CN102115469A - Preparation method for indoline-2-one derivative and application of same - Google Patents
Preparation method for indoline-2-one derivative and application of same Download PDFInfo
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- CN102115469A CN102115469A CN2011100677761A CN201110067776A CN102115469A CN 102115469 A CN102115469 A CN 102115469A CN 2011100677761 A CN2011100677761 A CN 2011100677761A CN 201110067776 A CN201110067776 A CN 201110067776A CN 102115469 A CN102115469 A CN 102115469A
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Abstract
The invention provides an indoline-2-one derivative and a pharmaceutically acceptable salt thereof. The condensation reaction of acid and amine is performed among 6-(dimethoxy-methyl)-2-one-1, 2-dihydropyridine-3-formic acid and substituted amine, then the deprotection at 6-posiiton is performed under the action of an acid catalyst to form aldehyde groups, and then the aldehyde groups react with substituted indole-2-one or an aza-derivative for the substituted indole-2-one under the action of an alkaline catalyst to obtain the indoline-2-one derivative. The experiment of the provided compound to the cytotoxicity of three tumor cells in vitro shows that the activity of partial compounds is basically same as that of a positive control anti-tumor drug, and the indoline-2-ketone derivative can be used for preparing a drug for preventing and controlling tumor diseases; and the general structural formula is as follows.
Description
Technical field
The invention belongs to pharmaceutical chemistry and area of pharmacology, relate to the preparation method of indole-2-ketone analog derivative, and the purposes of this compounds in the preparation antitumor drug.
Background technology
Cancer is a kind of common disease and frequently-occurring disease of serious threat human health, statistic data over past ten years shows: more than annual average about 1,000 ten thousand people of New Development cancer patient in the whole world, die from about more than 700 ten thousand people of cancer, the human mortality ratio that causes because of cancer is only second to cardiovascular and cerebrovascular diseases, second of row.Tyrosylprotein kinase is played an important role in tumour generation and evolution, thereby it mediates each vital processes such as growth, differentiation, migration and apoptosis that a lot of signal paths are regulated cells, and its overexpression can cause for example malignant tumour of numerous disease.In recent years, be that the research of inhibitor of target spot is more and more with the tyrosine protein kinase, and in oncotherapy, obtained challenging impressive progress.
Sutent (Sunitinib) is a kind of antitumor oral pharmaceutical of novel targeted a plurality of tyrosine protein kinase, be used for the treatment of the gastrointestinal stromal knurl and the metastatic renal cell cancer (Turner that do not have response maybe can not tolerate to standard treatment, M., Mee, P. J., Costello, P. S., Williams, O.
Nature1995,378,298).In January, 2006 U.S. food and drug administration (FDA) official approval Sutent be used for the treatment of above-mentioned two kinds of tumours, and examine the status by " fast passage " that FDA authorizes.Patent of the present invention has been carried out structure of modification based on the early-stage Study basis to Sutent, and active better tyrosine protein enzyme inhibitors tries to find out.
Summary of the invention
The purpose of this invention is to provide a kind of indole-2-ketone analog derivative, and their pharmaceutically useful salt, have following general structure:
Wherein: X, Y, Z, W is identical or different, selects carbon for use, nitrogen; R
1, R
2, R
3, R
4Identical or different, select hydrogen for use, nitro, halogen, hydroxyl, amido contains the saturated or unsaturated alkyl or the alkoxyl group of 1-8 carbon or contains the alkylamino radical of 1-8 carbon, and works as X, Y, Z, one of W is any when being nitrogen, is connected the substituent R on this atom accordingly
1, R
2, R
3, R
4Do not exist; Substituent R can be selected saturated or unsaturated alkyl, alkylamino radical methyl, alkylamino radical ethyl, the Heterocyclylalkyl of 1-5 carbon for use.Its preferred formula (1) compound is:
I-a:(
Z)-
N-[(2-dimethyl amine) ethyl]-6-(5-fluoro-2-ketone-indoline-3-alkene methyl)-2-ketone-1,2-dihydropyridine-3-acid amides
I-b:(
Z)-
N-[(2-diethylamide) ethyl]-6-(5-fluoro-2-ketone-indoline-3-alkene methyl)-2-ketone-1,2-dihydropyridine-3-amide hydrochloride
I-c:(
Z)-
N-(5-fluoro-2-ketone-indoline-3-alkene methyl)-
N-(2-morpholine ethyl)-2-ketone-1,2-dihydropyridine-3-acid amides
I-d:(
Z)-6-(5-fluoro-2-ketone-indoline-3-alkene methyl)-
N-(2-piperidines ethyl)-2-ketone-1,2-dihydropyridine-3-acid amides
I-e:(
Z)-
N-[(2-dimethyl amine) ethyl]-2-ketone-6-(2-ketone-1H-pyrroles [2,3-b] pyridine-3-alkene methyl)-1,2-dihydropyridine-3-acid amides
I-f:(
Z)-
N-[(2-diethylamide) ethyl]-2-ketone-6-(2-ketone-1H-pyrroles [3,2-b] pyridine-3-alkene methyl)-1,2-dihydropyridine-3-acid amides
Another object of the present invention provides the preparation method of a kind of indole-2-ketone analog derivative and pharmaceutically useful salt thereof; realize by following scheme: with 6-(dimethoxy-methyl)-2-ketone-1; the condensation reaction of acid and amine takes place in the amine of 2-dihydropyridine-3-formic acid and replacement under catalyst action; then 6 deprotections form aldehyde radical under the catalysis of acid, and the indole-2-ketone of aldehyde radical and aromatic ring replacement or azepine reacts under the catalysis of alkali and obtains the indole-2-ketone analog derivative.Reaction formula is:
Wherein: X, Y, Z, W and radicals R
1, R
2, R
3, R
4And identical in the definition of R and the formula (1).
Another purpose of the present invention provides indole-2-ketone analog derivative and the application of pharmaceutically useful salt in control tumor disease medicine thereof.Preliminary pharmacological evaluation shows that formula of the present invention (1) compound is external to Human Prostate Cancer Cells (PC-3), the chronic myelogone leukemia cell of people (K562), people's acute leukemia cells (HL60) growth-inhibiting effect preferably, external activity half-inhibition concentration (IC arranged
50Show that value) its inhibition to the part cell strain of part of compounds is active suitable with Sutent, shows that this analog derivative might develop into new control tumour medicine.
Usefulness of the present invention is: with the protein kinase B inhibitor Sutent is lead compound, obtains the indole-2-ketone analog derivative by appropriate design; The preparation method of this compounds and pharmaceutically useful salt thereof is provided; The indole-2-ketone analog derivative and the pharmaceutically useful salt thereof that provide have important biological, and external have restraining effect to many strains tumour cell, are expected to become new control tumour medicine.
Embodiment
Further specify the present invention below by specific embodiment.Following embodiment has provided the synthetic and dependency structure appraising datum of representative compounds.Mandatory declaration, following embodiment is used to illustrate the present invention rather than limitation of the present invention.Essence according to the present invention all belongs to the scope of protection of present invention to the simple modifications that the present invention carries out.
Embodiment 1: (
Z)-
N-[(2-dimethyl amine) ethyl]-6-(5-fluoro-2-ketone-indoline-3-alkene methyl)-2-ketone-1, the preparation of 2-dihydropyridine-3-acid amides (I-a)
This example relates to the general synthetic method of indoline-2-one analog derivative (I).Be specifically related to (
Z)-
N-[(2-dimethyl amine) ethyl]-6-(5-fluoro-2-ketone-indoline-3-alkene methyl)-2-ketone-1,2-dihydropyridine-3-acid amides (I-a) synthetic.Compound 6-(dimethoxy-methyl)-2-ketone-1,2-dihydropyridine-3-formic acid (213 mg, 1.0 mmol), EDC(229 mg, 1.2 mmol), HOBt(160 mg, 1.2 mmol) be dissolved in DMF(25 mL) in, ice bath is cooled to about 5 ° of C, react after ten minutes, add
N,
N-dimethyl-ethylenediamine (106 mg, 1.2 mmol), stirring is spent the night.Boil off DMF then and get yellow oil, then in this system, add 1 mL concentrated hydrochloric acid, 1 mL water and 5 mL Glacial acetic acid and under 60 ° of C, reacted 2.5 hours, and concentrating under reduced pressure gets the yellow oily material.In this system, add methyl alcohol (25 mL), regulating pH value with triethylamine is 7.0 must system B, in this system, add 5-fluoro-indole-2-ketone (50 mg, 0.33 mmol), piperidines (0.08 mL), the 4 hours a small amount of ether of cooling back adding that reflux are separated out yellow solid, suction filtration gets pure product I-a(38 mg), total recovery 30.4%.
1H?NMR?(500?MHz,?DMSO
-d 6):
?14.44?(1H,?s),?11.46?(1H,?s),?9.91?(1H,?t,?
J?=?6?Hz),?8.46?(1H,?d,?
J?=?7.5?Hz),?7.81?(1H,?s),?7.74?(1H,?dd,?
J?=?2.5?Hz,?8.5?Hz),?7.17-7.21?(1H,?m),?6.93-6.96?(2H,?m),?3.68?(2H,?q,?
J?=?6.0?Hz),?3.17-3.22?(2H,?m),?2.77?(6H,?s),?LCMS?
m/z?[M+H]
+?371?calcd?for?C
19H
19FN
4O
3?370?。
Embodiment 2: (
Z)-
N-[(2-diethylamide) ethyl]-6-(5-fluoro-2-ketone-indoline-3-alkene methyl)-2-ketone-1, the preparation of 2-dihydropyridine-3-amide hydrochloride (I-b)
According to the method for embodiment 1, use
N,
N-diethyl ethylenediamine substitutes
N,
N-dimethyl-ethylenediamine gets Compound I-b(total recovery: 29.6%).
1H?NMR?(500?MHz,?DMSO
-d 6):
?14.44?(1H,?s),?11.49?(1H,?s),?9.93-10.00?(1H,?br?s),?9.92?(1H,?t,?
J?=?6?Hz),?8.45?(1H,?d,?
J?=7.5?Hz),?7.82?(1H,?s),?7.74?(1H,?dd,?
J?=?2.5?Hz,?8.5?Hz),?7.16-7.20?(1H,?m),?6.93-6.95?(2H,?m),?3.71?(2H,?q,
?J?=?6.5?Hz),?3.27-3.23?(2H,?m),?3.23-3.16?(4H,?m),?1.23?(6H,?t,?
J?=?7.5?Hz);?
13C?NMR?(125?MHz,?DMSO-
d 6):?
?169.29,?164.05,?161.68,?158.84?(d,?
J?=?235.625?Hz),?144.22,?143.85,?138.44,?131.98,?129.50,?125.29?(d,?
J?=?9.25?Hz),?122.72,?117.94?(d,?
J?=?24.375?Hz),?114.50,?112.12?(d,?
J?=?8?Hz),?109.17?(d,?
J?=?25.75?Hz),?49.99,?47.36,?34.34,?8.96;?ESI-MS?
m/z?[M+H-HCl]
+?399,?calcd?for?C
21H
24ClFN
4O
3?434?。
Embodiment 3: (
Z)-
N-(5-fluoro-2-ketone-indoline-3-alkene methyl)-
N-(2-morpholine ethyl)-2-ketone-1, the preparation of 2-dihydropyridine-3-acid amides (I-c)
According to the method for embodiment 1, substitute with 2-morpholine ethamine
N,
N-dimethyl-ethylenediamine gets Compound I-c(total recovery: 30.8%).
1H?NMR?(500?MHz,?DMSO
-d 6):
?14.36?(1H,?s),?11.44?(1H,?s),?9.86?(1H,?t,?
J?=?5.5?Hz),?8.43?(1H,?d,?
J?=?7.5?Hz),?7.78?(1H,?s),?7.72?(1H,?dd,?
J?=?2.5?Hz,?8.5?Hz),?7.15-7.19?(1H,?m),?6.89-6.92?(2H,?m),?3.57?(4H,?t,?
J?=?4.5?Hz),?3.43?(2H,?q,?
J?=?6?Hz),?2.45?(2H,?t,?
J?=?6?Hz),?2.36-2.43?(4H,?m);?LCMS?
m/z?[M+H]
+?413?calcd?for?C
21H
21FN
4O
4?412?。
Embodiment 4: (
Z)-6-(5-fluoro-2-ketone-indoline-3-alkene methyl)-
N-(2-piperidines ethyl)-2-ketone-1, the preparation of 2-dihydropyridine-3-acid amides (I-d)
According to the method for embodiment 1, substitute with the 2-piperidine-1-ethanamine
N,
N-dimethyl-ethylenediamine gets Compound I-d(total recovery: 30.0%).
1H?NMR?(500?MHz,?DMSO-
d 6):
14.38?(1H,?s),?11.46?(1H,?s),?9.87?(1H,?t,?
J?=?5?Hz),?8.45?(1H,?d,?
J?=?7?Hz),?7.80?(1H,?s),?7.76?(1H,?dd,
?J?=?2.5?Hz,?9?Hz),?7.21-7.17?(1H,?m),?6.95-6.92?(2H,?m),?3.52-3.41?(2H,?m),?2.46-2.34?(4H,?m),?1.60-1.48?(4H,?m),?1.48-1.35?(2H,?m);?LCMS?m/z?[M+H]
+?411.36?calcd?for?C
22H
23FN
4O
3?410?。
Embodiment 5: (
Z)-
N-[(2-dimethyl amine) ethyl]-2-ketone-6-(2-ketone-1H-pyrroles [2,3-b] pyridine-3-alkene methyl)-1, the preparation of 2-dihydropyridine-3-acid amides (I-e)
According to the method for embodiment 1, substitute 5-fluoro-indole-2-ketone with 7-azaindole quinoline-2-ketone and get Compound I-e(total recovery: 26.9%).
1H?NMR?(500?MHz,?DMSO
-d 6):
?14.26?(1H,?s),?12.02?(1H,?br?s),?9.91?(1H,?t,?
J?=?6?Hz),?8.47?(1H,?d,?
J?=?7.5?Hz),?8.23?(1H,?dd,?
J?=?1.5?Hz,?5Hz),?8.14?(1H,?dd,?
J?=?1.5?Hz,?7.5?Hz),7.83?(1H,?s),?7.16?(1H,?dd,?
J?=?5?Hz,?7.5?Hz),?7.00?(1H,?dd,?
J?=?1.5?Hz,?7.5?Hz),?3.70?(2H,?q,?
J?=?6?Hz),?3.24?(2H,?t,?
J?=5?Hz),?2.80?(6H,?s);?LCMS?
m/z?[M+H]
+?354?calcd?for?C
18H
19N
5O
3?353。Wherein 7-azaindole quinoline-2-ketone is prepared through two-step reaction by the 7-azaindole.(1.5 g 12.7mmol) are dissolved in the mixing solutions of the 100 mL water and the 100 mL trimethyl carbinols 7-azaindole, slowly drip Br under the room temperature
2(2.6 mL, 50.5 mmol), filter yellow solid and dry intermediate 3,3-two bromo-7-azaindole quinoline-2-ketone.Intermediate (2.2g, 10mmol) join successively in the ethanol (50 mL) with 5% Pd-C (4g), through hydrogen reducing, filter yellow solution, adding triethylamine, to regulate pH value be neutrality, revolves ethanol, separates out solid after adding a spot of ether, suction filtration gets yellow solid 0.8 g, and two step total recoverys are: 51.8%;
1H NMR (500 MHz, CDCl
3):
(9.80 1H, br s), 8.29 (1H, d,
J=5Hz), 7.49 (1H, dd,
J=1.5Hz, 7.5Hz), 6.95 (1H, dd,
J=5Hz, 7.5Hz), 3.57 (2H, s); ESI-MS m/z [M+H]
+134.
Embodiment 6: (
Z)-
N-[(2-diethylamide) ethyl]-2-ketone-6-(2-ketone-1H-pyrroles [3,2-b] pyridine-3-alkene methyl)-1, the preparation of 2-dihydropyridine-3-acid amides (I-f)
According to the method for embodiment 1, substitute 5-fluoro-indole-2-ketone, use simultaneously with 4-azaindole quinoline-2-ketone
N,
N-diethyl ethylenediamine substitutes
N,
N-dimethyl-ethylenediamine prepares Compound I-f(total recovery: 28.8%).
1H?NMR?(500?MHz,?DMSO
-d 6):
?15.27?(1H,?br?s),?11.03?(1H,?br?s),?9.85?(1H,?t,?
J?=?5.5?Hz),?8.40?(1H,?d,?
J?=?7.5?Hz),?8.30?(1H,?dd,?
J?=?1.5?Hz,?5?Hz),?7.46-7.43?(3H,?m),?7.21?(1H,?d,?
J?=?7.5Hz),?3.42-3.38?(2H,?m),?2.59-2.54?(6H,?m),?0.99?(6H,?t,?
J?=?7.5Hz);?LCMS?
m/z?[M+H]
+?382?calcd?for?C
20H
23N
5O
3?381。Wherein 4-azaindole quinoline-2-ketone is according to literature method (Finch, N.; Robison, M. M.; Valerio, M. P.
J. Org. Chem. 1972,
37, 51.) prepare by raw material 2-chloro-3-nitropyridine.
In order to understand essence of the present invention better, embodiment further specifies the present invention below by pharmacology.Pharmacology embodiment has provided the part activity data of representative compounds.Mandatory declaration, following pharmacology embodiment is used to illustrate the present invention rather than limitation of the present invention, essence according to the present invention all belongs to the scope of protection of present invention to the simple modifications that the present invention carries out.
Embodiment 7:Compound I-a is to the cytotoxic activity of human leukemia cell (HL60)
Human leukemia cell (HL60) contains 10% calf serum, 100U/ ml penicillin and 100U/ milliliter Streptomycin sulphate with RPMI 1640 culture medium culturing in the substratum.Cell is with every hole 1 * 10
4Individual density is inoculated in 96 orifice plates, at 37 ℃, and 5%CO
2Cultivated 24 hours in the incubator of damp atmosphere.
The measuring method of cell survival rate is with improveing mtt assay.Cell is after 24 hours hatch, and the dimethyl sulfoxide solution of the Compound I-a that will newly join joins in each hole with concentration gradient respectively, makes that the ultimate density of compound is respectively 100 mcg/ml, 50 mcg/ml, 25 mcg/ml, 5 mcg/ml in the hole.After 72 hours, add the normal saline solution of 10 microlitre MTT (5 mg/ml), continue at 37 ℃ 5%CO again
2Cultivated 3 hours in the incubator of damp atmosphere, add 150 milliliters of methyl-sulphoxides in every hole, the MTT crystal Jia Za (formazan) that the vibration dissolving generates, formed Jia Za microplate reader colorimetric under 570 nm wavelength, cell survival rate is by the ratio calculation of sample OD value for contrast OD value.Wherein Compound I-a is to the half-inhibition concentration (IC of HL60 cell
50) obtain by dose effect curve.The IC of Compound I-a
50For: 34.7 μ M.
This test is with the positive contrast of an antitumor line medication Sutent, to human leukemia cell's (HL60) 503nhibiting concentration IC
50Be respectively 15.5 μ M.
This experiment shows that this type of new indole-2-ketone analog derivative has cytotoxicity to human leukemia cancer cells HL60 cell, might develop into the new medicine with leukemia resisting action.
Embodiment 8:Compound I-b is to the chronic myelogone leukemia cell's of people (K562) cytotoxic activity
The chronic myelogone leukemia cell of people (K562) contains 10% calf serum, 100U/ ml penicillin and 100U/ milliliter Streptomycin sulphate with RPMI 1640 culture medium culturing in the substratum.Cell is with every hole 1 * 10
4Individual density is inoculated in 96 orifice plates, at 37 ℃, and 5%CO
2Cultivated 24 hours in the incubator of damp atmosphere.
The measuring method of cell survival rate is with improveing mtt assay.Concrete grammar such as embodiment 7.
Wherein Compound I-b is to the half-inhibition concentration (IC of K562 cell
50) obtain the IC of Compound I-b by dose effect curve
50For: 26.8 μ M.
This test is with the positive contrast of an antitumor line medication Sutent, to the chronic myelogone leukemia cell's of people 503nhibiting concentration IC
50Be respectively 21.9 μ M.
This experiment shows that this type of new indole-2-ketone analog derivative has cytotoxicity to the chronic myelogone leukaemia cancer cell of people K562 cell, might develop into the new medicine with anti-chronic myelogone leukemia effect.
Embodiment 9:Compound I-f is to the cytotoxic activity of Human Prostate Cancer Cells (PC-3)
Human Prostate Cancer Cells (PC-3) is used the F-12 culture medium culturing, contains 10% foetal calf serum in the substratum, the Streptomycin sulphate of 100U/ ml penicillin and 100U/ milliliter.Cell is with every hole 5 * 10
3Concentration join in 96 orifice plates, contain 5%CO at 37 ℃
2Cultivated 24 hours in the incubator of damp atmosphere.
The mensuration of cell survival rate is with improveing mtt assay, concrete grammar such as embodiment 7.
Wherein Compound I-f is to PC-3 cell 503nhibiting concentration IC
50Obtain by dose effect curve.The IC of Compound I-f
50Be 60.0 μ M.
This test is with the positive contrast of an antitumor line medication Sutent, and Sutent is to the 503nhibiting concentration IC of Human Prostate Cancer Cells (PC-3)
50Be respectively 25.1 μ M.
Experiment shows that this type of new indole-2-ketone analog derivative has stronger cytotoxicity to Human Prostate Cancer Cells (PC-3), might develop into the new medicine with anti-effect on prostate carcinoma.
Claims (4)
1. an indole-2-ketone analog derivative and pharmaceutically useful salt thereof have following general structure:
Wherein: X, Y, Z, W is identical or different, selects carbon for use, nitrogen; R
1, R
2, R
3, R
4Identical or different, select hydrogen for use, nitro, halogen, hydroxyl, amido contains the saturated or unsaturated alkyl or the alkoxyl group of 1-8 carbon or contains the alkylamino radical of 1-8 carbon, and works as X, Y, Z, one of W is any when being nitrogen, is connected the substituent R on this atom accordingly
1, R
2, R
3, R
4Do not exist; Substituent R is selected saturated or unsaturated alkyl, alkylamino radical methyl, alkylamino radical ethyl, the Heterocyclylalkyl of 1-5 carbon for use.
2. a kind of indole-2-ketone analog derivative according to claim 1 and pharmaceutically useful salt thereof is characterized in that particular compound is:
I-a:(
Z)-
N-[(2-dimethyl amine) ethyl]-6-(5-fluoro-2-ketone-indoline-3-alkene methyl)-2-ketone-1,2-dihydropyridine-3-acid amides,
I-b:(
Z)-
N-[(2-diethylamide) ethyl]-6-(5-fluoro-2-ketone-indoline-3-alkene methyl)-2-ketone-1,2-dihydropyridine-3-amide hydrochloride,
I-c:(
Z)-
N-(5-fluoro-2-ketone-indoline-3-alkene methyl)-
N-(2-morpholine ethyl)-2-ketone-1,2-dihydropyridine-3-acid amides,
I-d:(
Z)-6-(5-fluoro-2-ketone-indoline-3-alkene methyl)-
N-(2-piperidines ethyl)-2-ketone-1,2-dihydropyridine-3-acid amides,
I-e:(
Z)-
N-[(2-dimethyl amine) ethyl]-2-ketone-6-(2-ketone-1H-pyrroles [2,3-b] pyridine-3-alkene methyl)-1,2-dihydropyridine-3-acid amides,
I-f:(
Z)-
N-[(2-diethylamide) ethyl]-2-ketone-6-(2-ketone-1H-pyrroles [3,2-b] pyridine-3-alkene methyl)-1,2-dihydropyridine-3-acid amides.
3. the preparation method of an indole-2-ketone analog derivative and pharmaceutically useful salt thereof; it is characterized in that; realize by following steps: with 6-(dimethoxy-methyl)-2-ketone-1; the condensation reaction of acid and amine takes place in the amine of 2-dihydropyridine-3-formic acid and replacement under catalyst action; then 6 deprotections form aldehyde radical under the catalysis of acid; the indole-2-ketone of aldehyde radical and aromatic ring replacement or azepine reacts under the catalysis of alkali and obtains the indole-2-ketone analog derivative, and reaction formula is:
Wherein: X, Y, Z, W and radicals R
1, R
2, R
3, R
4And identical in the definition of R and the claim 1.
4. the application in the medicine of the anti-curing oncoma of preparation of a kind of indole-2-ketone analog derivative according to claim 1 and 2 and pharmaceutically useful salt thereof.
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Cited By (4)
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| CN104876928A (en) * | 2015-05-07 | 2015-09-02 | 浙江司太立制药股份有限公司 | 7-azaindolinyl-2-one compounds and preparation method thereof |
| CN106397436A (en) * | 2016-09-06 | 2017-02-15 | 浙江司太立制药股份有限公司 | 5-bromo-7-azaindoline-2-one compounds and preparation method thereof |
| CN106432228A (en) * | 2016-09-06 | 2017-02-22 | 浙江司太立制药股份有限公司 | 4-oximido-1-piperidyl fragment containing 7-azaindolin-2-one compound and preparation method therefor |
| CN112321568A (en) * | 2020-09-22 | 2021-02-05 | 南京中医药大学 | 4-methylpyrrole substituted indolone derivative, preparation method and medical application thereof |
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| CN106397436A (en) * | 2016-09-06 | 2017-02-15 | 浙江司太立制药股份有限公司 | 5-bromo-7-azaindoline-2-one compounds and preparation method thereof |
| CN106432228A (en) * | 2016-09-06 | 2017-02-22 | 浙江司太立制药股份有限公司 | 4-oximido-1-piperidyl fragment containing 7-azaindolin-2-one compound and preparation method therefor |
| CN112321568A (en) * | 2020-09-22 | 2021-02-05 | 南京中医药大学 | 4-methylpyrrole substituted indolone derivative, preparation method and medical application thereof |
| CN112321568B (en) * | 2020-09-22 | 2023-02-17 | 南京中医药大学 | 4-methylpyrrole substituted indolone derivative, preparation method and medical application thereof |
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