CN116655518A - Isatin derivative and preparation method and application thereof - Google Patents

Isatin derivative and preparation method and application thereof Download PDF

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CN116655518A
CN116655518A CN202310598672.6A CN202310598672A CN116655518A CN 116655518 A CN116655518 A CN 116655518A CN 202310598672 A CN202310598672 A CN 202310598672A CN 116655518 A CN116655518 A CN 116655518A
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piperazine
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仲琰
高梦杰
王玉莹
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Southeast University
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Abstract

The invention discloses an isatoic derivative, and also discloses a preparation method of the isatoic derivative and application of the isatoic derivative in preparation of anti-cerebral ischemia neuroprotection drugs or drug components. The isatin derivative has good anti-cerebral ischemia neuroprotective activity, can overcome the defects of easy bleeding induction, difficult blood brain barrier permeation, poor oral bioavailability, low selectivity and high neurobehavioral toxicity of the existing active ingredients, and can be used as a cerebral nerve protecting active ingredient for treating ischemic cerebral apoplexy; animal experiments of screening cerebral nerve protection activity show that the compound can obviously prolong the survival time of acute cerebral ischemia mice after being prophylactically administered, and has good cerebral ischemia nerve protection effect.

Description

Isatin derivative and preparation method and application thereof
Technical Field
The invention relates to an isatin derivative, and also relates to a preparation method of the isatin derivative and application of the isatin derivative in preparation of anti-cerebral ischemia neuroprotection drugs or drug components.
Background
Cerebral stroke is one of the diseases with the highest mortality and disability rate nowadays, wherein nearly 80% of cerebral strokes belong to ischemic cerebral strokes. The survival of brain cells after the occurrence of a stroke depends on the extent to which neuronal cells are damaged, i.e. on the extent to which cerebral blood flow that supplies oxygen and nutrition to the cells is reduced. When ischemic cerebral apoplexy occurs, cerebral blood flow of an ischemic core part is seriously reduced, and brain tissues are irreversibly damaged after 60-90 min of ischemia; the ischemic penumbra at the periphery of the core part relatively reduces cerebral blood flow, but the cell metabolism is abnormally increased, abnormal electric activity and metabolic disturbance in the ischemic area form a chain reaction within a few hours after the ischemia occurs, which is called as an 'ischemic waterfall', and the outcome of the waterfall effect is that the ischemic core is continuously expanded and the penumbra gradually disappears, and the process is a time window for treating cerebral apoplexy.
Neuroprotective treatment of ischemic stroke was proposed abroad since the nineties of the twentieth century, and has evolved rapidly in the next decade. The goal of neuroprotection is to interfere with the pathological biochemical cascade of ischemic penumbra events, rescue the viable brain tissue, and prevent or delay cell death. At present, the neuroprotectants have various types and action mechanisms, such as voltage-dependent calcium channel blockers, glutamate receptor antagonists, antioxidants, free radical scavengers, nitric oxide synthase inhibitors and other medicaments, and become research hot spots for treating cerebral apoplexy.
Disclosure of Invention
The invention aims to: the invention aims to provide an isatoic derivative with good anti-cerebral ischemia neuroprotective activity; another object of the present invention is to provide a process for preparing the above isatin derivatives and their use in the preparation of anti-cerebral ischemia neuroprotective drugs or pharmaceutical compositions.
The technical scheme is as follows: the structural general formula of the isatin derivative is shown as follows:
wherein R is 1 Is H, halogen, hydrocarbyl, alkoxy, aralkoxy, heterocycloalkoxy, aryl, substituted heterocycle, or substituted aryl; r is R 2 Is a bridging group, in particular-O-CH 2 -CO-, -ch=ch-CO-or-O-CH 2 -CH 2 -any one of the following.
Wherein the R is 1 The aryl group in the representative aryl or aralkoxy is benzene, biphenyl or naphthalene, or F, cl, br, I, C 1～10 Alkyl, C 1～10 Alkoxy, nitro or amino substituted benzene, biphenyl or naphthalene.
Wherein the R is 1 Representative hydrocarbyl means a straight or branched alkyl group having 1 to 10 carbon atoms, or a straight or branched alkenyl group having 2 to 10 carbon atoms, or a straight or branched cycloalkyl group having 3 to 10 carbon atoms; the alkyl group in the alkoxy, aralkoxy or heterocycloalkoxy group means a straight-chain or branched alkyl group having 1 to 10 carbon atoms; the alkyl group is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, sec-butyl, pentyl, neopentyl, hexyl, heptyl, octyl, nonyl or decyl; the alkenyl is ethenyl, propenyl, allyl, butenyl, isobutenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl or decenyl; the cycloalkyl is cyclopropyl, cyclobutyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl or cyclodecyl.
Wherein the R is 1 Representative of the heterocyclic groups in the substituted heterocyclic ring or heterocyclic alkoxy group means a saturated heterocyclic ring or aromatic heterocyclic ring containing one or more hetero atoms selected from the group consisting of oxygen, nitrogen and sulfur atoms.
Wherein the R is 1 The representative halogen is F, cl, br or I.
Wherein the R is 1 The substituent of the substituted aryl is halogen.
Wherein when R is 2 is-O-CH 2 In the case of CO-, the structural general formula of the compound is shown in the formula (II):
the preparation method of the compound with the formula (II) comprises the following steps:
(1) Mixing the substituted aromatic phenol, ethyl chloroacetate, acetonitrile and potassium carbonate, heating to reflux temperature, filtering while the mixture is hot after reaction, and carrying out spin-drying on the filtrate, wherein if the filtrate is oily residual liquid, the distillation is carried out under reduced pressure; if the solid is obtained by concentration, the solid is recrystallized by absolute ethyl alcohol to obtain the corresponding substituted aryloxy ethyl acetate (V);
(2) Mixing substituted aryloxy ethyl acetate and anhydrous piperazine (diethylenediamine), introducing N 2 Heating to no less than 110deg.C, refluxing, standing, cooling, adding chloroform into the residue for dissolving, and dissolving with saturated NaHCO 3 Washing the solution, washing with water, and concentrating the organic phase to obtain white solid which is substituted aryloxyacetylpiperazine (VI);
(3) Slowly dropwise adding chlorosulfonic acid into isatin in ice water bath, stirring, heating for reaction, monitoring the reaction progress by TLC, and cooling to room temperature after the reaction is completed; slowly dripping the reaction solution into crushed ice, vigorously stirring until solid is separated out, adding ethyl acetate, stirring, dissolving, separating, washing an ethyl acetate layer with water and saturated sodium chloride solution in sequence, and drying anhydrous sodium sulfate overnight after washing; the next day, filtering, decompressing and evaporating the solvent to obtain brown sticky matter, and separating by column chromatography to obtain 3, 3-dichloro-2-oxoindoline-5-sulfonyl chloride (VII) and 2, 3-dioxoindoline-5-sulfonyl chloride (VIII);
(4) Mixing substituted aryloxy acetyl piperazine (VI) and N-ethyldiisopropylamine, adding tetrahydrofuran into the mixture under ice water bath, stirring and dissolving to obtain a reaction solution; dissolving 3, 3-dichloro-2-oxoindoline-5-sulfonyl chloride in tetrahydrofuran, and slowly dripping the solution into the reaction solution; after the dripping is finished, the temperature is raised to the room temperature and stirred overnight; the next day, filtering, evaporating the solvent under reduced pressure to obtain yellow sticky substance, using the mixed solution of ethyl acetate and petroleum ether as eluent, performing gradient elution, and performing column chromatography separation to obtain a compound shown in a general formula (II);
the synthetic route of the method is as follows:
wherein when R is 2 When the compound is-CH=CH-CO-, the structural general formula of the compound is shown as a formula (III):
the preparation method of the compound with the formula (III) comprises the following steps:
(1) Mixing substituted benzaldehyde, malonic acid and piperidine, adding pyridine into the mixture, stirring the mixture for dissolution, heating the mixture to not lower than 120 ℃ for stirring reaction, monitoring the reaction progress by TLC, removing the solvent by evaporation under reduced pressure after the reaction is finished, adding a concentrated hydrochloric acid/ice mixture, stirring the mixture vigorously, precipitating a large amount of white solid, carrying out suction filtration, and recrystallizing the crude product by absolute ethyl alcohol to obtain substituted benzene acrylic acid (IX);
(2) Mixing N-Boc-piperazine and triethylamine, adding dichloromethane into the mixture, and stirring and dissolving the mixture in ice bath to obtain a mixed solution; dissolving 3, 3-dichloro-2-oxoindoline-5-sulfonyl chloride (VII) or 2, 3-dioxoindoline-5-sulfonyl chloride (VIII) in methylene dichloride, slowly dripping the mixture into the mixed solution, heating to room temperature after dripping, monitoring the reaction progress by TLC, and obtaining 4- (3, 3-dichloro-2-oxoindoline-5-ylsulfonyl) piperazine-1-carboxylic acid tert-butyl ester (X) by column chromatography after the reaction is finished;
(3) Placing 4- (3, 3-dichloro-2-oxoindole-5-ylsulfonyl) piperazine-1-carboxylic acid tert-butyl ester (X) in a reaction bottle, mixing trifluoroacetic acid and dichloromethane to obtain a trifluoroacetic acid solution with the mass fraction of 25%, directly adding the trifluoroacetic acid solution into the reaction bottle, stirring at room temperature, monitoring the reaction progress by TLC, and evaporating the solvent under reduced pressure after the reaction is finished to obtain 3, 3-dichloro-5- (piperazine-1-ylsulfonyl) indol-2-one trifluoroacetate (XI);
(4) Placing 3, 3-dichloro-5- (piperazine-1-ylsulfonyl) indol-2-one trifluoroacetate (XI) into a reaction bottle, adding an aqueous acetic acid solution (acetic acid/water=50 mL/50 mL) into the reaction bottle, heating to not lower than 100 ℃ for reaction, monitoring the reaction progress by TLC, and evaporating the solvent under reduced pressure after the reaction is finished to obtain 5- (piperazine-1-ylsulfonyl) indoline-2, 3-dione trifluoroacetate (XII);
(5) Mixing 5- (piperazine-1-ylsulfonyl) indoline-2, 3-dione trifluoroacetate (XII), N-ethyldiisopropylamine (dipea) and tetrahydrofuran, stirring and dissolving under ice water bath condition to obtain a reaction solution; putting substituted benzene acrylic acid (IX), anhydrous dichloromethane and DMF into a reaction bottle, dropwise adding oxalyl chloride into the reaction bottle under ice bath condition, heating to room temperature after dropwise adding, stirring for reaction, and concentrating the reaction solution to obtain substituted benzene acrylic acid chloride; dissolving substituted benzene acryloyl chloride with tetrahydrofuran, slowly dripping into the reaction liquid, heating to room temperature after dripping, and stirring overnight; the next day, TLC monitors the reaction progress, after the reaction is finished, the yellow oily liquid is obtained by decompression concentration, the mixed liquid of ethyl acetate and petroleum ether is used as an eluent, gradient elution is carried out, and the compound of the general formula (III) is obtained by column chromatography separation;
the synthetic route of the method is as follows:
wherein when R is 2 In the case of-O-CH 2-CH2-, the structural general formula of the compound is shown in the formula (IV):
the preparation method of the compound with the formula (IV) comprises the following steps:
(1) Mixing substituted phenol, 1, 2-dibromoethane and water, stirring and heating to not lower than 95 ℃, dropwise adding sodium hydroxide aqueous solution into the mixture, continuously heating to 100 ℃ after the dropwise adding is finished, stirring and reacting, monitoring the reaction progress by TLC, cooling to room temperature after the reaction is finished, and extracting with dichloromethane; combining dichloromethane layers, washing sequentially by adopting a sodium hydroxide aqueous solution and a saturated sodium chloride solution, and drying by adopting anhydrous magnesium sulfate after washing; filtering, concentrating the filtrate under reduced pressure to obtain substituted phenoxyethyl bromide (XIII);
(2) Mixing substituted phenoxyethyl bromide, methanol and piperazine, heating to not lower than 70 ℃ for reaction, monitoring the reaction progress by TLC, and evaporating the solvent under reduced pressure after the reaction is finished; adding a mixed solution of dichloromethane and saturated sodium carbonate solution into the mixture for dissolution and liquid separation, sequentially washing a dichloromethane layer with saturated sodium bicarbonate solution and water, washing an organic phase with hydrochloric acid, adjusting the pH of a water layer with sodium hydroxide solution to be more than 10, separating out solids, extracting with dichloromethane, combining the organic phases, and drying with anhydrous sodium sulfate overnight; the next day, filtering, concentrating under reduced pressure to obtain substituted phenoxyethylpiperazine (XIV);
(3) Placing the substituted phenoxyethyl piperazine into a reaction bottle, adding tetrahydrofuran into the reaction bottle under ice water bath, stirring and dissolving, and then adding N-ethyldiisopropylamine into the reaction bottle, and continuously stirring to obtain a reaction solution; dissolving 3, 3-dichloro-2-oxoindoline-5-sulfonyl chloride or 2, 3-dioxoindoline-5-sulfonyl chloride with tetrahydrofuran, slowly dripping the solution into the reaction solution, heating to room temperature after dripping, stirring overnight, monitoring the reaction progress by TLC, and evaporating the solvent under reduced pressure after the reaction is finished to obtain substituted 3, 3-dichloro-5- (4- (2-phenoxyethyl) piperazin-1-ylsulfonyl) indol-2-one (XV);
(4) 3, 3-dichloro-5- (4- (2-phenoxyethyl) piperazine-1-ylsulfonyl) indol-2-one is placed in a reaction bottle, an aqueous solution of acetic acid (the mixing volume ratio of acetic acid to water is 1:1) is added, the temperature is raised to not lower than 96 ℃ for stirring reaction, TLC monitors the reaction progress, the reaction is cooled to room temperature after the reaction is finished, firstly, sodium hydroxide solution is added dropwise to adjust the pH to be 7, and then saturated sodium bicarbonate solution is added dropwise until no bubble is generated; extraction with ethyl acetate, combining the organic phases, washing with saturated sodium bicarbonate solution and drying over night with anhydrous sodium sulfate; the next day, filtering, concentrating the filtrate under reduced pressure to obtain yellow oily liquid, and performing gradient elution by taking a mixed solution of ethyl acetate and petroleum ether as an eluent, and performing column chromatography separation to obtain a compound shown in a general formula (IV);
the synthetic route of the method is as follows:
the isatin derivative is applied to the preparation of anti-cerebral ischemia neuroprotection drugs or drug components. In the application test, the free base of the compound and the hydrochloride salt form are used.
The beneficial effects are that: compared with the prior art, the invention has the following remarkable advantages: the isatin derivative has good anti-cerebral ischemia neuroprotective activity, can overcome the defects of easy bleeding induction, difficult blood brain barrier permeation, poor oral bioavailability, low selectivity and high neurobehavioral toxicity of the existing active ingredients, and can be used as a cerebral nerve protecting active ingredient for treating ischemic cerebral apoplexy; animal experiments of screening cerebral nerve protection activity show that the compound can obviously prolong the survival time of acute cerebral ischemia mice after being prophylactically administered, and has good cerebral ischemia nerve protection effect.
Detailed Description
Example 1
A preparation method of a compound {5- ((4- (2- (4-chlorophenoxy) acetyl) piperazine-1-yl) sulfonyl) indoline-2, 3-dione (ZJG-A1) } with a synthetic route is as follows:
the method specifically comprises the following steps:
(1) Placing parachlorophenol (31.2 mmol) into a 250mL eggplant-shaped bottle, adding ethyl chloroacetate (4.6 g,37.4 mmol), potassium carbonate (4.4 g,31.2 mmol) and acetonitrile 60mL, stirring, heating, refluxing for 5 hours, monitoring the reaction progress by TLC, filtering while the reaction is hot, and concentrating the filtrate under reduced pressure to obtain light yellow sticky liquid which is ethyl parachlorophenoxy acetate, wherein the crude product is directly used for the next reaction without purification;
(2) Ethyl p-chlorophenoxyacetate (16.1 mmol) and piperazine (5.5 g,64.4 mmol) were placed in a 100mL eggplant-shaped bottle, and N was passed through 2 Heating to 110 ℃ and refluxing for 4 hours, monitoring the reaction progress by TLC, cooling to room temperature after the reaction is finished, adding 40mL of dichloromethane and 30mL of saturated sodium carbonate solution for separating, washing an organic phase twice by 30mL of saturated sodium bicarbonate solution and once by 30mL of water, extracting the organic phase by 15mL of hydrochloric acid with the mass fraction of 10%, leading the pH value of a water layer to be less than 3, and reserving the water layer; dissolving with 10mL of 20% sodium hydroxide by mass fractionRegulating pH to more than 10, separating out solid, extracting with 30mL of dichloromethane for 3 times, mixing organic phases, and drying over night with anhydrous sodium sulfate; the next day, filtering, concentrating the filtrate under reduced pressure to obtain light yellow sticky liquid, namely 2- (4-chlorophenoxy) -1- (piperazin-1-yl) ethanone, wherein the crude product is directly used for the next reaction without purification;
(3) Putting isatin (8.22 g,55.9 mmol) into a 250mL eggplant-shaped bottle, carrying out ice-water bath, slowly dropwise adding chlorosulfonic acid (37 mL,559 mmol), heating to 70 ℃ after the dropwise addition, continuously stirring for 3 hours, monitoring the reaction progress by TLC, cooling to room temperature after the reaction is finished, slowly dripping the reaction solution into 250g of clean crushed ice, vigorously stirring until solid is separated out, adding 150mL of ethyl acetate, stirring, dissolving and separating liquid, washing an ethyl acetate layer twice with 100mL of water, washing a saturated sodium chloride solution once with 50mL, and drying anhydrous sodium sulfate overnight; the next day, filtering, concentrating the filtrate under reduced pressure to obtain brown sticky matter, and separating by column chromatography to obtain 2, 3-dioxoindoline-5-sulfonyl chloride, white powder, 9.8g and yield 58.3%;3, 3-dichloro-2-oxoindoline-5-sulfonyl chloride, yellow powder, 1.26g, yield 9.2%;
(4) 2- (4-chlorophenoxy) -1- (piperazin-1-yl) ethanone (1.1 g,4.0 mmol) and dipea (0.5 mL,4.0 mmol) were placed in a 100mL eggplant-shaped bottle, and were ice-water bathed and dissolved with stirring by adding 30mL tetrahydrofuran; 3, 3-dichloro-2-oxoindoline-5-sulfonyl chloride (0.8 g,3.3 mmol) was dissolved in 20mL of tetrahydrofuran, slowly dropped into a eggplant-shaped bottle, and after the dropping, the temperature was raised to room temperature and stirred overnight; TLC showed no purity, and gradient elution with ethyl acetate and petroleum ether as eluent, column chromatography gave 0.75g of yellow solid, yield 49.0%, m.p.271.5-274.6deg.C. HRMS (ESI-MS, m/z): calcd.for C 20 H 17 ClN 3 O 6 S[M-H] - 462.0527,found 462.0534. 1 H NMR(DMSO-d 6 ,300MHz)δ:2.90～2.97(m,4H,SO 2 N(CH 2 ) 2 ),3.53(s,4H,CON(CH 2 ) 2 ),4.79(s,2H,COCH 2 O),6.87～7.91(m,7H,ArH),11.52(s,1H,NH). 13 C NMR(DMSO-d 6 ,75MHz)δ:43.38,43.38,45.76,45.76,65.85,112.81,116.33,116.33,118.13,123.39,124.49,128.66,128.94,128.94,137.08,153.88,156.72,159.35,165.68,182.81。
Example 2
On the basis of example 1, R 1 Replacement of 4-chloro with 4-methoxy, with otherwise unchanged reaction conditions, gives the compound {5- ((4- (2- (4-methoxyphenoxy) acetyl) piperazin-1-yl) sulfonyl) indoline-2, 3-dione (ZJG-A2) }
Yellow solid, yield 61.3%, m.p.259.5-261.2 ℃. HRMS (ESI-MS, m/z): calcd.for C 21 H 20 N 3 O 7 S[M-H] - 458.1022,found 458.1029. 1 H NMR(DMSO-d 6 ,300MHz)δ:2.73～2.94(m,4H,SO 2 N(CH 2 ) 2 ),3.55(s,4H,CON(CH 2 ) 2 ),3.65(s,3H,OCH 3 ),4.67(s,2H,COCH 2 O),6.76～7.91(m,7H,ArH),11.49(s,1H,NH). 13 C NMR(DMSO-d 6 ,75MHz)δ:43.55,43.55,45.80,45.80,55.26,66.57,112.76,114.34,114.34,115.42,115.42,118.09,123.33,128.55,137.06,151.71,153.55,153.87,159.32,166.18,182.80。
Example 3
On the basis of example 1, R 1 4-methyl can be used to replace 4-chloro, other reaction conditions are unchanged, and the compound {5- ((4- (2- (4-methylphenoxy) acetyl) piperazin-1-yl) sulfonyl) indoline-2, 3-dione (ZJG-A3) }
Yellow solid, yield 88.2%, m.p.278.8-280.0 ℃. HRMS (ESI-MS, m/z): calcd.for C 21 H 20 N 3 O 6 S[M-H] - 442.1073,found 442.1083. 1 H NMR(DMSO-d 6 ,300MHz)δ:2.19(s,3H,PhCH 3 ),2.88～2.97(m,4H,SO 2 N(CH 2 ) 2 ),3.54(s,4H,CON(CH 2 ) 2 ),4.70(s,2H,COCH 2 O),6.72-7.93(m,7H,ArH),11.50(s,1H,NH). 13 C NMR(DMSO-d 6 ,75MHz)δ:19.90,43.50,43.50,45.63,45.79,65.91,112.76,114.31,114.31,118.07,123.35,128.63,129.52,129.52,129.52,137.03,153.84,155.64,159.29,166.06,182.77。
Example 4
On the basis of example 1, R 1 Replacement of 4-chloro with 2-methoxy, with otherwise unchanged reaction conditions, gives the compound {5- ((4- (2- (2-methoxyphenoxy) acetyl) piperazin-1-yl) sulfonyl) indoline-2, 3-dione (ZJG-A4) }
Yellow solid, yield 39.0%, m.p.278.2-279.5 ℃. HRMS (ESI-MS, m/z): calcd.for C 21 H 20 N 3 O 7 S[M-H] - 458.1022,found 458.1033. 1 H NMR(DMSO-d 6 ,300MHz)δ:2.90～2.96(m,4H,SO 2 N(CH 2 ) 2 ),3.56(s,4H,CON(CH 2 ) 2 ),3.72(s,3H,OCH 3 ),4.71(s,2H,COCH 2 O),6.78～7.92(m,7H,ArH),11.49(s,1H,NH). 13 C NMR(DMSO-d 6 ,75MHz)δ:43.71,43.71,45.69,45.84,55.49,66.88,112.32,112.80,113.84,118.14,120.41,121.44,123.31,128.63,137.03,147.19,148.95,153.88,159.32,165.98,182.79。
Example 5
On the basis of example 1, R 1 Replacement of 4-chloro with 2-methyl, with otherwise unchanged reaction conditions, gives the compound {5- ((4- (2- (2-methylphenoxy) acetyl) piperazin-1-yl) sulfonyl) indoline-2, 3-dione (ZJG-A5) }
Yellow solid, yield 77.6%, m.p.304.9-306.5 ℃. HRMS (ESI-MS, m/z): calcd.for C 21 H 20 N 3 O 6 S[M-H] - 442.1073,found 442.1079. 1 H NMR(DMSO-d 6 ,300MHz)δ:2.112(s,3H,PhCH 3 ),2.89～2.95(m,4H,SO 2 N(CH 2 ) 2 ),3.56(s,4H,CON(CH 2 ) 2 ),4.76(s,2H,COCH 2 O),6.76～7.91(m,7H,ArH),11.40(s,1H,NH). 13 C NMR(DMSO-d 6 ,75MHz)δ:15.84,43.59,43.59,45.73,45.73,66.10,111.34,112.81,118.05,120.44,123.33,125.61,126.61,128.57,130.34,137.05,153.89,155.81,159.30,166.08,182.81。
Example 6
On the basis of example 1, R 1 Replacement of 4-chloro with 4-bromo, with otherwise unchanged reaction conditions, gives the compound {5- ((4- (2- (4-bromophenoxy) acetyl) piperazin-1-yl) sulfonyl) indoline-2, 3-dione (ZJG-A6) }
Yellow solid, yield 38.9%, m.p.276.7-278.5 ℃. HRMS (ESI-MS, m/z): calcd.for C 21 H 17 N 3 O 6 SBr[M-H] - 506.0021,found 506.0026. 1 H NMR(DMSO-d 6 ,300MHz)δ:2.90～2.98(m,4H,SO 2 N(CH 2 ) 2 ),3.53(s,4H,CON(CH 2 ) 2 ),4.79(s,2H,COCH 2 O),6.82～7.93(m,7H,ArH),11.47(s,1H,NH). 13 C NMR(DMSO-d 6 ,75MHz)δ:43.36,43.36,45.60,45.66,65.77,112.16,112.79,116.84,116.84,118.07,123.35,128.72,131.80,131.80,137.04,153.87,157.15,159.28,165.61,182.79。
Example 7
On the basis of example 1, R 1 Replacing the 4-chlorophenyl group with 2-naphthyl, leaving the other reaction conditions unchanged, the compound {5- ((4- (2- (2-naphthoxy) acetyl) piperazin-1-yl) sulfonyl) indoline-2, 3-dione (ZJG-A7) }
Yellow solid, yield 48.5%, m.p.299.4-301.5 ℃. HRMS (ESI-MS, m/z)):Calcd.for C 24 H 20 N 3 O 6 S[M-H] - 478.1073,found 478.1082. 1 H NMR(DMSO-d 6 ,300MHz)δ:2.90～3.01(m,4H,SO 2 N(CH 2 ) 2 ),3.60(s,4H,CON(CH 2 ) 2 ),4.90(s,2H,COCH 2 O),7.11-7.93(m,10H,ArH),11.50(s,1H,NH). 13 C NMR(DMSO-d 6 ,75MHz)δ:43.54,43.54,45.66,45.82,65.82,107.25,112.78,118.05,118.29,123.36,123.62,126.31,126.46,127.38,128.52,128.65,129.14,133.87,137.05,153.85,155.63,159.29,165.79,182.77。
Example 8
On the basis of example 1, R 1 Replacement of 4-chloro with 3-methyl, with otherwise unchanged reaction conditions, gives the compound {5- ((4- (2- (3-methylphenoxy) acetyl) piperazin-1-yl) sulfonyl) indoline-2, 3-dione (ZJG-A8) }
Yellow solid, yield 46.1%, m.p.273.0-275.1 ℃. HRMS (ESI-MS, m/z): calcd.for C 21 H 20 N 3 O 6 S[M-H] - 442.1073,found 442.1081. 1 H NMR(DMSO-d 6 ,300MHz)δ:2.22(s,3H,PhCH 3 ),2.90～2.96(m,4H,SO 2 N(CH 2 ) 2 ),3.55(s,4H,CON(CH 2 ) 2 ),4.72(s,2H,COCH 2 O),6.63-7.92(m,7H,ArH),11.50(s,1H,NH). 13 C NMR(DMSO-d 6 ,75MHz)δ:21.01,43.55,43.55,45.72,45.88,65.74,111.53,112.83,115.13,118.15,121.60,123.40,128.62,129.02,137.09,138.79,153.90,157.82,159.37,166.05,182.82。
Example 9
On the basis of example 1, R 1 Replacement of 4-chloro with 4-tert-amyl, leaving the other reaction conditions unchanged, gives the compound {5- ((4- (2- (4-tert-pentylphenoxy) acetyl) piperazin-1-yl) sulfonyl) indoline-2, 3-dione (ZJG-A9) }
Yellow solid, yield 53.4%, m.p.135.7-137.6 ℃. HRMS (ESI-MS, m/z): calcd.for C 25 H 28 N 3 O 6 S[M-H] - 498.1699,found 498.1675. 1 H NMR(DMSO-d 6 ,300MHz)δ:0.56(t,3H,J＝7.5Hz,C(CH 3 ) 2 CH 2 CH 3 ),1.18(s,6H,C(CH 3 ) 2 CH 2 CH 3 ),1.51(q,2H,J＝7.5Hz,C(CH 3 ) 2 CH 2 CH 3 ),2.90～2.99(m,4H,SO 2 N(CH 2 ) 2 ),3.55(s,4H,CON(CH 2 ) 2 ),4.72(s,2H,COCH 2 O),6.76～7.94(m,7H,ArH),11.50(s,1H,NH). 13 CNMR(DMSO-d 6 ,75MHz)δ:8.89,28.28,28.28,36.08,36.78,43.53,43.53,45.76,45.76,65.84,112.77,113.96,113.96,118.09,123.35,126.43,126.43,128.77,137.04,141.26,153.85,155.43,159.28,166.08,182.77。
Example 10
On the basis of example 1, R 1 Replacement of 4-chloro with 2-chloro, with otherwise unchanged reaction conditions, gives the compound {5- ((4- (2- (2-chlorophenoxy) acetyl) piperazin-1-yl) sulfonyl) indoline-2, 3-dione (ZJG-A10) }
Yellow solid, yield 64.7%, m.p.299.9-302.7 ℃. HRMS (ESI-MS, m/z): calcd.for C 20 H 17 N 3 O 6 SCl[M-H] - 462.0527,found 462.0537. 1 H NMR(DMSO-d 6 ,300MHz)δ:2.91～2.99(m,4H,SO 2 N(CH 2 ) 2 ),3.55(s,4H,CON(CH 2 ) 2 ),4.89(s,2H,COCH 2 O),6.88-7.92(m,7H,ArH),11.50(s,1H,NH). 13 C NMR(DMSO-d 6 ,75MHz)δ:43.52,43.52,45.67,45.81,66.30,112.80,113.85,118.08,121.01,121.62,123.37,127.90,128.61,129.79,137.06,153.15,153.88,159.30,165.37,182.78。
Example 11
On the basis of example 1, R 1 Replacing the 4-chlorophenyl group with 1-naphthyl, leaving the other reaction conditions unchanged, the compound {5- ((4- (2- (1-naphthoxy) acetyl) piperazin-1-yl) sulfonyl) indoline-2, 3-dione (ZJG-A11) }
Yellow solid, yield 66.0%, m.p.296.0-298.4 ℃. HRMS (ESI-MS, m/z): calcd.for C 24 H 20 N 3 O 6 S[M-H] - 478.1073,found 478.1081. 1 H NMR(DMSO-d 6 ,300MHz)δ:2.96(s,4H,SO 2 N(CH 2 ) 2 ),3.61(s,4H,CON(CH 2 ) 2 ),4.97(s,2H,COCH 2 O),6.85-8.14(m,10H,ArH),11.50(s,1H,NH). 13 C NMR(DMSO-d 6 ,75MHz)δ:43.56,43.56,45.79,45.79,66.16,105.51,112.75,118.04,120.22,121.37,123.30,124.69,125.22,125.80,126.32,127.29,128.59,133.88,136.95,153.14,153.81,159.30,165.78,182.76。
Example 12
On the basis of example 1, R 1 Replacement of 4-chloro with 4-tert-butyl, with otherwise unchanged reaction conditions, gives the compound {5- ((4- (2- (4-tert-butylphenoxy) acetyl) piperazin-1-yl) sulfonyl) indoline-2, 3-dione (ZJG-A12) }
Yellow solid, yield 72.1%, m.p.229.4-230.8 ℃. HRMS (ESI-MS, m/z): calcd.for C 24 H 26 N 3 O 6 S[M-H] - 484.1542,found 484.1556. 1 H NMR(DMSO-d 6 ,300MHz)δ:1.223(s,9H,C(CH 3 ) 3 ),2.91～2.99(m,4H,SO 2 N(CH 2 ) 2 ),3.55(s,4H,CON(CH 2 ) 2 ),4.72(s,2H,COCH 2 O),6.76～7.94(m,7H,ArH),11.50(s,1H,NH). 13 C NMR(DMSO-d 6 ,75MHz)δ:31.20,31.20,31.20,33.63,43.49,43.49,45.61,45.80,65.80,112.76,113.97,113.97,118.10,123.35,125.79,125.79,128.69,137.04,143.03,153.84,155.50,159.29,166.07,182.76。
Example 13
A process for the preparation of compounds of the general formula (III) { (E) -5- ((4- (3- (benzo [ d ] [1,3] dioxol-5-yl) acryloyl) piperazin-1-yl) sulfonyl) indoline-2, 3-dione (ZJG-B1) } by the synthetic route:
the method specifically comprises the following steps:
(1) Piperonal (41.6 mmol), malonic acid 6.4g (62.4 mmol) and piperidine 1mL (10.4 mmol) are placed in a 250mL eggplant-shaped bottle, pyridine 40mL is added for dissolution and stirring, stirring is carried out for 5 hours at the temperature of 120 ℃, TLC monitors the reaction progress, after the reaction is finished, the solvent is distilled off under reduced pressure, 26mL/52g of concentrated hydrochloric acid/ice mixture (26 mL of concentrated hydrochloric acid is mixed with 52g of ice) is added, a large amount of white solid is stirred vigorously, a large amount of white solid is separated out, suction filtration is carried out, and the crude product is recrystallized by absolute ethyl alcohol, so that white powdery crystal (E) -3- (benzo [ d ] [1,3] dioxol-5-yl) acrylic acid is obtained, and the yield is 87.8%;
(2) 9.3g (49.9 mmol) of N-Boc-piperazine and triethylamine (7 mL,49.9 mmol) were placed in a 250mL eggplant-shaped bottle, 50mL of methylene chloride was added thereto, and the mixture was dissolved in an ice bath with stirring. In addition, 30mL of methylene chloride was dissolved in 3, 3-dichloro-2-oxoindoline-5-sulfonyl chloride or 2, 3-dioxoindoline-5-sulfonyl chloride (41.6 mmol), and the mixture was slowly dropped into a eggplant-shaped bottle. After the dripping is finished, the temperature is raised to room temperature, the stirring is carried out for 5 hours, TLC monitors the reaction progress, after the reaction is finished, decompression concentration is carried out, light yellow oily matter is obtained, and the 4- (3, 3-dichloro-2-oxo-indol-5-ylsulfonyl) piperazine-1-carboxylic acid tert-butyl ester is obtained through column chromatography, white powder is obtained, and the yield is 91.8%;
(3) Tert-butyl 4- (3, 3-dichloro-2-oxoindol-5-ylsulfonyl) piperazine-1-carboxylate (27.15 g,33.3 mmol) is placed in a 250mL eggplant-shaped bottle, 25mL of trifluoroacetic acid and 100mL of dichloromethane are mixed into a trifluoroacetic acid solution with the mass fraction of 25%, the trifluoroacetic acid solution is directly added into the eggplant-shaped bottle, the stirring is carried out at room temperature for 2 hours, TLC monitors the reaction progress, and after the reaction is finished, the solvent is removed by evaporation under reduced pressure, so that white solid 3, 3-dichloro-5- (piperazine-1-ylsulfonyl) indol-2-one trifluoroacetate is obtained, and the crude product is directly used for the next reaction without purification;
(4) 10g of 3, 3-dichloro-5- (piperazine-1-ylsulfonyl) indol-2-one trifluoroacetate is placed in a 250mL eggplant-shaped bottle, 100mL of acetic acid aqueous solution (acetic acid/water=50 mL/50 mL) is added, the temperature is raised to 100 ℃ and stirred for 24 hours, TLC monitors the reaction progress, and after the reaction is finished, the solvent is distilled off under reduced pressure, so that yellow solid 5- (piperazine-1-ylsulfonyl) indoline-2, 3-dione trifluoroacetate is obtained, and the crude product is directly used for the next reaction without purification;
(5) (E) -3- (benzo [ d ] [1,3] dioxol-5-yl) acrylic acid (0.58 g,3 mmol), anhydrous dichloromethane (25 mL) were placed in a 250mL eggplant-shaped bottle, stirred, and N, N-dimethylformamide 2 drops were added dropwise; oxalyl chloride (0.6 mL,6 mmol) and dried dichloromethane (2 mL) are mixed, slowly dripped into an eggplant-shaped bottle, stirred at room temperature for 2 hours after the dripping is finished, TLC monitors the reaction progress, and after the reaction is finished, dichloromethane is distilled off under low temperature and reduced pressure to obtain yellow oily liquid (E) -3- (benzo [ d ] [1,3] dioxol-5-yl) acryloyl chloride, and the crude product is directly used for the next reaction without purification;
(6) 5- (piperazine-1-ylsulfonyl) indoline-2, 3-dione (1.67 g,3.6 mmol), dipea (1.3 mL,7.5 mmol) and tetrahydrofuran (20 mL) were placed in a 100mL eggplant-shaped bottle, and stirred and dissolved under ice water bath conditions; dissolving (E) -3- (benzo [ d) with 10mL of tetrahydrofuran][1,3]Dioxol-5-yl) acryloyl chloride, slowly dripping into eggplant-shaped bottle; after the dripping is finished, the temperature is raised to the room temperature, and the mixture is stirred overnight; TLC showed no purity, and gradient elution with ethyl acetate and petroleum ether as eluent gave 0.54g of yellow solid as a yield of 38.3%, m.p.202.3-204.7 ℃. HRMS (ESI-MS, m/z): calcd.for C 22 H 18 N 3 O 7 S[M-H] - 468.0865,found 468.0873. 1 H NMR(CDCl 3 ,300MHz)δ:3.71(s,8H,SO 2 N(CH 2 ) 4 NCO),6.00(s,2H,OCH 2 O),6.63(d,1H,J＝15.3Hz,COCH＝),6.79～8.07(m,6H,ArH),7.59(d,1H,J＝15.3Hz,PhCH＝),11.05(s,1H,NH). 13 C NMR(CDCl 3 ,75MHz)δ:42.15,44.81,45.24,101.46,106.36,108.52,114.11,120.34,123.97,125.54,126.82,129.33,132.24,141.28,143.57,148.28,149.26,165.39,165.78,184.65。
Example 14
On the basis of example 13, R 1 Replacing 5-piperonyl with 4-chlorophenyl, the other reaction conditions are unchanged, resulting in the compound { (E) -5- ((4- (3- (4-chlorophenyl) acryloyl) piperazin-1-yl) sulfonyl) indoline-2, 3-dione (ZJG-B2)
Yellow solid, yield 29.0%, m.p.322.7-324.6 ℃. HRMS (ESI-MS, m/z): calcd.for C 21 H 17 N 3 O 5 SCl[M-H] - 458.0577,found 458.0588. 1 H NMR(CDCl 3 ,300MHz)δ:2.94(s,4H,SO 2 N(CH 2 ) 2 ),3.67(bs,4H,CON(CH 2 ) 2 ),7.09～7.72(m,7H,ArH),7.19(d,1H,J＝15.3Hz,COCH＝),7.40(d,1H,J＝15.3Hz,PhCH＝),11.45(s,1H,NH). 13 C NMR(CDCl 3 ,75MHz)δ:44.72,46.34,46.84,113.25,118.71,119.08,123.83,128.98,129.15,129.15,130.15,130.15,134.37,134.51,137.46,141.00,154.36,159.84,164.69,183.26。
Example 15
On the basis of example 13, R 1 Replacing 5-piperonyl with 4-methylphenyl, the other reaction conditions being unchanged, the compound { (E) -5- ((4- (3- (4-methylphenyl) acryloyl) piperazin-1-yl) sulfonyl) indoline-2, 3-dione (ZJG-B3) } was obtained
Yellow solid, yield 45.5%, m.p.308.8-310.5 ℃. HRMS (ESI-MS, m/z): calcd.for C 22 H 20 N 3 O 5 S[M-H] - 438.1124,found 438.1130. 1 H NMR(CDCl 3 ,300MHz)δ:2.31(s,3H,PhCH 3 ),2.93(s,4H,SO 2 N(CH 2 ) 2 ),3.66(bs,4H,CON(CH 2 ) 2 ),7.08～7.92(m,7H,ArH),7.15(d,1H,J＝15.3Hz,COCH＝),7.37(d,1H,J＝15.3Hz,PhCH＝),11.46(s,1H,NH). 13 C NMR(CDCl 3 ,75MHz)δ:20.85,44.13,44.33,45.89,46.34,112.75,116.49,118.24,123.29,127.93,127.93,128.33,129.24,129.24,132.14,136.94,139.36,141.97,154.03,159.44,164.48,182.85。
Example 16
On the basis of example 13, R 1 Replacing 5-piperonyl with 4-methoxyphenyl, the other reaction conditions are unchanged, yielding the compound { (E) -5- ((4- (3- (4-methoxyphenyl) propenoyl) piperazin-1-yl) sulfonyl) indoline-2, 3-dione (ZJG-B4) }
Yellow solid, yield 32.2%, m.p.312.1-314.8 ℃. HRMS (ESI-MS, m/z): calcd.for C 22 H 20 N 3 O 6 S[M-H] - 454.1073,found 454.1079. 1 H NMR(CDCl 3 ,300MHz)δ:2.94(s,4H,SO 2 N(CH 2 ) 2 ),3.78(s,3H,PhOCH 3 ),3.78(bs,4H,CON(CH 2 ) 2 ),6.93～7.93(m,7H,ArH),7.01(d,1H,J＝15.3Hz,COCH＝),7.38(d,1H,J＝15.3Hz,PhCH＝),11.45(s,1H,NH). 13 C NMR(CDCl 3 ,75MHz)δ:44.19,46.28,55.18,112.72,114.09,114.93,118.22,123.30,127.50,128.40,129.61,136.94,141.81,153.84,159.34,160.43,164.63,182.73。
Example 17
On the basis of example 13, R 1 Replacing 5-piperonyl with 2-methoxyphenyl, the other reaction conditions are unchanged, yielding the compound { (E) -5- ((4- (3- (2-methoxyphenyl) propenoyl) piperazin-1-yl) sulfonyl) indoline-2, 3-dione (ZJG-B5) }
Yellow solid, yield 30.8%, m.p.267.8-269.9 ℃. HRMS (ESI-MS, m/z): calcd.for C 22 H 20 N 3 O 6 S[M-H] - 454.1073,found 454.1081. 1 H NMR(CDCl 3 ,300MHz)δ:2.93(s,4H,SO 2 N(CH 2 ) 2 ),3.66(bs,4H,CON(CH 2 ) 2 ),3.82(s,3H,PhOCH 3 ),6.93(d,1H,J＝15.3Hz,COCH＝),7.03～7.93(m,7H,ArH),7.33(d,1H,J＝15.3Hz,PhCH＝),11.47(s,1H,NH). 13 C NMR(CDCl 3 ,75MHz)δ:44.23,45.84,46.42,55.53,111.56,112.75,117.40,118.27,120.45,123.21,123.34,127.79,128.37,131.13,136.56,136.98,153.87,157.36,159.39,164.67,182.77。
Example 18
On the basis of example 13, R 1 Replacing 5-piperonyl with 4-fluorophenyl, other reaction conditions are unchanged, resulting in the compound { (E) -5- ((4- (3- (4-fluorophenyl) acryloyl) piperazin-1-yl) sulfonyl) indoline-2, 3-dione (ZJG-B6) }
Yellow solid, yield 64.8%, m.p.289.8-299.1 ℃. HRMS (ESI-MS, m/z): calcd.for C 21 H 17 N 3 O 5 FS[M-H] - 442.0873,found 442.0883. 1 H NMR(CDCl 3 ,300MHz)δ:2.93(s,4H,SO 2 N(CH 2 ) 2 ),3.66(bs,4H,CON(CH 2 ) 2 ),7.03～7.93(m,7H,ArH),7.13(d,1H,J＝15.6Hz,COCH＝),7.41(d,1H,J＝15.6Hz,PhCH＝),11.47(s,1H,NH). 13 C NMR(CDCl 3 ,75MHz)δ:44.23,45.84,46.42,55.53,111.56,112.75,117.40,118.27,120.45,123.21,123.34,127.79,128.37,131.13,136.56,136.98,153.87,157.36,159.39,164.67,182.77。
Example 19
On the basis of example 13, R 1 Replacement of 5-piperonyl with 2-chlorophenyl with other reaction conditions unchanged gave the compound { (E) -5- ((4- (3- (2-chlorophenyl) acryloyl)Yl) piperazin-1-yl) sulfonyl) indoline-2, 3-dione (ZJG-B7) }
Yellow solid, yield 51.4%, m.p.297.2-299.2 ℃. HRMS (ESI-MS, m/z): calcd.for C 21 H 17 N 3 O 5 SCl[M-H] - 458.0577,found 458.0588. 1 H NMR(CDCl 3 ,300MHz)δ:2.95(s,4H,SO 2 N(CH 2 ) 2 ),3.68(bs,4H,CON(CH 2 ) 2 ),7.10～7.98(m,7H,ArH),7.23(d,1H,J＝15.3Hz,COCH＝),7.73(d,1H,J＝15.3Hz,PhCH＝),11.47(s,1H,NH). 13 C NMR(CDCl 3 ,75MHz)δ:44.24,45.77,46.32,112.74,118.22,120.81,123.31,127.40,128.11,128.47,129.73,131.01,132.56,133.29,136.82,136.97,153.85,159.34,163.89,182.75。
Example 20
On the basis of example 13, R 1 Replacing 5-piperonyl with 3-chlorophenyl, the other reaction conditions are unchanged, resulting in the compound { (E) -5- ((4- (3- (3-chlorophenyl) acryloyl) piperazin-1-yl) sulfonyl) indoline-2, 3-dione (ZJG-B8) }
Yellow solid, yield 58.1%, m.p.302.7-304.6 ℃. HRMS (ESI-MS, m/z): calcd.for C 21 H 17 N 3 O 5 SCl[M-H] - 458.0577,found 458.0568. 1 H NMR(CDCl 3 ,300MHz)δ:2.94(s,4H,SO 2 N(CH 2 ) 2 ),3.67(bs,4H,CON(CH 2 ) 2 ),7.10～7.94(m,7H,ArH),7.26(d,1H,J＝15.3Hz,COCH＝),7.39(d,1H,J＝15.3Hz,PhCH＝),11.47(s,1H,NH). 13 C NMR(CDCl 3 ,75MHz)δ:44.21,45.77,46.33,112.73,118.19,119.48,123.29,127.00,128.49,129.11,130.40,133.55,136.93,137.15,140.24,153.84,159.30,164.06,182.73。
Example 21
On the basis of example 13, R 1 Replacing 5-piperonyl with 2, 4-dichlorophenyl, other reaction conditions remain, resulting in the compound { (E) -5- ((4- (3- (2, 4-dichlorophenyl) acryloyl) piperazin-1-yl) sulfonyl) indoline-2, 3-dione (ZJG-B9) }
Yellow solid, yield 40.5%, m.p.340.5-342.9 ℃. HRMS (ESI-MS, m/z): calcd.for C 21 H 16 N 3 O 5 SCl 2 [M-H] - 492.0188,found 492.0196. 1 H NMR(CDCl 3 ,300MHz)δ:2.95(s,4H,SO 2 N(CH 2 ) 2 ),3.67(bs,4H,CON(CH 2 ) 2 ),7.09～8.02(m,6H,ArH),7.27(d,1H,J＝15.3Hz,COCH＝),7.73(d,1H,J＝15.3Hz,PhCH＝),11.47(s,1H,NH). 13 C NMR(CDCl 3 ,75MHz)δ:44.25,45.70,46.28,112.77,118.17,121.47,123.32,127.63,128.54,129.16,129.34,131.64,134.06,134.59,135.61,136.97,153.88,159.30,163.72,182.77。
Example 22
On the basis of example 13, R 1 Replacing 5-piperonyl with 3-bromophenyl, the other reaction conditions being unchanged, the compound { (E) -5- ((4- (3- (3-bromophenyl) acryloyl) piperazin-1-yl) sulfonyl) indoline-2, 3-dione (ZJG-B10) } was obtained
Yellow solid, yield 46.5%, m.p.299.9-302.8 ℃. HRMS (ESI-MS, m/z): calcd.for C 21 H 17 N 3 O 5 SBr[M-H] - 502.0072,found 502.0065. 1 H NMR(CDCl 3 ,300MHz)δ:2.94(s,4H,SO 2 N(CH 2 ) 2 ),3.66(bs,4H,CON(CH 2 ) 2 ),7.09～8.00(m,7H,ArH),7.25(d,1H,J＝15.3Hz,COCH＝),7.37(d,1H,J＝15.3Hz,PhCH＝),11.46(s,1H,NH). 13 C NMR(CDCl 3 ,75MHz)δ:44.21,45.83,46.40,112.76,118.26,119.45,122.19,123.23,127.49,128.40,129.87,130.72,132.08,136.97,137.44,140.26,153.87,159.37,164.07,182.76。
Example 23
On the basis of example 13, R 1 Replacing 5-piperonyl with 2-furyl, the other reaction conditions being unchanged, to give the compound { (E) -5- ((4- (3- (furan-2-yl) acryloyl) piperazin-1-yl) sulfonyl) indoline-2, 3-dione (ZJG-B11) }
Yellow solid, yield 48.1%, m.p.278.4-279.6 ℃. HRMS (ESI-MS, m/z): calcd.for C 19 H 16 N 3 O 6 S[M-H] - 414.0760,found 414.0768. 1 H NMR(CDCl 3 ,300MHz)δ:2.93(s,4H,SO 2 N(CH 2 ) 2 ),3.68(bs,4H,CON(CH 2 ) 2 ),6.57～7.92(m,6H,ArH&funan),6.81(d,1H,J＝15.0Hz,COCH＝),7.25(d,1H,J＝15.0Hz,PhCH＝),11.45(s,1H,NH). 13 C NMR(CDCl 3 ,75MHz)δ:44.23,46.03,112.40,112.73,114.06,114.47,118.19,123.30,128.49,129.14,136.93,144.83,150.97,153.83,159.33,164.01,182.74。
Example 24
On the basis of example 13, R 1 Replacing 5-piperonyl with 3, 4-dimethoxyphenyl, other reaction conditions are unchanged, resulting in the compound { (E) -5- ((4- (3, 4-dimethoxyphenyl) acryloyl) piperazin-1-yl) sulfonyl) indoline-2, 3-dione (ZJG-B12) }
Yellow solid, yield 57.6%, m.p.285.2-286.8 ℃. HRMS (ESI-MS, m/z): calcd.for C 23 H 22 N 3 O 7 S[M-H] - 484.1178,found 484.1186. 1 H NMR(CDCl 3 ,300MHz)δ:2.94(s,4H,SO 2 N(CH 2 ) 2 ),3.70(bs,4H,CON(CH 2 ) 2 ),3.78(bs,6H,Ph(OCH 3 ) 2 ),6.93～7.93(m,7H,ArH),7.02(d,1H,J＝15.0Hz,COCH＝),7.37(d,1H,J＝15.0Hz,PhCH＝),11.46(s,1H,NH). 13 C NMR(CDCl 3 ,75MHz)δ:44.14,45.97,46.24,55.48,55.65,110.39,111.47,112.74,114.90,118.24,122.38,123.34,127.72,128.39,136.97,142.39,148.86,150.35,153.87,159.36,164.68,182.76。
Example 25
A preparation method of a compound {5- ((4- (2- (2-methylphenoxy) ethyl) piperazine-1-yl) sulfonyl) indoline-2, 3-dione (ZJG-C1) } shown in the general formula (IV) comprises the following synthetic route:
the method specifically comprises the following steps:
(1) O-methylphenol (40.3 mmol), 11.3g (60.4 mmol) of 1, 2-dibromoethane and 25mL of water are placed in a 250mL eggplant-shaped bottle, stirred and heated to 95 ℃, 7.2mL of sodium hydroxide solution with the mass fraction of 25% is dropwise added, the mixture is continuously heated to 100 ℃ after the dropwise addition, the mixture is stirred for 12 hours, TLC monitors the reaction progress, after the reaction is completed, the mixture is cooled to room temperature, and 30mL of dichloromethane is used for extraction for 3 times; taking a dichloromethane layer, washing twice with 15mL of sodium hydroxide solution with the mass fraction of 5%, washing once with 15mL of saturated sodium chloride solution, drying for 5 hours with anhydrous magnesium sulfate, filtering, and evaporating the solvent under reduced pressure to obtain colorless liquid which is 1- (2-bromooxy) -2-methylbenzene, wherein the crude product is directly used for the next reaction without purification;
(2) 1- (2-Bromoxy) -2-methylbenzene (25.3 mmol), methanol 50mL and piperazine 8.7g (101.1 mmol) were placed in a 100mL eggplant-shaped bottle, the temperature was raised to 70℃and stirred for 3 hours, TLC monitored the progress of the reaction, and after the completion of the reaction, the solvent was distilled off under reduced pressure. Adding 60mL of dichloromethane and 30mL of saturated sodium carbonate solution for dissolution and liquid separation; the dichloromethane layer is washed twice with 30mL of saturated sodium bicarbonate solution and once with 30mL of water, the organic phase is extracted with 15mL of 10% hydrochloric acid with mass fraction, the pH of the water layer is less than 3, and the water layer is reserved; adjusting pH to be more than 10 with 10mL of sodium hydroxide solution with mass fraction of 20%, precipitating solid, extracting with 30mL of dichloromethane for 3 times, mixing organic phases, and drying over night with anhydrous sodium sulfate; the next day, filtering, concentrating under reduced pressure to obtain colorless viscous liquid, namely 1- (2- (2-methylphenoxy) ethyl) piperazine, wherein the crude product is directly used for the next reaction without purification;
(3) 1- (2- (2-methylphenoxy) ethyl) piperazine (1.94 g,8.8 mmol) was placed in a 100mL eggplant-shaped bottle, ice-water bath, 30mL of tetrahydrofuran was added and stirred for dissolution, dipea (3.4 mL,11 mmol) was added and stirring continued for 5min; dissolving 3, 3-dichloro-2-oxoindole-5-sulfonyl chloride (2.2 g,7.3 mmol) in 10mL of tetrahydrofuran, slowly dripping the 3, 3-dichloro-2-oxoindole-5-sulfonyl chloride into an eggplant-shaped bottle, heating to room temperature after dripping, stirring overnight, monitoring the reaction progress by TLC, and evaporating the solvent under reduced pressure after the reaction is finished to obtain 3, 3-dichloro-5- (4- (2- (2-methylphenoxy) ethyl) piperazin-1-yl) sulfonyl) indol-2-one which is directly used for the next reaction without purification;
(4) Placing the 3, 3-dichloro-5- (4- (2- (2-methylphenoxy) ethyl) piperazin-1-yl) sulfonyl) indol-2-one in a 100mL eggplant-shaped bottle, adding 40mL (V water: V acetic acid=1:1) of a mixed solution of water and acetic acid, heating to 96 ℃ and stirring for 30 hours, TLC monitoring the reaction progress, cooling to room temperature after the reaction is finished, dropwise adding 10% sodium hydroxide solution to pH=7, and dropwise adding saturated sodium bicarbonate solution until no bubbles are generated; extracting with ethyl acetate twice (40 mL×2), mixing organic phases, evaporating solvent under reduced pressure to obtain brown viscous liquid, performing TLC to show impurity, gradient eluting with mixed solution of ethyl acetate and petroleum ether as eluent, and performing column chromatography to obtain yellow solid 1.62g with yield of 42.9%, m.p.208.5-210.4deg.C. HRMS (ESI-MS, m/z): calcd.for C 21 H 22 N 3 O 5 S[M-H] - 428.1280,found 428.1273. 1 H NMR(DMSO-d 6 ,300MHz)δ:2.10(s,3H,PhCH 3 ),2.60(bs,4H,SO 2 N(CH 2 ) 2 ),2.71(t,2H,J＝5.4Hz,NCH 2 -),2.91(bs,4H,CN(CH 2 ) 2 ),3.80(t,2H,J＝5.4Hz,OCH 2 -),6.78～7.92(m,7H,ArH),11.46(s,1H,NH). 13 C NMR(DMSO-d 6 ,75MHz)δ:15.91,45.90,51.85,55.98,65.87,111.21,112.66,118.12,120.14,123.31,125.61,126.81,128.60,130.27,136.98,153.75,156.39,159.37,182.82。
Example 26
On the basis of example 25, R in o-methylphenol 1 2-methyl is replaced by 3-methyl, other reaction conditions are unchanged, and the compound {5- ((4- (2- (3-methylphenoxy) ethyl) piperazin-1-yl) sulfonyl) indoline-2, 3-dione (ZJG-C2) } is obtained
Yellow solid, yield 58.2%, m.p.208.1-210.0 ℃. HRMS (ESI-MS, m/z): calcd.for C 21 H 22 N 3 O 5 S[M-H] - 428.1280,found 428.1272. 1 H NMR(DMSO-d 6 ,300MHz)δ:2.24(s,3H,PhCH 3 ),2.56(bs,4H,SO 2 N(CH 2 ) 2 ),2.66(t,2H,J＝5.4Hz,NCH 2 -),2.90(bs,4H,CN(CH 2 ) 2 ),3.95(t,2H,J＝5.4Hz,OCH 2 -),6.65～7.92(m,7H,ArH),11.46(s,1H,NH). 13 C NMR(DMSO-d 6 ,75MHz)δ:20.97,45.87,51.74,55.89,65.19,111.34,112.64,115.04,118.12,121.19,123.30,128.49,129.06,136.98,138.81,153.76,158.29,159.36,182.80。
Example 27
On the basis of example 25, R in o-methylphenol 1 2-methyl was replaced with 4-chloro, and the other reaction conditions were unchanged, to give the compound {5- ((4- (2- (4-chlorophenoxy) ethyl) piperazin-1-yl) sulfonyl) indoline-2, 3-dione (ZJG-C3) }
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Yellow solid, yield 47.5%, m.p.198.9-200.6 ℃. HRMS (ESI-MS, m/z): calcd.for C 20 H 19 N 3 O 5 SCl[M-H] - 448.0734,found 448.0742. 1 H NMR(DMSO-d 6 ,300MHz)δ:2.56(bs,4H,SO 2 N(CH 2 ) 2 ),2.66(t,2H,J＝5.4Hz,NCH 2 -),2.90(bs,4H,CN(CH 2 ) 2 ),3.98(t,2H,J＝5.4Hz,OCH 2 -),6.89～7.92(m,7H,ArH),11.45(s,1H,NH). 13 CNMR(DMSO-d 6 ,75MHz)δ:45.82,51.70,55.73,65.73,112.64,116.15,118.08,123.29,124.14,128.55,129.05,136.96,153.75,157.14,159.34,182.79。
Example 28
On the basis of example 25, R in o-methylphenol 1 2-methyl is replaced by 4-methoxy, other reaction conditions are unchanged, and the compound {5- ((4- (2- (4-methoxyphenoxy) ethyl) piperazin-1-yl) sulfonyl) indoline-2, 3-dione (ZJG-C4) } is obtained
Yellow solid, yield 48.0%, m.p.202.1-203.6 ℃. HRMS (ESI-MS, m/z): calcd.for C 21 H 22 N 3 O 6 S[M-H] - 444.1229,found 444.1236. 1 H NMR(DMSO-d 6 ,300MHz)δ:2.56(bs,4H,SO 2 N(CH 2 ) 2 ),2.64(t,2H,J＝5.4Hz,NCH 2 -),2.90(bs,4H,CN(CH 2 ) 2 ),3.67(s,3H,PhOCH 3 ),3.91(t,2H,J＝5.4Hz,OCH 2 -),6.81～7.92(m,7H,ArH),11.45(s,1H,NH). 13 C NMR(DMSO-d 6 ,75MHz)δ:45.85,51.75,55.26,55.95,65.89,112.63,114.48,115.31,118.11,123.29,128.49,136.97,152.30,153.29,153.75,159.36,182.79。
Example 29
On the basis of example 25, R in o-methylphenol 1 2-methyl is replaced by 4-methyl, other reaction conditions are unchanged, and the compound {5- ((4- (2- (4-methylphenoxy) ethyl) piperazin-1-yl) sulfonyl) indoline-2, 3-dione (ZJG-C5) } is obtained
Yellow solid, yield 61.4%, m.p.212.6-213.6 ℃. HRMS (ESI-MS, m/z): calcd.for C 21 H 22 N 3 O 5 S[M-H] - 428.1280,found 428.1276. 1 H NMR(DMSO-d 6 ,300MHz)δ:2.20(s,3H,PhCH 3 ),2.56(bs,4H,SO 2 N(CH 2 ) 2 ),2.65(t,2H,J＝5.4Hz,NCH 2 -),2.90(bs,4H,CN(CH 2 ) 2 ),3.93(t,2H,J＝5.4Hz,OCH 2 -),6.75～7.92(m,7H,ArH),11.45(s,1H,NH). 13 C NMR(DMSO-d 6 ,75MHz)δ:19.95,45.85,51.76,55.90,65.35,112.65,114.23,118.12,123.31,128.53,129.09,129.67,136.98,153.76,156.17,159.36,182.81。
Example 30
On the basis of example 25, R in o-methylphenol 1 2-methyl was replaced with 4-bromo, and the other reaction conditions were unchanged, to give the compound {5- ((4- (2- (4-bromophenoxy) ethyl) piperazin-1-yl) sulfonyl) indoline-2, 3-dione (ZJG-C6) }
Yellow solid, yield 50.6%, m.p.207.5-208.7 ℃. HRMS (ESI-MS, m/z): calcd.for C 20 H 19 N 3 O 5 SBr[M-H] - 492.0229,found 492.0236. 1 H NMR(DMSO-d 6 ,300MHz)δ:2.56(bs,4H,SO 2 N(CH 2 ) 2 ),2.67(t,2H,J＝5.4Hz,NCH 2 -),2.90(bs,4H,CN(CH 2 ) 2 ),3.98(t,2H,J＝5.4Hz,OCH 2 -),6.85～7.92(m,7H,ArH),11.47(s,1H,NH). 13 CNMR(DMSO-d 6 ,75MHz)δ:45.82,51.70,55.71,65.66,111.83,112.65,116.70,118.09,123.30,128.52,131.96,136.97,153.75,157.59,159.34,182.80。
Example 31
On the basis of example 25, R in o-methylphenol 1 2-methyl was replaced with 2-chloro, and the other reaction conditions were unchanged, to give the compound {5- ((4- (2- (2-chlorophenoxy) ethyl) piperazin-1-yl) sulfonyl) indoline-2, 3-dione (ZJG-C7) }
Yellow solid, yield 47.7%, m.p.222.2-223.9 ℃. HRMS (ESI-MS, m/z): calcd.for C 20 H 19 N 3 O 5 SCl[M-H] - 448.0734,found 448.0742. 1 H NMR(DMSO-d 6 ,300MHz)δ:2.56(bs,4H,SO 2 N(CH 2 ) 2 ),2.74(t,2H,J＝5.4Hz,NCH 2 -),2.91(bs,4H,CN(CH 2 ) 2 ),4.08(t,2H,J＝5.4Hz,OCH 2 -),6.90～7.93(m,7H,ArH),11.47(s,1H,NH). 13 CNMR(DMSO-d 6 ,75MHz)δ:45.84,51.80,55.64,66.92,112.64,113.83,118.06,121.29,121.41,123.31,128.13,128.57,129.74,136.97,153.69,153.74,159.33,182.80。
Example 32
On the basis of example 25, R in o-methylphenol 1 2-methyl is replaced by 2-methoxy, other reaction conditions are unchanged, and the compound {5- ((4- (2- (2-methoxyphenoxy) ethyl) piperazin-1-yl) sulfonyl) indoline-2, 3-dione (ZJG-C8) } is obtained
Yellow solid, yield 49.8%, m.p.205.6-207.7 ℃. HRMS (ESI-MS, m/z): calcd.for C 21 H 22 N 3 O 6 S[M-H] - 444.1229,found 444.1236. 1 H NMR(DMSO-d 6 ,300MHz)δ:2.58(bs,4H,SO 2 N(CH 2 ) 2 ),2.67(t,2H,J＝5.4Hz,NCH 2 -),2.90(bs,4H,CN(CH 2 ) 2 ),3.71(s,3H,PhOCH 3 ),3.96(t,2H,J＝5.4Hz,OCH 2 -),6.83～7.92(m,7H,ArH),11.46(s,1H,NH). 13 C NMR(DMSO-d 6 ,75MHz)δ:45.86,51.80,55.46,55.94,66.44,112.29,112.65,113.68,118.12,120.62,121.03,123.32,128.51,136.99,147.90,149.12,153.77,159.37,182.82。
Example 33
On the basis of example 25, o-methylbenzene is reacted withR in phenol 1 2-methyl was replaced with 4-t-amyl, the other reaction conditions were unchanged, resulting in the compound {5- ((4- (2- (4-t-pentylphenoxy) ethyl) piperazin-1-yl) sulfonyl) indoline-2, 3-dione (ZJG-C9) }
Yellow solid, yield 73.1%, m.p.219.8-221.6 ℃. HRMS (ESI-MS, m/z): calcd.for C 25 H 30 N 3 O 5 S[M-H] - 484.1906,found 484.1916. 1 H NMR(DMSO-d 6 ,300MHz)δ:0.57(t,3H,J＝7.5Hz,C(CH 3 ) 2 CH 2 CH 3 ),1.19(s,6H,C(CH 3 ) 2 CH 2 CH 3 ),1.51(q,2H,J＝7.5Hz,C(CH 3 ) 2 CH 2 CH 3 ),2.57(bs,4H,SO 2 N(CH 2 ) 2 ),2.66(t,2H,J＝5.4Hz,NCH 2 -),2.90(bs,4H,CN(CH 2 ) 2 ),3.95(t,2H,J＝5.4Hz,OCH 2 -),6.78～7.92(m,7H,ArH),11.45(s,1H,NH). 13 C NMR(DMSO-d 6 ,75MHz)δ:8.9,28.32,36.13,36.76,45.85,51.76,55.92,65.26,112.64,113.77,118.09,123.30,126.53,128.51,136.98,140.76,153.75,155.93,159.34,182.79。
Example 34
On the basis of example 25, R in o-methylphenol 1 2-methyl is replaced by 4-tertiary butyl, other reaction conditions are unchanged, and the compound {5- ((4- (2- (4-tertiary butyl phenoxy) ethyl) piperazine-1-yl) sulfonyl) indoline-2, 3-dione (ZJG-C10) } is obtained
Yellow solid, yield 64.6%, m.p.236.2-238.1 ℃. HRMS (ESI-MS, m/z): calcd.for C 24 H 28 N 3 O 5 S[M-H] - 471.1750,found 471.1745. 1 H NMR(DMSO-d 6 ,300MHz)δ:1.23(s,9H,C(CH 3 ) 3 ),2.56(s,4H,SO 2 N(CH 2 ) 2 ),2.66(t,2H,J＝5.4Hz,NCH 2 -),2.90(s,4H,CN(CH 2 ) 2 ),3.95(t,2H,J＝5.4Hz,OCH 2 -),6.78～7.92(m,7H,ArH),11.46(s,1H,NH. 13 C NMR(DMSO-d 6 ,75MHz)δ:31.25,33.63,45.87,51.77,55.92,65.34,112.67,113.85,118.12,123.32,125.91,128.55,137.00,142.64,153.78,156.04,159.36,182.82。
Example 35
On the basis of example 25, R 1 2-naphthyl is used to replace 2-methylphenyl, other reaction conditions are unchanged, and the compound {5- ((4- (2- (2-naphthoxy) ethyl) piperazin-1-yl) sulfonyl) indoline-2, 3-dione (ZJG-C11) }
Yellow solid, yield 61.1%, m.p.260.1-262.5 ℃. HRMS (ESI-MS, m/z): calcd.for C 24 H 22 N 3 O 5 S[M-H] - 464.1280,found 464.1270. 1 H NMR(DMSO-d 6 ,300MHz)δ:2.60(s,4H,SO 2 N(CH 2 ) 2 ),2.75(t,2H,J＝5.4Hz,NCH 2 -),2.91(s,4H,CN(CH 2 ) 2 ),4.12(t,2H,J＝5.4Hz,OCH 2 -),7.09～7.92(m,10H,ArH),11.46(s,1H,NH. 13 CNMR(DMSO-d 6 ,75MHz)δ:45.86,51.77,55.84,65.44,106.73,112.64,118.08,118.55,123.31,123.43,126.24,126.52,127.36,128.37,128.51,129.13,134.14,136.97,153.75,156.19,159.34,182.80。
Example 36
On the basis of example 25, R 1 Replacing 2-methylphenyl with 1-naphthyl, leaving the other reaction conditions unchanged, to give the compound {5- ((4- (2- (1-naphthoxy) ethyl) piperazin-1-yl) sulfonyl) indoline-2, 3-dione (ZJG-C12) }
A yellow solid was used as the starting material,the yield is 64.0%, m.p.219.4-220.4 ℃. HRMS (ESI-MS, m/z): calcd.for C 24 H 22 N 3 O 5 S[M-H] - 464.1280,found 464.1286. 1 H NMR(DMSO-d 6 ,300MHz)δ:2.66(s,4H,SO 2 N(CH 2 ) 2 ),2.85(t,2H,J＝5.4Hz,NCH 2 -),2.91(s,4H,CN(CH 2 ) 2 ),4.18(t,2H,J＝5.4Hz,OCH 2 -),6.91～8.11(m,10H,ArH),11.46(s,1H,NH. 13 CNMR(DMSO-d 6 ,75MHz)δ:45.90,51.81,55.93,66.09,105.20,112.64,118.08,119.87,121.42,123.30,124.85,125.16,126.06,126.28,127.32,128.55,133.91,136.97,153.74,153.83,159.34,182.79。
Effect of the compounds prepared in examples 1 to 36 on survival time of acute cerebral ischemia mice.
Preparing a suspension with required concentration by using 0.5% wt of sodium carboxymethyl cellulose before using the target compound and the positive control medicine nimodipine; the test animals are ICR mice, the weight of which is 19-25 g, and the animals are male. The mice were randomly grouped, 10 mice per group; the test drug was administered by gavage at 0.2mL/10g, the blank control group was given equal volume of NS, the positive control group was given equal volume of nimodipine at 80mg/Kg, ether was anesthetized 1 hour after administration, the middle of the neck was cut after fixation, the common carotid artery and the vagus nerve on both sides were separated and ligated, and the survival time of the mice (5 times per minute of breathing was considered as death of the mice) was recorded, and the results are shown in Table 1.
Table 1 shows the effect (min) of the compounds prepared in examples 1 to 36 on the survival time of mice suffering from acute cerebral ischemia
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* P<0.05, ** P<0.01 is compared to the NS group, # P<0.05, ## P<0.01 compared to nimodipine group.
The test results show that the compounds of the invention have anti-cerebral ischemia effects, and the compounds ZJG-A1, ZJG-A2, ZJG-A4, ZJG-A5, ZJG-A8, ZJG-A11, ZJG-A12, ZJG-B1, ZJG-B2, ZJG-B3, ZJG-B4, ZJG-B6, ZJG-B11, ZJG-B12, ZJG-C4, ZJG-C7, ZJG-C8, ZJG-C10 can remarkably prolong the survival time of acute cerebral ischemia mice in each dosage group, and have good neuroprotective activity on the acute cerebral ischemia mice. The compounds ZJG-A6, ZJG-A7, ZJG-A10, ZJG-C2, ZJG-C3, ZJG-C5, ZJG-C11 can significantly prolong the death time of acute cerebral ischemic mice in the high dose group (200 mg/Kg), but have no obvious effect in the medium dose and low dose groups.
The compound can also resist oxidation, improve the survival rate of cells, and has a protective effect.
The pairs of compounds prepared in examples 1 to 36 were H 2 O 2 Effect of induced PC-12 cell viability.
PC-12 cells at 1.0X10 4 The density of each hole is inoculated in a 96-well plate, and after the cells are cultured for 24 hours in an incubator, the cell fusion degree is observed under a microscope, and the cell administration operation can be carried out when the cell fusion degree reaches about 60 percent. Blank control group, H are arranged in the 96-well plate 2 O 2 Group, drug-H 2 O 2 Groups of 5 duplicate wells. Blank control group 100. Mu.L of DMEM medium given only 2% BSA, H 2 O 2 The group was given only 450. Mu. Mol H 2 O 2 100. Mu.L of DMEM containing 2% BSA was incubated, and the drug groups were given different concentration gradients of drug (0.5. Mu. Mol, 2.5. Mu. Mol, 5.0. Mu. Mol), 100. Mu.L of DMEM medium containing 2% BSA, drug/H 2 O 2 The group was first incubated with different concentration gradient drugs (0.5. Mu. Mol, 2.5. Mu. Mol, 5.0. Mu. Mol) in 100. Mu.L of DMEM medium containing 2% BSA for 6H, after which different concentration gradient drugs, 450. Mu. Mol H were added 2 O 2 100. Mu.L of DMEM medium containing 2% BSA was incubated for 24h. Drug group and drug/H 2 O 2 The group is simultaneously given different concentration gradient drugs and placed in an incubator for 6 hours of incubation,at this time H 2 O 2 100. Mu.L of DMEM medium containing 2% BSA was administered to the group; after 6h, the drug group was incubated for 24h, H 2 O 2 The group culture solution is sucked and discarded, and the culture solution containing the corresponding concentration H is given 2 O 2 Is incubated for 24H, drug/H 2 O 2 The group culture solution is sucked and discarded, and medicines with different concentrations and corresponding H are given 2 O 2 The mixed culture solution is incubated for 24 hours. After 24h incubation, the medium was aspirated and 100. Mu.L of MTS with 1.0mg/mL serum-free medium was added to each well, incubation was stopped in an incubator for 1h, and the absorbance of each well was measured at 490nm on an microplate reader. Cell viability (%) was determined according to the following formula:
cell survival (%) = (Z-B)/(G-B) ×100%
Wherein Z, B, G each represents drug-H 2 O 2 Group, blank group, H 2 O 2 Average value of absorbance of group. The results are shown in Table 2.
Table 2 shows the pairs of compounds H obtained in examples 1 to 36 2 O 2 Effect of induced PC-12 cell viability (%).
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* P<0.05 and H 2 O 2 Group comparison.
The test results show that the compounds of the invention have antioxidant activity, and the compounds ZJG-A1, ZJG-A2, ZJG-A7, ZJG-A9, ZJG-B3, ZJG-B4, ZJG-B5, ZJG-B9, ZJG-B11, ZJG-B12, ZJG-C3, ZJG-C4, ZJG-C6, ZJG-C7, ZJG-C8 and ZJG-C10 can obviously improve H in each dosage group 2 O 2 The induced PC-12 cell survival rate is excellentThe positive control Melatonin (MLT) at the same concentration showed good antioxidant activity.

Claims (10)

1. An isatin derivative is characterized by having the following structural general formula:
wherein R is 1 Is H, halogen, hydrocarbyl, alkoxy, aralkoxy, heterocycloalkoxy, aryl, substituted heterocycle, or substituted aryl; r is R 2 Is a bridging group, in particular-O-CH 2 -CO-, -ch=ch-CO-or-O-CH 2 -CH 2 -any one of the following.
2. Isatin derivative according to claim 1, characterized in that: the R is 1 The aryl group in the representative aryl or aralkoxy is benzene, biphenyl or naphthalene, or F, cl, br, I, C 1～10 Alkyl, C 1～10 Alkoxy, nitro or amino substituted benzene, biphenyl or naphthalene.
3. Isatin derivative according to claim 1, characterized in that: the R is 1 Representative hydrocarbyl means a straight or branched alkyl group having 1 to 10 carbon atoms, or a straight or branched alkenyl group having 2 to 10 carbon atoms, or a straight or branched cycloalkyl group having 3 to 10 carbon atoms; the alkyl group in the alkoxy group, aralkoxy group or heterocyclic alkoxy group means a straight chain or branched alkyl group having 1 to 10 carbon atoms.
4. Isatin derivative according to claim 1, characterized in that: the R is 1 Representative of the heterocyclic groups in the substituted heterocyclic ring or heterocyclic alkoxy group means a saturated heterocyclic ring or aromatic heterocyclic ring containing one or more hetero atoms selected from the group consisting of oxygen, nitrogen and sulfur atoms.
5. According to claim 1The isatin derivative is characterized in that: the R is 1 The representative halogen is F, cl, br or I.
6. Isatin derivative according to claim 1, characterized in that: the R is 1 The substituent of the substituted aryl is halogen.
7. The process for preparing isatin derivatives according to claim 1, wherein when R 2 is-O-CH 2 In the case of CO-, the structural general formula of the compound is shown in the formula (II):
the preparation method of the compound with the formula (II) comprises the following steps:
(1) Mixing the substituted aromatic phenol, ethyl chloroacetate, acetonitrile and potassium carbonate, heating to reflux temperature, filtering while the mixture is hot after reaction, and carrying out spin-drying on the filtrate, wherein if the filtrate is oily residual liquid, the distillation is carried out under reduced pressure; if the solid is obtained by concentration, the solid is recrystallized by absolute ethyl alcohol to obtain the corresponding substituted aryloxy ethyl acetate (V);
(2) Mixing substituted aryloxy ethyl acetate with anhydrous piperazine, introducing N 2 Heating to no less than 110deg.C, refluxing, standing, cooling, adding chloroform into the residue for dissolving, and dissolving with saturated NaHCO 3 Washing the solution, washing with water, and concentrating the organic phase to obtain white solid which is substituted aryloxyacetylpiperazine (VI);
(3) Slowly dropwise adding chlorosulfonic acid into isatin in ice water bath, stirring, heating for reaction, monitoring the reaction progress by TLC, and cooling to room temperature after the reaction is completed; slowly dripping the reaction solution into crushed ice, vigorously stirring until solid is separated out, adding ethyl acetate, stirring, dissolving, separating, washing an ethyl acetate layer with water and saturated sodium chloride solution in sequence, and drying anhydrous sodium sulfate overnight after washing; the next day, filtering, decompressing and evaporating the solvent to obtain brown sticky matter, and separating by column chromatography to obtain 3, 3-dichloro-2-oxoindoline-5-sulfonyl chloride (VII) and 2, 3-dioxoindoline-5-sulfonyl chloride (VIII);
(4) Mixing substituted aryloxy acetyl piperazine (VI) and N-ethyldiisopropylamine, adding tetrahydrofuran into the mixture under ice water bath, stirring and dissolving to obtain a reaction solution; dissolving 3, 3-dichloro-2-oxoindoline-5-sulfonyl chloride in tetrahydrofuran, and slowly dripping the solution into the reaction solution; after the dripping is finished, the temperature is raised to the room temperature and stirred overnight; the next day, filtering, evaporating the solvent under reduced pressure to obtain yellow sticky substance, using the mixed solution of ethyl acetate and petroleum ether as eluent, performing gradient elution, and performing column chromatography separation to obtain a compound shown in a general formula (II);
the synthetic route of the method is as follows:
8. the process for preparing isatin derivatives according to claim 1, wherein when R 2 When the compound is-CH=CH-CO-, the structural general formula of the compound is shown as a formula (III):
the preparation method of the compound with the formula (III) comprises the following steps:
(1) Mixing substituted benzaldehyde, malonic acid and piperidine, adding pyridine into the mixture, stirring the mixture for dissolution, heating the mixture to not lower than 120 ℃ for stirring reaction, monitoring the reaction progress by TLC, removing the solvent by evaporation under reduced pressure after the reaction is finished, adding a concentrated hydrochloric acid/ice mixture, stirring the mixture vigorously, precipitating a large amount of white solid, carrying out suction filtration, and recrystallizing the crude product by absolute ethyl alcohol to obtain substituted benzene acrylic acid (IX);
(2) Mixing N-Boc-piperazine and triethylamine, adding dichloromethane into the mixture, and stirring and dissolving the mixture in ice water bath to obtain a mixed solution; dissolving 3, 3-dichloro-2-oxoindoline-5-sulfonyl chloride (VII) or 2, 3-dioxoindoline-5-sulfonyl chloride (VIII) in methylene dichloride, slowly dripping the mixture into the mixed solution, heating to room temperature after dripping, monitoring the reaction progress by TLC, and obtaining 4- (3, 3-dichloro-2-oxoindoline-5-ylsulfonyl) piperazine-1-carboxylic acid tert-butyl ester (X) by column chromatography after the reaction is finished;
(3) Placing 4- (3, 3-dichloro-2-oxoindole-5-ylsulfonyl) piperazine-1-carboxylic acid tert-butyl ester (X) in a reaction bottle, mixing trifluoroacetic acid and dichloromethane to obtain a trifluoroacetic acid solution with the mass fraction of 25%, directly adding the trifluoroacetic acid solution into the reaction bottle, stirring at room temperature, monitoring the reaction progress by TLC, and evaporating the solvent under reduced pressure after the reaction is finished to obtain 3, 3-dichloro-5- (piperazine-1-ylsulfonyl) indol-2-one trifluoroacetate (XI);
(4) Placing 3, 3-dichloro-5- (piperazine-1-ylsulfonyl) indol-2-one trifluoroacetate (XI) into a reaction bottle, adding an aqueous acetic acid solution into the reaction bottle, heating to not lower than 100 ℃ for reaction, monitoring the reaction progress by TLC, and evaporating the solvent under reduced pressure after the reaction is finished to obtain 5- (piperazine-1-ylsulfonyl) indoline-2, 3-dione trifluoroacetate (XII);
(5) Mixing 5- (piperazine-1-ylsulfonyl) indoline-2, 3-diketone trifluoroacetate (XII), N-ethyldiisopropylamine and tetrahydrofuran, stirring and dissolving under ice water bath condition to obtain a reaction solution; putting substituted benzene acrylic acid (IX), anhydrous dichloromethane and DMF into a reaction bottle, dropwise adding oxalyl chloride into the reaction bottle under ice bath condition, heating to room temperature after dropwise adding, stirring for reaction, and concentrating the reaction solution to obtain substituted benzene acrylic acid chloride; dissolving substituted benzene acryloyl chloride with tetrahydrofuran, slowly dripping into the reaction liquid, heating to room temperature after dripping, and stirring overnight; the next day, TLC monitors the reaction progress, after the reaction is finished, the yellow oily liquid is obtained by decompression concentration, the mixed liquid of ethyl acetate and petroleum ether is used as an eluent, gradient elution is carried out, and the compound of the general formula (III) is obtained by column chromatography separation;
the synthetic route of the method is as follows:
9. the process for preparing isatin derivatives according to claim 1, wherein when R 2 In the case of-O-CH 2-CH2-, the structural general formula of the compound is shown in the formula (IV):
the preparation method of the compound with the formula (IV) comprises the following steps:
(1) Mixing substituted phenol, 1, 2-dibromoethane and water, stirring and heating to not lower than 95 ℃, dropwise adding sodium hydroxide aqueous solution into the mixture, continuously heating to 100 ℃ after the dropwise adding is finished, stirring and reacting, monitoring the reaction progress by TLC, cooling to room temperature after the reaction is finished, and extracting with dichloromethane; combining dichloromethane layers, washing sequentially by adopting a sodium hydroxide aqueous solution and a saturated sodium chloride solution, and drying by adopting anhydrous magnesium sulfate after washing; filtering, concentrating the filtrate under reduced pressure to obtain substituted phenoxyethyl bromide (XIII);
(2) Mixing substituted phenoxyethyl bromide, methanol and piperazine, heating to not lower than 70 ℃ for reaction, monitoring the reaction progress by TLC, and evaporating the solvent under reduced pressure after the reaction is finished; adding a mixed solution of dichloromethane and saturated sodium carbonate solution into the mixture for dissolution and liquid separation, sequentially washing a dichloromethane layer with saturated sodium bicarbonate solution and water, washing an organic phase with hydrochloric acid, adjusting the pH of a water layer with sodium hydroxide solution to be more than 10, separating out solids, extracting with dichloromethane, combining the organic phases, and drying with anhydrous sodium sulfate overnight; the next day, filtering, concentrating under reduced pressure to obtain substituted phenoxyethylpiperazine (XIV);
(3) Placing the substituted phenoxyethyl piperazine into a reaction bottle, adding tetrahydrofuran into the reaction bottle under ice water bath, stirring and dissolving, and then adding N-ethyldiisopropylamine into the reaction bottle, and continuously stirring to obtain a reaction solution; dissolving 3, 3-dichloro-2-oxoindoline-5-sulfonyl chloride or 2, 3-dioxoindoline-5-sulfonyl chloride with tetrahydrofuran, slowly dripping the solution into the reaction solution, heating to room temperature after dripping, stirring overnight, monitoring the reaction progress by TLC, and evaporating the solvent under reduced pressure after the reaction is finished to obtain substituted 3, 3-dichloro-5- (4- (2-phenoxyethyl) piperazin-1-ylsulfonyl) indol-2-one (XV);
(4) Placing 3, 3-dichloro-5- (4- (2-phenoxyethyl) piperazine-1-ylsulfonyl) indol-2-one in a reaction bottle, adding an aqueous solution of acetic acid, heating to not lower than 96 ℃, stirring for reaction, monitoring the reaction progress by TLC, cooling to room temperature after the reaction is finished, firstly dropwise adding a sodium hydroxide solution to adjust the pH to be 7, and then dropwise adding a saturated sodium bicarbonate solution until no bubbles are generated; extraction with ethyl acetate, combining the organic phases, washing with saturated sodium bicarbonate solution and drying over night with anhydrous sodium sulfate; the next day, filtering, concentrating the filtrate under reduced pressure to obtain yellow oily liquid, and performing gradient elution by taking a mixed solution of ethyl acetate and petroleum ether as an eluent, and performing column chromatography separation to obtain a compound shown in a general formula (IV);
the synthetic route of the method is as follows:
10. use of an isatin derivative according to claim 1 for the preparation of an anti-cerebral ischemia neuroprotective drug or pharmaceutical component.
CN202310598672.6A 2023-05-25 2023-05-25 Isatin derivative and preparation method and application thereof Pending CN116655518A (en)

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