhibiting rate=(blank control group OD570- experimental group OD570)/blank control group OD570 × 100%, inhibiting rate of the compound to various cells is calculated, and IC is tried to achieve using the fitting of Graphpad softwares50Value.
3rd, experimental result
3.1 suppress activity of tumor cells
We have chosen BxPC-3 pancreas cancer cell strains, test propagation of 10 target compounds to this two groups of cell lines Inhibitory activity, test result are shown in Table 4.
Inhibitory activity of the 4 target compound 11a-11j of table to pancreatic cancer cell
From table 4, it can be seen that target compound 11a-11j has preferable proliferation inhibition activity to BxPC-3 cell lines (IC5010 μm of ol/L of ＜), and more preferably (11e is excellent for the inhibition that phenyl 4- substitution substitutes than phenyl 3- in these compounds In 11a, 11f is better than 11b, and 11g is better than 11c, and 11h is better than 11d, and 11j is better than 11i).
11e is best to the proliferation inhibition activity of BxPC-3 cell lines in all 10 target compounds, IC50Up to 2.28 μ mol/L。
3.2 toxicity of compound
In order to verify whether target compound prepared by the present invention is cell toxicant class compound simultaneously preliminary assessment compound Toxicity, we test target compound 11e under 50 μm of ol/L concentration to kinds of tumor cells and Human normal hepatocyte HL- 7702 suppression vigor, test result are shown in Table 5.
Inhibitory activity of the 11e to kinds of tumor cells and Human normal hepatocyte HL-7702 in 5 target compound of table
As can be seen from Table 5, compound 11e only have up to 91 to pancreas cancer cell strain BxPC-3 in 50 μm of ol/L ± 5% inhibiting rate, and to other tumour cells such as breast cancer cell MDA-MB-231, lymphoma mantle cell cell JeKo-1, lung Cancer cell PC-9 and liver cancer cells HUH7 etc. are almost without inhibitory activity.It is that specificity inhibits pancreas to show target compound 11e The propagation of cancer cell line BxPC-3, and cell inhibitory effect caused by non-cytotoxicity reason.In addition 11e is under 50 μm of ol/L concentration Inhibiting rate to Human normal hepatocyte HL-7702 is only 17 ± 2%, shows the compound secondary work almost non-toxic to human normal cell line With.In view of result above, target compound 11e is a preferable anti-pancreatic cancer symptom of a trend compound.
To sum up, the present invention provides a kind of new 3,5-, bis- substituted 1 H-indole derivatives, while provide and prepare the chemical combination The method of thing, is related to Wei Er David Smails-Haake reaction (Vilsmeier-Haack), the tertbutyloxycarbonyl (Boc) of secondary amine is protected altogether Eight steps such as shield, the reduction of aldehyde, the condensation of carboxylic acid and amine are reacted, and are often walked reaction yield and are above 60%, and wherein four-step reaction produces Rate is all higher than 90%, and all compound purities of the present invention are all higher than 95%, meets pure needed for the test of later stage Anti-tumor angiogenesis Degree.The compound 11a-11h that the present invention is prepared is respectively provided with preferable inhibitory activity to pancreas cancer cell strain BxPC-3, wherein The activity of compound shown in formula 11e is best, IC50Up to 2.28 μm of ol/L, and the compound is to the almost non-toxic pair of human normal cell line Effect.

Claims (8)

1. compound or its stereoisomer or its pharmaceutically acceptable salt or its solvate shown in formula 11 or its Pro-drug or its metabolite：
In formula, R is selected from halogen, C1~C6Methyl, C1~C6Methoxyl group ,-OH ,-COOH ,-SO3H or-SO2NH2。
2. compound according to claim 1, it is characterised in that：The position of the R substituent is compound shown in formula 11 3 substitution or 4 substitution.
3. compound according to claim 1 or 2, it is characterised in that：The R is selected from halogen, C1~C4Methyl or C1~C4 Methoxyl group.
4. compound according to claim 3, it is characterised in that：The structure of the compound is：
A kind of 5. method for preparing compound described in Claims 1 to 4 any one, it is characterised in that：It comprises the following steps：
(1) by POCl3Add in DMF, stir 0.5h, add compound shown in formula 1, compound shown in formula 2 is made；
(2) compound, di-tert-butyl dicarbonate, 4-dimethylaminopyridine shown in formula 2 are added in tetrahydrofuran, formula 3 is made Shown compound；
(3) successively by compound, NaBH shown in formula 34Add in methanol, be quenched, compound shown in formula 4 is made；
(4) compound, thionyl chloride shown in formula 4 are added in DCM successively, react 1.5h, be quenched, chemical combination shown in formula 5 is made Thing；
(5) by compound, K shown in compound shown in formula 5, formula 62CO3Add in DMF, compound shown in formula 7 is made；
(6) by compound, iron powder, NH shown in formula 74Cl is added in absolute ethyl alcohol and water, and compound shown in formula 8 is made；
(7) compound shown in compound shown in formula 8, formula 9, HOBT, EDCI, DIEA are added in DCM successively, are made shown in formula 10 Compound；
(8) compound shown in formula 10, trifluoroacetic acid are added in DCM, target compound 11 is made.
6. preparation method according to claim 5, it is characterised in that：
In step (1), the POCl3Temperature when adding in DMF is 0 DEG C；Compound, POCl shown in the formula 13, DMF rubs You are than being 1:8:10；Compound shown in the formula 2 is by the way that reaction solution obtained by after reaction is adjusted pH successively for 7, extraction, concentration Obtain；The adjusting pH is to adjust pH using 6N NaOH；The extraction is that profit is extracted with ethyl acetate 3 times；
In step (2), the reaction temperature is 25 ± 2 DEG C；The reaction time is 3h；Compound, two carbonic acid shown in the formula 2 Di tert butyl carbonate, 4-dimethylaminopyridine, the rate of charge of tetrahydrofuran are 18.9:20.8:1:76.9mmol/mmol/mmol/ml； Formula shown in the formula 3 by concentrating the reaction solution after reaction, being recrystallized to give successively；
In step (3), the reaction temperature is 25 ± 2 DEG C；The reaction time is 0.5h；Compound shown in the formula 3, NaBH4, methanol rate of charge be 1:2.16:5.26mmol/mmol/ml；Described be quenched is that reaction is quenched using acetone；It is described Compound shown in formula 4 is that concentration, column chromatography obtain；The column chromatography is with PE:EA=3:1 is eluant, eluent；
In step (4), the reaction temperature is 25 ± 2 DEG C；Compound, thionyl chloride, the rate of charge of DCM are shown in the formula 4 1:4:4.2mmol/mmol/ml；Described be quenched be plus water quenching is gone out reaction；Compound shown in the formula 5 be by extracting, drying, Concentration, column chromatography obtain；The extraction is extracted 3 times using DCM；The drying is dried using anhydrous magnesium sulfate；The column Chromatography is with PE:EA=4:1 is eluant, eluent；
In step (5), the reaction temperature is 25 ± 2 DEG C；The reaction time is 12h；Compound, K shown in the formula 52CO3、 Compound shown in formula 6, the rate of charge of DMF are 1:2:1.23:3.85mmol/mmol/mmol/ml；Compound shown in the formula 7 is By diluting, extracting, washing, drying, concentrating, column chromatography obtains；The dilution is plus 10 times of water dilute；The extraction is to utilize Ethyl acetate extracts 3 times；The washing is to utilize saturated common salt water washing；The drying is dried using anhydrous magnesium sulfate；Institute It is with PE to state column chromatography:EA=4:1 is eluant, eluent；
In step (6), the reaction temperature is 80 ± 2 DEG C；The reaction time is 0.5h；Compound, iron shown in the formula 7 Powder, NH4Cl, absolute ethyl alcohol, the rate of charge of water are 1:5:0.48:12.9:6.45mmol/mmol/mmol/ml/ml；The formula 8 Shown compound be by filtering, concentrating, diluting, extracting, washing, dry, concentrating, column chromatography obtains；The dilution is to add water Dilution；The extraction is that profit is extracted with ethyl acetate 3 times；The washing is to utilize saturated common salt water washing；The drying is profit Dried with anhydrous magnesium sulfate；The column chromatography is with PE:EA=1:1 is eluant, eluent；
In step (7), the reaction temperature is 25 ± 2 DEG C；The reaction time is 12h；Compound shown in the formula 8, the institute of formula 9 Show compound, the rate of charge of HOBT, EDCI, DIEA, DCM are 0.69:1:1:1:2.13:7.5mmol/mmol/mmol/mmol/ mmol/ml；Compound shown in the formula 10 be by concentrating, washing, extracting, washing, drying, concentrating, column chromatography obtains；It is described Washing is washed using saturated sodium bicarbonate；The extraction is that profit is extracted with ethyl acetate 3 times；The washing is eaten using saturation Salt water washing；The drying is dried using anhydrous magnesium sulfate；The column chromatography is with DCM:MeOH=60:1 is eluant, eluent；
In step (8), the reaction temperature is 25 ± 2 DEG C；The reaction time is 12h；Compound, trifluoro shown in the formula 10 Acetic acid, the rate of charge of DCM are 1:0.94:9.4mmol/ml/ml；The target compound 11 be by adjust PH for 8, extraction, Dry, concentration, column chromatography obtain；The adjusting pH is adjusted using saturated sodium bicarbonate；The extraction is to utilize ethyl acetate Extraction 3 times；The drying is dried using anhydrous magnesium sulfate；The column chromatography is with DCM:MeOH=20:1 is eluant, eluent.
7. compound or its stereoisomer shown in any one of Claims 1 to 4 formula 11 or its is pharmaceutically acceptable Salt or its solvate or its pro-drug or its metabolite are preparing the purposes in treating pancreatic cancer drug.
A kind of 8. drug regimen, it is characterised in that：It is different with compound described in Claims 1 to 4 any one or its solid Structure body or its pharmaceutically acceptable salt or its solvate or its pro-drug or its metabolite are active ingredient, are added Upper pharmaceutically acceptable auxiliary material or auxiliary element are prepared into pharmaceutically common preparation.
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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001032621A1 (en) * 1999-10-29 2001-05-10 Wakunaga Pharmaceutical Co., Ltd. Novel indole derivatives and drugs containing the same as the active ingredient
EP1902024B1 (en) * 2005-07-13 2013-04-17 Allergan, Inc. Kinase inhibitors
CN104072484A (en) * 2014-07-07 2014-10-01 渤海大学 N-(4-(aromatic thiol)-1-hydro-indazole-3-yl)-1-(heteroaromatic substituted) methylene imine compound and pharmaceutically acceptable salt thereof, and preparation method and application thereof
CN106478606A (en) * 2016-09-21 2017-03-08 沈阳药科大学 N substituted indole analog derivative and its application

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001032621A1 (en) * 1999-10-29 2001-05-10 Wakunaga Pharmaceutical Co., Ltd. Novel indole derivatives and drugs containing the same as the active ingredient
EP1902024B1 (en) * 2005-07-13 2013-04-17 Allergan, Inc. Kinase inhibitors
CN104072484A (en) * 2014-07-07 2014-10-01 渤海大学 N-(4-(aromatic thiol)-1-hydro-indazole-3-yl)-1-(heteroaromatic substituted) methylene imine compound and pharmaceutically acceptable salt thereof, and preparation method and application thereof
CN106478606A (en) * 2016-09-21 2017-03-08 沈阳药科大学 N substituted indole analog derivative and its application

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