CN101255154B - Substituted 2-indoline ketone derivatives as well as preparation method and uses thereof - Google Patents
Substituted 2-indoline ketone derivatives as well as preparation method and uses thereof Download PDFInfo
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- CN101255154B CN101255154B CN2008100142492A CN200810014249A CN101255154B CN 101255154 B CN101255154 B CN 101255154B CN 2008100142492 A CN2008100142492 A CN 2008100142492A CN 200810014249 A CN200810014249 A CN 200810014249A CN 101255154 B CN101255154 B CN 101255154B
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Abstract
The invention relates to a substituted 2-indolinone derivate, a preparation method and the applications thereof in antineoplastic. The substituted 2-indolinone derivate of the invention has a chemical general structure shown in the drawing, wherein X represents one of halogen and hydrogen, or nitro and alkoxyl; R1 and R2 are any one selected from hydrogen, alkyl, cycloalkyl, aryl and heteroary respectively; A represents any one of glycoside and isomer thereof, hydroxy and alkyl, and hydroxy and alkoxyl group. The substituted substituted 2-indolinone derivate of the invention generates nucleoside analogue of sunitinib by saccharification reaction or alkylation reaction of 2-indolinone, greatly increases the solubility, the antitumor activity and the virus resistance.
Description
Technical field
The present invention relates to a kind of 2-indoline ketone derivatives as well as, preparation method and the application in antitumor thereof of replacement.
Technical background
U.S. FDA was ratified the PTS Sutent of Pfizer (sunitinib Sutent) application for quotation (WO2001060814) in 2006, be used for the treatment of the gi tract mesenchymal neoplasm and late period renal cell carcinoma.Sutent can combine termination to the anti-angiogenic formation of tumour cell supply blood and antitumor two kinds of mechanism of action of directtissima tumour cell optionally at the novel targeted medicine of multiple tyrosine kinase receptor.It has represented the appearance of new round targeted therapies, can the directtissima tumour, do not have a toxic side effects of conventional chemotherapy again.But the serious resistance that causes as the long-term prescription of the Imatinib (imatinib) of similar medicine, inevitably can make people that the resistance of Sutent is produced worry (Nature Reviews Drug Discovery 6,734-745 (September 2007)). according to clinical reflection, the effect of Sutent focuses on the angiogenic growth that destroys noumenal tumour, and can not thoroughly remove cancer cells, therefore its effect promptly disappears in 4---7 days discontinuing medication, and tumour promptly begins continued growth again. so the more efficient medicine of Development of New Generation is clinical and continuous needs patient.
Sutent
Summary of the invention
The biomolecule action mechanism of Sutent is to suppress the phosphorylation of multiple tyrosine kinase receptor with the ATP effect, thus the blocking-up angiogenesis.
Nucleoside analog is usually used in the phosphorylation of arrestin and enzyme and acceptor, and usually has additional antitumour activity.
Therefore the objective of the invention is to by the saccharification of 2-indoles beautiful jade ketone or the nucleoside analog of alkylation reaction generation Sutent, to improve antitumour activity and to improve the water-soluble of medicine.
Another object of the present invention is to provide the preparation method of the 2-indoline ketone derivatives as well as of replacement, and the application on medicine.
The 2-indoline ketone derivatives as well as of replacement of the present invention, its chemical structure of general formula is:
Wherein X represent halogen, hydrogen or, nitro and alkoxyl group any;
R
1And R
2Represent any of hydrogen, alkyl, cycloalkyl, aryl and heteroaryl respectively;
A represents any of glucosides and their isomer, hydroxyalkyl and hydroxy alkoxy base.
Preferably, the 2-indoline ketone derivatives as well as of described replacement is the salt of described chemical structure of general formula.
Preferably, described X represents fluorine or methoxyl group; Described A is any of riboside, glucoside and polysaccharide glycosides.
Preferably, described A is any of following chemical structure of general formula, and wherein: R represents hydrogen or acyl group, P0 representation hydroxy, phosphate, ester group or bound phosphate groups, and Q represents hydrogen, oxygen or sulphur,
A also represents the hydroxyalkyl or the hydroxy alkoxy base of various straight or brancheds:
The preparation method of the 2-indoline ketone derivatives as well as of the described replacement of the invention described above, adopt following steps:
(1) the sugar compounds reaction with nuclear substituted 2-indolinone of benzene and protection generates the 2-indolinone saccharide compound that replaces;
(2), generate the α of aromatic acid or assorted fragrant acids condensation, β-undersaturated replacement 2-indolinone saccharide compound with the 2-indolinone saccharide compound and fragrant aldehydic acid or the condensation of assorted aromatic aldehyde acids that replace;
(3) with the α of aromatic acid or assorted fragrant acids condensation, β-undersaturated replacement 2-indolinone saccharide compound and amine reaction are condensed into the α of aromatic amides or the condensation of assorted aromatic amides class, β-undersaturated replacement 2-indolinone saccharide compound;
(4) α of aromatic amides or the condensation of assorted aromatic amides class; β-undersaturated replacement 2-indolinone saccharide compound removes the α that sugared protecting group generates unprotected aromatic amides or the condensation of assorted aromatic amides class, β-undersaturated replacement 2-indolinone saccharide compound with ammonia, amine, sodium alkoxide class alkali or other bases.
The preparation method of the 2-indoline ketone derivatives as well as of the described replacement of the invention described above, also can adopt following steps:
(1), generates the replacement 2-indolinone analogue of the 1-alkoxyalkylization of protection with the halogenated alkoxy alkyl reaction of nuclear substituted 2-indolinone of benzene and protection;
(2) with the replacement 2-indolinone analogue of the 1-alkoxyalkylization of protecting and the replacement 2-indolinone α of fragrant aldehydic acid or 1-alkoxyalkylization assorted aromatic aldehyde acids condensation generation aromatic acid or assorted fragrant acids condensation, protection, β-unsaturated analogue.
(3) with the replacement 2-indolinone α of 1-alkoxyalkylization aromatic acid or assorted fragrant acids condensation, protection; β-unsaturated analogue; with the replacement 2-indolinone α of 1-alkoxyalkylization amine condensation generation aromatic amides or the condensation of assorted aromatic amides class, protection, β-unsaturated analogue.
(4) the replacement 2-indolinone α of 1-alkoxyalkylization aromatic amides or the condensation of assorted aromatic amides class, protection; β-unsaturated analogue ammonia; amine; sodium alkoxide class alkali or other bases remove the replacement 2 indolinone α that protecting group generates the 1-alkoxyalkylization of unprotected aromatic amides or the condensation of assorted aromatic amides class, β-unsaturated analogue.
Among the above-mentioned preparation method; α with unprotected aromatic amides or the condensation of assorted aromatic amides class; β-undersaturated replacement 2-indolinone saccharide compound; the perhaps replacement 2-indolinone α of the 1-alkoxyalkylization of aromatic amides or the condensation of assorted aromatic amides class; β-unsaturated analogue and acid-respons generate salt.
Preferably, described acid is hydrochloric acid, phosphoric acid, sulfuric acid, Hydrogen bromide, L MALIC ACID, toxilic acid, fumaric acid, tartrate, methylsulfonic acid, perhaps Citric Acid.
The 2-indoline ketone derivatives as well as of the described replacement of the invention described above is used to prepare that treatment is antitumor, the application on the antiviral.Described medicine is solid preparation, injection, external preparation, spray or compound preparation.
The preparation method of compound and their salt can illustrate with the preparation feedback formula of following compound in the general formula of the present invention.
The preparation feedback route of compound 7:
The preparation feedback route of compound 13:
Beneficial effect of the present invention is: saccharification by 2-indoles beautiful jade ketone or alkylation reaction generate the nucleoside analog of Sutent, and its solvability is greatly improved, and its antitumour activity antivirally also is greatly improved.
Preparation method of the present invention, it is simple to have technology, the advantage that product yield is high.
Description of drawings
Fig. 1 is the restraining effect figures of compound 7 different concns to human microvascular endothelial cell (mvec) (HMVEC).
Fig. 2 is restraining effect and the time chart of compound 7 (1 μ M) to human microvascular endothelial cell (mvec) (HMVEC).
Fig. 3 is that the tyrosine kinase receptor inhibitor is to the proteic phosphorylation restraining effect of RTKs figure.
Specific embodiment
One. the preparation of compound of the present invention
Synthesizing of compound 3:
With compound 1 (1.51g, 0.01mol) and 50 milliliters of hmds mix and refluxed 1 hour, the dried solvent of underpressure distillation, remnants are dissolved in 50 milliliters anhydrous second eyeball, add compound 2 (3.18g again, 0.01mol) stir. add trifluoromethanesulfonic acid trimethylsilyl group (0.7mL down in 0 ℃, 0.03mol). mixture heating up refluxed 1 hour, cooling is as for room temperature, cooling slowly adds 20 milliliters saturated sodium bicarbonate solution down, and after the stirring, (3 * 30mL) extract with methylene dichloride, united extraction liquid, salt is washed once, anhydrous sodium sulfate drying. filter evaporate to dryness, remaining silica gel column chromatography separation (elutriant: ethyl acetate-normal hexane 1: 3) get compound 3 oily liquids (3.1g, 76%) .ESIMS:m/z 410 (M+1).
Synthesizing of compound 5:
With compound 3 (4g, 0.01mol), compound 4 (1.7g, 0.01mol) in piperidines (0.2mL) is mixed in 150 milliliters dehydrated alcohol, reflux 1 hour. cool to room temperature, be that 0 ℃ left standstill 3 hours, filter, gained solid heating for dissolving is in 90 milliliters dehydrated alcohol, be cooled to 0 ℃ 12 hours, filtering compound 5 (4.32g, 78%) .ESIMS:m/z 559.5 (M+1).
Synthesizing of compound 7:
With compound 5 (5.6g, 0.01mol) and N, N dimethylamine base quadrol (1.16g, 0.01mol) be mixed in 100 milliliters the anhydrous tetrahydro furan, in 0 ℃ add down EDCI (2g, 0.01mol). mixture was in stirring at room 12 hours, be poured in 200 milliliters of 0 ℃ of water, with dichloromethane extraction (2 * 150mL), the salt water washing once, anhydrous sodium sulfate drying, filter, filtrate decompression distillation is done to such an extent that oily matter 6. mixes sealing with the ammonia methanol solution of this oily matter 6 and 7N, places 7 days in room temperature, filters the solid of separating out, a little methyl alcohol is washed, 50 ℃ of dryings of vacuum 12 hours get compound 7 (2.9g, 56%) .ESIMS:m/z 531.4 (M+1).
Synthesizing of compound 9:
With compound 1 and (1.51g, 0.01mol) be dissolved among 30 milliliters the DMF. add compound 8 (1.97g, 0.01mol) and Anhydrous potassium carbonate (4g). mixture was in stirring at room 12 hours. filters, filtrate decompression distillation (less than 45 ℃) removes and desolvates. the separation of resistates silica gel column chromatography (elutriant: ethyl acetate-normal hexane 1: 3) get compound 9 oily liquids (1.39g, 52%) .ESIMS:m/z 268 (M+1).
Synthesizing of compound 10:
The synthetic method of reference compound 5 gets compound 10 (yield 80%) .ESIMS:m/z 417.2 (M+1).
Compound 11 and 12 synthetic:
The synthetic method of reference compound 7 gets compound 11 (yield 80%) .ESIMS:m/z 515.5 (M+1). and compound 12 (yield 66%) .ESIMS:m/z 473.4 (M+1).
Synthesizing of compound 13:
Compound 12 (0.46g) and L MALIC ACID (0.14g) be mixed in 20 milliliters of dehydrated alcohols be heated to CL. slow cool to room temperature, again in 0 ℃ 3 hours. compound 13 (0.43g, 74%).
Two. compound 7 different concns are to the restraining effect of human microvascular endothelial cell (mvec) (HMVEC), as shown in Figure 1.
Compound 7 (1 μ M) is to the restraining effect and the timing relationship of human microvascular endothelial cell (mvec) (HMVEC), as shown in Figure 2.
7 pairs of human microvascular endothelial cell (mvec)s of compound (human microvascular endothelial cell, inhibition method HMVEC):
1: human microvascular endothelial cell (mvec) places the plate (1 * 10 of 24 wells
4Cell/well). the solution of the DMSO of the compound 7 of second day adding different concns. harvested cell after four days, count with cell counter. see Fig. 1.
2: human microvascular endothelial cell (mvec) places the plate (1 * 10 of 24 wells in quadruplicate
4Cell/well). 1 μ M DMSO solution of second day adding compound 7 or simple DMSO. are respectively the six, the eight, and the tenth day harvested cell counted with cell counter. see Fig. 2.
Three. compound 7, the water-soluble contrast of compound 13 and Sutent, result such as following table:
| | Sutent | Compound | 7 | Compound 13 |
| Solubleness mg/mL | ?25 | ?30 | ?40 |
Claims (3)
1. the 2-indolinone derivative and the salt thereof of a replacement, its chemical structure of general formula is:
Wherein X represents halogen, hydrogen, nitro, and alkoxyl group is a kind of;
R
1And R
2Represent a kind of of hydrogen and alkyl respectively;
A representation hydroxy alkyl; Or following structural formula is a kind of
2. the 2-indolinone derivative of the described replacement of claim 1 or its salt is characterized in that, described salt is hydrochloric acid, phosphoric acid, sulfuric acid, Hydrogen bromide, L one oxysuccinic acid, toxilic acid, fumaric acid, tartrate, the salt of methylsulfonic acid or Citric Acid.
3. the application in the 2-indolinone derivative of claim 1 or 2 described replacements or its salt, the antiviral antitumor in the preparation treatment.
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| CN102115469A (en) * | 2011-03-21 | 2011-07-06 | 浙江大学 | Preparation method for indoline-2-one derivative and application of same |
| CN103254110B (en) * | 2012-02-17 | 2015-12-16 | 上海医药工业研究院 | The full ketone of halogenated pyrrole substituted indole, its intermediate and preparation method thereof |
| CN102977171A (en) * | 2012-12-18 | 2013-03-20 | 吉林大学 | Five-membered heterocycle modified 4'-spiro nucleoside compounds and application in virus resistance |
| CN105622680B (en) * | 2015-12-22 | 2018-01-19 | 杭州卢普生物科技有限公司 | A kind of Sutent derivative and its preparation method and application |
| CN113061153B (en) * | 2021-03-29 | 2022-07-29 | 武汉理工大学 | Indole glycoside compound, preparation method and application thereof |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN1439005A (en) * | 2000-02-15 | 2003-08-27 | 苏根公司 | Pyrrole substituted 2-indolinone protein kinase inhibitors |
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| CN1439005A (en) * | 2000-02-15 | 2003-08-27 | 苏根公司 | Pyrrole substituted 2-indolinone protein kinase inhibitors |
Non-Patent Citations (2)
| Title |
|---|
| 闵真立等.3-取代吲哚酮类化合物的合成及抗肿瘤活性.中国药物化学杂志15 3.2005,15(3),129-132. |
| 闵真立等.3-取代吲哚酮类化合物的合成及抗肿瘤活性.中国药物化学杂志15 3.2005,15(3),129-132. * |
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Effective date of registration: 20191024 Address after: 046000 12-2, yunhaiyuan, Shennong, Changzhi City, Shanxi Province Patentee after: Li Xiangyi Address before: 250014 Lixia District, Shandong City, Ji'nan Province, No. ten, No. 4, Quancheng Patent Office Patentee before: Jin Guangyi |
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Effective date of registration: 20211108 Address after: 046000 No. 3 Kangzhuang Avenue, Tunliu Kangzhuang Industrial Park, Changzhi City, Shanxi Province Patentee after: CHANGZHI SANBAO BIOCHEMICAL PHARMACEUTICAL CO.,LTD. Address before: 046000 12-2, yunhaiyuan, Shennong, Changzhi City, Shanxi Province Patentee before: Li Xiangyi |
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