CN116354901B - Thiazolidinedione compound and preparation method and application thereof - Google Patents

Thiazolidinedione compound and preparation method and application thereof Download PDF

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CN116354901B
CN116354901B CN202310384464.6A CN202310384464A CN116354901B CN 116354901 B CN116354901 B CN 116354901B CN 202310384464 A CN202310384464 A CN 202310384464A CN 116354901 B CN116354901 B CN 116354901B
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thiazolidinedione
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孙凯
刘勇刚
郑一超
赵兵
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Zhengzhou University
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Abstract

The invention belongs to the field of pharmaceutical chemistry, and particularly relates to a thiazolidinedione compound, and a preparation method and application thereof. The thiazolidinedione compound of the invention is a compound shown in a formula (I) or pharmaceutically acceptable salt thereof:

Description

Thiazolidinedione compound and preparation method and application thereof
Technical Field
The invention belongs to the field of pharmaceutical chemistry, and particularly relates to a thiazolidinedione compound, and a preparation method and application thereof.
Background
At present, tumor prevention and treatment become one of the most important public health problems in China. Histone lysine demethylase 1 (LYSINE SPECIFIC DEMETHYLASE L, LSD 1) was the first histone lysine demethylase discovered in 2004 by professor Shi Yang of harvard university. With the intensive study of tumors, more and more studies confirm that: LSD1 is closely related to the occurrence and development of various tumors such as prostate cancer, breast cancer, gastric cancer, lung cancer, colon cancer and the like, and the expression level of LSD1 in these cancer cell lines is higher than that of normal cells, and it is involved in the processes of division, differentiation, migration, invasion and the like of cancer cells. Inhibiting LSD1 expression in cancer cells can inhibit cancer cell growth, invasion and metastasis to some extent, and induce apoptosis of cancer cells. Therefore, LSD1 is a recognized potential anti-tumor target, and efficient LSD1 inhibitors are searched for to be effectively used for preventing and treating tumors, so that the LSD1 is a hotspot of current tumor drug research and is an important research direction in the future.
2,4-Thiazolidinedione (2, 4-thiazolidinedione, TZD) is a basic skeleton contained in drugs such as pioglitazone. The 3-position and the 5-position of the compound can be substituted, so that a new compound is designed and synthesized, and the 2,4-thiazolidinedione is favored by researchers because the carbonyl of the thiazolidine ketone is highly inactive and hardly undergoes side reactions, and the compound is a heterocyclic compound with wide application. In recent years, a plurality of thiazolidinedione structure-containing drugs are approved for marketing (the structures are shown below) or enter clinical studies, which indicate that the structure fragments have reliable drug formation and safety.
Liu et al synthesized a series of 3, 5-disubstituted thiazolidine analogues and found potent inhibitory effects on the growth of human histiocyte lymphoma cells (U937). Studies have reported that compounds containing TZD structure inhibit iNOS-mediated overproduction of NO, and are potentially useful drug targets for the treatment of inflammatory diseases, and have become potential drugs for the treatment of acute lung injury and acute respiratory distress syndrome. Abdellatif et al show COX-2 inhibitory activity comparable to celecoxib in vitro and show anti-inflammatory activity higher than that of celecoxib as a reference drug in vivo. Palekar and the like synthesize a series of novel thiazolidine derivatives and screen the inhibition effect on escherichia coli (ATTC-25922), klebsiella pneumoniae (ATCC-10031), bacillus cereus (ATTC-10702) and salmonella typhimurium (ATTC-23564), and the compounds are found to have good activity on bacillus cereus and typhoid bacillus. In addition, thiazolidinediones have been reported to be useful in the clinical treatment of polycystic ovary syndrome, correcting metabolic and endocrine disorders in PCOS, and restoring ovulation and conception in patients. It can be seen that none of the existing thiazolidinedione structure compounds are relevant for use as LSD1 inhibitors and their efficacy.
In addition, a plurality of LSD1 inhibitors with different structures enter the clinical research stage at present, and the good drug property of the LSD1 inhibitors serving as anti-tumor targets is fully demonstrated. Typical examples of these compounds are irreversible inhibitors such as TCP, ORY-1001, GSK-2879552, ORY-2001, INCB059872, IMG-7289, TAK-418 and LH-1802, and reversible inhibitors such as SP-2577 and CC-90011. However, all existing LSD1 inhibitors do not contain thiazolidinedione structures, and no research on application of the thiazolidinedione structures in LSD1 inhibitors exists.
Therefore, application of thiazolidinedione structure with good drug formation and safety to LSD1 inhibitor research and promotion of research and development of related antitumor drugs are technical problems to be solved.
Disclosure of Invention
The invention aims to provide a thiazolidinedione compound which has good inhibitory activity on histone lysine demethylase 1 (LSD 1) and can be used as an inhibitory drug or an anti-tumor drug of LSD 1.
The invention also aims to provide a preparation method of the thiazolidinedione compound, which has simple process and is suitable for industrial preparation and application of the thiazolidinedione compound.
The invention also aims to provide application of the thiazolidinedione compound.
In order to achieve the above purpose, the thiazolidinedione compound of the invention adopts the following technical scheme:
A thiazolidinedione compound, which is a compound represented by formula (i):
In the formula (I), R 1 is selected from one of methyl, ethyl, propyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl and substituted phenyl; r 1 is selected from substituted phenyl, wherein the substituted phenyl is phenyl which is monosubstituted or polysubstituted by halogen, hydroxy and alkoxy at any position;
R 2 is selected from one of C1-C8 linear saturated alkyl, branched saturated alkyl or cyclic saturated alkyl which are unsubstituted or substituted by a first substituent at any position; the first substituent is one of nitrogen atom, amino, monosubstituted or disubstituted amino, phenyl, substituted phenyl, benzyl, methylthiophene and methylfuran; when the first substituent is selected from substituted phenyl, the substituted phenyl is phenyl which is singly or multiply substituted at any position by halogen, nitrile, nitro, ester, amino, amido, methoxy, hydroxyl, methyl, ethyl, isopropyl, trifluoromethyl, trifluoro isopropyl, methyldioxy and ethyldioxy.
The thiazolidinedione structural fragment with good drug formation and safety is applied to the study of the LSD1 inhibitor for the first time, and the thiazolidinedione compound with novel skeleton, high efficiency and low toxicity is constructed. The LSD1 protein inhibition activity test proves that the thiazolidinedione compound with the characteristic structure has better inhibition activity on LSD1, reaches or exceeds the activity level of the compound in partial clinical research stage, has the potential of further developing into anti-tumor drugs, and can also provide a brand-new structural framework for developing high-efficiency anti-tumor drugs based on LSD1 targets.
In order to further increase the inhibitory activity of thiazolidinedione compounds against LSD1, preferably, the thiazolidinedione compounds are selected from the following structural compounds, which are sequentially designated as compounds 1 to 52:
In the present invention, the pharmaceutically acceptable salts of thiazolidinediones, such as acid addition salts of thiazolidinediones with: hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, boric acid, methanesulfonic acid, p-toluenesulfonic acid, naphthalenesulfonic acid, benzenesulfonic acid, citric acid, lactic acid, pyruvic acid, tartaric acid, acetic acid, trifluoroacetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, salicylic acid or phenylacetic acid.
The preparation method of the thiazolidinedione compound adopts the following synthetic route:
the preparation method of the thiazolidinedione compound comprises the following steps:
(1) Reacting the raw material a, bromoacetyl bromide and alkaline substances in a solvent A, extracting and concentrating after the reaction to obtain an intermediate b;
(2) Reacting the intermediate B, 2, 4-thiazolidinedione and alkali in a solvent B, extracting and concentrating after the reaction to obtain an intermediate c;
(3) Reacting the intermediate C with corresponding aldehyde and a catalyst in a solvent C, and extracting, concentrating and purifying after the reaction to obtain a thiazolidinedione compound shown in a formula (I);
In the step (1), the raw material a is R 2 group in R 2-NH2,R2-NH2, which corresponds to R 2 in the structural formula of the formula (I); in step (3), the corresponding aldehyde is an aldehyde corresponding to the R 1 group in the formula (I).
The preparation method provided by the invention has the advantages of mild reaction conditions, simplicity in operation and high yield. The thiazolidinedione compound is designed and synthesized by taking 2, 4-thiazolidinedione, aldehyde, amine and the like as raw materials and carrying out group modification through nucleophilic substitution, condensation and other multi-step reactions. The compound has good inhibiting effect on LSD1, reaches or exceeds the activity level of the compound in partial clinical research stage, and has good potential anti-tumor drug development prospect.
The product obtained after the extraction, concentration and purification in the step (3) is named as an intermediate d, and the step of further reacting the intermediate d with trifluoroacetic acid to obtain the thiazolidinedione compound shown in the formula (I). And (3) further reacting the product obtained in the step (3) with trifluoroacetic acid to prepare the corresponding thiazolidinedione compound containing the trifluoroacetate group.
In the invention, the choice of the solvent is not particularly limited, and only the dissolution of the reaction raw materials and the normal operation of the reaction are ensured. Preferably, in the step (1), the solvent A is one or more of tetrahydrofuran, acetonitrile, dimethylformamide, dichloromethane, chloroform and dioxane; the alkaline substance is one or more of triethylamine, N-diisopropylethylamine, cesium carbonate, potassium carbonate, sodium hydroxide and potassium hydroxide.
Further, in the step (2), the solvent B is one or more of tetrahydrofuran, acetonitrile, dimethylformamide and dimethyl sulfoxide; the alkali is one or more of cesium carbonate, potassium carbonate, sodium hydroxide and potassium hydroxide.
Preferably, in the step (3), the solvent C is one or more of water, methanol, ethanol, propylene glycol, dimethylformamide and dimethyl sulfoxide; the catalyst is one or more of ammonium acetate, sodium acetate, acetic acid, 2, 6-tetramethyl piperidine, cesium carbonate, sodium carbonate, potassium iodide, potassium carbonate, potassium bisulfate, ethanolamine and sodium bicarbonate.
In the step (1), the raw material a is selected from 3-methoxyaniline, 4-cyanoaniline, 2-nitroaniline, 4-fluoro-3-nitroaniline, 3-fluoro-4-nitroaniline, 4-aminobenzoic acid methyl ester, 3-aminobenzoic acid methyl ester, 2-aminobenzoic acid methyl ester, 3-acetamidophenylamine, 4-methoxyaniline, 3,4, 5-trimethoxyaniline, 3-hydroxy-4-methylaniline, 4-tert-butylaniline, 4-bromoaniline, 2-bromoaniline, 3-iodoaniline, 3-bromo-4-fluoroaniline, 4-methoxybenzylamine, 4-trifluoromethyl benzylamine, 3-bromobenzylamine, 3, 4-methylenedioxyaniline, 3, 4-ethylenedioxyaniline, indoline, octahydroisoindole, cyclohexylamine, 4-phenylpiperazine-1-amine, 4- (4-nitrophenyl) piperazine-1-amine, procaine, N- [2- (diethylamino) ethyl ] -4-aminobenzamide, 2-furanamine, 2-t-butoxycarbonyl-N-butoxycarbonyl-4-tert-butoxycarbonyl-piperidinecarboxylic acid tert-butylpiperidine, 3-butoxycarbonyl-3-tert-butylpiperidine-amino-1-carbonyl-3-tert-butylpiperidine and 3-butyloxycarbonyl-3-amino-1-tert-butylpiperidine, one of 4-aminoaniline, 3-aminoaniline, 1-t-butoxycarbonyl-4- (4-aminophenyl) piperazine, N-t-butoxycarbonyl-1, 2-ethylenediamine, N-t-butoxycarbonyl-1, 3-propylenediamine, N-t-butoxycarbonyl-1, 4-butanediamine, N-t-butoxycarbonyl-1, 5-pentylamines, N-t-butoxycarbonyl-1, 6-hexamethylenediamine, t-butyl 2-aminoethyl (ethyl) carbamate. Further, in the step (3), the corresponding aldehyde is selected from one of acetaldehyde, propionaldehyde, butyraldehyde, cyclopropyl formaldehyde, cyclobutyl formaldehyde, cyclopentyl formaldehyde, cyclohexyl formaldehyde, 3-methoxy-4-hydroxybenzaldehyde. The thiazolidinedione compounds 1-52 with the numbers as above can be prepared by reasonably selecting the raw material a and the corresponding aldehyde.
In the step (1), the reaction is carried out for 1 to 8 hours at the temperature of between 0 and 60 ℃ in order to improve the selectivity and the yield of the reaction; in the step (2), the reaction is carried out for 2 to 8 hours at the temperature of 20 to 100 ℃; in the step (3), the reaction is carried out for 4-8 hours at the temperature of 60-120 ℃.
The invention also provides application of the thiazolidinedione compounds in preparing inhibitors or antitumor drugs based on LSD1 targets.
The invention develops a new histone lysine enzyme 1 inhibitor containing a thiazolidinedione structure for the first time, and a protein inhibition activity experiment shows that the compound has good LSD1 inhibition activity, reaches or exceeds the activity level of the compound in a part of clinical research stages, can provide a brand-new skeleton for developing an efficient anti-tumor drug based on an LSD1 target, and has very important significance for research and development of the inhibitor or the anti-tumor drug based on the LSD1 target and research and treatment of related diseases.
Detailed Description
The invention is further described below in connection with examples which are given solely for the purpose of illustration and are not intended to limit the scope of the invention. The structures of the compounds referred to in the examples below were determined by Nuclear Magnetic Resonance (NMR) and High Resolution Mass Spectrometry (HRMS). The nuclear magnetic resonance apparatus is a Bruker DPX-400 type superconducting nuclear magnetic resonance apparatus, and Tetramethylsilane (TMS) is an internal standard; the high resolution mass spectrum was a Waters-Micromass Q-Tof mass spectrometer. The compounds related to the invention are all compounds prepared for the first time, and the structures of the compounds are confirmed by modern spectrum means such as melting point measurement, 1H NMR、13 C NMR, HRMS and the like.
The thiazolidinediones according to the following examples are designated as compounds 1 to 52 in this order, and their structural formulae are shown below, but the scope of the present invention is not limited thereto.
Example 1
The thiazolidinedione compound 9 was prepared in this example, and the preparation process is as follows:
(1) Synthesis of intermediate b-9:
4-cyanoaniline (starting material a-9, 200mg,1.0 eq.) and triethylamine (171 mg,1.0 eq.) were added to a 50mL eggplant-shaped bottle, followed by 15mL of dichloromethane, slowly dropwise addition of a dichloromethane solution of bromoacetyl bromide (376 mg,1.1 eq.) at 0 ℃, after 2h reaction at 0 ℃, the reaction was monitored by TLC (PE: ea=2:1). This was then extracted three times with dichloromethane and water, washed once with saturated brine and the organic phase was dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated to dryness to give crude intermediate b-9, which was used directly in the next reaction without purification.
(2) Synthesis of intermediate c-9:
Intermediate b-9 (400 mg,1.0 eq.) 2, 4-thiazolidinedione (216 mg,1.1 eq.) and potassium carbonate (347mg, 1.5 eq.) were added to a 50mL eggplant-shaped bottle, and 25mL of N, N-dimethylformamide was added. After heating to 55deg.C and incubation for 4h, the reaction was monitored by TLC (PE: EA=2:1). After the completion of the reaction, the product was extracted five times with ethyl acetate and water, washed once with saturated brine, and the organic phase was dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated to dryness to give crude intermediate c-9, which was used directly in the next reaction without purification.
(3) Synthesis of thiazolidinedione 9
Intermediate c-9 (460 mg,1.0 eq.) 3-methoxy-4-hydroxybenzaldehyde (280 mg,1.1 eq.) and ammonium acetate (258 mg,2 eq.) were added to a 50mL eggplant-shaped bottle, and 25mL of absolute ethanol was added. After heating to 80℃and incubation for 6h, the reaction was monitored by TLC (PE: EA=1:1). After the completion of the reaction, purification was performed using column chromatography (PE: ea=2:1) to give thiazolidinedione 9.
Compound 9: (Z) -N- (4-cyanophenyl) -2- (5- (4-hydroxy-3-methoxybenzylidene) -2, 4-dioxothiazolin-3-yl) acetamide as a yellow solid in 79% yield, melting point 304.8～305.0℃.1H NMR(400MHz,DMSO-d6)δ10.88(s,1H),10.03(s,1H),7.91(s,1H),7.84–7.72(m,4H),7.24(d,J＝2.1Hz,1H),7.15(m,1H),6.96(d,J＝8.3Hz,1H),4.56(s,2H),3.84(s,3H).13C NMR(101MHz,DMSO)δ167.21,165.31,164.80,149.89,148.00,142.54,134.44,133.34,124.40,124.14,119.22,118.88,116.39,116.24,114.40,114.37,105.47,55.65,55.60,44.04.HR-MS(ESI):Calcd.C20H15N3O5S.[M+Na]+m/z:432.0624,found:432.0626.
Example 2
This example is a preparation of thiazolidinedione 1, which is substantially identical to example 1, except that: in the step (1), 3-methoxyaniline is adopted to replace 4-cyanoaniline; step (3) adopts acetaldehyde to replace 3-methoxy-4-hydroxybenzaldehyde.
Thiazolidinedione compound 1: (Z) -2- (5-ethylene-2, 4-dioxothiazolin-3-yl) -N- (3-methoxyphenyl) acetamide as a brown solid in 35% yield, melting point 126.8–127.7℃.1H NMR(400MHz,DMSO-d6)δ10.36(s,1H),7.26–7.19(m,2H),7.16(q,J＝7.1Hz,1H),7.06(m,1H),6.66(m,1H),4.43(s,2H),3.72(s,3H),1.96(d,J＝7.2Hz,3H).13C NMR(101MHz,DMSO)δ166.88,163.86,163.78,159.52,139.53,135.21,129.63,125.06,111.29,109.21,104.77,54.97,54.92,54.86,43.74,16.99.HR-MS(ESI):Calcd.C14H14N2O4S.[M+Na]+m/z:329.0566,found:329.0571.
Example 3
This example is a preparation of thiazolidinedione 2, which is substantially identical to example 1, except that: in the step (1), 3-methoxyaniline is adopted to replace 4-cyanoaniline; in the step (3), propionaldehyde is adopted to replace 3-methoxy-4-hydroxybenzaldehyde.
Thiazolidinedione compound 2: (Z) -2- (2, 4-dioxo-5-propylethylidene thiazolin-3-yl) -N- (3-methoxyphenyl) acetamide as a brown solid in 34% yield, melting point 126.4～129.3℃.1H NMR(400MHz,DMSO-d6)δ10.36(s,1H),7.27–7.19(m,2H),7.13–7.04(m,2H),6.66(m,1H),4.44(s,2H),3.72(s,3H),2.27(m,2H),1.10(t,J＝7.5Hz,3H).13C NMR(101MHz,DMSO)δ166.90,164.06,163.79,159.52,140.65,139.53,129.64,123.65,111.28,109.23,104.76,54.97,54.92,43.77,24.78,12.03.HR-MS(ESI):Calcd.C15H16N2O4S.[M+Na]+m/z:343.0723,found:343.0726.
Example 4
This example is a preparation of thiazolidinedione 3, which is substantially identical to example 1, except that: in the step (1), 3-methoxyaniline is adopted to replace 4-cyanoaniline; and step (3) adopts butyraldehyde to replace 3-methoxy-4-hydroxybenzaldehyde.
Thiazolidinedione 3: (Z) -2- (5-butylene-2, 4-dioxothiazolin-3-yl) -N- (3-methoxyphenyl) acetamide as a yellow solid in 46% yield, melting point 120.7～122.5℃.1H NMR(400MHz,DMSO-d6)δ10.36(s,1H),7.26–7.24(m,1H),7.21(d,J＝8.2Hz,1H),7.13–7.04(m,2H),6.66(m,1H),4.44(s,2H),3.72(s,3H),2.24(q,J＝7.4Hz,2H),1.55(q,J＝7.3Hz,2H),0.93(t,J＝7.4Hz,3H).13C NMR(101MHz,DMSO)δ166.91,163.95,163.79,159.52,139.53,139.19,139.16,129.63,124.48,111.28,109.22,104.76,54.97,54.92,43.77,33.24,20.69,13.58.HR-MS(ESI):Calcd.C16H18N2O4S.[M+Na]+m/z:357.0879,found:357.0887.
Example 5
This example was conducted to prepare thiazolidinedione 4, which was prepared in substantially the same manner as in example 1 except that: in the step (1), 3-methoxyaniline is adopted to replace 4-cyanoaniline; and (3) adopting cyclopropyl formaldehyde to replace 3-methoxy-4-hydroxybenzaldehyde.
Thiazolidinedione compound 4: (Z) -2- (5- (cyclopropylmethylene) -2, 4-dioxothiazolinon-3-yl) -N- (3-methoxyphenyl) acetamide as a white solid in 74% yield, melting point 119.9–122.4℃.1H NMR(400MHz,DMSO-d6)δ10.34(s,1H),7.26–7.23(m,1H),7.21(d,J＝8.1Hz,1H),7.06(m,1H),6.69(d,J＝10.8Hz,1H),6.66(m,1H),4.42(s,2H),3.72(s,3H),1.49(m,1H),1.13(m,2H),0.95(m,2H).13C NMR(101MHz,DMSO)δ167.10,163.86,163.73,159.53,144.87,139.55,129.62,120.39,111.30,109.20,104.78,54.97,54.92,43.72,15.01,9.76.HR-MS(ESI):Calcd.C16H16N2O4S.[M+Na]+m/z:355.0723,found:355.0730.
Example 6
This example is a preparation of thiazolidinedione 5, which is substantially identical to example 1, except that: in the step (1), 3-methoxyaniline is adopted to replace 4-cyanoaniline; and (3) adopting cyclobutyl formaldehyde to replace 3-methoxy-4-hydroxybenzaldehyde.
Thiazolidinedione compound 5: (Z) -2- (5- (cyclobutylmethylene) -2, 4-dioxothiazolin-3-yl) -N- (3-methoxyphenyl) acetamide as a yellow solid in 45% yield, melting point 120.9–121.4℃.1H NMR(400MHz,DMSO-d6)δ10.35(s,1H),7.26–7.19(m,3H),7.05(m,1H),6.66(m,1H),4.43(s,2H),3.72(s,3H),3.12(q,J＝8.2Hz,1H),2.24(m,2H),2.09(m,2H),2.00–1.85(m,2H).13C NMR(101MHz,DMSO)δ166.91,164.22,163.78,159.52,142.42,142.39,139.53,129.63,122.06,111.28,109.22,104.76,54.96,54.92,43.78,36.74,27.54,18.50.HR-MS(ESI):Calcd.C17H18N2O4S.[M+Na]+m/z:369.0879,found:369.0879.
Example 7
This example was conducted to prepare thiazolidinedione 6, which was prepared in substantially the same manner as in example 1 except that: in the step (1), 3-methoxyaniline is adopted to replace 4-cyanoaniline; and (3) adopting cyclopentyl formaldehyde to replace 3-methoxy-4-hydroxybenzaldehyde.
Thiazolidinedione compound 6: (Z) -2- (5- (cyclopentylmethylene) -2, 4-dioxothiazolidin-3-yl) -N- (3-methoxyphenyl) acetamide in the form of a yellow solid with a yield of 41% and a melting point 121.0～123.6℃.1H NMR(400MHz,DMSO-d6)δ10.35(s,1H),7.27–7.19(m,2H),7.07(t,J＝8.5Hz,2H),6.66(m,1H),4.43(s,2H),3.72(s,3H),1.89(q,J＝10.0,7.4Hz,2H),1.71(m,2H),1.61(m,2H),1.52–1.44(m,2H),0.84(m,1H).13C NMR(101MHz,DMSO)δ166.95,164.10,163.80,159.52,143.56,143.53,139.53,129.62,122.83,111.28,109.22,104.75,54.96,54.91,54.86,43.76,42.37,31.96,25.03.HR-MS(ESI):Calcd.C18H20N2O4S.[M+Na]+m/z:383.1036,found:383.1039.
Example 8
This example was conducted to prepare thiazolidinedione 7, which was prepared in substantially the same manner as in example 1 except that: in the step (1), 3-methoxyaniline is adopted to replace 4-cyanoaniline; and (3) adopting cyclohexyl formaldehyde to replace 3-methoxy-4-hydroxybenzaldehyde.
Thiazolidinedione compound 7: (Z) -2- (5- (cyclohexylmethylene) -2, 4-dioxothiazolin-3-yl) -N- (3-methoxyphenyl) acetamide in a brown solid in 36% yield, melting point 124.3～124.8℃.1H NMR(400MHz,DMSO-d6)δ10.36(s,1H),7.27–7.20(m,2H),7.05(m,1H),6.97(d,J＝9.5Hz,1H),6.66(m,1H),5.75(s,1H),4.43(s,2H),3.72(s,3H),2.17(m,1H),1.67(m,6H),1.35–1.27(m,4H).13C NMR(101MHz,DMSO)δ166.93,164.27,163.78,159.52,143.15,139.52,129.62,122.53,111.27,109.23,104.74,54.96,54.91,54.85,43.78,40.69,30.36,25.06,24.62.HR-MS(ESI):Calcd.C19H22N2O4S.[M+H]+m/z:375.1373,found:375.1377.
Example 9
This example was conducted to prepare thiazolidinedione 8, which was prepared in substantially the same manner as in example 1 except that: in the step (1), 3-methoxyaniline is used instead of 4-cyanoaniline.
Thiazolidinedione compound 8: (Z) -2- (5- (4-hydroxy-3-methoxybenzylidene) -2, 4-dioxothiazolin-3-yl) -N- (3-methoxyphenyl) acetamide as a yellow solid in 58% yield, melting point 204.9～205.3℃.1H NMR(400MHz,DMSO-d6)δ10.38(s,1H),7.90(s,1H),7.29–7.20(m,3H),7.14(m,1H),7.10–7.06(m,1H),6.96(d,J＝8.2Hz,1H),6.69–6.64(m,1H),4.50(s,2H),3.84(s,3H),3.72(s,3H).13C NMR(101MHz,DMSO)δ167.25,165.39,163.88,159.53,149.90,148.02,139.56,134.32,129.64,124.37,124.15,116.49,116.25,114.41,111.32,109.22,104.81,55.66,55.60,54.97,54.91,43.91.HR-MS(ESI):Calcd.C20H18N2O6S.[M+Na]+m/z:437.0778,found:437.0776.
Example 10
This example is a preparation of thiazolidinedione 10, which is substantially identical to example 1, except that: in the step (1), 2-nitroaniline is used instead of 4-cyanoaniline.
Thiazolidinedione compound 10: (Z) -2- (5- (4-hydroxy-3-methoxybenzylidene) -2, 4-dioxothiazolin-3-yl) -N- (2-nitrophenyl) acetamide as a yellow solid in 75% yield, melting point 231.2～232.5℃.1H NMR(400MHz,DMSO-d6)δ10.69(s,1H),7.97(m,1H),7.90(s,1H),7.73(m,1H),7.66(m,1H),7.44–7.38(m,1H),7.24(d,J＝2.0Hz,1H),7.14(m,1H),6.95(d,J＝8.3Hz,1H),4.55(s,2H),3.84(s,3H).13C NMR(101MHz,DMSO-d6)δ167.11,165.21,164.63,149.92,148.02,142.39,134.41,134.04,130.29,125.77,125.46,124.98,124.40,124.12,116.40,116.25,114.38,114.35,43.72.HR-MS(ESI):Calcd.C19H15N3O7S.[M+Na]+m/z:452.0523,found:452.0528.
Example 11
This example is a preparation of thiazolidinedione 11, which is substantially identical to example 1, except that: in the step (1), 4-fluoro-3-nitroaniline is used instead of 4-cyanoaniline.
Thiazolidinedione compound 11: (Z) -N- (4-fluoro-3-nitrophenyl) -2- (5- (4-hydroxy-3-methoxybenzylidene) -2, 4-dioxothiazolin-3-yl) acetamide as a yellow solid in 73% yield, melting point 275.3～275.4℃.1H NMR(400MHz,DMSO-d6)δ10.88(s,1H),10.03(s,1H),7.91(s,1H),7.85(m,1H),7.58(m,1H),7.25(d,J＝2.0Hz,1H),7.15(m,1H),6.96(d,J＝8.3Hz,1H),4.55(s,2H),3.85(s,3H).13C NMR(101MHz,DMSO)δ167.22,165.32,164.67,151.85,149.87,149.28,148.00,136.35,136.27,135.05,135.02,134.44,126.53,126.45,124.39,124.14,119.09,118.87,116.39,116.23,115.69,114.38,55.65,55.60,43.88.HR-MS(ESI):Calcd.C19H14FN3O7S.[M+Na]+m/z:470.0428,found:470.0434.
Example 12
This example is a preparation of thiazolidinedione 12, which is substantially identical to example 1, except that: in the step (1), 3-fluoro-4-nitroaniline is used to replace 4-cyanoaniline.
Thiazolidinedione compound 12: (Z) -N- (3-fluoro-4-nitrophenyl) -2- (5- (4-hydroxy-3-methoxybenzylidene) -2, 4-dioxothiazolin-3-yl) acetamide as a yellow solid in 43% yield, melting point 292.0–295.6℃.1H NMR(400MHz,DMSO-d6)δ11.17(s,1H),10.05(s,1H),8.21(t,J＝8.9Hz,1H),7.92(s,1H),7.81(m,1H),7.47(m,1H),7.25(d,J＝2.1Hz,1H),7.15(m,1H),6.96(d,J＝8.3Hz,1H),4.59(s,2H),3.85(s,3H).13C NMR(101MHz,DMSO-d6)δ167.18,165.37,165.26,149.90,148.00,145.28,145.17,134.55,131.55,131.49,127.61,124.42,124.13,116.30,116.23,114.73,114.41,107.33,107.07,55.65,55.59,44.09.HR-MS(ESI):Calcd.C19H14FN3O7S.[M+Na]+m/z:470.0428,found:470.0427.
Example 13
This example is a preparation of thiazolidinedione 13, which is substantially identical to example 1, except that: in the step (1), 4-aminobenzoic acid methyl ester is adopted to replace 4-cyanoaniline.
Thiazolidinedione compound 13: (Z) -methyl 4- (2- (5- (4-hydroxy-3-methoxybenzylidene) -2, 4-dioxothiazolin-3-yl) acetamido) benzoate as a yellow solid in 86% yield, melting point 241.2～242.5℃.1H NMR(400MHz,DMSO-d6)δ10.75(s,1H),10.05(s,1H),7.96–7.90(m,3H),7.73–7.68(m,2H),7.25(d,J＝2.0Hz,1H),7.15(m,1H),6.96(d,J＝8.3Hz,1H),4.56(s,2H),3.84(d,J＝7.0Hz,6H).13C NMR(101MHz,DMSO-d6)δ167.23,165.68,165.35,164.53,149.86,148.01,142.67,134.39,130.35,124.40,124.17,118.60,116.45,114.40,55.66,55.61,44.03.HR-MS(ESI):Calcd.C21H18N2O7S.[M+Na]+m/z:465.0727,found:465.0732.
Example 14
This example was conducted to prepare thiazolidinedione 14, which was prepared in substantially the same manner as in example 1 except that: in the step (1), methyl 3-aminobenzoate is used instead of 4-cyanoaniline.
Thiazolidinedione 14: (Z) -methyl 3- (2- (5- (4-hydroxy-3-methoxybenzylidene) -2, 4-dioxothiazolin-3-yl) acetamido) benzoate as a yellow solid, 73% yield, melting point 208.1～209.6℃.1H NMR(400MHz,DMSO-d6)δ10.63(s,1H),10.05(s,1H),8.26(m,1H),7.91(s,1H),7.79(m,1H),7.68(d,J＝7.7Hz,1H),7.49(t,J＝7.9Hz,1H),7.25(d,J＝2.0Hz,1H),7.15(m,1H),6.96(d,J＝8.3Hz,1H),4.53(s,2H),3.85(s,3H),3.85(s,3H).13C NMR(101MHz,DMSO)δ167.18,165.82,165.31,164.20,149.76,147.93,138.65,134.27,130.11,129.32,124.26,124.18,124.10,123.50,119.53,116.43,116.17,114.37,55.54,52.09,43.87.HR-MS(ESI):Calcd.C21H18N2O7S.[M+Na]+m/z:465.0727,found:465.0731.
Example 15
This example is a preparation of thiazolidinedione 15, which is substantially identical to example 1, except that: in the step (1), methyl 2-aminobenzoate is used instead of 4-cyanoaniline.
Thiazolidinedione compound 15: (Z) -methyl 2- (2- (5- (4-hydroxy-3-methoxybenzylidene) -2, 4-dioxothiazolin-3-yl) acetamido) benzoate as a yellow solid in 64% yield, melting point 232.8～234.6℃.1H NMR(400MHz,DMSO-d6)δ10.80(s,1H),10.09(s,1H),8.01(d,J＝8.2Hz,1H),7.92(s,1H),7.88(m,1H),7.62(m,1H),7.29–7.22(m,2H),7.15(m,1H),6.98(d,J＝8.3Hz,1H),4.58(s,2H),3.84(d,J＝4.7Hz,6H).13C NMR(101MHz,DMSO-d6)δ167.27,167.22,165.29,164.32,149.98,148.02,137.94,134.46,133.58,130.45,124.38,124.10,122.04,119.79,116.37,116.26,114.39,55.62,52.33,44.25.HR-MS(ESI):Calcd.C21H18N2O7S.[M+Na]+m/z:465.0727,found:465.0733.
Example 16
This example was conducted to prepare thiazolidinedione compound 16, which was prepared in substantially the same manner as in example 1, except that: in the step (1), 3-acetamido aniline is used instead of 4-cyanoaniline.
Thiazolidinedione compound 16: (Z) -N- (3-Acetaminopheny) -2- (5- (4-hydroxy-3-methoxybenzylidene) -2, 4-dioxothiazolin-3-yl) acetamide as a yellow solid, 67% yield, melting point 232.4～232.9℃.1H NMR(400MHz,DMSO-d6)δ10.39(s,1H),10.03(s,1H),9.94(s,1H),7.91(d,J＝5.0Hz,2H),7.31–7.26(m,1H),7.25–7.19(m,3H),7.14(m,1H),6.96(d,J＝8.3Hz,1H),4.50(s,2H),3.84(s,3H),2.03(s,3H).13C NMR(101MHz,DMSO-d6)δ168.30,167.26,165.41,163.80,149.79,148.00,139.69,138.61,134.24,128.94,124.35,124.22,116.57,116.23,114.36,113.90,109.97,55.65,43.92,23.99.HR-MS(ESI):Calcd.C21H19N3O6S.[M+Na]+m/z:464.0887,found:464.0889.
Example 17
This example was conducted to prepare thiazolidinedione 17, which was prepared in substantially the same manner as in example 1 except that: in the step (1), 4-methoxyaniline is used instead of 4-cyanoaniline.
Thiazolidinedione 17: (Z) -2- (5- (4-hydroxy-3-methoxybenzylidene) -2, 4-dioxothiazolin-3-yl) -N- (4-methoxyphenyl) acetamide as a white solid in 70% yield, melting point 243.1～244.8℃.1H NMR(400MHz,DMSO-d6)δ10.41(d,J＝4.2Hz,1H),10.13(s,1H),7.90(s,1H),7.49(d,J＝8.5Hz,2H),7.24(d,J＝2.1Hz,1H),7.14(m,1H),6.99(d,J＝8.3Hz,1H),6.91–6.87(m,2H),4.48(s,2H),3.84(s,3H),3.72(s,3H).13C NMR(101MHz,DMSO)δ167.25,165.41,163.28,155.34,149.93,148.02,134.22,131.69,124.32,124.12,120.59,116.54,116.27,114.41,113.87,55.67,55.61,55.15,55.10,43.83.HR-MS(ESI):Calcd.C20H18N2O6S.[M+Na]+m/z:437.0778,found:437.0779.
Example 18
This example was conducted to prepare thiazolidinedione 18, which was prepared in substantially the same manner as in example 1 except that: in the step (1), 3,4, 5-trimethoxyaniline is used instead of 4-cyanoaniline.
Thiazolidinedione compound 18: (Z) -2- (5- (4-hydroxy-3-methoxybenzylidene) -2, 4-dioxothiazolin-3-yl) -N- (3, 4, 5-trimethoxyphenyl) acetamide as a yellow solid in 47% yield, melting point 238.6～242.4℃.1H NMR(400MHz,DMSO-d6)δ10.35(s,1H),10.03(s,1H),7.90(s,1H),7.25(d,J＝2.0Hz,1H),7.14(m,1H),6.95(d,J＝14.7Hz,3H),4.48(s,2H),3.84(s,3H),3.74(s,6H),3.62(s,3H).13C NMR(101MHz,DMSO)δ167.24,165.38,163.67,152.76,149.82,148.01,134.51,134.30,133.61,124.33,124.20,116.53,116.24,114.41,96.79,60.08,60.04,55.66,55.61,43.87.HR-MS(ESI):Calcd.C22H22N2O8S.[M+Na]+m/z:497.0989,found:497.0991.
Example 19
This example is a preparation of thiazolidinedione 19, which is substantially identical to example 1, except that: in the step (1), 3-hydroxy-4-methylaniline is used instead of 4-cyanoaniline.
Thiazolidinedione compound 19: (Z) -2- (5- (4-hydroxy-3-methoxybenzylidene) -2, 4-dioxothiazolin-3-yl) -N- (3-hydroxy-4-methylphenyl) acetamide as a yellow solid in 39% yield, melting point 268.0～269.1℃.1H NMR(400MHz,DMSO-d6)δ10.18(s,1H),10.07(s,1H),9.37(s,1H),7.90(s,1H),7.25(d,J＝2.0Hz,1H),7.16–7.10(m,2H),6.96(d,J＝7.9Hz,2H),6.85(m,1H),4.46(s,2H),3.84(s,3H),2.05(s,3H).13C NMR(101MHz,DMSO)δ167.26,165.43,163.37,155.31,155.29,149.78,147.98,136.94,134.21,130.35,124.20,119.19,116.56,114.37,109.72,105.91,55.63,55.57,43.89,15.49,15.45.HR-MS(ESI):Calcd.C20H18N2O6S.[M+Na]+m/z:437.0778,found:437.0786.
Example 20
This example is a preparation of thiazolidinedione 20, which is substantially identical to example 1, except that: in the step (1), 4-tert-butylaniline is used instead of 4-cyanoaniline.
Thiazolidinedione compound 20: (Z) -N- (4- (tert-butyl) phenyl) -2- (5- (4-hydroxy-3-methoxybenzylidene) -2, 4-dioxothiazolin-3-yl) acetamide as a yellow solid in 91% yield, melting point 159.5～160.2℃.1H NMR(400MHz,DMSO-d6)δ10.31(s,1H),10.03(s,1H),7.90(s,1H),7.47(d,J＝8.5Hz,2H),7.34(d,J＝8.5Hz,2H),7.24(d,J＝2.0Hz,1H),7.14(m,1H),6.96(d,J＝8.3Hz,1H),4.49(s,2H),3.84(s,3H),1.26(s,9H).13C NMR(101MHz,DMSO)δ167.24,165.40,163.58,149.81,148.01,145.97,135.82,134.25,125.42,124.33,124.21,118.89,116.58,116.24,114.42,55.67,55.62,43.85,34.00,31.13.HR-MS(ESI):Calcd.C23H24N2O5S.[M+Na]+m/z:463.1298,found:463.1299.
Example 21
This example was conducted to prepare thiazolidinedione 21, which was prepared in substantially the same manner as in example 1 except that: in the step (1), 4-bromoaniline is used instead of 4-cyanoaniline.
Thiazolidinedione compound 21: (Z) -N- (4-bromophenyl) -2- (5- (4-hydroxy-3-methoxybenzylidene) -2, 4-dioxothiazolin-3-yl) acetamide as a white solid in 76% yield, melting point 262.0～262.4℃.1H NMR(400MHz,DMSO-d6)δ10.52(s,1H),10.04(s,1H),7.90(s,1H),7.55–7.49(m,4H),7.24(d,J＝2.1Hz,1H),7.14(m,1H),6.96(d,J＝8.3Hz,1H),4.51(s,2H),3.84(s,3H).13C NMR(101MHz,DMSO)δ167.23,165.36,164.07,149.84,148.00,137.72,134.35,131.66,124.38,124.18,121.08,116.49,116.24,115.29,114.39,55.66,55.61,43.93.HR-MS(ESI):Calcd.C19H15BrN2O5S.[M+Na]+m/z:484.9777,found:484.9787.
Example 22
This example was conducted to prepare thiazolidinedione 22, which was prepared in substantially the same manner as in example 1, except that: in the step (1), 2-bromoaniline is used instead of 4-cyanoaniline.
Thiazolidinedione compound 22: (Z) -N- (2-bromophenyl) -2- (5- (4-hydroxy-3-methoxybenzylidene) -2, 4-dioxothiazolin-3-yl) acetamide as a yellow solid in 82% yield, melting point 274.1～274.2℃.1H NMR(400MHz,DMSO-d6)δ10.01(d,J＝15.5Hz,2H),7.90(s,1H),7.68(m,1H),7.58(m,1H),7.38(t,J＝7.7Hz,1H),7.24(d,J＝2.0Hz,1H),7.19–7.11(m,2H),6.95(d,J＝8.3Hz,1H),4.56(s,2H),3.84(s,3H).13C NMR(101MHz,DMSO)δ167.19,165.34,164.48,149.80,148.01,135.52,134.25,132.77,128.07,127.37,126.96,124.35,124.20,117.65,116.59,116.24,114.40,55.67,55.62,43.66.HR-MS(ESI):Calcd.C19H15BrN2O5S.[M+Na]+m/z:484.9777,found:484.9789.
Example 23
This example was conducted to prepare thiazolidinedione 23, which was prepared in substantially the same manner as in example 1 except that: in the step (1), 3-iodoaniline is used instead of 4-cyanoaniline.
Thiazolidinedione 23: (Z) -2- (5- (4-hydroxy-3-methoxybenzylidene) -2, 4-dioxothiazolin-3-yl) -N- (3-iodophenyl) acetamide as a white solid in 36% yield, melting point 237.2–237.5℃.1H NMR(400MHz,DMSO-d6)δ10.49(s,1H),10.04(s,1H),8.06(s,1H),7.91(s,1H),7.49(m,1H),7.45(d,J＝7.8Hz,1H),7.25(d,J＝2.0Hz,1H),7.14(t,J＝8.0Hz,2H),6.96(d,J＝8.3Hz,1H),4.50(s,2H),3.84(s,3H).13C NMR(101MHz,DMSO)δ167.23,165.35,164.20,149.84,148.01,139.70,134.35,132.21,130.88,127.38,124.37,124.18,118.36,116.49,116.25,114.41,94.58,55.68,55.62,43.92.HR-MS(ESI):Calcd.C19H15IN2O5S.[M+Na]+m/z:532.9638,found:484.9650.
Example 24
This example was conducted to prepare thiazolidinedione 24, which was prepared in substantially the same manner as in example 1, except that: in the step (1), 3-bromo-4-fluoroaniline is used instead of 4-cyanoaniline.
Thiazolidinedione compound 24: (Z) -N- (3-bromo-4-fluorophenyl) -2- (5- (4-hydroxy-3-methoxybenzylidene) -2, 4-dioxothiazolin-3-yl) acetamide as a white solid in 66% yield, melting point 267.4–267.9℃.1H NMR(400MHz,DMSO-d6)δ10.60(s,1H),10.03(s,1H),7.99(m,1H),7.91(s,1H),7.49(m,1H),7.36(t,J＝8.8Hz,1H),7.24(d,J＝2.0Hz,1H),7.14(m,1H),6.96(d,J＝8.3Hz,1H),4.51(s,2H),3.84(s,3H).13C NMR(101MHz,DMSO)δ167.22,165.34,164.23,155.57,153.17,149.87,148.01,135.80,135.77,134.38,124.38,124.15,123.42,120.19,120.12,116.94,116.71,116.44,116.24,114.41,107.77,107.56,55.66,55.60,43.86.HR-MS(ESI):Calcd.C19H14BrFN2O5S.[M+Na]+m/z:502.9683,found:502.9677.
Example 25
This example was conducted to prepare thiazolidinedione 25, which was prepared in substantially the same manner as in example 1 except that: in step (1), 4-methoxybenzylamine is used instead of 4-cyanoaniline.
Thiazolidinedione compound 25: (Z) -2- (5- (4-hydroxy-3-methoxybenzylidene) -2, 4-dioxothiazolin-3-yl) -N- (4-methoxybenzyl) acetamide as a yellow solid in 87% yield, melting point 238.0–238.2℃.1H NMR(400MHz,DMSO-d6)δ10.04(s,1H),8.72(t,J＝5.9Hz,1H),7.87(s,1H),7.23(d,J＝2.0Hz,1H),7.19(d,J＝8.4Hz,2H),7.12(m,1H),6.96(d,J＝8.3Hz,1H),6.92–6.86(m,2H),4.31(s,2H),4.23(d,J＝5.8Hz,2H),3.84(s,3H),3.74(s,3H).13C NMR(101MHz,DMSO)δ167.26,165.43,164.99,158.27,149.78,148.01,133.99,130.76,128.55,124.22,116.80,116.24,114.38,113.70,55.08,55.02,43.38,41.75.HR-MS(ESI):Calcd.C21H20N2O6S.[M+Na]+m/z:451.0934,found:451.0939.
Example 26
This example was conducted to prepare thiazolidinedione compound 26, which was prepared in substantially the same manner as in example 1, except that: in the step (1), 4-trifluoromethyl benzylamine is used instead of 4-cyanoaniline.
Thiazolidinedione compound 26: (Z) -2- (5- (4-hydroxy-3-methoxybenzylidene) -2, 4-dioxothiazolin-3-yl) -N- (4- (trifluoromethyl) benzyl) acetamide as a yellow solid in 64% yield, melting point 244.1–245.4℃.1H NMR(400MHz,DMSO-d6)δ10.02(s,1H),8.90(t,J＝5.9Hz,1H),7.88(s,1H),7.70(d,J＝8.0Hz,2H),7.49(d,J＝8.0Hz,2H),7.23(d,J＝2.0Hz,1H),7.13(m,1H),6.95(d,J＝8.2Hz,1H),4.40(d,J＝5.9Hz,2H),4.36(s,2H),3.84(s,3H).13C NMR(101MHz,DMSO)δ167.28,165.49,165.43,149.75,148.00,143.82,134.05,127.79,127.42,125.62,125.17,125.13,124.23,122.92,116.78,116.23,114.37,55.66,55.60,43.40,41.89.HR-MS(ESI):Calcd.C21H17F3N2O5S.[M+Na]+m/z:489.0702,found:489.0702.
Example 27
This example was conducted to prepare thiazolidinedione 27, which was prepared in substantially the same manner as in example 1 except that: in the step (1), 3-bromobenzylamine is used instead of 4-cyanoaniline.
Thiazolidinedione compound 27: (Z) -N- (3-bromobenzyl) -2- (5- (4-hydroxy-3-methoxybenzylidene) -2, 4-dioxothiazolin-3-yl) acetamide as a white solid in 39% yield, melting point 273.4℃.1H NMR(400MHz,DMSO-d6)δ10.15(s,1H),8.96(t,J＝6.0Hz,1H),7.88(s,1H),7.45(d,J＝9.2Hz,2H),7.32–7.25(m,2H),7.22(d,J＝2.0Hz,1H),7.12(m,1H),7.00(d,J＝8.3Hz,1H),4.36(s,2H),4.31(d,J＝5.9Hz,2H),3.83(s,3H).13C NMR(101MHz,DMSO)δ167.27,165.41,149.90,148.01,141.79,134.07,130.43,129.82,129.67,126.17,124.28,124.13,121.63,116.70,116.27,114.35,55.66,43.42.HR-MS(ESI):Calcd.C20H17BrN2O5S.[M+Na]+m/z:498.9934,found:498.9937.
Example 28
This example was conducted to prepare thiazolidinedione 28, which was prepared in substantially the same manner as in example 1 except that: in the step (1), 3, 4-methylenedioxyaniline is used instead of 4-cyanoaniline.
Thiazolidinedione 28: (Z) -N- (benzo [ d ] [1,3] dioxol-5-yl) -2- (5- (4-hydroxy-3-methoxybenzylidene) -2, 4-dioxothiazolin-3-yl) acetamide as a grey solid in 76% yield, melting point 273.4℃.1H NMR(400MHz,DMSO-d6)δ10.29(s,1H),10.03(s,1H),7.90(s,1H),7.24(d,J＝2.0Hz,2H),7.14(m,1H),6.98–6.91(m,2H),6.87(d,J＝8.4Hz,1H),5.99(s,2H),4.46(s,2H),3.84(s,3H).13C NMR(101MHz,DMSO)δ167.24,165.39,163.47,149.80,148.00,147.10,143.17,134.26,132.74,124.36,124.21,116.55,116.23,114.36,114.34,112.01,108.07,101.30,101.27,101.02,55.64,55.59,43.81.HR-MS(ESI):Calcd.C20H16N2O7S.[M+Na]+m/z:451.0570,found:451.0580.
Example 29
This example was conducted to prepare thiazolidinedione 29, which was prepared in substantially the same manner as in example 1 except that: in the step (1), 3, 4-ethylenedioxyaniline is used instead of 4-cyanoaniline.
Thiazolidinedione 29: (Z) -N- (2, 3-Dihydrobenzo [ b ] [1,4] dioxin-6-yl) -2- (5- (4-hydroxy-3-methoxybenzylidene) -2, 4-dioxothiazolin-3-yl) acetamide, yellow solid, 81% yield, melting point 271.2–273.2℃.1H NMR(400MHz,DMSO-d6)δ10.47(s,1H),10.15(s,1H),7.89(s,1H),7.22(m,2H),7.14(m,1H),7.03–6.97(m,2H),6.79(d,J＝8.7Hz,1H),4.47(s,2H),4.21(d,J＝3.9Hz,4H),3.84(s,3H).13C NMR(101MHz,DMSO)δ167.24,165.39,163.33,149.97,148.02,142.90,139.45,134.25,132.22,124.33,124.09,116.78,116.49,116.27,114.40,112.30,108.19,64.15,63.88,55.67,55.60,43.84.HR-MS(ESI):Calcd.C21H18N2O7S.[M+Na]+m/z:465.0727,found:465.0733.
Example 30
This example is a preparation of thiazolidinedione 30, which is substantially identical to example 1, except that: in the step (1), indoline is used instead of 4-cyanoaniline.
Thiazolidinedione compound 30: (Z) -5- (4-hydroxy-3-methoxybenzylidene) -3- (2- (indolin-1-yl) -2-oxoethyl) thiazolidine-2, 4-dione as a yellow solid, 63% yield, melting point 272.5–272.9℃.1H NMR(400MHz,DMSO-d6)δ10.05(s,1H),7.96(d,J＝8.1Hz,1H),7.92(s,1H),7.31–7.25(m,2H),7.15(m,2H),7.04(t,J＝7.4Hz,1H),6.97(d,J＝8.3Hz,1H),4.71(s,2H),4.26(t,J＝8.4Hz,2H),3.85(s,3H),3.22(t,J＝8.4Hz,2H).13C NMR(101MHz,DMSO)δ167.21,165.37,163.04,149.88,148.02,142.31,134.40,131.73,127.04,124.96,124.34,124.18,123.92,116.50,116.26,115.77,114.50,55.64,54.87,46.44,43.76,27.57.HR-MS(ESI):Calcd.C21H18N2O5S.[M+Na]+m/z:433.0828,found:465.0831.
Example 31
This example is a preparation of thiazolidinedione 31, which is substantially identical to example 1 except that: in step (1), octahydroisoindole is used instead of 4-cyanoaniline.
Thiazolidinedione 31: (Z) -5- (4-hydroxy-3-methoxybenzylidene) -3- (2- (octahydro-2H-isoindol-2-yl) -2-oxoethyl) thiazolidine-2, 4-dione as a yellow solid with 67% yield, melting point 233.4–234.9℃.1H NMR(400MHz,DMSO-d6)δ10.02(s,1H),7.87(s,1H),7.23(d,J＝2.0Hz,1H),7.13(m,1H),6.95(d,J＝8.3Hz,1H),4.55–4.39(m,2H),3.84(s,3H),3.61–3.54(m,1H),3.43(m,1H),3.29(d,J＝6.9Hz,1H),3.20(m,1H),2.30(m,1H),2.15(m,1H),1.65–1.24(m,8H).13C NMR(101MHz,DMSO)δ167.15,165.37,163.46,149.78,148.00,134.10,124.29,124.20,116.62,116.22,114.40,55.66,49.85,48.55,42.92,36.96,35.13,25.28,25.13,22.44,22.02.HR-MS(ESI):Calcd.C21H24N2O5S.[M+Na]+m/z:439.1298,found:439.1297.
Example 32
This example was conducted to prepare thiazolidinedione 32, which was prepared in substantially the same manner as in example 1, except that: in the step (1), cyclohexylamine is used instead of 4-cyanoaniline.
Thiazolidinedione compound 32: (Z) -N-cyclohexyl-2- (5- (4-hydroxy-3-methoxybenzylidene) -2, 4-dioxothiazolin-3-yl) acetamide A white solid, 59% yield, melting point 269.8–269.9℃.1H NMR(400MHz,DMSO-d6)δ10.13(s,1H),8.22(d,J＝7.7Hz,1H),7.86(s,1H),7.22(d,J＝2.0Hz,1H),7.12(m,1H),7.00(d,J＝8.3Hz,1H),4.24(s,2H),3.83(s,3H),3.51(m,1H),1.76–1.65(m,4H),1.54(m,1H),1.29–1.11(m,5H).13C NMR(101MHz,DMSO-d6)δ167.17,165.39,163.85,149.86,147.99,133.97,124.27,124.14,116.66,116.23,114.30,55.63,47.92,43.32,32.25,25.13,24.39.HR-MS(ESI):Calcd.C19H22N2O5S.[M+Na]+m/z:413.1141,found:413.1147.
Example 33
This example provides a thiazolidinedione compound 33 prepared in substantially the same manner as in example 1, except that: in step (1), 4-phenylpiperazin-1-amine is used instead of 4-cyanoaniline.
Thiazolidinedione compound 33: (Z) -5- (4-hydroxy-3-methoxybenzylidene) -3- (2-oxo-2- (4-phenylpiperazin-1-yl) ethyl) thiazolidine-2, 4-dione as a yellow solid with 80% yield and melting point 272.5℃.1H NMR(400MHz,DMSO-d6)δ10.03(s,1H),7.88(s,1H),7.28–7.20(m,3H),7.14(m,1H),6.97(t,J＝7.8Hz,3H),6.83(t,J＝7.3Hz,1H),4.66(s,2H),3.84(s,3H),3.65(m,4H),3.18(m,4H).13C NMR(101MHz,DMSO)δ167.21,165.41,163.29,150.67,149.81,148.01,134.19,128.98,124.32,124.18,119.41,116.58,116.23,115.93,114.42,48.56,48.14,43.93,42.54,41.55.HR-MS(ESI):Calcd.C23H23N3O5S.[M+Na]+m/z:476.1250,found:476.1257.
Example 34
This example was conducted to prepare thiazolidinedione 34, which was prepared in substantially the same manner as in example 1, except that: in step (1), 4- (4-nitrophenyl) piperazin-1-amine was used instead of 4-cyanoaniline.
Thiazolidinedione 34: (Z) -5- (4-hydroxy-3-methoxybenzylidene) -3- (2- (4- (4-nitrophenyl) piperazin-1-yl) -2-oxoethyl) thiazolidine-2, 4-dione as a yellow solid in 68% yield, melting point 267.9～268.2℃.1H NMR(400MHz,DMSO-d6)δ10.07(s,1H),8.09(d,J＝9.5Hz,2H),7.89(s,1H),7.25(d,J＝2.1Hz,1H),7.14(m,1H),7.04(m,2H),6.96(d,J＝8.3Hz,1H),4.68(s,2H),3.84(s,3H),3.74(m,2H),3.64–3.59(m,4H),3.53(m,2H).13C NMR(101MHz,DMSO)δ167.21,165.40,163.62,163.57,154.23,149.78,147.98,136.98,134.21,125.69,124.29,124.16,116.53,116.21,112.53,55.64,55.58,45.83,45.58,43.12,42.54,42.26.HR-MS(ESI):Calcd.C23H22N4O7S.[M+Na]+m/z:521.1101,found:521.1105.
Example 35
This example was conducted to prepare thiazolidinedione 35, which was prepared in substantially the same manner as in example 1 except that: in the step (1), procaine is adopted to replace 4-cyanoaniline.
Thiazolidinedione 35:2- (diethylamino) ethyl (Z) -4- (2- (5- (4-hydroxy-3-methoxybenzylidene) -2, 4-dioxothiazolin-3-yl) acetamido) benzoate, a brown solid, 51% yield, melting point 180.1–182.7℃.1H NMR(400MHz,DMSO-d6)δ10.79(s,1H),7.97–7.90(m,3H),7.71(d,J＝8.6Hz,2H),7.24(d,J＝2.0Hz,1H),7.15(m,1H),6.97(d,J＝8.3Hz,1H),4.56(s,2H),4.33(t,J＝5.9Hz,2H),3.84(s,3H),2.88(s,2H),2.65(s,4H),1.91(s,2H),1.01(t,J＝7.1Hz,6H).13C NMR(101MHz,DMSO-d6)δ167.23,165.35,165.11,164.54,149.89,148.02,142.73,134.39,130.36,124.50,124.38,124.15,118.60,116.45,116.25,114.42,62.19,55.67,50.48,47.01,44.02,11.35.HR-MS(ESI):Calcd.C26H29N3O7S.[M+H]+m/z:528.1799,found:528.1797.
Example 36
This example was conducted to prepare thiazolidinedione 36, which was prepared in substantially the same manner as in example 1 except that: in step (1) N- [2- (diethylamino) ethyl ] -4-aminobenzamide was used instead of 4-cyanoaniline.
Thiazolidinedione 36: (Z) -N- (2- (diethylamino) ethyl) -4- (2- (5- (4-hydroxy-3-methoxybenzylidene) -2, 4-dioxothiazolin-3-yl) acetamido) benzamide as a yellow solid in 62% yield, melting point 150.1–150.7℃.1H NMR(400MHz,DMSO-d6)δ10.69(s,1H),8.37(t,J＝5.6Hz,1H),7.91(s,1H),7.82(d,J＝8.4Hz,2H),7.64(d,J＝8.4Hz,2H),7.25(d,J＝2.0Hz,1H),7.15(m,1H),6.97(d,J＝8.2Hz,1H),4.54(s,2H),3.84(s,3H),3.37(m,2H),2.68(m,2H),2.62(m,2H),1.91(s,1H),1.01(t,J＝7.1Hz,6H).13C NMR(101MHz,DMSO)δ167.24,165.53,165.37,164.26,149.95,148.03,140.87,134.36,129.38,128.06,124.12,118.35,116.43,116.26,114.42,55.68,55.62,51.19,46.73,43.98,36.87,11.23.HR-MS(ESI):Calcd.C26H29N3O7S.[M+H]+m/z:527.1959,found:527.1957.
Example 37
This example was conducted to prepare thiazolidinedione 37, which was prepared in substantially the same manner as in example 1 except that: in the step (1), 2-furanmethanamine is used to replace 4-cyanoaniline.
Thiazolidinedione 37: (Z) -N- (furan-2-ylmethyl) -2- (5- (4-hydroxy-3-methoxybenzylidene) -2, 4-dioxothiazolin-3-yl) acetamide as a white solid in 43% yield, melting point 244.3–244.5℃.1H NMR(400MHz,DMSO-d6)δ10.02(s,1H),8.75(t,J＝5.6Hz,1H),7.87(s,1H),7.60(d,J＝1.7Hz,1H),7.23(d,J＝2.0Hz,1H),7.13(m,1H),6.95(d,J＝8.3Hz,1H),6.41(m,1H),6.27(d,J＝3.2Hz,1H),4.30(s,4H),3.84(s,3H).13C NMR(101MHz,DMSO)δ167.24,165.40,165.05,151.64,149.74,147.99,142.25,142.22,134.02,124.27,124.23,116.76,116.22,114.36,110.44,107.07,55.66,55.61,43.25,35.66.HR-MS(ESI):Calcd.C18H16N2O6S.[M+Na]+m/z:411.0621,found:411.0626.
Example 38
This example was conducted to prepare thiazolidinedione 38, which was prepared in substantially the same manner as in example 1 except that: in the step (1), 2-thiophenemethylamine is used instead of 4-cyanoaniline.
Thiazolidinedione 38: (Z) -2- (5- (4-hydroxy-3-methoxybenzylidene) -2, 4-dioxothiazolin-3-yl) -N- (thiophen-2-ylmethyl) acetamide as a yellow solid, 79% yield, melting point 249.5–250.3℃.1H NMR(400MHz,DMSO-d6)δ10.08(s,1H),8.92(t,J＝5.8Hz,1H),7.88(s,1H),7.41(m,1H),7.23(d,J＝2.0Hz,1H),7.13(m,1H),7.00–6.95(m,3H),4.46(d,J＝5.8Hz,2H),4.30(s,2H),3.83(s,3H).13C NMR(101MHz,DMSO)δ167.22,165.38,165.02,149.83,148.01,141.64,134.03,126.65,125.55,125.17,124.26,124.19,116.75,116.25,114.39,55.67,43.29,37.33.HR-MS(ESI):Calcd.C18H16N2O5S2.[M+Na]+m/z:427.0393,found:427.0394.
Example 39
The preparation of thiazolidinedione 39 was carried out in this example as follows:
The preparation of intermediate compound d used in the preparation of thiazolidinedione 39 was substantially the same as in example 1, except that: in the step (1), N-tert-butylcarbonyl-4-aminopiperidine is adopted to replace 4-cyanoaniline, and the compound finally obtained in the step (3) is named as an intermediate compound d. In the structural formula of the intermediate compound d, boc is tert-butylcarbonyl.
Intermediate compound d (300 mg,1.0 eq.) of compound 39 was added to a 50mL eggplant-shaped bottle, and 10mL of trifluoroacetic acid and dichloromethane each were added. Stirred overnight at room temperature and the reaction was monitored by TLC (PE: ea=1:2). After completion of the reaction, the solution pH was adjusted to neutral by adding saturated sodium bicarbonate solution, and then the reaction solution was extracted three times with methylene chloride, and the organic phase was dried over anhydrous sodium sulfate. After filtration, the solvent was dried by spin-drying, and recrystallized from ethyl acetate to give compound 39.
Thiazolidinedione 39: (Z) -3- (2- (4-aminopiperidin-1-yl) -2-oxoethyl) -5- (4-hydroxy-3-methoxybenzylidene) thiazoline-2, 4-dione 2, 2-trifluoroacetate salt as a yellow solid, 41% yield, melting point 293.7℃.1H NMR(400MHz,DMSO-d6)δ7.74(s,1H),7.06–7.00(m,2H),6.65(d,J＝8.3Hz,1H),4.52(s,2H),3.76(s,3H),3.43(m,3H),3.36(m,3H),2.83–2.56(m,3H).13C NMR(101MHz,DMSO)δ167.49,165.32,163.29,149.39,134.91,126.79,117.45,113.41,55.21,42.39.HR-MS(ESI):Calcd.C18H21N3O5S.[M+H]+m/z:392.1275,found:392.1275.
Example 40
This example was conducted to prepare thiazolidinedione 40, which was prepared in substantially the same manner as in example 39 except that: in the preparation of intermediate compound d, N-t-butoxycarbonyl-3-aminopiperidine was used in place of 4-cyanoaniline in step (1).
Thiazolidinedione compound 40: (Z) -3- (2- (3-aminopiperidin-1-yl) -2-oxoethyl) -5- (4-hydroxy-3-methoxybenzylidene) thiazolidine-2, 4-dione 2, 2-trifluoroacetate salt as a white solid, 68% yield, melting point 236.2–236.4℃.1H NMR(400MHz,DMSO-d6)δ8.09(s,2H),7.88(s,1H),7.24(s,1H),7.13(d,J＝8.3Hz,1H),6.96(d,J＝8.3Hz,1H),4.62(s,2H),4.29–4.21(m,1H),3.98–3.86(m,1H),3.84(m,3H),3.77(m,1H),3.27(m,1H),3.21–3.04(m,1H),3.00–2.86(m,1H),2.00(m,1H),1.77(m,1H),1.56(m,2H).13C NMR(101MHz,DMSO)δ167.16,165.33,163.82,163.42,158.62,158.31,149.88,147.99,134.23,124.32,124.11,124.09,118.56,116.51,116.42,116.21,115.58,114.35,55.60,55.55,46.64,46.06,43.98,42.52,27.81,22.77.HR-MS(ESI):Calcd.C18H21N3O5S.[M+H]+m/z:392.1275,found:392.1283.
Example 41
This example was conducted to prepare thiazolidinedione compound 41, which was prepared in substantially the same manner as in example 39 except that: in the preparation of intermediate compound d, tert-butyl (4-amino-1-methylcyclohexyl) carbamate is used in step (1) instead of 4-cyanoaniline.
Thiazolidinedione compound 41: (Z) -3- (2- (4-amino-4-methylpiperidin-1-yl) -2-oxoethyl) -5- (4-hydroxy-3-methoxybenzylidene) thiazolidine-2, 4-dione 2, 2-trifluoroacetate salt, white solid, 57% yield, melting point 230.3–231.8℃.1H NMR(400MHz,DMSO-d6)δ10.10(s,1H),8.04(s,3H),7.88(s,1H),7.24(d,J＝2.0Hz,1H),7.16–7.11(m,1H),6.96(m,1H),4.71–4.55(m,2H),3.98–3.90(m,1H),3.84(s,3H),3.79(d,J＝13.7Hz,1H),3.40(d,J＝7.4Hz,1H),3.16–3.08(m,1H),1.78–1.73(m,2H),1.64(m,2H),1.36(s,3H).13C NMR(101MHz,DMSO)δ167.22,165.39,163.13,158.41,149.83,147.99,134.19,124.31,124.12,116.52,116.21,114.37,55.62,55.56,51.72,42.52,37.51,34.97,34.14,21.84.HR-MS(ESI):Calcd.C19H23N3O5S.[M+Na]+m/z:428.1250,found:428.1258.
Example 42
This example was conducted to prepare thiazolidinedione 42, which was prepared in substantially the same manner as in example 39 except that: in the preparation of intermediate compound d, 1-t-butoxycarbonyl-3-aminopiperidine was used instead of 4-cyanoaniline in step (1) in place of 4-cyanoaniline.
Thiazolidinedione compound 42: (Z) -2- (5- (4-hydroxy-3-methoxybenzylidene) -2, 4-dioxothiazolin-3-yl) -N- (piperidin-3-yl) acetamide 2, 2-trifluoroacetate salt as a yellow solid with 58% yield, melting point 197.8–200.8℃.1H NMR(400MHz,DMSO-d6)δ8.16(s,2H),7.87(s,1H),7.23(d,J＝2.0Hz,1H),7.13(m,1H),6.96(d,J＝8.3Hz,1H),4.70–4.53(m,2H),3.92(m,1H),3.84(s,3H),3.82–3.74(m,1H),3.41(d,J＝7.5Hz,1H),3.14(m,1H),1.77(m,2H),1.70–1.58(m,2H),1.36(s,3H).13C NMR(101MHz,DMSO)δ167.18,165.35,164.99,163.14,158.62,158.31,149.86,148.01,134.16,124.33,124.14,116.57,116.23,114.37,55.65,51.70,45.98,42.76,27.69,20.52.HR-MS(ESI):Calcd.C18H21N3O5S.[M+H]+m/z:392.1275,found:392.1278.
Example 43
This example was conducted to prepare thiazolidinedione 43, which was prepared in substantially the same manner as in example 39 except that: in the preparation of intermediate compound d, step (1) employs 3-aminopyrrolidine-1-carboxylic acid tert-butyl ester instead of 4-cyanoaniline.
Thiazolidinedione 43: (Z) -2- (5- (4-hydroxy-3-methoxybenzylidene) -2, 4-dioxothiazolin-3-yl) -N- (pyrrolidin-3-yl) acetamide 2, 2-trifluoroacetate in a yellow solid with 63% yield, melting point 192.5–194.4℃.1H NMR(400MHz,DMSO-d6)δ10.12(s,1H),9.03(d,J＝37.2Hz,2H),8.71(d,J＝6.2Hz,1H),7.87(s,1H),7.22(d,J＝2.0Hz,1H),7.13(m,1H),6.96(d,J＝8.3Hz,1H),4.29(s,2H),3.89(s,1H),3.84(s,3H),3.26(m,2H),3.00(m,1H),2.23–2.11(m,2H),1.86(m,1H).13C NMR(101MHz,DMSO)δ171.95,167.19,165.45,165.33,156.94,149.86,148.01,134.18,124.33,124.13,116.54,116.22,114.34,55.64,55.58,49.05,47.60,43.66,29.64.HR-MS(ESI):Calcd.C17H19N3O5S.[M+H]+m/z:378.1118,found:378.1125.
Example 44
This example was conducted to prepare thiazolidinedione compound 44, which was prepared in substantially the same manner as in example 1, except that: in the step (1), 4-amino aniline is used instead of 4-cyano aniline.
Thiazolidinedione compound 44: (Z) -N- (4-aminophenyl) -2- (5- (4-hydroxy-3-methoxybenzylidene) -2, 4-dioxothiazolin-3-yl) acetamide as a yellow solid in 64% yield, melting point 291.1℃.1H NMR(400MHz,DMSO-d6)δ9.93(s,1H),7.70(s,1H),7.19(d,J＝8.7Hz,2H),7.02(m,1H),6.94(d,J＝2.2Hz,1H),6.50(d,J＝8.7Hz,3H),4.88(s,1H),4.37(s,2H),3.73(s,3H).13C NMR(101MHz,DMSO)δ167.53,165.36,162.92,149.48,145.00,134.93,127.63,126.85,120.79,119.24,117.46,113.80,113.41,110.91,55.29,55.25,43.58.HR-MS(ESI):Calcd.C19H17N3O5S.[M+Na]+m/z:422.0781,found:422.0777.
Example 45
This example was conducted to prepare thiazolidinedione 45, which was prepared in substantially the same manner as in example 1 except that: in the step (1), 3-amino aniline is used instead of 4-cyano aniline.
Thiazolidinedione compound 45: (Z) -N- (3-aminophenyl) -2- (5- (4-hydroxy-3-methoxybenzylidene) -2, 4-dioxothiazolin-3-yl) acetamide as a yellow solid in 47% yield, melting point 239.9–240.4℃.1H NMR(400MHz,DMSO-d6)δ10.08(s,1H),10.04(s,1H),7.90(s,1H),7.24(d,J＝2.0Hz,1H),7.14(m,1H),6.94(m,2H),6.87(d,J＝2.1Hz,1H),6.70–6.66(m,1H),6.29(m,1H),5.30–5.15(m,2H),4.46(s,2H),3.84(s,3H).13C NMR(101MHz,DMSO)δ167.26,165.43,163.38,149.79,148.77,148.00,139.00,134.18,129.03,124.32,124.21,116.61,116.24,114.40,109.82,107.19,104.96,55.67,55.62,43.93.HR-MS(ESI):Calcd.C19H17N3O5S.[M+Na]+m/z:422.0781,found:422.0786.
Example 46
This example was conducted to prepare thiazolidinedione 46, which was prepared in substantially the same manner as in example 39 except that: in the preparation of intermediate compound d, 1-t-butoxycarbonyl-4- (4-aminophenyl) piperazine was used in step (1) instead of 4-cyanoaniline.
Thiazolidinedione 46: (Z) -2- (5- (4-hydroxy-3-methoxybenzylidene) -2, 4-dioxothiazolin-3-yl) -N- (4- (piperazin-1-yl) phenyl) acetamide 2, 2-trifluoroacetate as a yellow solid, 59% yield, melting point 171.6–171.9℃.1H NMR(400MHz,DMSO-d6)δ10.26(s,1H),10.10(s,1H),8.77(s,2H),7.90(s,1H),7.45(d,J＝8.6Hz,2H),7.25(d,J＝2.0Hz,1H),7.14(d,J＝8.3Hz,1H),6.99–6.94(m,3H),4.47(s,2H),3.84(s,3H),3.28(m,4H),3.23(m,4H).13C NMR(101MHz,DMSO)δ167.28,165.42,163.30,158.78,149.85,147.99,146.28,134.23,131.40,124.33,124.15,120.23,116.53,116.46,116.22,114.34,55.61,55.55,45.91,43.77,42.65.HR-MS(ESI):Calcd.C23H24N4O5S.[M+Na]+m/z:469.1540,found:469.1553.
Example 47
This example was conducted to prepare thiazolidinedione 47, which was prepared in substantially the same manner as in example 39 except that: in the preparation of intermediate compound d, N-t-butoxycarbonyl-1, 2-ethylenediamine was used in place of 4-cyanoaniline in step (1).
Thiazolidinedione compound 47: (Z) -N- (2-aminoethyl) -2- (5- (4-hydroxy-3-methoxybenzylidene) -2, 4-dioxothiazolin-3-yl) acetamide 2, 2-trifluoroacetate salt as a yellow solid in 37% yield, melting point 185.2–187.7℃.1H NMR(400MHz,DMSO-d6)δ10.09(s,1H),8.50(t,J＝5.7Hz,1H),7.87(s,4H),7.22(d,J＝2.1Hz,1H),7.13(m,1H),6.96(d,J＝8.3Hz,1H),4.32(s,2H),3.84(s,3H),3.32(d,J＝6.4Hz,2H),2.88(t,J＝6.5Hz,2H).13C NMR(101MHz,DMSO)δ167.21,165.99,165.37,149.83,148.02,134.12,124.31,124.16,116.63,116.24,114.39,55.68,55.61,43.31,38.28,36.57.HR-MS(ESI):Calcd.C15H17N3O5S.[M+Na]+m/z:374.0781,found:374.0782.
Example 48
This example was conducted to prepare thiazolidinedione 48, which was prepared in substantially the same manner as in example 39 except that: in the preparation of intermediate compound d, N-t-butoxycarbonyl-1, 3-propanediamine was used in place of 4-cyanoaniline in step (1).
Thiazolidinedione 48: (Z) -N- (3-aminopropyl) -2- (5- (4-hydroxy-3-methoxybenzylidene) -2, 4-dioxothiazolin-3-yl) acetamide 2, 2-trifluoroacetate salt, brown solid, 68% yield, melting point 219.6–219.8℃.1H NMR(400MHz,DMSO-d6)δ10.08(s,1H),8.42(t,J＝5.7Hz,1H),7.87(s,1H),7.73(s,3H),7.22(d,J＝2.0Hz,1H),7.12(m,1H),6.96(d,J＝8.2Hz,1H),4.27(s,2H),3.84(s,3H),3.16(m,2H),2.79(m,2H),1.70(m,2H).13C NMR(101MHz,DMSO)δ167.25,165.49,165.39,149.84,148.01,134.03,124.15,116.70,116.23,114.31,55.65,55.59,43.30,36.70,35.90,27.27.HR-MS(ESI):Calcd.C16H19N3O5S.[M+Na]+m/z:388.0937,found:388.0937.
Example 49
This example was conducted to prepare thiazolidinedione 49, which was prepared in substantially the same manner as in example 39 except that: in the preparation of intermediate compound d, N-t-butoxycarbonyl-1, 4-butanediamine was used in place of 4-cyanoaniline in step (1).
Thiazolidinedione 49: (Z) -N- (4-aminobutyl) -2- (5- (4-hydroxy-3-methoxybenzylidene) -2, 4-dioxothiazolin-3-yl) acetamide 2, 2-trifluoroacetate salt as yellow solid with 64% yield, melting point 224.2～225.2℃.1H NMR(400MHz,DMSO-d6)δ10.07(s,1H),8.32(t,J＝5.7Hz,1H),7.86(s,1H),7.71(s,3H),7.22(d,J＝2.0Hz,1H),7.12(m,1H),6.96(d,J＝8.3Hz,1H),4.25(s,2H),3.84(s,3H),3.10(q,J＝6.3Hz,2H),2.80(m,2H),1.57–1.50(m,2H),1.49–1.41(m,2H).13C NMR(101MHz,DMSO)δ167.23,165.40,165.01,149.80,148.01,133.98,124.28,124.18,116.76,116.23,114.33,55.66,55.60,43.29,38.48,38.15,25.94,24.45.HR-MS(ESI):Calcd.C17H21N3O5S.[M+Na]+m/z:402.1094,found:402.1096.
Example 50
This example was conducted to prepare thiazolidinedione 50, which was prepared in substantially the same manner as in example 39 except that: in the preparation of intermediate compound d, N-t-butoxycarbonyl-1, 5-pentanediamine was used in place of 4-cyanoaniline in step (1).
Thiazolidinedione 50: (Z) -N- (5-aminopentyl) -2- (5- (4-hydroxy-3-methoxybenzylidene) -2, 4-dioxothiazolin-3-yl) acetamide 2, 2-trifluoroacetate salt as a yellow solid in 77% yield, melting point 214.4～216.3℃.1H NMR(400MHz,DMSO-d6)δ10.07(s,1H),8.27(t,J＝5.6Hz,1H),7.86(s,1H),7.73(s,3H),7.22(d,J＝2.0Hz,1H),7.12(m,1H),6.96(d,J＝8.3Hz,1H),4.25(s,2H),3.84(s,3H),3.08(m,2H),2.76(m,2H),1.54(m,2H),1.43(m,2H),1.35–1.26(m,2H).13C NMR(101MHz,DMSO)δ167.23,165.41,164.89,149.80,148.01,133.96,124.19,116.76,116.23,114.33,55.66,55.60,43.31,38.68,38.42,28.32,26.54,23.03.HR-MS(ESI):Calcd.C18H23N3O5S.[M+Na]+m/z:416.1250,found:416.1251.
Example 51
This example was conducted to prepare thiazolidinedione 51, which was prepared in substantially the same manner as in example 39 except that: in the preparation of intermediate compound d, N-t-butoxycarbonyl-1, 6-hexamethylenediamine was used in place of 4-cyanoaniline in step (1).
Thiazolidinedione 51: (Z) -N- (6-aminohexyl) -2- (5- (4-hydroxy-3-methoxybenzylidene) -2, 4-dioxothiazolin-3-yl) acetamide 2, 2-trifluoroacetate salt as a yellow solid in 79% yield, melting point 149.9～150.3℃.1H NMR(400MHz,DMSO-d6)δ10.07(s,1H),8.26(t,J＝5.6Hz,1H),7.87(s,1H),7.72(s,3H),7.23(d,J＝2.0Hz,1H),7.13(m,1H),6.96(d,J＝8.3Hz,1H),4.25(s,2H),3.84(s,3H),3.08(m,2H),2.78(m,2H),1.53(m,2H),1.42(m,2H),1.29(m,5H),0.84(m,1H).13C NMR(101MHz,DMSO)δ167.22,165.41,164.83,149.79,148.01,133.95,124.20,116.78,116.23,114.36,55.67,55.60,43.32,28.70,26.88,25.72,25.39.HR-MS(ESI):Calcd.C19H25N3O5S.[M+H]+m/z:408.1588,found:408.1592.
Example 52
This example was conducted to prepare thiazolidinedione 52, which was prepared in substantially the same manner as in example 39 except that: in the preparation of intermediate compound d, step (1) employs tert-butyl 2-aminoethyl (ethyl) carbamate instead of 4-cyanoaniline.
Thiazolidinedione 52: (Z) -N- (2- (ethylamino) ethyl) -2- (5- (4-hydroxy-3-methoxybenzylidene) -2, 4-dioxothiazolin-3-yl) acetamide 2, 2-trifluoroacetate salt as a yellow solid, 34% yield, melting point 164.7～164.9℃.1H NMR(400MHz,DMSO-d6)δ10.10(s,1H),8.56(m,1H),8.50(m,2H),7.87(s,1H),7.22(d,J＝2.1Hz,1H),7.13(m,1H),6.96(d,J＝8.3Hz,1H),4.32(s,2H),3.84(s,3H),2.98(s,6H),1.17(m,4H).13C NMR(101MHz,DMSO)δ171.52,167.21,165.97,165.95,165.36,149.85,148.02,134.12,124.31,124.15,116.62,116.23,114.38,55.66,55.60,45.29,43.29,41.88,35.32,10.88.HR-MS(ESI):Calcd.C17H21N3O5S.[M+H]+m/z:380.1275,found:380.1284.
Experimental example
LSD1 inhibitory activity assay: the samples are thiazolidinedione compounds synthesized in examples 1 to 52; sample stock solution: 1-2 mg of the sample was weighed and placed in a 1.5mL EP tube, and 100% DMSO was added to prepare 10mM stock solutions of the compound, respectively. The same solution was used for dilution according to the measured concentration. Then 5nM of recombinant LSD1 protein, 25mM of a mixture of substrate H3K4me2, fluorescent reagent and horseradish peroxidase were added and incubated for 30min at room temperature. The fluorescence value at the wavelength of 530nm/590nm is monitored by an enzyme-labeled instrument, and the IC50 value is calculated by adopting SPSS software. The inhibition rate calculation formula is shown below. Experimental results IC 50 values were calculated using SPSS software and the results are shown in table 1.
TABLE 1 LSD1 inhibitory Activity of thiazolidinediones according to the invention
Numbering of compounds LSD1 IC50(μM) Numbering of compounds LSD1 IC50(μM)
1 ＞10 28 ＞10
2 ＞10 29 0.12
3 ＞10 30 ＞10
4 ＞10 31 0.25
5 1.83 32 0.43
6 4.97 33 0.33
7 ＞10 34 ＞10
8 0.09 35 0.039
9 ＞10 36 0.49
10 ＞10 37 0.06
11 0.45 38 ＞10
12 0.40 39 0.41
13 ＞10 40 0.10
14 0.71 41 0.55
15 ＞10 42 0.81
16 1.24 43 1.13
17 0.25 44 1.02
18 0.32 45 0.17
19 ＞10 46 0.35
20 ＞10 47 0.039
21 ＞10 48 0.33
22 ＞10 49 0.74
23 ＞10 50 0.60
24 0.94 51 0.65
25 ＞10 52 0.53
26 0.13 TCP 27.23
27 0.28
As shown in Table 1, the thiazolidinedione compound provided by the invention has good histone lysine demethylase inhibitory activity, and is obviously superior to positive control drug phencyclized propylamine (TCP). Wherein, the IC 50 of 28 compounds (specifically, the compounds 8, 11-12, 14, 17-18, 24, 26-27, 29, 31-33, 35-37, 39-42, 45-52) in the compounds are less than 1 mu M, especially, the IC 50 of the compound 35 and the compound 47 is only 0.039 mu M, which is 1/698 of the positive control drug TCP, and achieves or is obviously better than the partial clinical study drugs (IMG-7289 is 0.1 mu M, ORY-2001 is 0.1 mu M, GSK2879552 is 0.024 mu M, SP-2577 is 0.127 mu M, etc.).
In conclusion, the thiazolidinedione compound provided by the invention has good inhibitory activity on LSD1, and part of the compound has obvious advantages compared with the clinical-stage inhibitor at the present stage, shows good development potential, provides new compound entity and research direction for developing novel anti-tumor drugs and combined drugs of the drugs and novel LSD1 inhibitor drugs, and has good application prospect.

Claims (7)

1. A thiazolidinedione compound, characterized by being a compound of the following structure:
2. the method for preparing thiazolidinedione compounds according to claim 1, wherein the following synthetic route is adopted:
The preparation method of the thiazolidinedione compound shown in the formula 35 comprises the following steps:
(1) Procaine, bromoacetyl bromide and alkaline substances react in a solvent A, and after the reaction, the reaction is extracted and concentrated to obtain an intermediate b;
(2) Reacting the intermediate B, 2, 4-thiazolidinedione and alkali in a solvent B, extracting and concentrating after the reaction to obtain an intermediate c;
(3) Reacting the intermediate C, 3-methoxy-4-hydroxybenzaldehyde and a catalyst in a solvent C, and extracting, concentrating and purifying after the reaction to obtain a thiazolidinedione compound of formula 35;
the preparation method of the thiazolidinedione compound shown in the formula 47 comprises the following steps:
(a) Reacting N-tert-butoxycarbonyl-1, 2-ethylenediamine, bromoacetyl bromide and an alkaline substance in a solvent A, extracting and concentrating after the reaction to obtain an intermediate b;
(b) Reacting the intermediate B, 2, 4-thiazolidinedione and alkali in a solvent B, extracting and concentrating after the reaction to obtain an intermediate c;
(c) Reacting the intermediate C, 3-methoxy-4-hydroxybenzaldehyde and a catalyst in a solvent C, and extracting, concentrating and purifying after the reaction to obtain an intermediate d; intermediate d is reacted with trifluoroacetic acid to provide the thiazolidinedione compound of formula 47.
3. The method for preparing thiazolidinedione compounds according to claim 2, wherein in step (1) and step (a), the solvent a is one or more of tetrahydrofuran, acetonitrile, dimethylformamide, dichloromethane, chloroform, and dioxane; the alkaline substance is one or more of triethylamine, N-diisopropylethylamine, cesium carbonate, potassium carbonate, sodium hydroxide and potassium hydroxide.
4. The method for preparing thiazolidinedione compounds according to claim 2, wherein in step (2) and step (B), the solvent B is one or more of tetrahydrofuran, acetonitrile, dimethylformamide and dimethyl sulfoxide; the alkali is one or more of cesium carbonate, potassium carbonate, sodium hydroxide and potassium hydroxide.
5. The method for preparing thiazolidinedione compounds according to claim 2, wherein in step (3) and step (C), the solvent C is one or more of water, methanol, ethanol, propylene glycol, dimethylformamide, and dimethyl sulfoxide; the catalyst is one or more of ammonium acetate, sodium acetate, acetic acid, 2, 6-tetramethyl piperidine, cesium carbonate, sodium carbonate, potassium iodide, potassium carbonate, potassium bisulfate, ethanolamine and sodium bicarbonate.
6. The method for producing thiazolidinedione compounds according to claim 2, wherein in step (1) and step (a), the reaction is carried out at a temperature of 0 to 60 ℃ for 1 to 8 hours; in the step (2) and the step (b), the reaction is carried out for 2 to 8 hours at the temperature of 20 to 100 ℃; in the step (3) and the step (c), the reaction is carried out for 4-8 hours at the temperature of 60-120 ℃.
7. The use of thiazolidinediones according to claim 1, wherein the use of thiazolidinediones for the preparation of inhibitors based on LSD1 targets.
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