CN104119329A - Novel benzisoselenazolone modified pyrrole formate substituted indolone compound and application thereof - Google Patents

Novel benzisoselenazolone modified pyrrole formate substituted indolone compound and application thereof Download PDF

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CN104119329A
CN104119329A CN201310146382.4A CN201310146382A CN104119329A CN 104119329 A CN104119329 A CN 104119329A CN 201310146382 A CN201310146382 A CN 201310146382A CN 104119329 A CN104119329 A CN 104119329A
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compound
dimethyl
pyrroles
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曾慧慧
田永亮
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Peking University
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Peking University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D421/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having selenium, tellurium, or halogen atoms as ring hetero atoms
    • C07D421/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having selenium, tellurium, or halogen atoms as ring hetero atoms containing three or more hetero rings

Abstract

The invention relates to a novel benzisoselenazolone modified pyrrole formate substituted indolone compound and application thereof. The benzisoselenazolone modified pyrrole formate substituted indolone compound provided by the invention is shown as a general formula I, wherein n represents the number of carbon between truss arms and is 2 or 3. The 2-indolone compound of the invention has excellent antitumor activity, and can be widely used in preparing antitumor medicines.

Description

Indole ketone compound and application thereof that the minaline ester that novel Benzisoelenazolone is modified replaces
Technical field
The present invention relates to a kind of 2-indole ketone derivative and its preparation method and application, belong to chemical field.
Background technology
Malignant tumour is a kind of common disease of serious threat human health, and the death that the mankind cause because of malignant tumour at present accounts for the second of all mortalities, is only second to cardiovascular and cerebrovascular diseases.And tumour morbidity improves year by year, take China as example, the data presentation disclosing in the Chinese tumour registration of the < < 2012 annual report > > of whole nation tumour Register issue, China on average just has a people to be diagnosed as cancer in every 6 minutes, and annual new cases of cancer is about 3,120,000 examples.Oncotherapy has become the severe challenge that institute of Pharmaceutical Research faces.
At present, conventional antitumor drug is mainly cytotoxic drug clinically, and this kind anti-cancer drugs has the poor selectivity, the toxic side effect that are difficult to avoid and by force, easily produces the shortcomings such as resistance.Completing and continuous understanding and the elaboration of molecular biology to pathogenic mechanism of human genome examining order in recent years, the various primary processes such as interaction of the signal transduction in malignant cell, the regulation and control of cell cycle, apoptotic induction, vasculogenesis and cell and extracellular matrix are progressively illustrated.The key enzyme of signal transduction pathway is as drug screening target spot, and development target is the field that global Pharma Inc. and national governments pay close attention to and develop with tropism's antitumor drug always.
Tyrosylprotein kinase is the enzyme of one group of catalytic proteins tyrosine residues phosphorylation, and the phosphate group on energy catalysis ATP is transferred on many important tyrosine residuess, makes its residue phosphorylation.In intracellular signal transduction, play a very important role, it participates in Normocellular adjusting, signal transmission and growth, also closely related with propagation, differentiation, migration and the apoptosis of tumour cell.It is disorderly that the abnormal activation of Tyrosylprotein kinase or overexpression will cause cell proliferation to regulate, and finally lead oncogenic development.Therefore, take exploitation that Tyrosylprotein kinase carries out antitumor drug as target spot has become the forward position of international research.
A kind of multiple receptor tyrosine kinases inhibitor of Sutent (sunitinib, Sutent) Shi You Pfizer exploitation.Within 2006, obtain FDA approval listing, be used for the treatment for the treatment of with imatinib failure or not tolerant gastrointestinal stromal tumor and late period renal cell carcinoma.In vitro study shows: the Tyrosylprotein kinase that Sutent can effectively suppress comprises PDGFR-α and PDGFR-β, VEGFR-1, VEGFR-2 and VEGFR-3, C-Kit class FMS Tyrosylprotein kinase-3 (FLT3), colony-stimulating factor 1 acceptor (CSF-1R) and glial cell line-derived neurotrophic factor acceptor (RET).The propagation that can suppress the human umbilical vein endothelial cell (HUVECs) of VEGF induction and the l cell (NIH-3T3) of PDGF induction.
Sutent shows the effect that suppresses tumor growth and propagation in a lot of cell strains and animal-transplanted tumor model.In to the research of HT229 and Colo205 colorectal carcinoma, NCI2H226 nonsmall-cell lung cancer, WM226624 melanoma, 78620 renal cell carcinomas, A431 epidermoid carcinoma transplanted tumor animal model, be administered once every day and can make tumor regression, and do not produce resistance phenomenon.
The toxicity of Sutent is mainly manifested in following several respects:
(1) gastrointestinal toxicity
Gastrointestinal toxicity is the common untoward reaction of antitumor drug, and the gastrointestinal symptom of Sutent may betide any time section of pharmacological agent, and symptom mainly comprises diarrhoea, feels sick, vomiting, abdominal distension, pain etc.The diarrhoea that medicine is relevant often shows as just rare that number of times increases, rather than watery stool, through suitable processing, can effectively control.The demonstration of III phase clinical study result, moderate Incidence of Diarrhea is that 53%, 3～4 grades of Incidence of Diarrheas are 5% [51].
(2) hematotoxicity
Take anti-VEGF as the impact of the large multipair blood of basic anti-angiogenic medicaments and hepatic and renal function less, but the incidence of Sutent hematotoxicity is 60%～70%, 3～4 grades of neutrophilic granulocytopenia Sutents are that 12%, 3～4 grades of thrombocytopenia Sutents are 8% [51].The Sutent rate of causing bleeding is 26%, and it causes hemorrhage mechanism it be unclear that.
(3) dermal toxicity
The dermal toxicity of Sutent comprises hand-foot skin reaction (HFSR), fash and xerosis cutis.The HFSR incidence of Sutent is 20%.
(4) dysthyroid
U.S. Wong etc. [52]result of study show, the patient of Sutent treatment has accepted thyroid function test (TFT).Thyrotropin during 53% patient treatment (TSH) level rising (meta TSH is 21.4Mu/L).Given this, investigator's suggestion is carried out thyroid function monitoring to accepting the patient of Sutent treatment.Rini etc. [53]studies show that 84% patient occurs that first subtracts symptom and (or) sign.
(5) Cardiovascular Toxicity
At the beginning of 2008, Wu etc. points out, all VEGF inhibitor all may cause elevation of the blood pressure, and Sutent mortality of hypertension is 22.5%, and comparing hypertension occurrence risk with placebo has increased by 3.9 times.
Benzisoelenazolone representation compound Ethaselen is a kind of target thioredoxin reductase, for the organic selenium compounds of antineoplaston, carrying out now clinical study, the clinical I phase completing shows, Ethaselen toxicity is low, compare with the performance of Sutent toxicity, show good tolerance.Early-stage Study shows (Zhou Haiyan, Peking University's doctorate paper, 2008), and Benzisoelenazolone structure is as the main pharmacodynamics group of this medicine, can initiative recognition target enzyme active center and embody the targeting to tumour and related tissue.The internal metabolism of medicine studies show that, Ethaselen far above Plasma, has shown good tumor-targeting in the concentration of tumor tissues.
Sutent is introduced to Benzisoelenazolone structure in C-4 ' position, obtain a class novel, 3-pyrroles-2-indolone structure with Benzisoelenazolone structure, according to Benzisoelenazolone medicine (Ethaselen) feature, this compounds can target thioredoxin reductase, and there is tumor-targeting, and thioredoxin reductase activity is the important elements of tumor growth, therefore 3-pyrroles-2-indolone structure of Benzisoelenazolone structure will have many target spots feature, this class formation is with respect to improved the targeting of medicine for Buddhist nun's structure simultaneously, therefore can reach the effect of efficacy enhancing and toxicity reducing.
For Sutent, in C-4 ' position, introduce Benzisoelenazolone structure and applied for the patent protection of " oxindole compounds and the application thereof of the minaline ester replacement that a kind of Benzisoelenazolone is modified; application number: 201210121353.8 " (hereinafter to be referred as patent applied for); follow-up study is found; the compound, the Benzisoelenazolone part C-5 that in indolone part C-4 position and C-7 position, have replacement " and C-6 " compound that substituting group is methyl, more obvious anti-tumor activity can be obtained.Wherein, (5-fluoro-1 for O-[2-, 2-benzisoxa selenazoles-3 (2H)-one) base-ethyl]-5-[(Z)-4-chloro-1,2-dihydro-2-oxo--3H-indol-3-yl methylene radical]-2, the activity that the anti-tumor activity of 4-dimethyl-1H-pyrroles-3-manthanoate in LOVO, RKO clone is 29 than the compound number that patent applied for is announced is before this good, has more valuable antitumor action meaning.Therefore, the application has carried out special further application to this compounds; With stylish research, find, the novel Benzisoelenazolone amalgamation indolone structure that C-4 ' position introducing 3-hydroxypropyl synthesizes as connecting arm is compared with patent applied for, shows significant anti-tumor activity.This is because be hydrolyzed in vivo with metabolism different as the drug metabolism feature of connecting arm with 2-hydroxyethyl as the connecting arm 3-hydroxypropyl structure of novel Benzisoelenazolone amalgamation indolone structure, and drug metabolism has great importance in the value of medicine.Because different connecting arms has different metabolic characteristics, so the application carried out special synthetic and antitumor action research for the formed series compound of connecting arm 3-hydroxypropyl, and this compounds shows external good anti-tumor activity, its IC 50value is also lower than contrast medicine Sutent or suitable with it.
Summary of the invention
The object of the invention is to provides a kind of 2-indole ketone derivative based on above theory, and measures by experiment its anti-tumor activity.
The present invention is achieved through the following technical solutions:
The compound of following structure,
General formula I n is the number n=2 or 3 of carbon between connecting arm
Wherein, R 1, R 2, R 3, R 4, R 5, R 6, R 7, R 8being respectively H, Me or halogen replaces.
Wherein, R 1-4respectively that H, Me or halogen replace;
R 5-8being respectively H, Me or halogen replaces.
N is the number of carbon between connecting arm.
Wherein, R 1h, Cl, F, R 2be H, Cl, F,, R 3h, Cl, F; R 4h, Me, F or Cl, R 5h, Cl, F, R 6h, Me, F or Cl, R 7h, F or Cl, R 8h.
Wherein n is the carbon number between connecting arm, is 2 or 3.
Described compound is:
O-[2-(1,2-benzisoxa selenazoles-3 (2H)-one) base-ethyl]-5-[(Z)-7-is fluoro-1,2-dihydro-2-oxo--3H-indol-3-yl methylene radical]-2,4-dimethyl-1H-pyrroles-3-manthanoate,
O-[2-(6-fluoro-1,2-benzisoxa selenazoles-3 (2H)-one) base-ethyl]-5-[(Z)-7-is fluoro-1,2-dihydro-2-oxo--3H-indol-3-yl methylene radical]-2,4-dimethyl-1H-pyrroles-3-manthanoate,
O-[2-(5-fluoro-1,2-benzisoxa selenazoles-3 (2H)-one) base-ethyl]-5-[(Z)-7-is fluoro-1,2-dihydro-2-oxo--3H-indol-3-yl methylene radical]-2,4-dimethyl-1H-pyrroles-3-manthanoate,
O-[2-(5-methyl isophthalic acid, 2-benzisoxa selenazoles-3 (2H)-one) base-ethyl]-5-[(Z)-7-is fluoro-1,2-dihydro-2-oxo--3H-indol-3-yl methylene radical]-2,4-dimethyl-1H-pyrroles-3-manthanoate,
O-[2-(5-methyl isophthalic acid, 2-benzisoxa selenazoles-3 (2H)-one) base-ethyl]-5-[(Z)-5-is chloro-1,2-dihydro-2-oxo--3H-indol-3-yl methylene radical]-2, the preparation of 4-dimethyl-1H-pyrroles-3-manthanoate,
O-[2-(5-chloro-1,2-benzisoxa selenazoles-3 (2H)-one) base-ethyl]-5-[(Z)-5-is chloro-1,2-dihydro-2-oxo--3H-indol-3-yl methylene radical]-2,4-dimethyl-1H-pyrroles-3-manthanoate,
O-[2-(5-fluoro-1,2-benzisoxa selenazoles-3 (2H)-one) base-ethyl]-5-[(Z)-5-is chloro-1,2-dihydro-2-oxo--3H-indol-3-yl methylene radical]-2,4-dimethyl-1H-pyrroles-3-manthanoate,
O-[2-(4-fluoro-1,2-benzisoxa selenazoles-3 (2H)-one) base-ethyl]-5-[(Z)-5-is chloro-1,2-dihydro-2-oxo--3H-indol-3-yl methylene radical]-2,4-dimethyl-1H-pyrroles-3-manthanoate,
O-[2-(5-fluoro-1,2-benzisoxa selenazoles-3 (2H)-one) base-ethyl]-5-[(Z)-4-is chloro-1,2-dihydro-2-oxo--3H-indol-3-yl methylene radical]-2,4-dimethyl-1H-pyrroles-3-manthanoate,
O-[2-(5-fluoro-1,2-benzisoxa selenazoles-3 (2H)-one) base-ethyl]-5-[(Z)-7-methyl isophthalic acid, 2-dihydro-2-oxo--3H-indol-3-yl methylene radical]-2,4-dimethyl-1H-pyrroles-3-manthanoate
O-[2-(5-fluoro-1,2-benzisoxa selenazoles-3 (2H)-one) base-ethyl]-5-[(Z)-7-is chloro-1,2-dihydro-2-oxo--3H-indol-3-yl methylene radical]-2,4-dimethyl-1H-pyrroles-3-manthanoate
O-[3-(6-fluoro-1,2-benzisoxa selenazoles-3 (2H)-one) base-propyl group]-5-[(Z)-5-is fluoro-1,2-dihydro-2-oxo--3H-indol-3-yl methylene radical]-2,4-dimethyl-1H-pyrroles-3-manthanoate
O-[3-(6-fluoro-1,2-benzisoxa selenazoles-3 (2H)-one) base-propyl group]-5-[(Z)-5-is chloro-1,2-dihydro-2-oxo--3H-indol-3-yl methylene radical]-2,4-dimethyl-1H-pyrroles-3-manthanoate
Another object of the present invention is to provide a kind of method of preparing the above compound, specifically comprises the steps:
(1) prepare compound 1
Compound 1 n=2 or 3
Under existing, Sodium Nitrite makes react under ice bath with hydrochloric acid, obtain villaumite, gained villaumite is reacted with sodium diselenide to reaction mixture and be alkaline, gained mixture is obtained to solid with hcl acidifying, and then toilet obtains solid and refluxes in sulfur oxychloride and DMF, obtains residue, residue obtained with petroleum ether extraction, cooling crystallize out, crystal reacts with thanomin (Propanolamine) in methylene dichloride, obtains compound 1;
(2) prepare compound 2
Compound 2
Methyl aceto acetate reacts under Sodium Nitrite and zinc powder existence with Glacial acetic acid, obtain 3,5-dimethyl-1H-pyrroles-2,4-diethyl dicarboxylate, by 3,5-dimethyl-1H-pyrroles-2,4-diethyl dicarboxylate is dissolved under trifluoroacetic acid ice bath and stirs 10 minutes, adds triethyl orthoformate, move under 40 ℃ of water-baths and react, chloroform extraction, underpressure distillation obtains solid, and dehydrated alcohol recrystallization obtains crystal.Under aqueous sodium hydroxide solution exists, gained yellow solid is refluxed in methyl alcohol, obtain compound 2;
(3) methylene dichloride, as solvent, under EDC and DMAP existence, makes compound 1 react with compound 2, obtains intermediate;
(4) under Pyrrolidine exists, intermediate and compound 1 that step (4) obtains are refluxed in dehydrated alcohol, obtain compound of Formula I.
Embodiment
Below in conjunction with embodiment, the invention will be further described, it should be understood that these embodiment, only for the object of illustration, never limit the scope of the invention.
Below the synthetic route of the compounds of this invention:
Synthesizing of compound 1:
Compound 1
Synthesizing of compound 2:
Compound 2
Synthesizing of the synthetic and compound of Formula I of compound 3:
The 13 kinds of compounds of take below illustrate preparation and the anti-tumor activity of compound of Formula I as example.
These 13 kinds of compounds are as shown in table 1.
Table 1
The preparation of embodiment 1N-phenyl-2-oximinoacetamide
Anhydrous sodium sulphate (35g at 40 ℃, 246mmol) add Chloral Hydrate (5g in batches, after in water 30.5mmol) (90ml) solution, splash into aniline (2.57g, 27.6mmol) He 36% concentrated hydrochloric acid (3ml, water 36mmol) (20ml) solution, splash into again oxammonium hydrochloride (6.1g, water 88.4mmol) (27.5ml) solution, drips the complete 85 ℃ of reaction 2h that are warming up to, and is cooled to 50 ℃, suction filtration, cold water washing, the cotton-shaped solid of white (3.53g, 78%) that filter cake is dried.
The preparation of embodiment 2 isatin
98% vitriol oil (46ml) is heated to 60 ℃, under stirring, add N-phenyl-2-oximinoacetamide (1.8g in batches, 11mmol), in 0.5h, add, finish and be warming up to 80 ℃ of reaction 15min, be cooled to after room temperature in impouring 250g trash ice, stirring at room 0.5h, suction filtration, frozen water washing, obtain safran solid (1.2g, 75%).
1H?NMR(400MHz，DMSO-d 6)：6.89(d，1H)，7.04(m，1H)，7.48(d，1H)，7.57(m，1H)，11.02(s，br，1H)
Embodiment 31, the preparation of 3-Indolin-2-one
Take isatin (0.8g, 5.4mmol), first wherein 0.3g adds in 80% hydrazine hydrate (10ml), be heated to 100 ℃ of backflows, add remaining 0.5g in batches, in 2h, finish, be warming up to 110 ℃ and continue backflow 4h, be cooled to room temperature, drip 36% concentrated hydrochloric acid and be adjusted to pH=3, under room temperature, continue to stir 12h, separate out solid, suction filtration, washes with water, obtain brown solid (0.44g, 61%).
1H?NMR(400MHz，DMSO-d 6)：3.44(s，2H)，6.79(d，1H)，6.90(t，1H)，7.13(d，1H)，7.18(d，1H)，10.33(s，br，1H)
The preparation of embodiment 4N-(4-fluorophenyl)-2-oximinoacetamide
In the mode identical with embodiment 1, obtain this compound.
The preparation of embodiment 55-fluoro indigo red
In the mode identical with embodiment 2, obtain this compound.
1H?NMR(400MHz，DMSO-d 6)：6.90(dd，1H)，7.38(dd，1H)，7.43(m，1H)，11.02(s，br，1H)
Embodiment 65-is fluoro-1, the preparation of 3-Indolin-2-one
In the mode identical with embodiment 3, obtain this compound.
1H?NMR(400MHz，DMSO-d 6)：3.47(s，2H)，6.76(m，1H)，6.97(m，1H)，7.08(m，1H)，10.35(s，br，1H)
The preparation of embodiment 7N-(4-chloro-phenyl-)-2-oximinoacetamide
In the mode identical with embodiment 1, obtain this compound.
The preparation of embodiment 85-chlorisatide
In the mode identical with embodiment 2, obtain this compound.
1H?NMR(400MHz，DMSO-d 6)：6.91(d，1H)，7.53(d，1H)，7.59(dd，1H)，11.11(s，br，1H)
Embodiment 95-is chloro-1, the preparation of 3-Indolin-2-one
In the mode identical with embodiment 3, obtain this compound.
1H?NMR(400MHz，DMSO-d 6)：3.48(s，2H)，6.78(d，1H)，7.19(dd，1H)，7.24(d，1H)，10.46(s，br，1H)
The preparation of embodiment 10N-(4-aminomethyl phenyl)-2-oximinoacetamide
In the mode identical with embodiment 1, obtain this compound.
The preparation of embodiment 115-methylisatin
In the mode identical with embodiment 2, obtain this compound.
1H?NMR(400MHz，DMSO-d 6)：2.23(s，3H)，6.78(d，1H)，7.30(s，1H)，7.38(d，1H)，10.92(s，br，1H)
Embodiment 125-methyl isophthalic acid, the preparation of 3-Indolin-2-one
In the mode identical with embodiment 3, obtain this compound.
1H?NMR(400MHz，DMSO-d 6)：2.21(s，3H)，3.39(s，2H)，6.67(d，1H)，6.94(d，1H)，6.99(s，1H)，10.23(s，br，1H)
The preparation of embodiment 13N-(3-fluorophenyl)-2-oximinoacetamide
In the mode identical with embodiment 1, obtain this compound.
The preparation of embodiment 146-fluoro indigo red
In the mode identical with embodiment 2, obtain this compound.
1H?NMR(400MHz，DMSO-d 6)：6.72(m，1H)，6.85(m，1H)，7.59(m，1H)，11.17(s，br，1H)
Embodiment 156-is fluoro-1, the preparation of 3-Indolin-2-one
In the mode identical with embodiment 3, obtain this compound.
1H?NMR(400MHz，DMSO-d 6)：3.42(s，2H)，6.60(m，1H)，6.69(m，1H)，7.18(m，1H)，10.48(s，br，1H)
The preparation of embodiment 16N-(2-fluorophenyl)-2-oximinoacetamide
In the mode identical with embodiment 1, obtain this compound.
The preparation of embodiment 177-fluoro indigo red
In the mode identical with embodiment 2, obtain this compound.
Embodiment 187-is fluoro-1, the preparation of 3-Indolin-2-one
In the mode identical with embodiment 3, obtain this compound.
1H?NMR(400MHz，DMSO-d 6)3.59(s，2H)，6.90(t，1H)，7.18(d，1H)，7.1(d，1H)，10.89(s，br，1H)
The preparation of embodiment 194-chlorisatide
In the mode identical with embodiment 2, obtain the mixture 1.6g of 4-chlorisatide and 6-chlorisatide.Mixture is dissolved in 60ml10%NaOH solution to heating for dissolving in 60 ℃ of oil baths.Filter to obtain clarification dark red solution.Drip 18ml glacial acetic acid, pH=5, stirs suction filtration.Be dried to obtain red solid.
Embodiment 204-is chloro-1, the preparation of 3-Indolin-2-one
In the mode identical with embodiment 3, obtain this compound.
1H?NMR(400MHz，DMSO-d 6)：3.50(s，2H)，6.78(d，1H)，6.96(dd，1H)，7.20(s，1H)，10.59(s，br，1H)
The preparation of embodiment 21N-(2-chloro-phenyl-)-2-oximinoacetamide
In the mode identical with embodiment 1, obtain this compound.
The preparation of embodiment 227-chlorisatide
In the mode identical with embodiment 2, obtain this compound.
Embodiment 237-is chloro-1, the preparation of 3-Indolin-2-one
In the mode identical with embodiment 3, obtain this compound.
1H?NMR(400MHz，DMSO-d 6)：3.59(s，2H)，6.94(t，1H)，7.17(d，1H)，7.22(d，1H)，10.78(s，br，1H)
The preparation of embodiment 24N-(2-methyl-phenyl)-2-oximinoacetamide
In the mode identical with embodiment 1, obtain this compound.
The preparation of embodiment 257-methylisatin
In the mode identical with embodiment 2, obtain this compound.
Embodiment 267-methyl isophthalic acid, the preparation of 3-Indolin-2-one
In the mode identical with embodiment 3, obtain this compound.
1H?NMR(400MHz，DMSO-d 6)：2.19(s，3H)，3.46(s，2H)，6.83(t，1H)，6.97(d，1H)，7.01(d，1H)，10.40(s，br，1H)
Embodiment 272, the two benzoic preparations of 2 '-bis-selenizings
1) anthranilic acid (14.0g) and 1: 1 hydrochloric acid (40ml) under ice bath, be uniformly mixed, make 5 ℃ of <, slowly splash into therein the solution of the water (20ml) of Sodium Nitrite (9.0g), drip off and continue reaction 2h, obtain chlorination 2-phenylformic acid diazonium salt.Product is not purified is directly used in next step.
2) in 60ml water, add selenium powder (8.8g) and sodium hydroxide (4.4g), the powder (8.8g) that slowly takes a policy under stirring, 50 ℃ of reaction 2h.Obtain sodium diselenide solution, be not purifiedly directly used in next step reaction.
3) solution of chlorination 2-phenylformic acid diazonium salt step 1 being obtained under stirring is added drop-wise in the sodium diselenide solution that step 2 obtains, and mixture continues to stir 2h until the nitrogen producing is drained.Litmus paper proof solution is alkalescence.Reaction mixture hcl acidifying, filtering-depositing solid, washes in rearmounted moisture eliminator and is dried, and obtains product (20.0g, yield 90%).
1H?NMR(400MHz，DMSO-d 6)：7.34(t，2H)，7.46(t，2H)，7.67(d，2H)，8.02(d，2H)，13.69(s，br，2H)
The preparation of embodiment 282-selenium chloro-benzoyl chloride
The two phenylformic acid (40.0g, 100mmol) of 2,2 '-bis-selenizings, sulfur oxychloride (200ml) and DMF (0.15ml, 1.8mmol) stirring and refluxing 3h, revolves to steam and removes unnecessary thionyl chloride, residue sherwood oil recrystallization, obtain yellow needle crystal (48.5g, 90%).
The preparation of embodiment 292-hydroxyethyl-[1,2-benzisoxa selenazoles-3 (2H)-one]
Thanomin (1.6ml) is dissolved in methylene dichloride (15ml) solution, slowly splashes into therein the methylene dichloride (15ml) of 2-selenium chloro-benzoyl chloride (2.7g), room temperature reaction 2h, and suction filtration, obtains white solid (2.2g, 85%).
1H?NMR(400MHz，DMSO-d 6)：3.61(q，2H)，3.78(t，2H)，5.08(t，1H)，7.38(m，1H)，7.57(m，1H)，7.80(dd，1H)，8.01(d，1H)
Embodiment 304, the two benzoic preparations of 4 '-bis-fluoro-2,2 '-bis-selenizings
In the mode identical with embodiment 27, obtain this compound.
1H?NMR(400MHz，DMSO-d 6)：7.23(m，2H)，7.40(dd，2H)，8.11(m，2H)，13.93(s，br，2H)
The preparation of the chloro-4-fluorobenzoyl chloride of embodiment 312-selenium
In the mode identical with embodiment 28, obtain this compound.
Embodiment 322-hydroxyethyl-[6-fluorine 1,2-benzisoxa selenazoles-3 (2H)-one]
In the mode identical with embodiment 29, obtain this compound.
1H?NMR(400MHz，DMSO-d 6)：3.60(q，2H)，3.77(t，2H)，5.13(t，1H)，7.24(m，1H)，7.81(m，2H)
Embodiment 332-hydroxypropyl-[6-fluorine 1,2-benzisoxa selenazoles-3 (2H)-one]
In the mode identical with embodiment 29, obtain this compound.
1H?NMR(400MHz，DMSO-d 6)：1.80(q，2H)3.60(q，2H)，3.77(t，2H)，5.13(t，1H)，7.24(m，1H)，7.81(m，2H)
Embodiment 345,5 '-dimethyl-2, the two benzoic preparations of 2 '-bis-selenizings
In the mode identical with embodiment 27, obtain this compound.
1H?NMR(400MHz，DMSO-d 6)：2.30(s，3H)，7.43(m，2H)，7.66(m，2H)，7.79(dd，2H)，13.50(s，br，2H)
The preparation of the chloro-5-methyl benzoyl chloride of embodiment 352-selenium
In the mode identical with embodiment 28, obtain this compound.
The preparation of embodiment 362-hydroxyethyl-[5-methyl 1,2-benzisoxa selenazoles-3 (2H)-one]
In the mode identical with embodiment 29, obtain this compound.
1H?NMR(400MHz，DMSO-d 6)：2.69(s，3H)，3.61(q，2H)，3.78(t，2H)，5.12(t，1H)，7.51(m，2H)，8.04(m，1H)
Embodiment 375, the two benzoic preparations of 5 '-bis-chloro-2,2 '-bis-selenizings
In the mode identical with embodiment 27, obtain this compound.
1H?NMR(400MHz，DMSO-d 6)：7.59(dd，2H)，7.64(d，2H)，7.99(d，2H)，14.16(s，br，2H)
The preparation of the chloro-5-chloro-benzoyl chloride of embodiment 382-selenium
In the mode identical with embodiment 28, obtain this compound.
The preparation of embodiment 392-hydroxyethyl-[5-chlorine 1,2-benzisoxa selenazoles-3 (2H)-one]
In the mode identical with embodiment 29, obtain this compound.
1H?NMR(400MHz，DMSO-d 6)：3.61(q，2H)，3.78(t，2H)，5.11(t，1H)，7.63(dd，1H)，7.75(d，1H)，8.03(d，1H)
Embodiment 406, the two benzoic preparations of 6 '-bis-fluoro-2,2 '-bis-selenizings
In the mode identical with embodiment 27, obtain this compound.
1H?NMR(400MHz，DMSO-d 6)：7.24(dd，2H)，7.45(d，2H)，7.56(d，2H)，13.87(s，br，2H)
The preparation of the chloro-6-fluorobenzoyl chloride of embodiment 412-selenium
In the mode identical with embodiment 28, obtain this compound.
The preparation of embodiment 422-hydroxyethyl-[4-fluoro-1,2-benzisoxa selenazoles-3 (2H)-one]
In the mode identical with embodiment 29, obtain this compound.
1H?NMR(400MHz，DMSO-d 6)：3.61(q，2H)，3.76(t，2H)，5.14(t，1H)，7.15(t，1H)，7.56(d，1H)，7.85(d，1H)
Embodiment 434, the two benzoic preparations of 4 '-bis-chloro-2,2 '-bis-selenizings
In the mode identical with embodiment 27, obtain this compound.
1H?NMR(400MHz，DMSO-d 6)：7.44(dd，2H)，7.60(d，2H)，8.02(d，2H)，14.01(s，br，2H)
The preparation of the chloro-4-chloro-benzoyl chloride of embodiment 442-selenium
In the mode identical with embodiment 28, obtain this compound.
Embodiment 452-hydroxyethyl-[6-chlorine 1,2-benzisoxa selenazoles-3 (2H)-one]
In the mode identical with embodiment 29, obtain this compound.
1H?NMR(400MHz，DMSO-d 6)：3.61(t，2H)，3.78(t，2H)，5.13(t，1H)，7.43(dd，1H)，7.77(d，1H)，8.07(d，1H)
Embodiment 463,5-dimethyl-1H-pyrroles-2,4-diethyl dicarboxylate's preparation
Methyl aceto acetate (15ml, 0.12mol) stirs lower water (6ml) solution that drips Sodium Nitrite (4.06g, 0.06mol) with Glacial acetic acid (30ml) in ice bath, in 15min, drip and finish, ice bath reaction 2.5h slowly adds zinc powder (7.7g in batches under stirring, 0.12mol), finish backflow 1h, in reaction solution impouring 200ml frozen water, separate out faint yellow solid, suction filtration, filter cake washs with frozen water, dehydrated alcohol recrystallization, dries to obtain white solid (8.6g, 61%).
1H?NMR(400MHz，DMSO-d 6)：1.26(q，6H)，2.39(s，3H)，2.44(s，3H)，4.19(m，4H)，11.79(s，br，1H)
Embodiment 473, the preparation of 5-dimethyl-1H-pyrroles-4-ethoxycarbonyl-2-carboxylic acid
3,5-dimethyl-1H-pyrroles-2,4-diethyl dicarboxylate (8.0g, 0.033mol) be dissolved in ethanol (108ml), add water (28ml) solution of potassium hydroxide (2.28g, 0.041mol), backflow 2.5h, is cooled to room temperature, is evaporated to about 40ml, in impouring frozen water (80ml), add 10% hydrochloric acid and be adjusted to pH=4, suction filtration, filter cake washes with water, dry to obtain white solid (6.5g, 92%).
1H?NMR(400MHz，DMSO-d 6)：1.25(t，3H)，2.37(s，3H)，2.43(s，3H)，4.15(q，2H)，11.71(s，br，1H)，12.33(s，br，1H)
Embodiment 482, the preparation of 4-dimethyl-5-formyl radical-1H-pyrroles-3-carboxylic acid, ethyl ester
In 10ml trifluoroacetic acid, add 2,4-dimethyl-1H-pyrroles-4-ethoxycarbonyl 3-carboxylic acid, ethyl ester (2.1g, 10mmol) stir 40min, under ice bath, stir 10min, be added dropwise to triethyl orthoformate 7ml, move to 40 ℃ of stirred in water bath 1h, add in 100ml frozen water, chloroform extraction 3 times, each 100ml.Organic addition 150ml5% ammonia scrubbing, organic phase dried overnight, underpressure distillation obtains solid yellow solid (1.5g, 97%).Ethyl alcohol recrystallization, obtains white crystal (0.95g, 48%).
1H?NMR(400MHz，DMSO-d 6)：1.26(t，3H)，2.40(s，3H)，2.44(s，3H)，4.17(q，2H)，9.60(s，1H)，12.15(s，br，1H)
Embodiment 492, the preparation of 4-dimethyl-5-formyl radical-1H-pyrroles-3-formic acid
Water (8ml) solution that adds sodium hydroxide (1.0g) in methyl alcohol (5ml) solution of 2,4-dimethyl-5-formyl radical-1H-pyrroles-3-carboxylic acid, ethyl ester (0.9g, 4.6mmol); reflux 4h; be cooled to room temperature hypsokinesis to frozen water (16ml), add methylene dichloride (10ml), stratification; collect water layer and be adjusted to pH3 with 10% hydrochloric acid; filter, filter cake cold water washing, dry; obtain light yellow solid 11 (0.71g, 92%).
1H?NMR(400MHz，DMSO-d 6)：2.42(s，3H)，2.52(s，3H)，9.61(s，1H)，12.09(s，br，2H)。
Embodiment 50O-[2-(1,2-benzisoxa selenazoles-3 (2H)-one) base-ethyl]-2, the preparation of 4-dimethyl-5-formyl radical-1H-pyrroles-3-manthanoate
2; 4-dimethyl-5-formyl radical-1H-pyrroles-3-formic acid (334mg; 2mmol) be dissolved in methylene dichloride (20ml); add successively EDC (760mg, 4mmol), DMAP (293mg; 2.4mmol); 2-hydroxyethyl-[1,2-benzisoxa selenazoles-3 (2H)-one] (486mg, 2mmol); room temperature reaction 36h; impouring water (60ml), extracts anhydrous sodium sulfate drying with methylene dichloride (3 * 20ml) afterwards; filter; decompression is spin-dried for, column chromatography (methylene dichloride: methyl alcohol=70: 1) the separated sterling (365mg, 47%) that obtains.
1H?NMR(400MHz，DMSO-d 6)：2.37(s，3H)，2.41(s，3H)，4.08(t，2H)，4.39(t，2H)，7.39(t，1H)，7.58(t，1H)，7.80(d，1H)，8.03(d，1H)，9.59(s，1H)，12.16(s，br，1H)
Embodiment 51O-[2-(6-fluoro-1,2-benzisoxa selenazoles-3 (2H)-one) base-ethyl]-2, the preparation of 4-dimethyl-5-formyl radical-1H-pyrroles-3-manthanoate
In the mode identical with embodiment 49, obtain this compound.
1H?NMR(400MHz，DMSO-d 6)：2.37(s，3H)，2.41(s，3H)，4.07(t，2H)，4.39(t，2H)，7.25(m，1H)，7.81(m，2H)，9.59(s，1H)，12.16(s，br，1H)
Embodiment 52O-[2-(4-fluoro-1,2-benzisoxa selenazoles-3 (2H)-one) base-ethyl]-2, the preparation of 4-dimethyl-5-formyl radical-1H-pyrroles-3-manthanoate
In the mode identical with embodiment 49, obtain this compound.
1H?NMR(400MHz，DMSO-d 6)：2.40(s，3H)，2.45(s，3H)，4.06(t，2H)，4.40(t，2H)，7.17(t，1H)，7.58(d，1H)，7.85(d，1H)，9.59(s，1H)，12.16(s，br，1H)
Embodiment 53O-[2-(5-chloro-1,2-benzisoxa selenazoles-3 (2H)-one) base-ethyl]-2, the preparation of 4-dimethyl-5-formyl radical-1H-pyrroles-3-manthanoate
In the mode identical with embodiment 49, obtain this compound.
1H?NMR(400MHz，DMSO-d 6)：2.36(s，3H)，2.39(s，3H)，4.08(t，2H)，4.39(t，2H)，7.61(d，1H)，7.74(s，1H)，8.01(d，1H)，9.57(s，1H)，12.14(s，br，1H)
Embodiment 54O-[2-(5-methyl isophthalic acid, 2-benzisoxa selenazoles-3 (2H)-one) base-ethyl]-2, the preparation of 4-dimethyl-5-formyl radical-1H-pyrroles-3-manthanoate
In the mode identical with embodiment 49, obtain this compound.
1H?NMR(400MHz，DMSO-d 6)：2.36(s，6H)，2.39(s，3H)，4.08(t，2H)，4.39(t，2H)，7.44(d，1H)，7.65(s，1H)，7.89(d，1H)，9.57(s，1H)，12.14(s，br，1H)
Embodiment 55O-[2-(6-fluoro-1,2-benzisoxa selenazoles-3 (2H)-one) base-propyl group]-2, the preparation of 4-dimethyl-5-formyl radical-1H-pyrroles-3-manthanoate
With feed ratio reaction identical with embodiment 49, when column chromatography for separation is purified, eluent changes chloroform into: ethyl acetate=3: 1 ratio is carried out wash-out and obtained this compound.
1H?NMR(400MHz，DMSO-d 6)：2.00(m，2H)，2.37(s，3H)，2.41(s，3H)，3.47(t，2H)，4.32(t，2H)，7.25(m，1H)，7.81(m，2H)，9.59(s，1H)，12.16(s，br，1H)
Embodiment 56O-[2-(1,2-benzisoxa selenazoles-3 (2H)-one) base-ethyl]-5-[(Z)-7-is fluoro-1,2-dihydro-2-oxo--3H-indol-3-yl methylene radical]-2, the preparation of 4-dimethyl-1H-pyrroles-3-manthanoate
O-[2-(1; 2-benzisoxa selenazoles-3 (2H)-one) base-ethyl]-2; 4-dimethyl-5-formyl radical-1H-pyrroles-3-manthanoate (94mg; 0.24mmol) with 7-fluoro-1; 3-Indolin-2-one (36mg; 0.24mmol) be dissolved in dehydrated alcohol (10ml), splash into 5 Pyrrolidines, backflow 5h.Room temperature to be chilled to, suction filtration, filter cake is washed with dehydrated alcohol, dry, obtains yellow solid (105mg, 84%).
1H?NMR(400MHz，DMSO-d 6)：2.44(s，3H)，2.49(s，3H)，4.12(t，2H)，4.43(t，2H)，6.97(m，1H)，7.05(t，1H)，7.37(t，1H)，7.59(t，1H)7.63(s，2H)，7.83(m，1H)，8.01(d，1H)，11.48(s，br，1H)，13.83(s，br，1H)
MS(ESI +)calcd?for?C 25H 20FN 3O 4Se 1(MH +)，526.06703；found，526.06661
Embodiment 57O-[2-(6-fluoro-1,2-benzisoxa selenazoles-3 (2H)-one) base-ethyl]-5-[(Z)-7-is fluoro-1,2-dihydro-2-oxo--3H-indol-3-yl methylene radical]-2, the preparation of 4-dimethyl-1H-pyrroles-3-manthanoate
In the mode identical with embodiment 56, obtain this compound.
1H?NMR(400MHz，DMSO-d 6)：2.25(s，3H)，2.49(s，3H)，2.52(s，3H)4.13(t，2H)，4.48(t，2H)，7.01(m，2H)，7.24(d，1H)，7.32(d，1H)，7.55(t，1H)，7.71(s，1H)，7.83(m，1H)，8.01(d，1H)，11.44(s，br，1H)，13.84(s，br，1H)
MS(ESI +)calcd?for?C 25H 19F 2N 3O 4Se 1(MH +)，544.05832；found，544.05820.
Embodiment 58O-[2-(5-fluoro-1,2-benzisoxa selenazoles-3 (2H)-one) base-ethyl]-5-[(Z)-7-is fluoro-1,2-dihydro-2-oxo--3H-indol-3-yl methylene radical]-2, the preparation of 4-dimethyl-1H-pyrroles-3-manthanoate
In the mode identical with embodiment 56, obtain this compound.
1H?NMR(400MHz，DMSO-d 6)：2.43(s，3H)，2.53(s，3H)，2.52(s，3H)，3.99(t，2H)，4.40(t，2H)，，7.02(dd，1H)，7.24(t，1H)，7.36(m，1H)，7.62(dd，1H)，7.75(d，2H)，8.07(m，1H)，11.48(s，br，1H)，13.86(s，br，1H)
MS(ESI +)calcd?for?C 25H 19F 2N 3O 4Se 1(MH +)，544.05832；found，544.05812.
Embodiment 59O-[2-(5-methyl isophthalic acid, 2-benzisoxa selenazoles-3 (2H)-one) base-ethyl]-5-[(Z)-7-is fluoro-1,2-dihydro-2-oxo--3H-indol-3-yl methylene radical]-2, the preparation of 4-dimethyl-1H-pyrroles-3-manthanoate
In the mode identical with embodiment 56, obtain this compound.
1H?NMR(400MHz，DMSO-d 6)：2.43(s，3H)，2.49(s，3H)，2.52(s，3H)，4.12(t，2H)，4.42(t，2H)，6.68(m，1H)，6.99(d，1H)，7.04(dd，1H)，7.48(m，1H)，7.66(dd，2H)，7.72(d，1H)，7.91(m，2H)，11.48(s，br，1H)，13.86(s，br，1H)
MS(ES +)calcd?for?C 25H 22FN 3O 4Se 1(MNa +)，540.08；found，540.16.
Embodiment 60O-[2-(5-methyl 1,2-benzisoxa selenazoles-3 (2H)-one) base-ethyl]-5-[(Z)-5-is chloro-1,2-dihydro-2-oxo--3H-indol-3-yl methylene radical]-2, the preparation of 4-dimethyl-1H-pyrroles-3-manthanoate
In the mode identical with embodiment 56, obtain this compound.
1H?NMR(400MHz，DMSO-d 6)：1.25(m，3H)，2.22(s，3H)，2.40(s，6H)，4.11(t，2H)，4.43(t，2H)，6.68(d，1H)，7.06(d，1H)，7.14(m，1H)，7.44(d，1H)，7.62(s，1H)，7.79(d，1H)，8.03(s，1H)，11.05(s，br，1H)，13.90(s，br，1H)
MS(ESI +)calcd?for?C 26H 22Cl 1N 3O 4Se 1(MH +)，556.05358；found，556.05367.
Embodiment 61O-[2-(5-fluoro-1,2-benzisoxa selenazoles-3 (2H)-one) base-ethyl]-5-[(Z)-5-is chloro-1,2-dihydro-2-oxo--3H-indol-3-yl methylene radical]-2, the preparation of 4-dimethyl-1H-pyrroles-3-manthanoate
In the mode identical with embodiment 56, obtain this compound.
1H?NMR(400MHz，DMSO-d 6)：2.43(s，3H)，2.49(s，3H)，4.11(t，2H)，4.41(t，2H)，6.90(d，1H)，7.06(t，1H)，7.18(m，1H)，7.49(m，1H)，7.57(m，1H)，7.83(dd，1H)，8.05(d，1H)，11.09(d，br，1H)，13.91(d，br，1H)
MS(ESI +)calcd?for?C 25H 19ClFN 3O 4Se 1(MH +)，560.02850；found，560.02834.
Embodiment 62O-[2-(5-chloro-1,2-benzisoxa selenazoles-3 (2H)-one) base-ethyl]-5-[(Z)-5-is chloro-1,2-dihydro-2-oxo--3H-indol-3-yl methylene radical]-2, the preparation of 4-dimethyl-1H-pyrroles-3-manthanoate
In the mode identical with embodiment 56, obtain this compound.
1H?NMR(400MHz，DMSO-d 6)：2.08(s，3H)，2.40(s，6H)，3.69(t，2H)，4.38(t，2H)，6.88(d，1H)，7.18(d，1H)，7.46(m，1H)，7.66(d，1H)，7.81(s，1H)，7.90(d，1H)，8.03(s，1H)，11.05(s，br，1H)，13.92(s，br，1H)
MS(ES +)calcd?for?C 25H 19Cl 2N 3O 4Se 1(MH +)，575.99873；found，575.99957.
Embodiment 63O-[2-(4-fluoro-1,2-benzisoxa selenazoles-3 (2H)-one) base-ethyl]-5-[(Z)-5-is chloro-1,2-dihydro-2-oxo--3H-indol-3-yl methylene radical]-2, the preparation of 4-dimethyl-1H-pyrroles-3-manthanoate
In the mode identical with embodiment 56, obtain this compound.
H?NMR(400MHz，DMSO-d 6)：2.24(s，3H)，2.47(s，6H)，4.07(t，2H)，4.46(t，2H)，6.91(d，1H)，7.10(d，1H)，7.17(m，1H)，7.54(d，1H)，7.66(s，1H)，7.88(d，1H)，8.03(s，1H)，11.07(s，br，1H)，13.92(s，br，1H)
MS(ESI +)calcd?for?C 25H 19ClFN 3O 4Se 1(MH +)，560.02850；found，560.02842.
Embodiment 64O-[2-(5-fluoro-1,2-benzisoxa selenazoles-3 (2H)-one) base-ethyl]-5-[(Z)-4-is chloro-1,2-dihydro-2-oxo--3H-indol-3-yl methylene radical]-2, the preparation of 4-dimethyl-1H-pyrroles-3-manthanoate
In the mode identical with embodiment 56, obtain this compound.
1H?NMR(400MHz，DMSO-d 6)：2.43(s，3H)，2.49(s，3H)，4.14(t，2H)，4.45(t，2H)，6.89(d，1H)，7.00(m，1H)，7.16(m，1H)，7.55(m，1H)，7.79(s，1H)，8.09(d，1H)，8.31(d，1H)，11.27(s，br，1H)，13.86(s，br，1H)
MS(ESI +)calcd?for?C 25H 19ClFN 3O 4Se 1(MH +)，560.02850；found，560.02834
Embodiment 65O-[2-(5-fluoro-1,2-benzisoxa selenazoles-3 (2H)-one) base-ethyl]-5-[(Z)-7-is chloro-1,2-dihydro-2-oxo--3H-indol-3-yl methylene radical]-2, the preparation of 4-dimethyl-1H-pyrroles-3-manthanoate
In the mode identical with embodiment 56, obtain this compound.
1H?NMR(400MHz，DMSO-d 6)：1.24(m，3H)，2.43(s，3H)，2.49(s，3H)，4.13(t，2H)，4.43(t，2H)，6.91(m，1H)，7.18(d，1H)，7.56(m，2H)，7.77(m，1H)，7.85(s，1H)，8.09(d，1H)，11.29(s，br，1H)，13.86(s，br，1H)
MS(ESI +)calcd?for?C 25H 19ClFN 3O 4Se 1(MH +)，560.02850；found，560.02895
Embodiment 66O-[2-(5-fluoro-1,2-benzisoxa selenazoles-3 (2H)-one) base-ethyl]-5-[(Z)-7-methyl isophthalic acid, 2-dihydro-2-oxo--3H-indol-3-yl methylene radical]-2, the preparation of 4-dimethyl-1H-pyrroles-3-manthanoate
In the mode identical with embodiment 56, obtain this compound.
1H?NMR(400MHz，DMSO-d 6)：2.43(s，3H)，2.56(s，3H)，4.13(t，2H)，4.42(t，2H)，6.90(dd，1H)，7.06(t，1H)，7.27(m，1H)，7.55(s，1H)7.61(dd，1H)，7.76(d，1H)，8.04(m，2H)，10.98(s，br，1H)，13.94(s，br，1H)
HRMS(ESI +)calcd?for?C 26H 22FN 3O 4Se 1(MH +)，540.08339；found，540.08362.
Embodiment 67O-[3-(6-fluoro-1,2-benzisoxa selenazoles-3 (2H)-one) base-propyl group]-5-[(Z)-5-is fluoro-1,2-dihydro-2-oxo--3H-indol-3-yl methylene radical]-2, the preparation of 4-dimethyl-1H-pyrroles-3-manthanoate
In the mode identical with embodiment 56, obtain this compound.
1H?NMR(400MHz，DMSO-d 6)：2.00(t，2H)2.43(s，3H)，2.49(s，3H)，3.47(t，2H)，4.32(t，2H)，6.86(dd，1H)，6.94(m，1H)，7.26(m，1H)，7.46(s，1H)，7.81(dd，2H)，7.97(m，1H)，10.97(s，br，1H)，13.96(s，br，1H)
HRMS(ES +)cal?cd?for?C 26H 21F 2N 3O 4Se 1(MH +)，558.07；found，558.10.
Embodiment 68O-[3-(6-fluoro-1,2-benzisoxa selenazoles-3 (2H)-one) base-propyl group]-5-[(Z)-5-is chloro-1,2-dihydro-2-oxo--3H-indol-3-yl methylene radical]-2, the preparation of 4-dimethyl-1H-pyrroles-3-manthanoate
In the mode identical with embodiment 56, obtain this compound.
1H?NMR(400MHz，DMSO-d 6)：2.01(t，2H)2.44(s，3H)，2.53(s，3H)，3.47(t，2H)，4.30(t，2H)，6.88(dd，1H)，7.03(dd，1H)，7.46(m，1H)，7.63(s，1H)，7.78(dd，2H)，7.86(m，1H)，10.97(s，br，1H)，14.00(s，br，1H)
HRMS(ES +)calcd?for?C 26H 21Cl 1F 1N 3O 4Se 1(MH +)，574.02；found，574.17.
The mensuration of the anti tumor activity in vitro of 13 kinds of compounds of experimental example
Adopt mtt assay, measure these 13 kinds of compounds to Lovo, RKO, Mia-paca2, it is active that the growth in vitro of Panc-1 cell suppresses.
Get the RKO in logarithmic phase, Lovo, Mia-paca2, Panc-1 cell is inoculated in 96 orifice plates, and inoculum density is 4 * 10 4individual/ml, 180 μ l/ holes; After cell attachment, every hole adds the liquid of 20 μ l, makes medicine final concentration be respectively 0 μ M, 1 μ M, and 5 μ M, 10 μ M, 20 μ M, 50 μ M, after effect 48h, add the MTT solution (20 μ l/ hole) of 5mg/ml, put into CO 2incubator is cultivated after 3～4h, carefully abandons supernatant, after residual liquid is air-dry, adds DMSO, 200 μ l/ holes, and jolting 0.5-1h on shaking table, after dissolving completely to be crystallized, surveys absorbancy OD value in microplate reader 492nm place.The results are shown in Table 2.
Inhibitory rate of cell growth=(negative control OD value-dosing group OD value)/(negative control OD value-blank group OD value) * 100%
Table 2
The experimental result of table 2 shows, in Lovo clone, has the IC of 7 compounds (being numbered 2,3,4,5,7,8,9) 50value is lower than contrast medicine (Sutent, patent applied for are numbered 29 compounds) or with to contrast medicine suitable; In RKO clone, there is the IC of 5 compounds (being numbered 4,5,7,8,9) 50value is lower than contrast medicine (Sutent, patent applied for are numbered 29 compounds) or with to contrast medicine suitable; In Mia-paca2 clone, there is the IC of 2 compounds (being numbered 7,8) 50value is lower than contrast medicine or with to contrast medicine suitable.Visible, the indole ketone compound that the minaline ester that this class Benzisoelenazolone is modified replaces has shown good anti-tumor activity.
Experimental example
Measure the solvability of 3 compounds
Measure respectively and be numbered 12,13 compounds and patent applied for is numbered the solubleness of 29 compounds in common solvent.
Respectively get this 3 kinds of compound 25mg, every kind of compound is divided into 5 parts, and every part of 5mg is dissolved in respectively in following 5 in solvent in 10ml, observes its dissolving situation, and it the results are shown in Table 3
Table 3
Result in table can find out, compound 12,13 than patent applied for, be numbered 29 compound common solvent as methylene dichloride, ethanol, acetonitrile in solubleness all increase.
The foregoing is only preferred embodiment of the present invention, is only illustrative for the purpose of the present invention, and nonrestrictive.Those skilled in the art is understood, and in the spirit and scope that limit, can carry out many changes to it in the claims in the present invention, revise, and even equivalence, but all will fall within the scope of protection of the present invention.

Claims (7)

1. the compound of following structure,
General formula I n is the number n=2 or 3 of carbon between connecting arm
Wherein, R 1, R 2, R 3, R 4, R 5, R 6, R 7, R 8being respectively H, Me or halogen replaces.
Wherein, R 1-4respectively that H, Me or halogen replace;
R 5-8being respectively H, Me or halogen replaces.
N is that the number of carbon between connecting arm is 2 or 3.
2. compound according to claim 1, is characterized in that, described halogen is F, Cl.
3. compound according to claim 1, is characterized in that, R 1h, Cl, F, R 2be H, Cl, F,, R 3h, Cl, F; R 4h, Me, F or Cl, R 5h, Cl, F, R 6h, Me, F or Cl, R 7h, F or Cl, R 8h.
4. according to compound described in claim 1, it is characterized in that, n is the carbon number between connecting arm, is 2 or 3.
5. according to the compound described in claim 1-4 any one, it is characterized in that, described compound is
O-[2-(1,2-benzisoxa selenazoles-3 (2H)-one) base-ethyl]-5-[(Z)-7-is fluoro-1,2-dihydro-2-oxo--3H-indol-3-yl methylene radical]-2,4-dimethyl-1H-pyrroles-3-manthanoate,
O-[2-(6-fluoro-1,2-benzisoxa selenazoles-3 (2H)-one) base-ethyl]-5-[(Z)-7-is fluoro-1,2-dihydro-2-oxo--3H-indol-3-yl methylene radical]-2,4-dimethyl-1H-pyrroles-3-manthanoate,
O-[2-(5-fluoro-1,2-benzisoxa selenazoles-3 (2H)-one) base-ethyl]-5-[(Z)-7-is fluoro-1,2-dihydro-2-oxo--3H-indol-3-yl methylene radical]-2,4-dimethyl-1H-pyrroles-3-manthanoate,
O-[2-(5-methyl isophthalic acid, 2-benzisoxa selenazoles-3 (2H)-one) base-ethyl]-5-[(Z)-7-is fluoro-1,2-dihydro-2-oxo--3H-indol-3-yl methylene radical]-2,4-dimethyl-1H-pyrroles-3-manthanoate,
O-[2-(5-methyl isophthalic acid, 2-benzisoxa selenazoles-3 (2H)-one) base-ethyl]-5-[(Z)-5-is chloro-1,2-dihydro-2-oxo--3H-indol-3-yl methylene radical]-2, the preparation of 4-dimethyl-1H-pyrroles-3-manthanoate,
O-[2-(5-chloro-1,2-benzisoxa selenazoles-3 (2H)-one) base-ethyl]-5-[(Z)-5-is chloro-1,2-dihydro-2-oxo--3H-indol-3-yl methylene radical]-2,4-dimethyl-1H-pyrroles-3-manthanoate,
O-[2-(5-fluoro-1,2-benzisoxa selenazoles-3 (2H)-one) base-ethyl]-5-[(Z)-5-is chloro-1,2-dihydro-2-oxo--3H-indol-3-yl methylene radical]-2,4-dimethyl-1H-pyrroles-3-manthanoate,
O-[2-(4-fluoro-1,2-benzisoxa selenazoles-3 (2H)-one) base-ethyl]-5-[(Z)-5-is chloro-1,2-dihydro-2-oxo--3H-indol-3-yl methylene radical]-2,4-dimethyl-1H-pyrroles-3-manthanoate,
O-[2-(5-fluoro-1,2-benzisoxa selenazoles-3 (2H)-one) base-ethyl]-5-[(Z)-4-is chloro-1,2-dihydro-2-oxo--3H-indol-3-yl methylene radical]-2,4-dimethyl-1H-pyrroles-3-manthanoate,
O-[2-(5-fluoro-1,2-benzisoxa selenazoles-3 (2H)-one) base-ethyl]-5-[(Z)-7-methyl isophthalic acid, 2-dihydro-2-oxo--3H-indol-3-yl methylene radical]-2,4-dimethyl-1H-pyrroles-3-manthanoate
O-[2-(5-fluoro-1,2-benzisoxa selenazoles-3 (2H)-one) base-ethyl]-5-[(Z)-7-is chloro-1,2-dihydro-2-oxo--3H-indol-3-yl methylene radical]-2,4-dimethyl-1H-pyrroles-3-manthanoate
O-[3-(6-fluoro-1,2-benzisoxa selenazoles-3 (2H)-one) base-propyl group]-5-[(Z)-5-is fluoro-1,2-dihydro-2-oxo--3H-indol-3-yl methylene radical]-2,4-dimethyl-1H-pyrroles-3-manthanoate
O-[3-(6-fluoro-1,2-benzisoxa selenazoles-3 (2H)-one) base-propyl group]-5-[(Z)-5-is chloro-1,2-dihydro-2-oxo--3H-indol-3-yl methylene radical]-2,4-dimethyl-1H-pyrroles-3-manthanoate.
6. prepare in claim 1-5 a method for compound described in any one, it is characterized in that, comprise the steps:
(1) prepare compound 1
Compound 1 n=2 or 3
Under existing, Sodium Nitrite makes react under ice bath with hydrochloric acid, obtain villaumite, gained villaumite is reacted with sodium diselenide to reaction mixture and be alkaline, gained mixture is obtained to solid with hcl acidifying, then make gained solid reflux in sulfur oxychloride and DMF, obtain residue, residue obtained with petroleum ether extraction, cooling crystallize out, crystal reacts with thanomin (Propanolamine) in methylene dichloride, obtains compound 1;
(2) prepare compound 2
Compound 2
Methyl aceto acetate reacts under Sodium Nitrite and zinc powder existence with Glacial acetic acid, obtain 3,5-dimethyl-1H-pyrroles-2,4-diethyl dicarboxylate, by 3,5-dimethyl-1H-pyrroles-2,4-diethyl dicarboxylate is dissolved under trifluoroacetic acid ice bath and stirs 10 minutes, adds triethyl orthoformate, move under 40 ℃ of water-baths and react, chloroform extraction, underpressure distillation obtains solid, and dehydrated alcohol recrystallization obtains crystal.Under aqueous sodium hydroxide solution exists, gained yellow solid is refluxed in methyl alcohol, obtain compound 3;
(3) methylene dichloride, as solvent, under EDC and DMAP existence, makes compound 1 react with compound 2, obtains intermediate;
(4) under Pyrrolidine exists, intermediate and compound 1 that step (4) obtains are refluxed in dehydrated alcohol, obtain compound of Formula I.
7. the application of compound in preparing antitumor drug described in any one in claim 1-5.
In a preferred embodiment of the invention, described pharmaceutically acceptable salt selects the hydrochlorate of free mineral acid or organic acid adduction gained, any or its combination of example hydrochloric acid salt, hydrobromate, hydriodate, vitriol, nitrate, tosilate, mesylate, phosphoric acid salt, vitriol, perchlorate, acetate, trifluoroacetate, propionic salt, citrate, malonate, succinate, lactic acid salt, oxalate, tartrate, benzoate; Or by mineral alkali or organic bases, add the alkali salt with gained, as any or its combination of alkaline earth salt, organic amine salt.
In a preferred embodiment of the invention, described alkaline earth salt is selected from any or its combination of magnesium salts or calcium salt.
In a preferred embodiment of the invention, described organic amine salt is selected from any or its combination of alkylbenzyldimethylasaltsum saltsum, piperidinium salt, trialkyl amine salt, pyridinium salt, dimethylamine salt, diethyl amine salt.
Another aspect of the present invention is to provide a kind of pharmaceutical composition, on said composition inclusion compound 1-37 or its pharmacology acceptable salt any or its combination and pharmacology on acceptable vehicle or carrier.
In a preferred embodiment of the invention, described pharmaceutical composition is applicable to (for example oral or rectal administration) in intestines, part or administered parenterally, for example, and oral, injection, implantation, external application, spraying, suction etc.
In a preferred embodiment of the invention, described combination of oral medication is selected from tablet (ordinary tablet, lozenge, Sublingual tablet, mouth paster, chewable tablet, dispersible tablet, fuse, effervescent tablet, vaginal tablet or vagina effervescence, slow releasing tablet, controlled release tablet, enteric coated tablet, oral dosage form etc.), capsule (hard capsule, soft capsule, slow releasing capsule, controlled release capsule, enteric coated capsule etc.), pill (dripping pill, sugar-pill, piller), oral liquid (syrup, suspensoid, oral solution, oral suspensions, Orally taken emulsion, syrup, mixture, distillate medicinal water or medicinal tea), granule (mix suspension grain, effervescent granule, enteric coated particles, slow-releasing granules, controlled release granule etc.), any of powder.
In a preferred embodiment of the invention, described injection comprises any of injection liquid, injectable sterile powder or aseptic block (comprising the preparation such as the technique that adopts solvent crystallization, spray-drying process or freeze-drying), transfusion, concentrated solution for injection.
In a preferred embodiment of the invention, described external preparation is selected from any of suppository, aerosol, powder inhalation, sprays, film, gelifying agent, patch, jelly, emplastrum, plaster, ointment, liniment, lotion, basting agent, solidifying paste.
In a preferred embodiment of the invention, can adopt preparation technique means well known in the art to prepare the present composition.
In a preferred embodiment of the invention, described pharmaceutical composition is selected from inclusion preparation or dispersible preparation.
In a preferred embodiment of the invention, described pharmaceutically acceptable carrier is the well known usual excipients for the preparation of above-mentioned preparation or auxiliary material, wherein, the vehicle that oral preparations or external preparation are conventional or auxiliary material include but are not limited to weighting agent or thinner, lubricant or glidant or antitack agent, dispersion agent, wetting agent, tackiness agent, conditioning agent, solubilizing agent, oxidation inhibitor, fungistat, emulsifying agent etc.Tackiness agent, for example syrup, gum arabic, gelatin, sorbyl alcohol, tragacanth, Mierocrystalline cellulose and derivative thereof, gelatine size, syrup, starch slurry or polyvinylpyrrolidone, preferred derivatived cellulose is Microcrystalline Cellulose, Xylo-Mucine, ethyl cellulose, HPMC; Weighting agent, for example lactose, Icing Sugar, dextrin, starch and derivative thereof, Mierocrystalline cellulose and derivative thereof, inorganic calcium salt, sorbyl alcohol or glycine, preferably inorganic calcium salt is calcium sulfate, calcium phosphate, secondary calcium phosphate, precipitated calcium carbonate; Lubricant, for example micropowder silica gel, Magnesium Stearate, talcum powder, aluminium hydroxide, boric acid, hydrogenated vegetable oil, polyoxyethylene glycol; Disintegrating agent, for example starch and derivative thereof, polyvinylpyrrolidone or Microcrystalline Cellulose, preferred starch derivative is sodium starch glycolate, Explotab, pregelatinized Starch, modified starch, hydroxypropylated starch, W-Gum; Wetting agent, such as sodium lauryl sulphate, water or alcohol etc., preferred pharmaceutically acceptable carrier is cyclodextrin (alpha-cylodextrin, beta-cyclodextrin or γ-cyclodextrin), Celldone102CG, Polyplasdone XL-10, talcum powder, Magnesium Stearate or ethanol etc.
In a preferred embodiment of the invention, vehicle or auxiliary material that described injection is conventional include but are not limited to: oxidation inhibitor, such as Sulfothiorine, S-WAT, sodium bisulfite, dibutyl benzoic acid or Sodium Pyrosulfite etc.; Fungistat, for example 0.5% phenol, 0.3% cresols, 0.5% trichloro-butyl alcohol; PH adjusting agent, for example hydrochloric acid, Citric Acid, potassium hydroxide (sodium), Sodium Citrate and buffer reagent phosphoric acid dioxy sodium and Sodium phosphate dibasic; Emulsifying agent, for example Tween-80, do not have that sour sorb is smooth, pluronic gram F-68, lecithin, fabaceous lecithin; Solubilizing agent, such as tween-80, glycerine etc.
In a preferred embodiment of the invention, also activeconstituents can be mixed by its preparation requirement with pharmaceutically acceptable slow controlled release carrier, again according to the preparation method of sustained-release preparation well known in the art, as add retarding agent dressing or by making again micropill after active principle microcapsules, as sustained release pellet or controlled release micro pill; Described slow controlled release carrier includes but are not limited to oil agent, hydrophilic colloid or the dressing retarding agent etc. of mixing, and described oil to mix agent be glyceryl monostearate, hydrogenated castor oil, Dormant oils, polysiloxane, dimethyl siloxane; Described hydrophilic colloid is the derivatived celluloses such as Xylo-Mucine, hydroxypropylcellulose, Vltra tears, or PVP, gum arabic, tragcanth or carbopol etc.; Described dressing retarding agent is ethyl cellulose (EC), HPMC (HMPC), polyvinylpyrrolidone (PVP), cellulose acetate-phthalate (CAP), acrylic resin etc.
In a preferred embodiment of the invention, according to required administering mode, any or its combination of acceptable salt on the compound 1-37 that pharmaceutically acceptable composition comprises about 1-99 % by weight or its pharmacology, and the suitable pharmaceutical excipient of 1-99 % by weight.
In a preferred embodiment of the invention, on the compound 1-37 that comprises about 5-75 % by weight in described pharmaceutical composition or its pharmacology acceptable salt any or its combination, surplus is pharmaceutical excipient.
Another aspect of the present invention is to provide on compound 1-37 or its pharmacology acceptable salt or its pharmaceutical composition for the preparation of the application in anti-tumor drug.
In a preferred embodiment of the invention, described antitumor action refers to for prevention or treatment abnormal cell growth, described abnormal cell growth can show as tumour, described tumour is selected from brain tumor, lung cancer, liver cancer, leukemia, osteocarcinoma, carcinoma of the pancreas, skin carcinoma, melanoma, uterus carcinoma, ovarian cancer, the rectum cancer, cancer of the stomach, colorectal carcinoma, mammary cancer, uterus carcinoma, carcinoma of fallopian tube, carcinoma of endometrium, cervical cancer, carcinoma of vagina, carcinoma vulvae, esophagus cancer, carcinoma of small intestine, endocrine system cancer, soft tissue sarcoma, urethral carcinoma, prostate cancer, lymphocytoma, bladder cancer, kidney, carcinoma of ureter, Vertebral Neoplasms:, brain stem neurospongioma, pituitary adenoma, lung cancer, liver cancer, any of leukemia.
In a preferred embodiment of the invention, the dosage of the indole ketone compound that the minaline ester that Benzisoelenazolone of the present invention is modified replaces when treatment tumour is about 0.05-250mg/Kg body weight, be preferably 0.5-200mg/Kg body weight, more preferably 2-125mg/Kg body weight, the most more preferably 5-85mg/Kg body weight.
CN201310146382.4A 2013-04-25 2013-04-25 Novel benzisoselenazolone modified pyrrole formate substituted indolone compound and application thereof Pending CN104119329A (en)

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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN108017570A (en) * 2017-12-21 2018-05-11 常州大学 A kind of production method of isatin
CN112079764A (en) * 2020-10-12 2020-12-15 山东汇海医药化工有限公司 Synthesis method of sunitinib intermediate 5-fluoroindole-2-ketone
CN112707917A (en) * 2020-12-24 2021-04-27 石家庄学院 Benzisoselenazolone dihydroartemisinin derivative and preparation method and application thereof
CN113527301A (en) * 2020-04-13 2021-10-22 凯熙医药（武汉）股份有限公司 Tetrazine substituent-containing aromatic isoselenazole compound and synthetic method and application thereof
CN113527329A (en) * 2020-04-22 2021-10-22 上海中医药大学附属龙华医院 Selenium-containing compound and medical application thereof
CN113616642A (en) * 2020-05-06 2021-11-09 上海元熙医药科技有限公司 Use of benzisoselenazole derivatives for preparing anti-coronavirus medicaments

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN108017570A (en) * 2017-12-21 2018-05-11 常州大学 A kind of production method of isatin
CN113527301A (en) * 2020-04-13 2021-10-22 凯熙医药（武汉）股份有限公司 Tetrazine substituent-containing aromatic isoselenazole compound and synthetic method and application thereof
CN113527329A (en) * 2020-04-22 2021-10-22 上海中医药大学附属龙华医院 Selenium-containing compound and medical application thereof
CN113616642A (en) * 2020-05-06 2021-11-09 上海元熙医药科技有限公司 Use of benzisoselenazole derivatives for preparing anti-coronavirus medicaments
WO2021223780A2 (en) 2020-05-06 2021-11-11 上海元熙医药科技有限公司 Use of benzisoselazole derivative for anti-coronavirus and control of interstitial lung disease (ild) related to coronavirus
WO2021223780A3 (en) * 2020-05-06 2021-12-30 上海元熙医药科技有限公司 Use of benzisoselazole derivative for anti-coronavirus and control of interstitial lung disease (ild) related to coronavirus
CN113616642B (en) * 2020-05-06 2023-02-28 上海元熙医药科技有限公司 Use of benzisoselenazole derivatives for preparing anti-coronavirus medicines
CN112079764A (en) * 2020-10-12 2020-12-15 山东汇海医药化工有限公司 Synthesis method of sunitinib intermediate 5-fluoroindole-2-ketone
CN112079764B (en) * 2020-10-12 2023-08-01 山东汇海医药化工有限公司 Synthesis method of sunitinib intermediate 5-fluoroindol-2-one
CN112707917A (en) * 2020-12-24 2021-04-27 石家庄学院 Benzisoselenazolone dihydroartemisinin derivative and preparation method and application thereof

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