CN100432071C - Substituted 1H-indole-2-ketone compound and its preparation method and uses - Google Patents

Substituted 1H-indole-2-ketone compound and its preparation method and uses Download PDF

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CN100432071C
CN100432071C CNB2004100679042A CN200410067904A CN100432071C CN 100432071 C CN100432071 C CN 100432071C CN B2004100679042 A CNB2004100679042 A CN B2004100679042A CN 200410067904 A CN200410067904 A CN 200410067904A CN 100432071 C CN100432071 C CN 100432071C
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ethoxy carbonyl
indol
pyrroles
methyl
alkyl
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CN1769284A (en
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蒋华良
罗小民
李海泓
谭金芝
丁健
林莉萍
柳红
陈凯先
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Shanghai Institute of Materia Medica of CAS
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Abstract

The present invention relates to a novel substituted 1H-indole-2-ketone compound and an application thereof. The structure of the compound is disclosed in the right formula. A pharmacological experiment indicates that the compound has certain pharmacology performance and especially has the inhibitory action on the tyrosine kinase of an epidermal growth factor receptor and the associated hyperplasia of various tumor cells thereof. The present invention also relates to a preparation method of the compound.

Description

Substituted 1 H-indole-2-ketone compound and its production and use
Technical field
The present invention relates to a class substituted 1 H-indole-2-ketone compound, be specifically related to a class, the invention still further relates to the preparation method of this compounds the inhibited substituted 1 H-indole-2-ketone compound of Urogastron Tyrosylprotein kinase.
Background technology
The effect of protein tyrosine kinase (PTKs) is that the phosphate of ATP is transferred on the specific tyrosine residues of functional protein, and the growth of this tyrosine phosphorylation process energy regulating cell, processes such as propagation and differentiation.The quantity of protein tyrosine kinase is estimated to surpass 1000 kinds, wherein has 100 kinds sequence determined.Protein tyrosine kinase plays crucial effect in the tumour generating process, having known has expression of proto-oncogenes over half to possess the active albumen of PTK, and the vital role of protein tyrosine kinase in cancer cell multiplication makes it become the cancer therapy target of very attractive.
Research is EGF-R ELISA (EGFR) the most widely in the protein tyrosine kinase, EGFR is the transmembrane glycoprotein of a 170KDa, and its structure comprises the outer ligand binding domain of film, membrane-spanning domain, cell intracellular domain (possessing the PTK activity) and a C-terminal structural domain.Epidermal Growth Factor Receptor Family comprises four member: EGFR (ErbB-1), ErbB-2 (HER2), ErbB-3 (HER3), ErbB-4 (HER4).The cancer clinical study shows that this receptor and its part all have important relation with a lot of tumours, the overexpression of EGFR occurs in 60% the cancer.This exception table has a variety of forms now, but every kind all can cause excessive tyrosine phosphorylation signal to import cell into unusually.In cell system, EGF or other ErbB family part often cause uncontrollable cell proliferation, thereby make cell be converted into typical abnormal morphology by normal morphology.Outer part of film and EGFR combination cause the EGFR acceptor to form dimer (homodimer or special-shaped dimerization), activate Tyrosylprotein kinase, import proliferation signal into cell.Utilize drug effect in EGFR, can end the proliferation signal that it mediates, thereby stop the excessive breeding of cancer cells.Have two class medicines can play such effect: a class is a monoclonal antibody, and another kind of is small-molecule drug.The mode of action of monoclonal antibody drug is the outer part of film that occupies EGFR, endogenous ligands such as EGF can't be combined with EGFR, thereby stop signal to import cell into.Small-molecule drug then by Tyrosylprotein kinase catalytic domain in the blocking-up EGFR born of the same parents, stops tyrosine phosphorylation, thereby has blocked the cell proliferation signal.
Small molecules EGFR inhibitor comprises natural inhibitor and organic synthesis compound.Natural inhibitor has better inhibited activity to EGFR, but because the reason of aspects such as cytotoxicity, enzyme selectivity (especially kinases selectivity) and the mechanism of action, not finding as yet at present has the natural inhibitor of drug development future parent nucleus.The research of natural inhibitor mainly be by the natural product structural modification is sought the EGFR inhibitor (Alexander J.Bridges, Chem.Rev.2001,101,2541-2571).
The organic synthesis type small molecular inhibitor can be divided into reversible inhibitor and irreversible inhibitor according to the mode of action with EGFR, can be divided into 4-phenylamino (mixing) ring miazines and 4-phenylamino-3-cyano quinolines class according to the parent nucleus type.4-phenylamino (mixing) ring miazines is to study a class EGFR inhibitor the most widely, comprises 4-phenylamino quinazoline ditosylate salt, 4-phenylamino Pyridopyrimidine class and 4-phenylamino Pyrrolopyrimidine etc., and wherein 4-phenylamino quinazoline ditosylate salt is the most representative.
Zeneca company discloses the IC of a kind of EGFR of inhibition 50Value reaches 20-40nM, and optionally 4-phenylamino quinazoline compounds (European Patent Publication No 0520722A, 1992) is arranged preferably; Fry has reported the IC of a kind of EGFR of inhibition 50Value is for 29pM, and is single-minded EGFR inhibitor compound, this compound be reversible ATP in conjunction with the territory competitive inhibitor, in the cell levels experiment, showed good enzyme selectivity, suppress the IC of EGFR autophosphorylation process 50Value is 14nM, but has poorly soluble shortcoming.(Fry，Science，1994，265：1093-1095)。
Figure C20041006790400061
Be the EGFR inhibitor that obtains FDA approval listing in May, 2003, belong to 4-phenylamino quinazoline compounds, be reversible ATP in conjunction with territory bonded competitive inhibitor, it suppresses active IC at the EGFR of enzyme level 50Value is 23nM, EGF is stimulated the inhibiting IC of the oral epithelium squamous cell carcinoma KB of breeding 50Value is 80nM, possesses the EGFR enzyme specificity of height, and is very low to other kinase whose inhibition abilities.Studies show that Iressa has good bioavailability and extremely low toxicity, also has the obvious treatment effect to nonsmall-cell lung cancer and mammary cancer.But part Study shows that Iressa can not improve survival rate or improve symptom when combined chemotherapy; In addition, find have the small portion patient serious toxic side effects to occur,, and the part patient death is arranged as interstitial pneumonia (ILD) in clinical practice in a year of Japan.The main toxic side effects of Iressa comprises: diarrhoea, feel sick, and vomiting, fash and acne etc. may make the patient who takes the anticoagulant warfarin bleeding occur in addition.
It is reported, 6,7-dimethoxy-4 '-phenylamino-3-cyano quinolines suppresses active IC to the EGFR enzyme level 50Value is 190nM; Replace on 3 of parent nucleus with formyl radical, it suppresses activity and reaches μ M level, but this class inhibitor is poor slightly aspect enzyme selectivity, and they also have c-SRC and MEK to suppress active.(Wang Y.D., Miller K., Boschelli D.H. etc., Bioorg.Med.Chem.Lett.2000,10:2477-2480; Boschelli D.H., Yang Y.D., Ye F. etc., J.Med.Chem.2001,44:822-846) in addition, 2,3-dihydro-2-thioketones-indoles-3-alkyl carboxylic acid compound and 2, the two indoles of 2 '-two sulphur-3-alkyl carboxylic acid all is in the news as the inhibitor of EGFR (Zhang N., Wu B., Powell D., Wissner A. etc., Bioorg.Med.Chem.Lett.2000,10:2825-2829).
Above-mentioned inhibitor all is and ATP competition bonded reversible inhibitor, though but be retroactive inhibition, the speed of dissociating of they and enzyme is very slow.The investigator thinks and the what is called " hydrophobicity collapse " that can cause acceptor after these " accurate irreversible inhibitors " and the receptors bind has caused the sealing in the kinases district of acceptor, has stoped the protein phosphorylation process.The concentration of ATP in cell is the mM level, so the dosage of clinical stage reversible inhibitor is all very big in early days, purpose is exactly to keep required Plasma Concentration, wherein block enzyme and ATP bonded maximum duration can reach 4 hours, and it is more effective than easily molten drug molecule to be difficult for molten drug molecule.Given this, be necessary to seek the irreversible inhibitor of EGFR.
The at present existing EGFR irreversible inhibitor that enters clinical experimental stage comprise 4-phenylamino quinazoline compounds and 4-phenylamino 3-cyano quinoline compound (Alexander J.Bridges, Chem.Rev.2001,101,2541-2571).
Still there are a lot of problems in the exploitation of EGFR inhibitor, causes the unknown toxic problem of 4-phenylamino quinazoline compounds that people pay close attention to, the problem of enzyme selectivity etc. as Iressa in the failure of Japanese clinical experiment.Address these problems, the EGFR inhibitor of development of new is the popular research topic of present world the world of medicine.
Summary of the invention
The novel substituted 1 H-indole-2-ketone compound that the object of the present invention is to provide a class to have to suppress Urogastron to express and reach antitumor drug effect effect.
Another object of the present invention provides the preparation method of The compounds of this invention.
A further object of the present invention provides The compounds of this invention at the inhibitor as the Urogastron Tyrosylprotein kinase, as the application in the preparation antitumor drug.
The substituted 1 H-indole-2-ketone compound of compound of the present invention for having following general formula (I) structure:
Wherein:
R 1Be selected from hydrogen, C 1-5Alkyl, C 2-5Alkenyl, C 3-10Cycloalkyl, hydroxyl, C 1-5Alkoxyl group, ethanoyl, carboxyl, amide group, thioamides base, alkylsulfonyl and three halo methylsulfonyls;
R 2, R 3, R 4, R 5Be selected from hydrogen, C independently of one another 1-5Alkyl, C 1-4Alkoxyl group, aryl, aryloxy, C 1-5Alkylaryl, C 1-5Alkyl-aryloxy, C 3-10Cycloalkyl, sulfydryl, C 1-5Alkane sulfydryl, aromatic thiohydroxy, inferior mercapto acyl group, halogen, trihalogenmethyl, amino, cyano group, nitro, carboxyl, oxygen carboxyl, amide group, thioamides base, sulfoamido, three halo methylsulfonyls, N-sulfonamido, S-sulfonamido, three halo methanesulfinyl, O-formamyl, O-thiocarbamoyl and-NR 11R 12, R wherein 3And R 4, R 4And R 5Can be in conjunction with forming hexa-atomic aromatic ring, methylene-dioxy or ethylenedioxy;
R 4, R 5Can also be selected from following group at the same time or separately:
Figure C20041006790400081
R wherein 13Be selected from hydrogen; C 1-5Alkyl; C 1-5Alkoxyl group; Aryl; Aryloxy; C 1-5Alkylaryl; C 1-5Alkyl-aryloxy; Trihalogenmethyl; Pyridyl; Pyrimidyl; Thienyl; Above-mentioned each group can be replaced by following group: trifluoromethoxy; Fluorine; Chlorine; Bromine; Iodine; C 1-3-alkoxyl group or replacement C 1-3-alkoxyl group wherein replaces C 1-3-alkoxyl group is meant in 2-or 3-position by amino, C 1-3-alkyl amine group, 2-(C 1-3-alkyl) amido, phenyl-(C 1-3-alkyl) amido, N-(C 1-3-alkyl)-phenyl-(C 1-3-alkyl) amido, pyrrolidyl or piperidyl replace; Phenyl-C 1-3-alkyl amine group-C 1-3-alkyl, this substituting group can also be with trifluoromethyl, fluorine, chlorine, bromine, iodine, C 1-5-alkyl or C 1-3-alkoxyl group carries out list to phenyl nuclear and replaces or two replacements, and when carrying out two replacements, substituting group can be identical, also can be different;
R 6Be selected from hydrogen, C 3-10Cycloalkyl, C 1-5Alkyl, halogen;
R 7And R 8Be selected from hydrogen, C separately 1-5Alkyl, C 1-4Alkoxyl group, aryloxy, C 1-5Alkylaryl, C 1-5Alkyl-aryloxy, three halo C 1-5Alkyl, C 3-10Cycloalkyl, sulfydryl, C 1-5Alkane sulfydryl, aromatic thiohydroxy, inferior mercapto acyl group, halogen, trihalogenmethyl, amino, cyano group, nitro, carboxyl, oxygen carboxyl, amide group, thioamides base, sulfoamido, three halo methylsulfonyls, N-sulfonamido, S-sulfonamido, three halo methanesulfinyl, O-formamyl, O-thiocarbamoyl and-NR 11R 12
R 9Be selected from hydrogen, C 1-5Alkyl, C 1-5Alkoxyl group, aryl, aryloxy, C 1-5Alkylaryl, C 1-5Alkyl-aryloxy, halogen, trihalogenmethyl, sulfydryl, hydroxyl, sulfo-C 1-5Alkyl and-NR 11R 12
R 10Be selected from hydrogen, C 3-10Cycloalkyl, C 1-5Alkyl, C 2-5Alkenyl, aryl, heteroaryl, hydroxyl and heterolipid cyclic group;
R 11And R 12Independently be selected from hydrogen, C 1-5Alkyl, C 2-5Alkenyl, C 3-10Cycloalkyl, ethanoyl, alkylsulfonyl, trifyl.
A preferred compound of The compounds of this invention is for to have 1 of general formula (I) structure, 4-disubstituted benzenes compounds, wherein R 4Be selected from C 1-5Alkyl, halogen, sulfoamido, amino, cyano group, nitro, carboxyl and-NR 11R 12R 1, R 2, R 3, R 5, R 6, R 7, R 8, R 9, R 10, R 11, R 12Definition with the definition of aforementioned compound.
The preferred preferred compound of another of The compounds of this invention is for to have 1 of general formula (I) structure, 4-disubstituted benzenes compounds, wherein R 4, R 5Be selected from following group at the same time or separately:
Figure C20041006790400082
R 1, R 2, R 3, R 4, R 7, R 8, R 9, R 10, R 11, R 12, R 13Definition with the definition of aforementioned compound.
In the present invention, aryl or the aryl that contains in the group of aryl refer to phenyl, naphthyl and xenyl; Heteroaryl refer to monocycle with thick with the ring (promptly having the ring of adjacency pair atom mutually) group, it has on ring, and 1-3 is individual to be selected from the atom of nitrogen, oxygen and sulphur and to have the π-electronic system that is connected fully in addition, for example pyrroles, furans, thiophene, imidazoles, thiazole, pyrazoles, pyridine, pyrimidine, quinoline, isoquinoline 99.9, purine and carbazole etc.; The heterolipid cyclic group refers to has monocycle or the thick and ring (C that is selected from nitrogen, oxygen and sulphur atom on ring 3-15), described ring also can contain 1 to 7 two key, however described ring does not have the π-electronic system that connects fully, as piperidines, tetrahydrofuran (THF), Pyrrolidine, tetramethylene sulfide, hexanaphthene and pyrroles etc.
The preferred compound of the present invention comprises: (E)-3-[(3-ethoxy carbonyl methyl-2-ethoxy carbonyl-5-methyl isophthalic acid H-pyrroles-4-yl) methylene radical]-the 1H-indol-2-one; (E)-and 5-bromo-3-[(3-ethoxy carbonyl methyl-2-ethoxy carbonyl-5-methyl isophthalic acid H-pyrroles-4-yl) methylene radical]-the 1H-indol-2-one; (E)-and 3-[(3-methoxycarbonyl methyl-2-methoxycarbonyl-5-methyl isophthalic acid H-pyrroles-4-yl) methylene radical]-(1H)-indol-2-one; (E)-and 5-bromo-3-[(3-methoxycarbonyl methyl-2-methoxycarbonyl-5-methyl isophthalic acid H-pyrroles-4-yl) methylene radical]-(1H)-indol-2-one; (E) 3-[(3,5 dimethyl-2-ethoxy carbonyl-1H-pyrroles-4-yl) methylene radical]-(1H)-indol-2-one; (E)-and 5-bromo-3-[(3,5 dimethyl-2-ethoxy carbonyl-1H-pyrroles-4-yl) methylene radical]-(1H)-indol-2-one; (E)-and 5-nitro-3-[(3,5 dimethyl-2-ethoxy carbonyl-1H-pyrroles-4-yl) methylene radical]-(1H)-indol-2-one; (E) 3-[(3,5 dimethyl-2-methoxycarbonyl-1H-pyrroles-4-yl) methylene radical]-(1H)-indol-2-one; (E)-and 5-nitro-3-[(3,5 dimethyl-2-methoxycarbonyl-1H-pyrroles-4-yl) methylene radical]-(1H)-indol-2-one; (E)-and 5-nitro-3-[(3-ethoxy carbonyl methyl-2-ethoxy carbonyl-5-methyl isophthalic acid H-pyrroles-4-yl) methylene radical]-(1H)-indol-2-one; (E)-and 5-carboxyl-3-[(3-ethoxy carbonyl methyl-2-ethoxy carbonyl-5-methyl isophthalic acid H-pyrroles-4-yl) methylene radical]-(1H)-indol-2-one; (E)-and 5-amino-sulfonyl-3-[(3-ethoxy carbonyl methyl-2-ethoxy carbonyl-5-methyl isophthalic acid H-pyrroles-4-yl) methylene radical]-(1H)-indol-2-one; (E)-and 5-methylamino alkylsulfonyl-3-[(3-ethoxy carbonyl methyl-2-ethoxy carbonyl-5-methyl isophthalic acid H-pyrroles-4-yl) methylene radical]-(1H)-indol-2-one; (E)-and 5-(N-morpholinyl) amino-sulfonyl-3-[(3-ethoxy carbonyl methyl-2-ethoxy carbonyl-5-methyl isophthalic acid H-pyrroles-4-yl) methylene radical]-(1H)-indol-2-one; (E)-and 5-(3-chloro-phenyl-) amino-sulfonyl-3-[(3-ethoxy carbonyl methyl-2-ethoxy carbonyl-5-methyl isophthalic acid H-pyrroles-4-yl) methylene radical]-(1H)-indol-2-one; (E)-and 5-(3-fluorophenyl) amino-sulfonyl-3-[(3-ethoxy carbonyl methyl-2-ethoxy carbonyl-5-methyl isophthalic acid H-pyrroles-4-yl) methylene radical]-(1H)-indol-2-one; (E)-and 5-dimethylamino alkylsulfonyl-3-[(3-ethoxy carbonyl methyl-2-ethoxy carbonyl-5-methyl isophthalic acid H-pyrroles-4-yl) methylene radical]-(1H)-indol-2-one; (E)-and 5-(3-fluoro-4-chloro-phenyl-) amino-sulfonyl-3-[(3-ethoxy carbonyl methyl-2-ethoxy carbonyl-5-methyl isophthalic acid H-pyrroles-4-yl) methylene radical]-(1H)-indol-2-one; (E)-and 5-(hexahydropyridine base) amino-sulfonyl-3-[(3-ethoxy carbonyl methyl-2-ethoxy carbonyl-5-methyl isophthalic acid H-pyrroles-4-yl) methylene radical]-(1H)-indol-2-one; (E)-and 5-(3-bromophenyl) amino-sulfonyl-3-[(3-ethoxy carbonyl methyl-2-ethoxy carbonyl-5-methyl isophthalic acid H-pyrroles-4-yl) methylene radical]-(1H)-indol-2-one.
The preparation of The compounds of this invention is implemented through the following steps:
Figure C20041006790400091
The compounds of this invention (Compound I) is made by substituted 1 H-indole-2-ketone (Compound I I) and replacement 3-formyl radical 1H-pyrroles (compound III) condensation: under the catalysis of alkali, equimolar Compound I I and compound III are carried out condensation reaction in organic solvent, according to the response situation of particular compound, temperature of reaction is 65 ℃～90 ℃; Reaction times is 3～6 hours, and the general post-treating method that adopts comprised cooling concentration, recrystallization, column chromatography for separation etc. after reaction finished.Final product (I) detects proof with nucleus magnetic resonance or mass spectrum.
Among the present invention, organic solvent refers to protonic solvent or aprotic solvent, and wherein protonic solvent is water or alcohols (as ethanol, methyl alcohol, propyl carbinol); Aprotic solvent is polarity or proton inert non-polar solvent, the feature of aprotic solvent is not contain acidic hydrogen, promptly do not contain can with solute bonded hydrogen, preferred proton inert non-polar solvent is pentane, hexane, benzene, toluene, methylene dichloride or tetracol phenixin, and preferred polar proton inert solvent is chloroform, tetrahydrofuran (THF), dimethyl sulfoxide (DMSO) or dimethyl formamide.Alkaline catalysts refers to organic nitrogen(ous) base and mineral alkali, wherein organic nitrogen(ous) base can adopt triethylamine, pyridine, hexahydropyridine, Trimethylamine 99, aniline, diisopropylamine, 1,8-diazabicylo [5.4.1] 11-7-alkene, tetramethyleneimine, piperidines etc., mineral alkali can adopt ammonia, alkali metal hydroxide or alkaline earth metal hydroxides (as lithium hydroxide, sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, hydrated barta) phosphoric acid salt, carbonate, supercarbonate, hydrosulfate etc.When solvent was protonic solvent, described alkaline catalysts was alkali metal hydroxide or alkaline earth metal hydroxides.
Among the present invention, the synthetic method referenced patent method (WO9961442) of Compound I I;
Among the present invention, the synthetic method reference method of compound III (Alan R.Battersby., Eric Hunt et a1., J.Chem.Soc.Perk.I 1976:1008-1035; Woodward, R.B.J.Am.Chem.Soc.1960,82,3800-3892.).
Beneficial effect
The present invention designs and has synthesized the novel substituted 1 H-indole-2-ketone compound of a class, huamn autosomal dominant inheritance type multicystic kidney disease (ADPKD) cyst lining epithelial cells, A-549 human lung adenocarcinoma cell, A-431 human skin squamous cell carcinoma and MDA-MB-468 human breast cancer cell there are the inhibition effect, can be used for preparing the medicine that the excessive or undesired hyperplasia of treatment causes disease.The The compounds of this invention structure is simple relatively, is easy to preparation.
Embodiment
The present invention is further elaborated below in conjunction with specific embodiment, but do not limit the present invention.
In the following preparation example, the X-4 type fusing point instrument that fusing point adopts Shanghai Precision Scientific Apparatus Co., Ltd to produce is measured, and temperature is not calibrated; Nucleus magnetic resonance is by Bruker AMX-400 type and INVOA-600 type nmr determination, and TMS is interior mark, and chemical shift unit is ppm; Mass spectrum is measured by MAT-711 type and MAT-95 type mass spectrograph; Column chromatography silica gel 200-300 order, Haiyang Chemical Plant, Qingdao produces; The HSGF-254 type thin-layer chromatography precoated plate that the TLC silica-gel plate is produced for the chemical plant, Yantai; The sherwood oil boiling range is 60-90 ℃; Adopt ultraviolet lamp, the colour developing of iodine cylinder.If do not particularly point out working method, described concentrated finger steams with the solvent that Rotary Evaporators will prepare in the compound solution in the preparation example; Described drying refers to will prepare the compound oven dry with the DHG-9240A thermostatic drying chamber at 80 ℃.
Embodiment 1 (E)-3-[(3-ethoxy carbonyl methyl-2-ethoxy carbonyl-5-methyl isophthalic acid H-pyrroles-4-yl) methylene radical]-preparation of 1H-indol-2-one (Compound I-1)
Under 0-10 ℃ of ice bath, (Sodium Nitrite 29g, water 60ml) joins 2-carbonyl-1 with sodium nitrite in aqueous solution, stirs 5 hours in acetate (140ml) solution of 3-diethyl malonate (80g).Acetate (140ml) solution of benzyl acetoacetate (76g) is joined in the reaction solution, add zinc powder (46g) and anhydrous sodium acetate (40g), continue to stir 15 minutes.Remove ice bath, be heated to 80 ℃ with oil bath, stir after 4 hours, reaction solution is poured in the trash ice (1Kg), placement is spent the night, and filters, and concentrates, and obtains the 60g faint yellow solid.Use ethyl alcohol recrystallization, obtain 51g white solid 4-benzyloxycarbonyl-3-ethoxy carbonyl methyl-2-ethoxy carbonyl-5-methyl isophthalic acid H-pyrroles, productive rate 33%.
With 4-benzyloxycarbonyl-3-ethoxy carbonyl methyl-2-ethoxy carbonyl-5-methyl isophthalic acid H-pyrroles (51g, 136mmol) be dissolved in the tetrahydrofuran (THF) (50ml), add 10% palladium carbon (10g), room temperature, feed hydrogen, stir 1 hour after-filtration and fall palladium carbon, behind tetrahydrofuran (THF) (50ml) washing leaching cake, the filtrate concentrate drying is obtained 36g white solid 3-ethoxy carbonyl methyl-2-ethoxy carbonyl-5-methyl isophthalic acid H-pyrroles-4-carboxylic acid, productive rate 95%.
3-ethoxy carbonyl methyl-2-ethoxy carbonyl-5-methyl isophthalic acid H-pyrroles-4-carboxylic acid (36g) is dissolved in 1, and in the 2-ethylene dichloride (200ml), oil bath is heated to 50 ℃.Add sodium bicarbonate aqueous solution (sodium bicarbonate 40g: water 200ml), stir, have bubble to emerge and afterwards drip iodine aqueous solution (the iodine 240g: water 200ml) that contains sodium iodide (20g).Continue heated and stirred half an hour, after thin-layer chromatography detection method tracking and measuring reacts completely, add sodium bisulfite and remove excessive iodine.Separate organic layer, dry back concentrates, and obtains the 42g crude product.With 1,2-ethylene dichloride recrystallization obtains the pure product 3-of 40g ethoxy carbonyl methyl-2-ethoxy carbonyl-4-iodo-5-methyl isophthalic acid H-pyrroles, white solid, productive rate 91%.
3-ethoxy carbonyl methyl-2-ethoxy carbonyl-4-iodo-5-methyl isophthalic acid H-pyrroles (40g) is dissolved in the methyl alcohol (200ml), and oil bath is heated to back heats up in a steamer.The aqueous solution (the sodium iodide 25g: water 30ml), add concentrated hydrochloric acid (37%) (10ml), after 15 minutes, add sodium bisulfite (500mg) and remove excessive iodine that adds sodium iodide.Methyl alcohol in the reaction solution steam is removed (75 ℃), with 1,2-ethylene dichloride (100ml) extraction, concentrated organic layer, drying obtains 3-ethoxy carbonyl methyl-2-ethoxy carbonyl-5-methyl isophthalic acid H-pyrroles of 29g, white solid, productive rate 87%.
With the N that under 0～5 ℃, is added dropwise to of phosphorus oxychloride (15ml), in the dinethylformamide (15ml).Stir after 15 minutes, slowly drip 3-ethoxy carbonyl methyl-2-ethoxy carbonyl-5-methyl isophthalic acid H-pyrroles (29g) 1,2-ethylene dichloride (100ml) solution, after continue stirring 15 minutes under 0～5 ℃ of ice bath.Remove ice bath, be heated to 50 ℃, after half an hour, add the aqueous solution (the anhydrous sodium acetate 10g: water 50ml) of sodium acetate with oil bath.After half an hour, the cooling reaction solution separates organic layer and concentrated with separating funnel; use ethyl acetate: the elutriant of sherwood oil=1: 3 separates on silicagel column; obtain 3-ethoxy carbonyl methyl-2-ethoxy carbonyl-4-formyl radical-5-methyl isophthalic acid H-pyrroles of 26g, white solid, productive rate 80%.
3-ethoxy carbonyl methyl-2-ethoxy carbonyl-4-formyl radical-5-methyl isophthalic acid H-pyrroles (1g) and 1H-indol-2-one (0.5g) are mixed in ethanol (20ml), and oil bath is heated to 80 ℃, drips hexahydropyridine (0.1g).React concentration of reaction solution after 3 hours, with 1,2-ethylene dichloride (10ml) dissolving back concentrates organic layer with 20ml water and the dry washing of 20ml 2N hydrochloric acid back, use ethyl acetate: sherwood oil=elutriant purifying on silicagel column of 1: 4 obtains (E)-3-[(3-ethoxy carbonyl methyl-2-ethoxy carbonyl-5-methyl isophthalic acid H-pyrroles-4-yl of 1.2g) methylene radical]-the 1H-indol-2-one, yellow solid, productive rate 83%.
H 1NMR(CDCl 3)9.20(s，1H，N-H)9.90(s，1H，N-H)7.82(s，1H，vinyl-H)7.20(t，2H，Ph-H)7.09(t，1H，Ph-H)6.90(m，2H，Ph-H)4.33(q，2H，CO 2C H 2 CH 3)4.08(q，2H，CO 2C H 2 CH 3)3.80(s，3H，CH 2CO 2CH 2CH 3)2.21(s，3H，C H 3 )1.36(t，3H，CO 2CH 2C H 3 )1.20(t，3H，CO 2CH 2C H 3 )。
Embodiment 2 (E)-5-bromo-3-[(3-ethoxy carbonyl methyl-2-ethoxy carbonyl-5-methyl isophthalic acid H-pyrroles-4-yl) methylene radical]-preparation of 1H-indol-2-one (Compound I-2):
To be cooled to-10 ℃ at the 1H-indol-2-one (1.3g) in the acetonitrile (20ml) and also under agitation slowly add N-bromosuccinimide (2g).Under-10 ℃, reactant was stirred 1 hour and stirred 2 hours down at 0 ℃.Collecting precipitation with 20ml water washing and dry, obtains the 5-bromo-1H-indol-2-one of 1.9g, productive rate 90%.
With 3-ethoxy carbonyl methyl-2-ethoxy carbonyl-4-formyl radical-5-methyl isophthalic acid H-pyrroles (0.95g; 3.6mmol) and 5-bromo-(1H)-indol-2-one (0.8g; 3.6mmol) in 20ml ethanol, mix and stir; oil bath is heated to 80 ℃; drip hexahydropyridine (0.1g); react concentration of reaction solution after 2.5 hours; add 1; 2-ethylene dichloride (10ml); with 20ml water and the dry washing of 20ml 2N hydrochloric acid; concentrate organic layer, use ethyl acetate: elutriant purifying (R on silicagel column of sherwood oil=1: 4 f=0.6) obtain 1.56g yellow solid (E)-5-bromo-3-[(3-ethoxy carbonyl methyl-2-ethoxy carbonyl-5-methyl isophthalic acid H-pyrroles-4-yl) methylene radical]-(1H)-and indol-2-one, productive rate 90%.
H 1NMR(DMSO-d6)7.48(s，1H，vinyl-H)7.38(d，2H，Ph-H)6.96(s，1H，Ph-H)6.80(q，2H，Ph-H)4.23(q，2H，CO 2C H 2 CH 3)3.98(q，2H，CO 2C H 2 CH 3)3.75(s，C H 2 CO 2CH 2CH 3)2.09(s，3H，C H 3 )1.36(t，3H，CO 2CH 2C H 3 )1.20(t，3H，CO 2CH 2C H 3 )。MS?m/e?460(M +)。
Embodiment 3 (E)-3-[(3-methoxycarbonyl methyl-2-methoxycarbonyl-5-methyl isophthalic acid H-pyrroles-4-yl) methylene radical]-(1H)-preparation of indol-2-one (Compound I-3):
Under 0-10 ℃ of ice bath, with sodium nitrite in aqueous solution (Sodium Nitrite 19.8g: water 100ml) be added drop-wise to 2-carbonyl-1, the 3-dimethyl malonate (50g in acetate 287mmol) (150ml) solution, removes ice bath, stirring at room 5 hours, solution is red-brown.In ice bath, (59g 287mmol) joins in the reaction solution with benzyl acetoacetate, replenish acetate (50ml) then, add zinc powder (25g) and anhydrous sodium acetate (20g), continue to stir after 15 minutes, remove ice bath, be heated to 80 ℃ with oil bath, solid all dissolves, stir after 4 hours, reaction solution is poured in the frozen water solution, and placement is spent the night, and filters, concentrated filtrate obtains the 35g faint yellow solid.With the 4-benzyloxycarbonyl that obtains 34g behind the ethyl alcohol recrystallization-3-methoxycarbonyl methyl-2-methoxycarbonyl-5-methyl isophthalic acid H-pyrroles, productive rate 33%.Mp148℃。H 1NMR(CDCl 3)：9.0(broad，1-H)，7.3-7.4(m，5H，Ph-H)，5.25(s，2H，C H 2 Ph)，4.2(s，2H， CH 2 CO 2Me)，2.5(s，3H， CH 3 )，1.35(s，3H，CO 2C H 3 )，1.2(s，3H，CO 2C H 3 )。
30g 4-benzyloxycarbonyl-3-methoxycarbonyl methyl-2-methoxycarbonyl-5-methyl isophthalic acid H-pyrroles (87mmol) is dissolved in the tetrahydrofuran (THF) (50ml), add 10% palladium carbon (5g), room temperature, logical hydrogen, stir 1 hour after-filtration and fall palladium carbon, behind tetrahydrofuran (THF) (50ml) washing leaching cake, the filtrate concentrate drying is obtained 3-methoxycarbonyl methyl-2-methoxycarbonyl-5-methyl isophthalic acid H-pyrroles-4-carboxylic acid of 22g, productive rate 95%.Mp243℃。H 1NMR(CDCl 3)：9.6(br，1-H，COO H)，3.80(s，2H， CH 2 CO 2Me)，2.3(s，3H，C H 3 )，1.3(s，3H，CO 2C H 3 )，1.2(s，3H，CO 2C H 3 )。
20g 3-methoxycarbonyl methyl-2-methoxycarbonyl-5-methyl isophthalic acid H-pyrroles-4-carboxylic acid (74mmol) is dissolved in 1, in the 2-ethylene dichloride (100ml), oil bath is heated to 50 ℃, add sodium bicarbonate aqueous solution (sodium bicarbonate 24g: water 100ml), stir, drip iodine aqueous solution (the iodine 23g: water 100ml) that contains sodium iodide (20g) after having bubble to emerge, continue heated and stirred half an hour, thin-layer chromatography detects to reacting completely, add hydrogen persulfate sodium and remove excessive iodine, separate organic layer with separating funnel, dry back concentrates, with 1,2-ethylene dichloride recrystallization obtains 3-methoxycarbonyl methyl-2-methoxycarbonyl-4-iodo-5-methyl isophthalic acid H-pyrroles of 23g, productive rate 91%.Mp?102℃。EIMS?m/e?336(M +)。
With 3-methoxycarbonyl methyl-2-methoxycarbonyl-4-iodo-5-methyl isophthalic acid H-pyrroles (23g, 65mmol) be dissolved in the methyl alcohol (100ml), oil bath is heated to backflow, stir, the aqueous solution (the sodium iodide 11g: water 10ml), add concentrated hydrochloric acid (37%) (2ml), have iodine to separate out that adds sodium iodide, solution becomes scarlet rapidly, after 15 minutes, add hydrogen persulfate sodium and remove excessive iodine, the methyl alcohol in the reaction solution is boiled off, with 1,2-ethylene dichloride (50ml) extraction, drying concentrates organic layer, obtain 3-methoxycarbonyl methyl-2-methoxycarbonyl-5-methyl isophthalic acid H-pyrroles of 12g, productive rate 87%.Mp?238℃。H 1NMR(DMSO)：5.98(s，1H，3-pyrrole-H)，3.80(s，2H， CH 2 CO 2Me)，2.3(s，3H，C H 3 )，1.3(s，3H，CO 2C H 3 )，1.2(s，3H，CO 2C H 3 )。
Phosphorus oxychloride (8ml) is added dropwise to N under 0-5 ℃ of ice bath, in the dinethylformamide (8ml), after stirring 15 minutes under the same temperature, 3-methoxycarbonyl methyl-2-methoxycarbonyl-5-methyl isophthalic acid H-pyrroles's (53mmol) of slow dropping 12g 1,2-ethylene dichloride (50ml) solution, continue stirring down after 15 minutes at 0-5 ℃, remove ice bath, be heated to 50 ℃ with oil bath, stir half an hour after, add the aqueous solution (the anhydrous sodium acetate 5g: water 20ml) of sodium acetate, after stirring half an hour, the cooling reaction solution separates organic layer and concentrates with separating funnel, uses ethyl acetate: the elutriant of sherwood oil=1: 3 separates (R on silicagel column f=0.5), obtains 3-methoxycarbonyl methyl-2-methoxycarbonyl-4-formyl radical-5-methyl isophthalic acid H-pyrroles of 10g, productive rate 80%.Mp?132℃。H 1NMR(CDCl 3)：10.0(s，1H，C HO)，9.1(br，1H，N-H)，4.3(q，2H，CO 2C H 2 CH 3)，2.3(s，3H，C H 3 )，1.3(t，3H，CO 2C H 3 )，1.2(t，3H，CO 2C H 3 )。
(0.86g, 3.6mmol) (0.82g 3.6mmol) mixes stirring in 20ml ethanol, oil bath is heated to 80 ℃ with 5-bromo-(1H)-indol-2-one with 3-methoxycarbonyl methyl-2-methoxycarbonyl-4-formyl radical-5-methyl isophthalic acid H-pyrroles.Drip hexahydropyridine (0.1g), react concentration of reaction solution after 3 hours, add 1,2-ethylene dichloride (10ml), with 20ml water and 20ml 2N salt acid elution, concentrated organic layer is used ethyl acetate: elutriant purifying (R on silicagel column of sherwood oil=1: 2 f=0.5) obtain 1.16g yellow solid (E)-3-[(3-methoxycarbonyl methyl-2-methoxycarbonyl-5-methyl isophthalic acid H-pyrroles-4-yl) methylene radical]-(1H)-and indol-2-one, productive rate 91%.Mp215℃。
H 1NMR(CDCl 3)：9.10(s，1H，N-H)，7.70(s，1H，vinyl-H)，7.38(t，2H，Ph-H)，7.19(s，1H，Ph-H)，6.78(t，2H，Ph-H)，3.90(s，3H，CO 2CH 2C H 3 )，3.88(s，2H，CO 2C H 2 CH 3)，3.67(s，3H，CO 2C H 3 )，2.20(s，3H，C H 3 )。EIMS?m/e?354(M +)。
Embodiment 4 (E)-5-bromo-3-[(3-methoxycarbonyl methyl-2-methoxycarbonyl-5-methyl isophthalic acid H-pyrroles-4-yl) methylene radical]-(1H)-preparation of indol-2-one (Compound I-4):
With 3-methoxycarbonyl methyl-2-methoxycarbonyl-4-formyl radical-5-methyl isophthalic acid H-pyrroles (0.95g; 3.6mmol) and 5-bromo-(1H)-indol-2-one (0.8g; 3.6mmol) in 20ml ethanol, mix and stir, oil bath is heated to 80 ℃, drips hexahydropyridine (0.1g); react concentration of reaction solution after 2.5 hours; add 1,2-ethylene dichloride (10ml) is with 20ml water and 20ml 2N salt acid elution; concentrate organic layer, use ethyl acetate: elutriant purifying (R on silicagel column of sherwood oil=1: 4 f=0.6) obtain 1.4g yellow solid (E)-5-bromo-3-[(3-methoxycarbonyl methyl-2-methoxycarbonyl-5-methyl isophthalic acid H-pyrroles-4-yl) methylene radical]-(1H)-and indol-2-one, productive rate 91%.Mp?243℃。
H 1NMR(CDCl 3)：9.10(s，1H，N-H)，7.70(s，1H，vinyl-H)，7.38(t，2H，Ph-H)，7.19(s，1H，Ph-H)，6.78(t，2H，Ph-H)，3.90(s，3H，CO 2CH 2C H 3 )，3.88(s，2H，CO 2C H 2 CH 3)，3.67(s，3H，CO 2C H 3 )，2.20(s，3H，C H 3 )。EMS?m/e?432(M +)。
Embodiment 5 (E) 3-[(2,5 dimethyl-2-ethoxy carbonyl-1H-pyrroles-3-yl) methylene radical]-(1H)-preparation of indol-2-one (Compound I-5):
With 1H-indol-2-one (6.5g) be dissolved in the vitriol oil (98%) (25ml) in and mixture maintained-10 ℃ to-15 ℃ be added dropwise to nitrosonitric acid (20ml).After adding nitric acid (20ml), under 0 ℃, reaction mixture is stirred half an hour and be poured in the frozen water, by filtering collecting precipitation, and from 50% acetate recrystallization filtering for crystallizing product then, dry under the vacuum, obtain 5-nitro-2-1H-indol-2-one of 6g, productive rate 70%.
Acetate (10ml) and sodium hydroxide (1.2g 30mmol) is heated to 80 ℃, treat that sodium hydroxide dissolves fully after, continue reacting by heating liquid to refluxing.(4.5g 34mmol) joins in the reactor, slowly drips the aqueous solution (8g, 0.11mol, 10ml water) of Sodium Nitrite with methyl aceto acetate.After drip finishing, slowly cool to room temperature, places after four hours the adularescent crystal and separate out filtration.This resolution of precipitate in acetate (10ml), is heated to 80 ℃, and (3.4g is 34mmol) with Zn powder (2g) to add methyl ethyl diketone.After two hours reaction solution is poured in the frozen water, the adularescent precipitation is separated out.Filter, with the unnecessary Zn powder of acetate (10ml) flush away, drying obtains 3.6g white solid 3,5 dimethyl-2-ethoxy carbonyl-1H-pyrroles, productive rate 65%.Mp126℃。H 1NMR(CDCl 3)：8.76(br，1H，N-H)，5.79(s，1H，C H)，4.29(q，2H，C H 2 CH 3)，2.30(s，3H，C H 3 )，2.24(s，3H，C H 3 )，1.350(t，3H，CH 2C H 3 )。
Phosphorus oxychloride (4ml) is added dropwise to N under 0-5 ℃ of ice bath, in the dinethylformamide (4ml).After stirring 15 minutes under the same temperature, slowly drip 3,5 dimethyl-2-ethoxy carbonyl-1H-pyrroles (3g, 18mmol) 1,2-ethylene dichloride (20ml) solution.Continue stirring down after 15 minutes at 0-5 ℃, remove ice bath, be heated to 50 ℃, after continuing to stir half an hour, add the aqueous solution (the anhydrous sodium acetate 1g: water 10ml) of sodium acetate with oil bath.After half an hour, the cooling reaction solution separates organic layer and concentrates with separating funnel, uses ethyl acetate: the elutriant of sherwood oil=1: 1 separates (R on silicagel column f=0.5), obtains 3, the 5 dimethyl-4-formyl radical-2-ethoxy carbonyl-1H-pyrroles of 2.8g white solid, productive rate 80%.Mp?182℃。H 1NMR(CDCl 3)：10.0(s，1H，C HO)，9.76(br，1H，N-H)，4.29(q，2H，C H 2 CH 3)，2.30(s，3H，C H 3 )，2.24(s，3H，C H 3 )，1.350(t，3H，CH 2C H 3 )。
With 3; 5 dimethyl-4-formyl radical-2-ethoxy carbonyl-1H-pyrroles (1g, 5.1mmol) and 2-(1H)-indol-2-one (0.6g 5.1mmol) mix to stir in 20ml ethanol; oil bath is heated to 80 ℃; drip hexahydropyridine (0.1g), react concentration of reaction solution after 4 hours, add 1; 2-ethylene dichloride (10ml); with 20ml water and 20ml 2N salt acid elution, concentrate organic layer, use ethyl acetate: elutriant purifying (R on silicagel column of sherwood oil=1: 1 f=0.35) obtain (E) 3-[(3 of 1.48g yellow solid, 5 dimethyl-2-ethoxy carbonyl-1H-pyrroles-4-yl) methylene radical]-(1H)-and indol-2-one, productive rate 94%.Mp?185℃。
H 1NMR(DMCO)：7.55(s，1H，vinyl-H)，6.83-7.20(m，4H，Ph-H)，4.35(q，2H，CO 2C H 2 CH 3)，2.19(s，3H，C H 3)，2.06(s，3H，C H 3 )，1.36(t，3H，CO 2CH 2CH H 3 )。EIMS?m/e?310(M +)。
Embodiment 6 (E)-5-bromo-3-[(3,5 dimethyl-2-ethoxy carbonyl-1H-pyrroles-4-yl) methylene radical]-(1H)-preparation of indol-2-one (Compound I-6):
With 3; 5 dimethyl-4-formyl radical-2-ethoxy carbonyl-1H-pyrroles (1g, 5.1mmol) (1g 5.1mmol) mixes stirring in 20ml ethanol with 5-bromo-2-(1H)-indol-2-one; oil bath is heated to 80 ℃; drip hexahydropyridine (0.1g), react concentration of reaction solution after 3 hours, add 1; 2-ethylene dichloride (10ml); the dry washing of 20ml water and 20ml 2N hydrochloric acid concentrates organic layer, uses ethyl acetate: elutriant purifying (R on silicagel column of sherwood oil=1: 2 f=0.4) obtain (E)-5-bromo-3-[(3 of 1.8g yellow solid, 5 dimethyl-2-ethoxy carbonyl-1H-pyrroles-4-yl) methylene radical]-(1H)-and indol-2-one, productive rate 95%.Mp?213℃。
H 1NMR(CDCl 3)：9.08(s，1H，N-H)，7.81(s，1H，N-H)，7.72(s，1H，vinyl-H)，7.31(d，2H，Ph-H)，7.17(s，1H，Ph-H)，6.75(d，2H，Ph-H)，4.35(q，2H，CO 2C H 2 CH 3)，2.19(s，3H，C H 3)，2.06(s，3H，C H 3 )，1.36(t，3H，CO 2CH 2C H 3 )。EIMS?m/e?388(M +)。
Embodiment 7 (E)-5-nitro-3-[(3,5 dimethyl-2-ethoxy carbonyl-1H-pyrroles-4-yl) methylene radical]-(1H)-preparation of indol-2-one (Compound I-7):
With 3; 5 dimethyl-4-formyl radical-2-ethoxy carbonyl-1H-pyrroles (1g, 5.1mmol) (0.9g 5.1mmol) mixes stirring in 20ml ethanol with 5-nitro-2-(1H)-indol-2-one; oil bath is heated to 80 ℃; drip hexahydropyridine (0.1g), react concentration of reaction solution after 3 hours, add 1; 2-ethylene dichloride (10ml); the dry washing of 20ml water and 20ml 2N hydrochloric acid concentrates organic layer, uses ethyl acetate: elutriant purifying (R on silicagel column of sherwood oil=2: 1 f=0.4) obtain (E)-5-nitro-3-[(3 of 1.8g yellow solid, 5 dimethyl-2-ethoxy carbonyl-1H-pyrroles-4-yl) methylene radical]-(1H)-and indol-2-one, productive rate 95%.Mp?286℃。
H 1NMR(DMSO-d6)：8.18(d，2H，Ph-H)，7.70(s，1H，vinyl-H)，7.65(s，1H，Ph-H)，7.05(d，2H，Ph-H)，4.22(q，2H，CO 2C H 2 CH 3)，3.98(q，2H，CO 2 CH 2 CH 3)，3.77(s，2H，C H 2 CO 2CH 2CH 3)，2.09(s，3H，C H 3 )，1.36(t，3H，CO 2 CH 2 CH 3)，1.20(t，3H，CO 2CH 2C H 3 )。EIMS?m/e?355(M +)。
Embodiment 8 (E) 3-[(3,5 dimethyl-2-methoxycarbonyl-1H-pyrroles-4-yl) methylene radical]-(1H)-preparation of indol-2-one (Compound I-8):
Acetate (10ml) and sodium hydroxide (1.2g 30mmol) is heated to 80 ℃, treat that sodium hydroxide dissolves fully after, continue reacting by heating liquid to refluxing.(4.7g 34mmol) joins in the reactor, slowly drips the aqueous solution (8g, 0.11mol, 10ml water) of Sodium Nitrite with methyl acetoacetate.After drip finishing, slowly cool to room temperature, places after four hours the adularescent crystal and separate out filtration.This resolution of precipitate in acetate (10ml), is heated to 80 ℃, and (3.4g is 34mmol) with Zn powder (2g) to add methyl ethyl diketone.After two hours reaction solution is poured in the frozen water, the adularescent precipitation is separated out.Filtering-depositing, with the unnecessary Zn powder of acetate (10ml) flush away, drying obtains 3.8g white solid 3,5 dimethyl-2-ethoxy carbonyl-1H-pyrroles, productive rate 68%.Mp?76℃。H 1NMR(CDCl 3)：8.76(br，1H，N-H)，5.80(s，1H，C H)，3.82(s，3H，C H 3 )，2.30(s，3H，C H 3 )，2.24(s，3H，C H 3 )。
Phosphorus oxychloride (4ml) under 0-5 ℃ of ice bath, is added dropwise to N, in the dinethylformamide (4ml).After stirring 15 minutes under the same temperature, slowly drip 3,5 dimethyl-2-methoxycarbonyl-1H-pyrroles (3.4g, 18mmol) 1,2-ethylene dichloride (20ml) solution.Continue stirring down after 15 minutes at 0-5 ℃, remove ice bath, be heated to 50 ℃, after continuing to stir half an hour, add the aqueous solution (the anhydrous sodium acetate 1g: water 10ml) of sodium acetate with oil bath.After half an hour, the cooling reaction solution separates organic layer and concentrates with separating funnel, uses ethyl acetate: the elutriant of sherwood oil=1: 1 separates (R on silicagel column f=0.6), obtains 3, the 5 dimethyl-4-formyl radical-2-methoxycarbonyl-1H-pyrroles of 3.1g white solid, productive rate 82%.H 1NMR(CDCl 3)：9.76(s，1H，C HO)，3.82(s，3H，C H 3 )，2.30(s，3H，C H 3 )，2.24(s，3H，C H 3 )。
With 3,5 dimethyl-4-formyl radical-2-methoxycarbonyl-1H-pyrroles (1g, 5.5mmol) and 2-(1H)-indol-2-one (0.7g 5.1mmol) mix to stir in 20ml ethanol, and oil bath is heated to 80 ℃.Drip hexahydropyridine (0.1g), react concentration of reaction solution after 4 hours,, concentrate organic layer after 20ml water and 20ml 2N salt acid elution are used in 2-ethylene dichloride (10ml) dissolving back with 1.Use ethyl acetate: elutriant purifying (R on silicagel column of sherwood oil=1: 1 f=0.55) obtain (E) 3-[(3 of 1.46g yellow solid, 5 dimethyl-2-methoxycarbonyl-1H-pyrroles-4-yl) methylene radical]-(1H)-and indol-2-one, productive rate 94%.Mp213℃。
H 1NMR(DMCO)：7.55(s，1H，vinyl-H)，6.83-7.20(m，4H，Ph-H)，3.75(s，CO 2C H 3 )，2.20(s，3H，C H 3 )，2.06(s，3H，C H 3 )。EIMS?m/e?296(M +)。
Embodiment 9 (E)-5-nitro-3-[(3,5 dimethyl-2-methoxycarbonyl-1H-pyrroles-4-yl) methylene radical]-(1H)-preparation of indol-2-one (Compound I-9):
(1g, 5.5mmol) (0.98g 5.5mmol) mixes stirring in 20ml ethanol, oil bath is heated to 80 ℃ with 5-nitro-2-(1H)-indol-2-one with 3,5 dimethyl-4-formyl radical-2-methoxycarbonyl-1H-pyrroles.Drip hexahydropyridine (0.1g), react concentration of reaction solution after 3 hours, add 1,2-ethylene dichloride (10ml), with 20ml water and 20ml 2N salt acid elution, concentrated organic layer is used ethyl acetate: elutriant purifying (R on silicagel column of sherwood oil=2: 1 f=0.3) obtain (E)-5-nitro-3-[(3 of 1.9g yellow solid, 5 dimethyl-2-methoxycarbonyl-1H-pyrroles-4-yl) methylene radical]-(1H)-and indol-2-one, productive rate 95%.Mp?218℃。
H 1NMR(DMSO)：8.15(d，2H，Ph-H)，7.71(s，1H，vinyl-H)，7.66(s，1H，Ph-H)，7.00(d，2H，Ph-H)，3.75(s，3H，CO 2C H 3 )，2.20(s，3H，C H 3 )，2.06(s，3H，C H 3 )。EIMS?m/e?341(M +)。
Embodiment 10 (E)-5-nitro-3-[(3-ethoxy carbonyl methyl-2-ethoxy carbonyl-5-methyl isophthalic acid H-pyrroles-4-yl) methylene radical]-(1H)-preparation of indol-2-one (Compound I-10):
(1g, 3.7mmol) (0.78g 3.7mmol) mixes stirring in 20ml ethanol, oil bath is heated to 80 ℃ with 5-nitro-2-(1H)-indol-2-one with 3-ethoxy carbonyl methyl-2-ethoxy carbonyl-4-formyl radical-5-methyl isophthalic acid H-pyrroles.Drip hexahydropyridine (0.1g), react that concentration of reaction solution adds 1 after 5 hours, 2-ethylene dichloride (10ml), the dry washing of 20ml water and 20ml 2N hydrochloric acid, concentrated organic layer is used ethyl acetate: elutriant purifying (R on silicagel column of sherwood oil=1: 1 f=0.5) obtain (the E)-5-nitro-3-[(3-ethoxy carbonyl methyl-2-ethoxy carbonyl-5-methyl isophthalic acid H-pyrroles-4-yl of 1.43g yellow solid) methylene radical]-(1H)-and indol-2-one, productive rate 91%.Mp?341℃。
H 1NMR(DMSO-d6)：8.18(d，2H，Ph-H)，7.70(s，1H，vinyl-H)，7.65(s，1H，Ph-H)，7.05(d，2H，Ph-H)，4.22(q，2H，CO 2C H 2 CH 3)，3.98(q，2H，CO 2C H 2 CH 3)，3.77(s，C H 2 CO 2CH 2CH 3)，2.09(s，3H，C H 3 )，1.36(t，3H，CO 2CH 2C H 3 )，1.20(t，3H，CO 2CH 2C H 3 )。EIMS?m/e?427(M +)。
Embodiment 11 (E)-5-carboxyl-3-[(3-ethoxy carbonyl methyl-2-ethoxy carbonyl-5-methyl isophthalic acid H-pyrroles-4-yl) methylene radical]-(1H)-preparation of indol-2-one (Compound I-11):
(6.7g 50mmol) joins the 23g aluminum chloride at 1 of 30ml, in the suspension in the 2-ethylene dichloride, slowly adds chloroacetyl chloride (11.3g) and emits hydrogen chloride gas with (1H)-indol-2-one.Stir after 10 minutes, reaction solution is heated to 40 to 50 ℃.Thin layer chromatography (ethyl acetate, silica gel) shows does not have remaining raw material.Mixture is cooled to room temperature and is poured in the frozen water by the vacuum filtration collecting precipitation, dry under water (80ml) washing and the vacuum, obtain the 5-chloracetyl of 10.3g-(1H)-indol-2-one, white solid, productive rate 98%.
Under 80 to 90 ℃, (9.3g, 49mmol) suspension in pyridine (9g) stirs 3 hours then, is cooled to room temperature with 5-chloracetyl-(1H)-indol-2-one.Wash by the vacuum filtration collecting precipitation and with ethanol (20ml).Solid is dissolved in the 2.5N sodium hydroxide of 90ml, and stirred 3 hours down at 70 to 80 ℃.Mixture is cooled to room temperature and uses the 0.5N hcl acidifying to pH=2.By vacuum filtration collecting precipitation and thoroughly washing of water (100ml), obtain 5-carboxyl-2-(1H)-indol-2-one as dark brown solid.With filtrate place spend the night after, obtain 2g and be the 5-carboxyl of yellow solid-(1H)-indol-2-one.The dark-brown product is dissolved in the hot ethanol (20ml),, removes insolubles and concentrated filtrate, obtain 5-carboxyl-2-(1H)-indol-2-one as the 5.6g brown solid by filtering.The yield that merges is 97%.Mp?286℃。H 1NMR(DMSO)：12.56(br，1H，COO H)，10.70(s，1H，NH-1)，7.81(dd，1H，Ph-H)，7.74(s，1H，Ph-H)，3.53(s，2H，C H 2 )。
(1g, 3.7mmol) (0.65g 3.7mmol) mixes stirring in 20ml ethanol, oil bath is heated to 80 ℃ with 5-carboxyl-2-(1H)-indol-2-one with 3-ethoxy carbonyl methyl-2-ethoxy carbonyl-4-formyl radical-5-methyl isophthalic acid H-pyrroles.Drip hexahydropyridine (0.1g), react concentration of reaction solution after 5 hours, with 1, after 20ml water and 20ml 2N salt acid elution were used in 2-ethylene dichloride (10ml) dissolving back, concentrated organic layer was used ethyl acetate: elutriant purifying (R on silicagel column of sherwood oil=4: 1 f=0.25) obtain (the E)-5-carboxyl-3-[(3-ethoxy carbonyl methyl-2-ethoxy carbonyl-5-methyl isophthalic acid H-pyrroles-4-yl of 1.49g red solid) methylene radical]-(1H)-and indol-2-one, productive rate 95%.Mp?214℃。
H 1NMR(DMSO-d6)：7.82(d，2H，Ph-H)，7.56(s，1H，vinyl-H)，7.54(s，1H，Ph-H)，6.98(q，2H，Ph-H)，4.21(q，2H，CO 2C H 2 CH 3)，3.98(q，2H，CO 2C H 2 CH 3)，3.77(s，2H，C H 2 CO 2CH 2CH 3)，2.09(s，3H，C H 3 )，1.36(t，3H，CO 2CH 2C H 3 )，1.20(t，3H，CO 2CH 2C H 3 )。EIMS?m/e?426(M +)。
Embodiment 12 (E)-5-amino-sulfonyl-3-[(3-ethoxy carbonyl methyl-2-ethoxy carbonyl-5-methyl isophthalic acid H-pyrroles-4-yl) methylene radical]-(1H)-preparation of indol-2-one (Compound I-12):
In the 100ml flask that fills the 27ml chlorsulfonic acid, slowly add 13.3g (1H)-indol-2-one.During the adding temperature of reaction maintained and be lower than 30 ℃.After the adding, at room temperature reaction mixture was stirred 1.5 hours, be heated to 68 ℃; reacted 1 hour, cooling, and be poured in the water; wash (50ml) precipitation and dry in vacuum drying oven with water, obtain the 5-chlorosulfonyl of 11g-(1H)-indol-2-one, productive rate 50%.
5-chlorosulfonyl-(1H)-indol-2-one (2.1g) is joined in 10mL alcoholic acid ammoniacal liquor (10ml), and at room temperature stir and spend the night.Enriched mixture is also collected solid by vacuum filtration, obtains the 5-amino-sulfonyl of 0.4g pale solid-(1H)-indol-2-one, productive rate 20%.Mp?125℃。H 1NMR(DMSO)：10.67(s，1H， NH-1)，7.63-7.66(m，2H，Ph-H)，7.13(s，2H， H 2 NSO 2-5)，6.91(d，1H，Ph-H)，3.56(s，2H，C H 2 )。MS?m/e341(M +)。
With 3-ethoxy carbonyl methyl-2-ethoxy carbonyl-4-formyl radical-5-methyl isophthalic acid H-pyrroles (1g; 3.7mmol) and the 5-amino-sulfonyl-(1H)-indol-2-one (0.543g; 3.7mmol); in 20ml ethanol, mix and stir; oil bath is heated to 80 ℃; drip hexahydropyridine (0.1g), react concentration of reaction solution after 5 hours, use ethyl acetate: elutriant purifying (R on silicagel column of sherwood oil=1: 3 f=0.85) obtain (the E)-5-amino-sulfonyl-3-[(3-ethoxy carbonyl methyl-2-ethoxy carbonyl-5-methyl isophthalic acid H-pyrroles-4-yl of 1.2g orange/yellow solid) methylene radical]-(1H)-and indol-2-one, productive rate 70%.Mp?148-150℃。
H 1NMR(CDCl 3)：7.60(s，1H，vinyl-H)，7.59(d，1H，Ph-H)，7.22(s，1H，Ph-H)，7.06(d，1H，Ph-H)，4.25(q，2H，CO 2 CH 2 CH 3)，3.98(q，2H，CO 2C H 2 CH 3)，3.80(s，2H，C H 2 CO 2CH 2CH 3)，2.10(s，3H，C H 3 )，1.28(t，3H，CO 2CH 2C H 3 )，1.05(t，3H，CO 2CH 2C H 3 )。EIMS?m/e?461(M +)。
Embodiment 13 (E)-5-methylamino alkylsulfonyl-3-[(3-ethoxy carbonyl methyl-2-ethoxy carbonyl-5-methyl isophthalic acid H-pyrroles-4-yl) methylene radical]-(1H)-preparation of indol-2-one (Compound I-13):
At room temperature, (2.3g 10mmol) stirred 4 hours in methyl alcohol (10ml) suspension of methylamine (10ml), formed white solid therebetween with 5-chlorosulfonyl-2-(1H)-indol-2-one.Filter collecting precipitation, with sodium hydroxide (5ml, 1N) and hydrochloric acid (5ml, 1N) washing also vacuum-drying spend the night, obtain 2.2g orange solids 5-methylamino alkylsulfonyl-2-(1H)-indol-2-one, yield 82%.EIMS?m/e?225(M +-1)。
(1g, 3.7mmol) (0.9g 3.7mmol) mixes stirring in 20ml ethanol, oil bath is heated to 80 ℃ with 5-methylamino alkylsulfonyl-2-(1H)-indol-2-one with 3-ethoxy carbonyl methyl-2-ethoxy carbonyl-4-formyl radical-5-methyl isophthalic acid H-pyrroles.Drip hexahydropyridine (0.01g), react concentration of reaction solution after 6 hours, use ethyl acetate: elutriant purifying (R on silicagel column of sherwood oil=1: 4 f=0.55) obtain (the E)-5-methylamino alkylsulfonyl-3-[(3-ethoxy carbonyl methyl-2-ethoxy carbonyl-5-methyl isophthalic acid H-pyrroles-4-yl of 1.08g yellow solid) methylene radical]-(1H)-and indol-2-one, productive rate 67%.Mp126℃。
H 1NMR(CDCl 3)：9.31(s，1H，N-H)，8.41(s，1H，N-H)，7.8(s，1H，vinyl-H)，7.63(d，1H，Ph-H)，7.42(s，1H，Ph-H)，7.00(d，1H，Ph-H)，4.32(q，2H，CO 2C H 2 CH 3)，4.10(q，2H，CO 2C H 2 CH 3)，3.80(s，2H，C H 2 CO 2CH 2CH 3)，2.42(s，3H，NC H 3 )，2.10(s，3H， CH 3 )，1.36(t，3H，CO 2CH 2C H 3 )，1.20(t，2H，CO 2CH 2C H 3 )。EIMS?m/e?475(M +)。
Embodiment 14 (E)-5-(N-morpholinyl) amino-sulfonyl-3-[(3-ethoxy carbonyl methyl-2-ethoxy carbonyl-5-methyl isophthalic acid H-pyrroles-4-yl) methylene radical]-(1H)-preparation of indol-2-one (Compound I-14):
At room temperature, (2.3g 10mmol) is dissolved in the tetrahydrofuran (THF) (10ml), and (750mg 10mmol), stirred 4 hours, formed white solid therebetween to add morpholine with 5-chlorosulfonyl-2-(1H)-indol-2-one.Filter collecting precipitation, with sodium hydroxide (5ml, 1N) and hydrochloric acid (5ml, IN) washing also vacuum-drying spend the night, obtain 5-(N-morpholinyl) amino-sulfonyl of 2.53g white solid-(1H)-indol-2-one, yield 90%.EIMS?m/e?282(M +)。
With 3-ethoxy carbonyl methyl-2-ethoxy carbonyl-4-formyl radical-5-methyl isophthalic acid H-pyrroles (1g; 3.7mmol) and 5-(N-morpholinyl) amino-sulfonyl-(1H)-indol-2-one (1.03g; 3.7mmol) in 20ml ethanol, mix and stir, oil bath is heated to 80 ℃.Drip hexahydropyridine (0.01g), react concentration of reaction solution after 6 hours, use ethyl acetate: elutriant purifying (R on silicagel column of sherwood oil=1: 4 f=0.75) obtain (E)-5-(N-morpholinyl) amino-sulfonyl-3-[(3-ethoxy carbonyl methyl-2-ethoxy carbonyl-5-methyl isophthalic acid H-pyrroles-4-yl of 1.21g yellow solid) methylene radical]-(1H)-and indol-2-one, productive rate 62%.Mp185℃。
H 1NMR(CDCl 3)：9.31(s，1H，N-H)，8.41(s，1H，N-H)，7.80(s，1H，vinyl-H)，7.63(d，1H，Ph-H)，7.42(s，1H，Ph-H)，7.00(d，1H，Ph-H)，4.32(q，2H，CO 2C H 2 CH 3)，4.10(q，2H，CO 2C H 2 CH 3)，3.80(s，2H，C H 2 CO 2CH 2CH 3)，3.67(t，2H，1.4-morpholinyl)，2.90(t，2H，2.3-morpholinyl)，2.10(s，3H， CH 3 )，1.36(t，3H，CO 2CH 2C H 3 )，1.20(t，2H，CO 2CH 2C H 3 )。EIMS?m/e?531(M +)。
Embodiment 15 (E)-5-(3-chloro-phenyl-) amino-sulfonyl-3-[(3-ethoxy carbonyl methyl-2-ethoxy carbonyl-5-methyl isophthalic acid H-pyrroles-4-yl) methylene radical]-(1H)-preparation of indol-2-one (Compound I-15):
At room temperature, with 5-chlorosulfonyl-(1H)-indol-2-one (2.1g, 9mmol), the 3-chloroaniline (1.8g, 14mmol) and pyridine (1.4g) in the suspension of 20mL methylene dichloride, stirred 4 hours.By the precipitation that vacuum filtration collect to form, spend the night with twice of 15ml water washing and in 40 ℃ of following vacuum-dryings, obtain 5-(3-chloro-phenyl-) amino-sulfonyl of 2.5g pink solid-(1H)-indol-2-one, productive rate 86%.EIMS?m/e?321(M +-1)。
With 3-ethoxy carbonyl methyl-2-ethoxy carbonyl-4-formyl radical-5-methyl isophthalic acid H-pyrroles (1g; 3.7mmol) and 5-(3-chloro-phenyl-) amino-sulfonyl-(1H)-indol-2-one (1.19g; 3.7mmol) in 20ml ethanol, mix and stir, oil bath is heated to 80 ℃.Drip hexahydropyridine (0.01g), react concentration of reaction solution after 6 hours, use ethyl acetate: elutriant purifying (R on silicagel column of sherwood oil=1: 5 f=0.8) obtain (E)-5-(3-chloro-phenyl-) amino-sulfonyl-3-[(3-ethoxy carbonyl methyl-2-ethoxy carbonyl-5-methyl isophthalic acid H-pyrroles-4-yl of 1.52g yellow solid) methylene radical]-(1H)-and indol-2-one, productive rate 72%.Mp?118-120℃。
H 1NMR(DMSO)：7.56(m，2H，Ph-H)，7.38(s，1H，vinyl-H)，6.80-6.98(m，5H，Ph-H)，4.21(q，2H，CO 2C H 2 CH 3)，3.98(q，2H，CO 2C H 2 CH 3)，3.77(s，2H，C H 2 CO 2CH 2CH 3)，2.00(s，3H，C H 3 )，1.36(t，3H，CO 2CH 2C H 3 )，1.20(t，3H，CO 2CH 2C H 3 )。EIMS?m/e?571(M +)。
Embodiment 16 (E)-5-(3-fluorophenyl) amino-sulfonyl-3-[(3-ethoxy carbonyl methyl-2-ethoxy carbonyl-5-methyl isophthalic acid H-pyrroles-4-yl) methylene radical]-(1H)-preparation of indol-2-one (Compound I-16):
With 3-ethoxy carbonyl methyl-2-ethoxy carbonyl-4-formyl radical-5-methyl isophthalic acid H-pyrroles (1g; 3.7mmol) and 5-(3-fluorophenyl) amino-sulfonyl-(1H)-indol-2-one (1.13g; 3.7mmol) in 20ml ethanol, mix and stir, oil bath is heated to 80 ℃.Drip hexahydropyridine (0.01g), react concentration of reaction solution after 6 hours, use ethyl acetate: elutriant purifying (R on silicagel column of sherwood oil=1: 4 f=0.85) obtain (E)-5-(3-fluorophenyl) amino-sulfonyl-3-[(3-ethoxy carbonyl methyl-2-ethoxy carbonyl-5-methyl isophthalic acid H-pyrroles-4-yl of 1.49g yellow solid) methylene radical]-(1H)-and indol-2-one, productive rate 73%.Mp＞130 ℃ decomposition.
H 1NMR(DMSO)：7.55(m，2H，Ph-H)，7.39(s，1H，vinyl-H)，6.80-6.98(m，5H，Ph-H)，4.21(q，2H，CO 2C H 2 CH 3)，3.98(q，2H，CO 2C H 2 CH 3)，3.77(s，2H，C H 2 CO 2CH 2CH 3)，2.00(s，3H，C H 3 )，1.36(t，CO 2CH 2C H 3 )，1.20(t，3H，CO 2CH 2C H 3 )。EIMS?m/e?555(M +)。
Embodiment 17 (E)-5-dimethylamino alkylsulfonyl-3-[(3-ethoxy carbonyl methyl-2-ethoxy carbonyl-5-methyl isophthalic acid H-pyrroles-4-yl) methylene radical]-(1H)-preparation of indol-2-one (Compound I-17):
At room temperature, (10mL, suspension 2M) stirred 4 hours, formed white solid therebetween 5-chlorosulfonyl-2-(1H) of 2.3g-indol-2-one to be added the methyl alcohol of dimethyl amine.By the vacuum filtration collecting precipitation, with sodium hydroxide (5ml, 1N) and hydrochloric acid (5ml, IN) washing also vacuum-drying spend the night, obtain 5-dimethylamino-alkylsulfonyl-2-(1H)-indol-2-one of 1.8g, productive rate 77%.EIMS?m/e?240(M +)。
With 3-ethoxy carbonyl methyl-2-ethoxy carbonyl-4-formyl radical-5-methyl isophthalic acid H-pyrroles (1g; 3.7mmol) and 5-dimethylamino-alkylsulfonyl-2-(1H)-indol-2-one (0.94g; 3.7mmol) in 20ml ethanol, mix and stir, oil bath is heated to 80 ℃.Drip hexahydropyridine (0.01g), react concentration of reaction solution after 6 hours, use ethyl acetate: elutriant purifying (R on silicagel column of sherwood oil=1: 4 f=0.60) obtain (the E)-5-dimethylamino alkylsulfonyl-3-[(3-ethoxy carbonyl methyl-2-ethoxy carbonyl-5-methyl isophthalic acid H-pyrroles-4-yl of 1.17g yellow solid) methylene radical]-(1H)-and indol-2-one, productive rate 65%.Mp145℃。
H 1NMR(CDCl 3)：9.32(s，1H，N-H)，8.43(s，1H，N-H)，7.80(s，1H，vinyl-H)，7.63(d，1H，Ph-H)，7.42(s，1H，Ph-H)，7.00(d，1H，Ph-H)，4.32(q，2H，CO 2C H 2 CH 3)，4.10(q，2H，CO 2C H 2CH 3)，3.80(s，2H，C H 2 CO 2CH 2CH 3)，2.43(s，6H，N(C H 3 ) 2)，2.10(s，3H，CH 3)，1.36(t，3H，CO 2CH 2C H 3 )，1.20(t，2H，CO 2CH 2C H 3 )。EIMS?m/e?489(M +)。
Embodiment 18 (E)-5-(3-fluoro-4-chloro-phenyl-) amino-sulfonyl-3-[(3-ethoxy carbonyl methyl-2-ethoxy carbonyl-5-methyl isophthalic acid H-pyrroles-4-yl) methylene radical]-(1H)-preparation of indol-2-one (Compound I-18):
At room temperature, with 5-chlorosulfonyl-(1H)-indol-2-one (2.1g, 9mmol), 3-fluoro-4-chloroaniline (2.03g, 14mmol) and pyridine (1.4g) in the 20ml methylene dichloride, stirred 4 hours.Filter, precipitation is spent the night with twice of 15ml water washing and in 40 ℃ of following vacuum-dryings, obtains 2.5g pink solid 5-(3-fluoro-4-chloro-phenyl-) amino-sulfonyl-(1H)-indol-2-one, productive rate 80%.EIMS?m/e?340(M +)。
With 3-ethoxy carbonyl methyl-2-ethoxy carbonyl-4-formyl radical-5-methyl isophthalic acid H-pyrroles (1g; 3.7mmol) and 5-(3-fluoro-4-chloro-phenyl-) amino-sulfonyl-(1H)-indol-2-one (1.25g; 3.7mmol) in 20ml ethanol, mix and stir, oil bath is heated to 80 ℃.Drip hexahydropyridine (0.01g), react concentration of reaction solution after 6 hours, use ethyl acetate: elutriant purifying (R on silicagel column of sherwood oil=1: 4 f=0.75) obtain 1.52g yellow solid (E)-5-(3-fluoro-4-chloro-phenyl-) amino-sulfonyl-3-[(3-ethoxy carbonyl methyl-2-ethoxy carbonyl-5-methyl isophthalic acid H-pyrroles-4-yl) methylene radical]-(1H)-and indol-2-one, productive rate 70%.Mp＞130 ℃ decomposition.
H 1NMR(DMSO)：7.56(m，2H，Ph-H)，7.38(s，1H，vinyl-H)，6.87-6.98(m，4H，Ph-H)，4.21(q，2H，CO 2C H 2 CH 3)，3.98(q，2H，CO 2C H 2 CH 3)，3.77(s，2H，C H 2 CO 2CH 2CH 3)，2.00(s，3H，C H 3 )，1.36(t，3H，CO 2CH 2C H 3 )，1.20(t，CO 2CH 2C H 3 )。EIMS?m/e?589(M +)。
Embodiment 19 (E)-5-(hexahydropyridine base) amino-sulfonyl-3-[(3-ethoxy carbonyl methyl-2-ethoxy carbonyl-5-methyl isophthalic acid H-pyrroles-4-yl) methylene radical]-(1H)-preparation of indol-2-one (Compound I-19):
At room temperature, (2.3g 10mmol) is dissolved in the tetrahydrofuran (THF) (10ml), and (750mg 10mmol), stirred 4 hours, formed white solid therebetween to add hexahydropyridine with 5-chlorosulfonyl-2-(1H)-indol-2-one.Filter collecting precipitation, with sodium hydroxide (5ml, 1N) and hydrochloric acid (5ml, 1N) washing also vacuum-drying spend the night, obtain 2.53g white solid 5-(N-hexahydropyridine base) amino-sulfonyl-(1H)-indol-2-one, yield 90%.EIMS?m/e?282(M +)。
With 3-ethoxy carbonyl methyl-2-ethoxy carbonyl-4-formyl radical-5-methyl isophthalic acid H-pyrroles (1g; 3.7mmol) and 5-(N-hexahydropyridine base) amino-sulfonyl-(1H)-indol-2-one (1.03g; 3.7mmol) in 20ml ethanol, mix and stir, oil bath is heated to 80 ℃.Drip hexahydropyridine (0.01g), react concentration of reaction solution after 6 hours, use ethyl acetate: elutriant purifying (R on silicagel column of sherwood oil=1: 1 f=0.70) obtain 1.21g yellow solid (E)-5-(hexahydropyridine base) amino-sulfonyl-3-[(3-ethoxy carbonyl methyl-2-ethoxy carbonyl-5-methyl isophthalic acid H-pyrroles-4-yl) methylene radical]-(1H)-and indol-2-one, productive rate 60%.Mp145℃。
H 1NMR(DMCO)：11.20(s，1H，N-H)，9.99(s，1H，N-H)，7.70(s，1H，vinyl-H)，7.62(d，2H，Ph-H)，6.42(s，1H，Ph-H)，7.17(q，2H，Ph-H)，4.28(q，2H，CO 2C H 2 CH 3)，4.00(q，2H，CO 2C H 2 CH 3)，3.95(s，2H，C H 2 CO 2CH 2CH 3)，2.11(s，3H，C H 3 )，1.60(m，6H，4.5-(C H 2 ) 33-hexapyridinyl)，1.42(m，4H，1.2-(C H 2 ) 2-hexapyridinyl)，1.30(t，3H，CO 2CH 2C H 3 )，1.15(t，3H，CO 2CH 2C H 3 )。EIMS?m/e?530(M ++1)。
Embodiment 20 (E)-5-(3-bromophenyl) amino-sulfonyl-3-[(3-ethoxy carbonyl methyl-2-ethoxy carbonyl-5-methyl isophthalic acid H-pyrroles-4-yl) methylene radical]-(1H)-preparation of indol-2-one (Compound I-20):
At room temperature, with 5-chlorosulfonyl-(1H)-indol-2-one (2.1g, 9mmol), (2.3g 14mmol) and pyridine (1.4g), stirred 4 hours in the 20ml methylene dichloride 3-bromaniline.Filter, precipitation is spent the night with twice of 15ml water washing and in 40 ℃ of following vacuum-dryings, obtains 5-(3-bromophenyl) amino-sulfonyl of 2.9g pink solid-(1H)-indol-2-one, productive rate 82%, EIMS m/e 365 (M +).
With 3-ethoxy carbonyl methyl-2-ethoxy carbonyl-4-formyl radical-5-methyl isophthalic acid H-pyrroles (1g; 3.7mmol) and 5-(3-bromophenyl) amino-sulfonyl-(1H)-indol-2-one (1.39g; 3.7mmol) in 20ml ethanol, mix and stir, oil bath is heated to 80 ℃.Drip hexahydropyridine (0.01g), react concentration of reaction solution after 6 hours, use ethyl acetate: elutriant purifying (R on silicagel column of sherwood oil=1: 5 f=0.65) obtain 1.72g yellow solid (E)-5-(3-bromophenyl) amino-sulfonyl-3-[(3-ethoxy carbonyl methyl-2-ethoxy carbonyl-5-methyl isophthalic acid H-pyrroles-4-yl) methylene radical]-(1H)-and indol-2-one, productive rate 73%.Mp?134-138℃。
H 1NMR(DMSO)：7.56(m，2H，Ph-H)，7.38(s，1H，vinyl-H)，6.80-6.98(m，5H，Ph-H)，4.21(q，2H，CO 2C H 2 CH 3)，3.98(q，2H，CO 2C H 2 CH 3)，3.77(s，2H，C H 2 CO 2CH 2CH 3)，2.00(s，3H，C H 3)，1.36(t，3H，CO 2CH 2C H 3 )，1.20(t，3H，CO 2CH 2C H 3 )。EIMS?m/e?615(M +)。
Embodiment 21 The compounds of this invention are tested the inhibition effect of huamn autosomal dominant inheritance type multicystic kidney disease (ADPKD) cyst lining epithelial cells:
1, reagent and instrument
Human multicystic kidney disease cyst lining epithelial cells strain: set up and preserve by Shanghai Long March Hospital Urology Department laboratory;
DMEM: F12 (1: 1) nutrient solution (GIBCO company);
Calf serum (Changzhou folium ilicis chinensis company);
Recombinant human Urogastron (rhEGF) (Calbiochem company);
Microplate reader (LabsysteEIMS MK3)
Testing compound: according to Compound I-1, I-2, I-3, I-4, I-5, I-6, I-7, I-8, I-9, I-10, I-11, I-12, I-13, I-14, I-15, the I-16 of embodiment 1-16 preparation.
Testing compound dilutes with nutrient solution, and concentration gradient is 50 μ M, 5 μ M, 500nM, 50nM, 5nM, 0.5nM, 0.05nM
2, experimental technique
Adopt mtt assay to measure cell proliferation.The cyst lining epithelial cells of logarithmic phase is inoculated in 96 orifice plates (1 * 103/ hole), after 24 hours, changed serum-free medium synchronous 24 hours, make cell be still in resting stage.Abandon supernatant liquor, use instead and contain each concentration drug solution of 2% calf serum, each dosage group is established 9 multiple holes, 37 ℃ hatch 72 hours after, each dosage group adds 1ng/mlrhEGF stimulates 24 hours (the optimal stimulus concentration of determining according to preliminary experiment).The blank group of setting up no drug treating, no EGF to stimulate only adds nutrient solution (2% calf serum) all the time.Get 6 multiple holes, every hole adds 10 μ l MTT, hatches after 4 hours and abandons supernatant, and it is dissolving crystallized that every hole adds 100 μ l DMSO, reads the absorbance of 490nm with microplate reader, and experiment repeats 5 times.
Inhibiting rate=(A490 control wells-A490 dosing holes)/A490 control wells * 100%
According to each concentration inhibiting rate, adopt the same Logit of logarithm (I) linear regression with the competition substrate concentration, obtain the competition substrate concentration IC when suppressing 50% binding substances 50More than each experiment repeat 2 times, obtain the average IC of 2 experiments 50Value as the final index of the ability of inhibition, records the inhibition percentage of experimental compound.
3, experimental result
Experimental result sees Table 1.
Table 1. The compounds of this invention is at the inhibition percentage (%) of each concentration to human multicystic kidney disease cyst lining epithelial cells
Figure C20041006790400231
Embodiment 22 The compounds of this invention are to the inhibition effect experiment of A-549 human lung adenocarcinoma cell, A-431 human skin squamous cell carcinoma and MDA-MB-468 human breast cancer cell
1, reagent and instrument
RPMII640 is available from Gibco company; The sulphonyl rhodamine B is available from Sigma company; Tricholroacetic Acid (TCA), acetic acid (HAC) and Tris base unbuffer are homemade analytical pure; Microplate reader (VERSAmax).
Testing compound: according to Compound I-1, I-2, I-3, I-4, I-5, I-6, I-7, I-8, I-9, I-10, I-11, I-12, I-13, I-14, I-15, I-16, I-17, I-18, I-19, the I-20 of embodiment 1-20 preparation.
Testing compound dilutes with DMSO, and concentration gradient is 10 -4M, 10 -5M, 10 -6M
2, experimental technique (sulphonyl rhodamine B (SRB) protein staining method)
According to cell growth rate, A-549 human lung adenocarcinoma cell, A-431 human skin squamous cell carcinoma and the MDA-MB-468 human breast cancer cell that will be in logarithmic phase respectively are inoculated in 96 well culture plates with 90 μ l/ holes, adherent growth 24 hours, dosing 10 μ l/ holes again.Each concentration is established three multiple holes.And the physiological saline solvent of establishing respective concentration contrasts and acellular withered hole.Tumour cell is at 37 ℃, 5%CO 2Cultivated 72 hours under the condition, the nutrient solution that inclines then with 10% cold TCA fixed cell, is placed after 1 hour, is used distilled water wash 5 times, seasoning in the air for 4 ℃.Add SRB (Sigma) the 4mg/ml solution 100 μ l/ holes by the preparation of 1% Glacial acetic acid then, dyeing is 15 minutes in the room temperature, removes supernatant liquor, with 1% acetic acid washing 5 times, dry air adds the Tris solution in 150 μ l/ holes at last, and microplate reader 540nm wavelength is measured the A value down.
Calculate the inhibiting rate of growth of tumour cell with following formula:
Inhibiting rate=(A540 control wells-A540 dosing holes)/A540 control wells * 100%
3, experimental result
Experimental result sees Table 2-4.
Table 2. The compounds of this invention is to the inhibiting rate (%) of A-549 human lung adenocarcinoma cell growth
Figure C20041006790400241
Table 3. The compounds of this invention is to the inhibiting rate (%) of A-431 human skin squamous cell carcinoma growth
Figure C20041006790400251
Table 4. The compounds of this invention is to the inhibiting rate (%) of MDA-MB-468 human breast cancer cell growth
Figure C20041006790400252
As can be seen, The compounds of this invention is higher to the inhibition activity of the tumour cell that is rich in EGFR from table 1-4.The IC that eight compounds (Compound I-4, I-5, I-15, I-6, I-12, I-3, I-9 and I-11) arranged in the experiment of ADPKD cyst lining epithelial cells growth-inhibiting 50Reached 10 -5M has the IC of two compounds 50Reached 10 -6M, the IC of Compound I-4 50Reached 10 -7M.Two compounds (I-7 and I-8) are 10 in concentration -6During M, be 86%, show as potent inhibitor the inhibition percentage of A-549 human lung adenocarcinoma cell, A-431 human skin squamous cell carcinoma and MDA-MB-468 human breast cancer cell.

Claims (10)

1, the substituted 1 H-indole-2-ketone compound that has following general formula (I) structure:
Figure C2004100679040002C1
Wherein:
R 1Be selected from hydrogen, C 1-5Alkyl, C 2-5Alkenyl, C 3-10Cycloalkyl, hydroxyl, C 1-5Alkoxyl group, ethanoyl, carboxyl, amide group, thioamides base, alkylsulfonyl and three halo methylsulfonyls;
R 2, R 3, R 4, R 5Independently be selected from hydrogen, C separately 1-5Alkyl, C 1-4Alkoxyl group, aryl, aryloxy, C 1-5Alkylaryl, C 1-5Alkyl-aryloxy, C 3-10Cycloalkyl, sulfydryl, C 1-5Alkane sulfydryl, aromatic thiohydroxy, inferior mercapto acyl group, halogen, trihalogenmethyl, amino, cyano group, nitro, carboxyl, oxygen carboxyl, amide group, thioamides base, sulfoamido, three halo methylsulfonyls, N-sulfonamido, S-sulfonamido, three halo methanesulfinyl, O-formamyl, O-thiocarbamoyl and-NR 11R 12, R wherein 3And R 4, R 4And R 5Can be in conjunction with forming hexa-atomic aromatic ring, methylene-dioxy or ethylenedioxy;
R 4, R 5Can also be selected from following group at the same time or separately:
Figure C2004100679040002C2
R wherein 13Be selected from hydrogen; C 1-5Alkyl; C 1-5Alkoxyl group; Aryl; Aryloxy; C 1-5Alkylaryl; C 1-5Alkyl-aryloxy; Trihalogenmethyl; Pyridyl; Pyrimidyl; Thienyl; Above-mentioned each group can be replaced by following group: trifluoromethoxy; Fluorine; Chlorine; Bromine; Iodine; C 1-3-alkoxyl group or replacement C 1-3-alkoxyl group wherein replaces C 1-3-alkoxyl group is meant in 2-or 3-position by amino, C 1-3-alkyl amine group, 2-(C 1-3-alkyl) amido, phenyl-(C 1-3-alkyl) amido, N-(C 1-3-alkyl)-phenyl-(C 1-3-alkyl) amido, pyrrolidyl or piperidyl replace; Phenyl-C 1-3-alkyl amine group-C 1-3-alkyl, this substituting group can also be with trifluoromethyl, fluorine, chlorine, bromine, iodine, C 1-5-alkyl or C 1-3-alkoxyl group carries out list to phenyl nuclear and replaces or two replacements, and when carrying out two replacements, substituting group can be identical, also can be different;
R 6Be selected from hydrogen, C 3-10Cycloalkyl, C 1-5Alkyl, halogen;
R 7And R 8Be selected from hydrogen, C separately 1-5Alkyl, C 1-4Alkoxyl group, aryloxy, C 1-5Alkylaryl, C 1-5Alkyl-aryloxy, three halo C 1-5Alkyl, C 3-10Cycloalkyl, sulfydryl, C 1-5Alkane sulfydryl, aromatic thiohydroxy, inferior mercapto acyl group, halogen, trihalogenmethyl, amino, cyano group, nitro, carboxyl, oxygen carboxyl, amide group, thioamides base, sulfoamido, three halo methylsulfonyls, N-sulfonamido, S-sulfonamido, three halo methanesulfinyl, O-formamyl, O-thiocarbamoyl and-NR 11R 12
R 9Be selected from hydrogen, C 1-5Alkyl, C 1-5Alkoxyl group, aryl, aryloxy, C 1-5Alkylaryl, C 1-5Alkyl-aryloxy, halogen, trihalogenmethyl, sulfydryl, hydroxyl, sulphur C 1-5Alkyl and-NR 11R 12
R 10Be selected from hydrogen, C 3-10Cycloalkyl, C 1-5Alkyl, C 2-5Alkenyl, aryl, heteroaryl, hydroxyl and heterolipid cyclic group;
R 11And R 12Independently be selected from hydrogen, C 1-5Alkyl, C 2-5Alkenyl, C 3-10Cycloalkyl, ethanoyl, alkylsulfonyl, trifyl.
2, substituted 1 H-indole-2-ketone compound according to claim 1 is characterized in that wherein R 4Be selected from C 1-5Alkyl, halogen, sulfoamido, amino, cyano group, nitro, carboxyl and-NR 11R 12
3, substituted 1 H-indole-2-ketone compound according to claim 1 is characterized in that wherein R 4, R 5Be selected from following structure at the same time or separately:
Figure C2004100679040003C1
4, substituted 1 H-indole-2-ketone compound according to claim 1 is characterized in that comprising following compound: (E)-3-[(3-ethoxy carbonyl methyl-2-ethoxy carbonyl-5-methyl isophthalic acid H-pyrroles-4-yl) methylene radical]-the 1H-indol-2-one; (E)-and 5-bromo-3-[(3-ethoxy carbonyl methyl-2-ethoxy carbonyl-5-methyl isophthalic acid H-pyrroles-4-yl) methylene radical]-the 1H-indol-2-one; (E)-and 3-[(3-methoxycarbonyl methyl-2-methoxycarbonyl-5-methyl isophthalic acid H-pyrroles-4-yl) methylene radical]-(1H)-indol-2-one; (E)-and 5-bromo-3-[(3-methoxycarbonyl methyl-2-methoxycarbonyl-5-methyl isophthalic acid H-pyrroles-4-yl) methylene radical]-(1H)-indol-2-one; (E)-and 3-[(3,5 dimethyl-2-ethoxy carbonyl-1H-pyrroles-4-yl) methylene radical]-(1H)-indol-2-one; (E)-and 5-bromo-3-[(3,5 dimethyl-2-ethoxy carbonyl-1H-pyrroles-4-yl) methylene radical]-(1H)-indol-2-one; (E)-and 5-nitro-3-[(3,5 dimethyl-2-ethoxy carbonyl-1H-pyrroles-4-yl) methylene radical]-(1H)-indol-2-one; (E)-and 3-[(3,5 dimethyl-2-methoxycarbonyl-1H-pyrroles-4-yl) methylene radical]-(1H)-indol-2-one; (E)-and 5-nitro-3-[(3,5 dimethyl-2-methoxycarbonyl-1H-pyrroles-4-yl) methylene radical]-(1H)-indol-2-one; (E)-and 5-nitro-3-[(3-ethoxy carbonyl methyl-2-ethoxy carbonyl-5-methyl isophthalic acid H-pyrroles-4-yl) methylene radical]-(1H)-indol-2-one; (E)-and 5-carboxyl-3-[(3-ethoxy carbonyl methyl-2-ethoxy carbonyl-5-methyl isophthalic acid H-pyrroles-4-yl) methylene radical]-(1H)-indol-2-one; (E)-and 5-amino-sulfonyl-3-[(3-ethoxy carbonyl methyl-2-ethoxy carbonyl-5-methyl isophthalic acid H-pyrroles-4-yl) methylene radical]-(1H)-indol-2-one; (E)-and 5-methylamino alkylsulfonyl-3-[(3-ethoxy carbonyl methyl-2-ethoxy carbonyl-5-methyl isophthalic acid H-pyrroles-4-yl) methylene radical]-(1H)-indol-2-one; (E)-and 5-(N-morpholinyl) amino-sulfonyl-3-[(3-ethoxy carbonyl methyl-2-ethoxy carbonyl-5-methyl isophthalic acid H-pyrroles-4-yl) methylene radical]-(1H)-indol-2-one; (E)-and 5-(3-chloro-phenyl-) amino-sulfonyl-3-[(3-ethoxy carbonyl methyl-2-ethoxy carbonyl-5-methyl isophthalic acid H-pyrroles-4-yl) methylene radical]-(1H)-indol-2-one; (E)-and 5-(3-fluorophenyl) amino-sulfonyl-3-[(3-ethoxy carbonyl methyl-2-ethoxy carbonyl-5-methyl isophthalic acid H-pyrroles-4-yl) methylene radical]-(1H)-indol-2-one; (E)-and 5-dimethylamino alkylsulfonyl-3-[(3-ethoxy carbonyl methyl-2-ethoxy carbonyl-5-methyl isophthalic acid H-pyrroles-4-yl) methylene radical]-(1H)-indol-2-one; (E)-and 5-(3-fluoro-4-chloro-phenyl-) amino-sulfonyl-3-[(3-ethoxy carbonyl methyl-2-ethoxy carbonyl-5-methyl isophthalic acid H-pyrroles-4-yl) methylene radical]-(1H)-indol-2-one; (E)-and 5-(hexahydropyridine base) amino-sulfonyl-3-[(3-ethoxy carbonyl methyl-2-ethoxy carbonyl-5-methyl isophthalic acid H-pyrroles-4-yl) methylene radical]-(1H)-indol-2-one; (E)-and 5-(3-bromophenyl) amino-sulfonyl-3-[(3-ethoxy carbonyl methyl-2-ethoxy carbonyl-5-methyl isophthalic acid H-pyrroles-4-yl) methylene radical]-(1H)-indol-2-one.
5, the preparation method of the described substituted 1 H-indole-2-ketone compound of claim 1 is characterized in that by under the catalysis of alkali, and compound (I) carries out condensation reaction by equimolar Compound I I and compound III and makes in organic solvent:
Figure C2004100679040004C1
6, the preparation method of substituted 1 H-indole-2-ketone compound according to claim 5 is characterized in that described alkaline catalysts is organic nitrogen(ous) base or mineral alkali, and organic solvent is protonic solvent or aprotic solvent, and temperature of reaction is 65 ℃～90 ℃; Reaction times is 3～6 hours.
7, the preparation method of substituted 1 H-indole-2-ketone compound according to claim 6, it is characterized in that organic nitrogen(ous) base can adopt triethylamine, pyridine, hexahydropyridine, Trimethylamine 99, aniline, diisopropylamine, 1,8-diazabicylo [5.4.1] 11-7-alkene, tetramethyleneimine, piperidines, mineral alkali can adopt ammonia, alkali metal hydroxide, alkaline earth metal hydroxides, phosphoric acid salt, carbonate, supercarbonate or hydrosulfate.
8, the preparation method of substituted 1 H-indole-2-ketone compound according to claim 6, it is characterized in that protonic solvent is water or alcohols, described aprotic solvent is polarity or proton inert non-polar solvent, and do not contain acidic hydrogen, promptly do not contain can with solute bonded hydrogen, wherein proton inert non-polar solvent can adopt pentane, hexane, benzene, toluene, methylene dichloride or tetracol phenixin, and polar proton inert solvent can adopt chloroform, tetrahydrofuran (THF), dimethyl sulfoxide (DMSO) or dimethyl formamide.
9,, it is characterized in that when solvent is protonic solvent described alkaline catalysts is alkali metal hydroxide or alkaline earth metal hydroxides according to the preparation method of claim 6 or 7 described substituted 1 H-indole-2-ketone compounds.
10, the described substituted 1 H-indole-2-ketone compound of claim 1 is as epidermal growth factor receptor inhibitor, the application in the preparation antitumor drug.
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