CN111349033A - Derivative broad-spectrum antitumor drug based on disulfiram structure and preparation method thereof - Google Patents

Derivative broad-spectrum antitumor drug based on disulfiram structure and preparation method thereof Download PDF

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CN111349033A
CN111349033A CN201811606503.8A CN201811606503A CN111349033A CN 111349033 A CN111349033 A CN 111349033A CN 201811606503 A CN201811606503 A CN 201811606503A CN 111349033 A CN111349033 A CN 111349033A
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章余妹
杜剑平
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Abstract

The invention discloses a derivative broad-spectrum anti-tumor medicament based on a disulfiram structure and a preparation method thereof. The invention provides a compound shown in structural formula I-structural formula IX, a preparation method thereof and application of the compound in preparing medicaments for treating tumors.

Description

Derivative broad-spectrum antitumor drug based on disulfiram structure and preparation method thereof
Technical Field
The invention relates to a broad-spectrum antitumor drug based on disulfiram (metabolite) structure derivatives and a preparation method thereof
Background
Disulfiram is an anti-alcohol drug with more than sixty years history, and a small amount of alcohol after the alcohol addict takes the drug can immediately generate disulfiram reaction, thereby achieving the aim of giving up the alcohol. In 1977, Lewison first reported that disulfiram has a potential effect of inhibiting tumor thought cells: a female patient with multiple metastases of breast cancer experienced tumor regression during the 10 years of administration of disulfiram for alcohol dependence. A series of drug analyses later found that disulfiram had cytotoxic effects in human cancer cell lines, ranging from acute and chronic lymphocytic leukemia, lymphoma, breast cancer, colorectal cancer, non-small cell lung cancer, ovarian cancer and renal cancer. An article from nature, 12 months 2017 reported by Skrott et al, which screened 3000 patients taking disulfiram on a 24-thousand cancer patient epidemiological survey in denmark, wherein the mortality rate of patients who continued to take 1177 patients decreased by 34%. The article demonstrates that: the disulfiram metabolite DDTC and copper ions form a copper-containing complex CuET which can target the nucleoprotein localization factor-4 (NPL4), bind with the CuET and induce aggregation, and inhibit a p97-NPL4 signal channel, wherein the channel supports tumor growth. Apparently disulfiram may be a small molecule drug with a broad spectrum of anti-tumor effects.
From the analysis of the currently published clinical epidemic data, the effect of inhibiting the tumor is not clear when the disulfiram is taken alone, the disulfiram has the effect of inhibiting the tumor only by being complexed with copper ions or being combined with ethanol, and based on the knowledge, the hydroxyl is added on the side chain of the disulfiram by an organic synthesis method, or disulfiram metabolite (DTC) copper ion complex, etc. 2 ways to synthesize the novel derivative, the novel derivative is absorbed by tumor cells and metabolized by the tumor cells, the effect is equivalent to that the disulfiram and ethanol jointly act on the tumor cells, or the DTC and copper ion complex (copper complex CuET) acts on the tumor cells (at the moment, the migration of copper ions between normal somatic cells and the tumor cells is avoided, and the influence on the functions of the normal somatic cells caused by the lack of the copper ions is avoided), so that the effect of inhibiting the tumor cells is achieved.
Disclosure of Invention
The invention aims to provide a derivative broad-spectrum anti-tumor medicament based on a disulfiram structure so as to provide more medicament selection ways for treating tumors in human beings.
Specifically, the invention provides compounds shown in structural formulas I to IX, a preparation method thereof and application of the compounds in preparing medicaments for treating tumors.
The compound of the invention is selected from two types of compounds, one type is disulfiram derivatives such as a compound I, a compound II, a compound III, a compound IV, a compound V and a compound VI; another class is derivatives of copper ion complexes of disulfiram metabolites such as compound VII, compound VIII or compound IX.
Wherein the chemical structural formula, the molecular formula and the molecular weight of the disulfiram derivative are respectively as follows:
a compound of formula I, having a molecular formula of C10H20N2002S4 and a molecular weight of 328.5200;
Figure BSA0000176604190000011
a compound of formula II, having a molecular formula of C17H26N204S5 and a molecular weight of 482.7050;
Figure BSA0000176604190000012
the compound with the structural formula III has the molecular formula of C10H20N200S4 and the molecular weight of 312.5230;
Figure BSA0000176604190000021
the compound with the structural formula IV has the molecular formula of C10H18N20S4 and the molecular weight of 310.5070;
Figure BSA0000176604190000022
a compound of formula V, molecular formula C10H18N202S4, molecular weight 326.5200;
Figure BSA0000176604190000023
the compound with the structural formula VI has the molecular formula of C12H22N202S4 and the molecular weight of 354.5600;
Figure BSA0000176604190000024
the chemical structural formula, the molecular formula and the molecular weight of the derivative of the disulfiram metabolite copper ion complex are respectively as follows: the compound with the structural formula VII has the molecular formula of C10H18CuN202S4 and the molecular weight of 390.0520;
Figure BSA0000176604190000025
a compound with a structural formula of VIII, wherein the molecular formula is C10H20CuN20S4, and the molecular weight is 376.0690;
Figure BSA0000176604190000026
the compound with the structural formula of IX has the molecular formula of C10H20CuN202S4 and the molecular weight of 392.0680.
Figure BSA0000176604190000031
The technical scheme adopted by the invention is that the preparation method of the compounds shown in structural formulas I to IX comprises the following steps:
(1) a compound of formula I is prepared as follows:
dissolving 17.8g (0.2 mol) of N-hydroxyethyl ethylamine in 100mL of chloroform, and sequentially adding 6.0mL (0.1 mol) of carbon disulfide and 12.7g (0.05 mol) of iodine under ice bath; washing the reaction solution twice after 3 hours, adding organic phase and anhydrous sodium sulfate, drying, evaporating the solvent, and purifying the residue by column chromatography to obtain dihydroxy disulfiram;
Figure BSA0000176604190000032
(2) a compound of formula II is prepared as follows:
13.6g of bis-hydroxy disulfiram, namely 41.4mmol and 6.68mL of pyridine, namely 82.8mmol are dissolved in 414mL of dichloromethane, and 9.4g of p-toluenesulfonyl chloride, namely 40mL of dichloromethane solution of 49.5mmol is slowly dropped under ice bath; adding dichloromethane for dilution after 2 days at room temperature, and washing for 2 times; washing the organic phase with hydrochloric acid and saturated brine successively, and drying over anhydrous sodium sulfate; carrying out column chromatography after concentration to obtain mono-protected dihydroxydisulfiram;
Figure BSA0000176604190000033
(3) a compound of formula III is prepared as follows:
dissolving 14.5g (30 mmol) of mono-protected dihydrocarbyl disulfiram in 310mL of dry DMF, adding 5.88g (165 mmol) of sodium borohydride, stirring at room temperature for 2 hours, slowly dropping a saturated ammonium chloride solution, extracting for 2 times by ethyl acetate, combining organic phases, washing by adding saturated saline solution, drying by anhydrous sodium sulfate, and purifying by column chromatography to obtain monohydroxy disulfiram;
Figure BSA0000176604190000034
(4) a compound of formula IV, prepared as follows:
dissolving 8.8g (28.4 mmol) of monothiodisulfiram in 200mL of dichloromethane, adding 15g (35.6 mmol) of Dess-Martin periodinane, and stirring at room temperature for 1 hour; adding 5% sodium sulfite and saturated sodium bicarbonate in turn, quenching, vigorously stirring for 1 hour, separating out an organic phase, washing with saturated sodium bicarbonate and water in turn, drying with anhydrous sodium sulfate, concentrating, and performing column chromatography to obtain disulfiram formaldehyde;
Figure BSA0000176604190000035
(5) the compound with the structural formula V is prepared by the following method;
dissolving 6.54g (21.06 mmol) of disulfiram formaldehyde in 100mL of a solvent mixed by tetrahydrofuran, tert-butyl alcohol and isoamylene according to the ratio of 1: 1.3, placing the mixture in an ice-water bath, and slowly adding 51mL of aqueous solution of 15g (165.6 mmol) of sodium chlorite and 17.7g (128.3 mmol) of sodium dihydrogen phosphate monohydrate; stirring for 10 min and removing ice bath; slowly heating to room temperature, reacting for 1 hour, evaporating off volatile matters, diluting the residue with water, adding 1N hydrochloric acid, and acidifying until the pH value is 3; extracting with dichloromethane for 2 times, drying with anhydrous sodium sulfate, concentrating, and performing column chromatography to obtain disulfiram carboxylic acid;
Figure BSA0000176604190000041
(6) the compound with the structural formula VI is prepared by the following method;
dissolving 3.46g (10.6 mmol) of disulfiram carboxylic acid in 200mL of anhydrous dichloromethane, and sequentially adding 0.75mL (12.6 mmol) of anhydrous ethanol, 1.29g (10.6 mmol) of DMAP and 2.18g (10.6 mmol) of DCC; filtering insoluble substances after the mixture is kept at room temperature overnight, concentrating the filtrate, and directly performing column chromatography to obtain the disulfiram ethyl carboxylate.
Figure BSA0000176604190000042
(7) A compound of formula VII is prepared as follows:
dissolving 0.2mmol of diethylamine in 2mL of methanol, sequentially adding 0.5mmol of carbon disulfide and 0.5mL of ammonia water, stirring at room temperature for 1 hour, adding 0.2mmol of N-ethylglycine, continuously stirring for 1 hour, slowly dropwise adding a methanol solution of 0.2mmol of copper chloride, stirring for 20 minutes, and evaporating to dryness to obtain [ (N-carboxymethyl) ethylamino thiocarbamic acid mercapto ] diethylamino thiocarbamic acid mercapto copper (II);
Figure BSA0000176604190000043
(8) a compound of formula VIII is prepared as follows:
dissolving 0.2mmol of diethylamine in 2mL of methanol, sequentially adding 0.5mmol of carbon disulfide and 0.5mL of ammonia water, stirring at room temperature for 1 hour, adding 0.2mmol of N-hydroxyethyl ethylamine, continuously stirring for 1 hour, slowly dropwise adding 0.2mmol of copper chloride in methanol, stirring for 20 minutes, and evaporating to dryness to obtain [ (N-hydroxyethyl) ethylamino thiocarbamate mercapto ] diethylamino thiocarbamate mercaptocopper (II);
Figure BSA0000176604190000044
(9) a compound of formula IX is prepared as follows:
dissolving 0.4mmol of N-hydroxyethyl ethylamine in 2mL of methanol, sequentially adding 0.5mmol of carbon disulfide and 0.5mL of ammonia water, stirring at room temperature for 1 hour, slowly dropwise adding a methanol solution of 0.2mmol of copper chloride, stirring for 20 minutes, and evaporating to dryness to obtain bis [ (N-hydroxymethyl) ethylamino thiocarbamic acid mercapto ] copper (II).
Figure BSA0000176604190000051
The inventor finds that the compound I, the compound II, the compound III, the compound IV, the compound V, the compound VI, the compound VII, the compound VIII or the compound IX have good treatment effect on tumors.
The compound I, the compound II, the compound III, the compound IV, the compound V, the compound VI, the compound VII, the compound VIII or the compound IX can be used for preparing medicaments for treating tumors.
The invention has the beneficial effects that:
① the side chain of disulfiram combines with hydroxyl, or the metabolite complexes with copper ion complex (CuET), after metabolism in tumor cells, the action is equivalent to that of disulfiram and ethanol, or CuET acts on tumor cells to inhibit the tumor cells;
② after the disulfiram side chain is combined with hydroxyl or a metabolite is complexed with copper ions to form CuET, the disulfiram reaction caused by the tumor patients taking disulfiram and ethanol at the same time is avoided, the discomfort of the patients taking the medicine is relieved, or the copper ions are taken at the same time to cause the copper poisoning of the patients, the patients can take the medicine for a long time to play the role of inhibiting tumors;
③ has single and high-efficiency broad-spectrum antitumor effect and extremely low toxic and side effects.
Detailed Description
Example 1
1. The compound with the structural formula I is dihydroxydisulfiram, the molecular formula is C10H20N2002S4, and the molecular weight is 328.5200;
Figure BSA0000176604190000052
2. the preparation of the compound of formula I is as follows:
dissolving 17.8g (0.2 mol) of N-hydroxyethyl ethylamine in 100mL of chloroform, and sequentially adding 6.0mL (0.1 mol) of carbon disulfide and 12.7g (0.05 mol) of iodine under ice bath; and after 3 hours, washing the reaction liquid twice by using water, adding organic phase and anhydrous sodium sulfate, drying, evaporating the solvent, and purifying residues by using column chromatography to obtain the dihydroxy disulfiram.
The following is a specific synthetic route for compound I.
Figure BSA0000176604190000053
3. The pharmacological test results are shown later.
Example 2
1. The compound with the structural formula II is dihydroxydisulfiram, the molecular formula is C17H26N204S5, and the molecular weight is 482.7050;
Figure BSA0000176604190000061
2. a compound of formula II is prepared as follows:
13.6g of bis-hydroxy disulfiram, namely 41.4mmol and 6.68mL of pyridine, namely 82.8mmol are dissolved in 414mL of dichloromethane, and 9.4g of p-toluenesulfonyl chloride, namely 40mL of dichloromethane solution of 49.5mmol is slowly dropped under ice bath; adding dichloromethane for dilution after 2 days at room temperature, and washing for 2 times; washing the organic phase with hydrochloric acid and saturated brine successively, and drying over anhydrous sodium sulfate; and carrying out column chromatography after concentration to obtain the mono-protected dihydroxy disulfiram. The following is a specific synthetic route for compound II.
Figure BSA0000176604190000062
3. The pharmacological test results are shown later.
Example 3
The compound with the structural formula III is monohydroxy disulfiram, the molecular formula is C10H20N200S4, and the molecular weight is 312.5230;
Figure BSA0000176604190000063
2. a compound of formula III is prepared as follows:
dissolving 14.5g (30 mmol) of mono-protected dihydrocarbyl disulfiram in 310mL of dry DMF, adding 5.88g (165 mmol) of sodium borohydride, stirring at room temperature for 2 hours, slowly dropping saturated ammonium chloride solution, extracting for 2 times with ethyl acetate, combining organic phases, washing with saturated saline solution, drying with anhydrous sodium sulfate, and purifying by column chromatography to obtain monohydroxy disulfiram.
The following is a specific synthetic route for compound III.
Figure BSA0000176604190000064
3. The pharmacological test results are shown later.
Example 4
The compound with the structural formula IV is disulfiram formaldehyde, the molecular formula is C10H18N20S4, and the molecular weight is 310.5070;
Figure BSA0000176604190000071
2. a compound of formula IV, prepared as follows:
dissolving 8.8g (28.4 mmol) of monothiodisulfiram in 200mL of dichloromethane, adding 15g (35.6 mmol) of Dess-Martin periodinane, and stirring at room temperature for 1 hour; adding 5% sodium sulfite and saturated sodium bicarbonate in turn, quenching, vigorously stirring for 1 hour, separating out the organic phase, washing with saturated sodium bicarbonate and water in turn, drying with anhydrous sodium sulfate, concentrating, and performing column chromatography to obtain disulfiram formaldehyde.
The following is a specific synthetic route for compound IV.
Figure BSA0000176604190000072
3. The pharmacological test results are shown later.
Example 5
The compound with the structural formula V is disulfiram carboxylic acid, the molecular formula is C10H18N202S4, and the molecular weight is 326.5200;
Figure BSA0000176604190000073
2. dissolving 6.54g (21.06 mmol) of disulfiram formaldehyde in 100mL of a solvent mixed by tetrahydrofuran, tert-butyl alcohol and isoamylene according to the ratio of 1: 1.3, placing the mixture in an ice-water bath, and slowly adding 51mL of aqueous solution of 15g (165.6 mmol) of sodium chlorite and 17.7g (128.3 mmol) of sodium dihydrogen phosphate monohydrate; stirring for 10 min and removing ice bath; slowly heating to room temperature, reacting for 1 hour, evaporating off volatile matters, diluting the residue with water, adding 1N hydrochloric acid, and acidifying until the pH value is 3; extracting with dichloromethane for 2 times, drying with anhydrous sodium sulfate, concentrating, and performing column chromatography to obtain disulfiram carboxylic acid.
The following is a specific synthetic route for compound V.
Figure BSA0000176604190000074
The pharmacological test results are shown later.
Example 6
1. The compound with the structural formula VI is disulfiram ethyl carboxylate, the molecular formula is C12H22N202S4, and the molecular weight is 354.5600;
Figure BSA0000176604190000081
2. the compound with the structural formula VI is prepared by the following method;
dissolving 3.46g (10.6 mmol) of disulfiram carboxylic acid in 200mL of anhydrous dichloromethane, and sequentially adding 0.75mL (12.6 mmol) of anhydrous ethanol, 1.29g (10.6 mmol) of DMAP1 and 2.18g (10.6 mmol) of DCC; filtering insoluble substances after the mixture is kept at room temperature overnight, concentrating the filtrate, and directly performing column chromatography to obtain the disulfiram ethyl carboxylate.
The following is a specific synthetic route for compound VI.
Figure BSA0000176604190000082
3. The pharmacological test results are shown later.
Example 7
1. The compound with the structural formula VII is [ (N-carbomethyl) ethylamino thioformic mercapto ] diethyl thioformic mercapto copper (II), the molecular formula is C10H18CuN202S4, and the molecular weight is 390.0520;
Figure BSA0000176604190000083
2. a compound of formula VII is prepared as follows:
dissolving 0.2mmol of diethylamine in 2mL of methanol, sequentially adding 0.5mmol of carbon disulfide and 0.5mL of ammonia water, stirring at room temperature for 1 hour, adding 0.2mmol of N-ethylglycine, continuously stirring for 1 hour, slowly dropwise adding a methanol solution of 0.2mmol of copper chloride, stirring for 20 minutes, and evaporating to dryness to obtain [ (N-carboxymethyl) ethylamino thiocarbamic acid mercapto ] diethylamino thiocarbamic acid mercapto copper (II).
The following is a specific synthetic route for compound VII.
Figure BSA0000176604190000084
3. The pharmacological test results are shown later.
Example 8
1. The compound with the structural formula VIII is [ (N-ethoxyl) ethylamino thioformic mercapto ] diethyl thioformic mercapto copper (II), the molecular formula is C10H20CuN20S4, and the molecular weight is 376.0690;
Figure BSA0000176604190000091
2. a compound of formula VIII is prepared as follows:
dissolving diethylamine 0.2mmol in methanol 2mL, sequentially adding carbon disulfide 0.5mmol and ammonia water 0.5mL, stirring at room temperature for 1 hour, adding N-hydroxyethyl ethylamine 0.2mmol, stirring for 1 hour, slowly dropwise adding methanol solution of copper chloride 0.2mmol, stirring for 20 minutes, and evaporating to dryness to obtain [ (N-hydroxyethyl) ethylamino thiocarbamic mercapto ] diethylamino thiocarbamic mercapto copper (II).
The following is a specific synthetic route for compound VIII.
Figure BSA0000176604190000092
The pharmacological test results are shown later.
Example 9
The compound with the structural formula IX is bis [ (N-hydroxymethyl) ethylamino thiocarbamic acid mercapto ] copper (II), the molecular formula is C10H20CuN202S4, and the molecular weight is 392.0680.
Figure BSA0000176604190000093
2. A compound of formula IX is prepared as follows:
dissolving 0.4mmol of N-hydroxyethyl ethylamine in 2mL of methanol, sequentially adding 0.5mmol of carbon disulfide and 0.5mL of ammonia water, stirring at room temperature for 1 hour, slowly dropwise adding a methanol solution of 0.2mmol of copper chloride, stirring for 20 minutes, and evaporating to dryness to obtain bis [ (N-hydroxymethyl) ethylamino thiocarbamic acid mercapto ] copper (II).
The following is a specific synthetic route for compound IX.
Figure BSA0000176604190000094
3. The pharmacological test results are shown later.
Pharmacological tests:
as described in the background art, all published documents at present show that the effect of disulfiram on inhibiting various tumor cells depends on the synergistic effect of copper ions, in the research of the invention, hydroxyl is complexed on a side chain of disulfiram or is re-complexed on a side chain of a copper ion complex of a disulfiram metabolite, so that the disulfiram side chain becomes a novel micromolecule compound, and the activity of related tumor cells in the intervention of the novel micromolecule compound for 48 hours is detected by adopting a CCK-8 method:
the use of 0.01. mu.M, 0.05. mu.M, 0.1. mu.M, 0.25. mu.M, 0.5. mu.M, 1.0. mu.M concentration gradient of disulfiram derivatives (i.e., compounds I to VI) and disulfiram metabolite copper ion complex derivatives (i.e., compounds VII to IX) respectively intervenes in cultured colon cancer cells SW116, LS-174-T and normal epithelial cells NCM460 thereof, gastric cancer cells SGC-7901, MKN-49P and normal epithelial cells GES-1 thereof, breast cancer cells MDA-MB-231, SKBR3 and normal epithelial cells MCF10A, lung cancer cells H1975, A549 and normal epithelial cells thereof, and prostate cancer cells LNCaP VCaP and normal epithelial cells RWPE-1, respectively, and the activity of the tumor cells shows no toxicity and no-cliff-type decrease in the vicinity of 0.25. mu.M and the vicinity of 0.10. mu.M respectively, but the corresponding decrease in the activity of normal cells is not obvious, thus demonstrating that the 2-class compounds of the invention act strongly on tumor cells but almost on normal epithelial cells And (4) sexual function.
The above-described embodiments of the present invention do not limit the scope of the present invention. Any modification, equivalent replacement, and improvement made within the spirit and principle of the present invention should be included in the scope of the claims of the present invention.

Claims (6)

1. A compound selected from the group consisting of:
a compound of formula I;
Figure FSA0000176604180000011
a compound of formula II;
Figure FSA0000176604180000012
a compound of formula III;
Figure FSA0000176604180000013
a compound of formula IV;
Figure FSA0000176604180000014
a compound of formula V;
Figure FSA0000176604180000015
Figure FSA0000176604180000021
a compound of formula VI.
Figure FSA0000176604180000022
2. A process for the preparation of a compound according to claim 1, wherein:
(1) a compound of formula I is prepared as follows:
dissolving 17.8g (0.2 mol) of N-hydroxyethyl ethylamine in 100mL of chloroform, and sequentially adding 6.0mL (0.1 mol) of carbon disulfide and 12.7g (0.05 mol) of iodine under ice bath; washing the reaction solution twice after 3 hours, adding organic phase and anhydrous sodium sulfate, drying, evaporating the solvent, and purifying the residue by column chromatography to obtain dihydroxy disulfiram;
Figure FSA0000176604180000023
(2) a compound of formula II is prepared as follows:
13.6g of bis-hydroxy disulfiram, namely 41.4mmol and 6.68mL of pyridine, namely 82.8mmol are dissolved in 414mL of dichloromethane, and 9.4g of p-toluenesulfonyl chloride, namely 40mL of dichloromethane solution of 49.5mmol is slowly dropped under ice bath; adding dichloromethane for dilution after 2 days at room temperature, and washing for 2 times; washing the organic phase with hydrochloric acid and saturated brine successively, and drying over anhydrous sodium sulfate; carrying out column chromatography after concentration to obtain mono-protected dihydroxydisulfiram;
Figure FSA0000176604180000024
(3) a compound of formula III is prepared as follows:
dissolving 14.5g (30 mmol) of mono-protected dihydrocarbyl disulfiram in 310mL of dry DMF, adding 5.88g (165 mmol) of sodium borohydride, stirring at room temperature for 2 hours, slowly dropping a saturated ammonium chloride solution, extracting for 2 times by ethyl acetate, combining organic phases, washing by adding saturated saline solution, drying by anhydrous sodium sulfate, and purifying by column chromatography to obtain monohydroxy disulfiram;
Figure FSA0000176604180000031
(4) a compound of formula IV, prepared as follows:
dissolving 8.8g (28.4 mmol) of monothiodisulfiram in 200mL of dichloromethane, adding 15g (35.6 mmol) of Dess-Martin periodinane, and stirring at room temperature for 1 hour; adding 5% sodium sulfite and saturated sodium bicarbonate in turn, quenching, vigorously stirring for 1 hour, separating out an organic phase, washing with saturated sodium bicarbonate and water in turn, drying with anhydrous sodium sulfate, concentrating, and performing column chromatography to obtain disulfiram formaldehyde;
Figure FSA0000176604180000032
(5) the compound with the structural formula V is prepared by the following method;
dissolving 6.54g (21.06 mmol) of disulfiram formaldehyde in 100mL of a solvent mixed by tetrahydrofuran, tert-butyl alcohol and isoamylene according to the ratio of 1: 1.3, placing the mixture in an ice-water bath, and slowly adding 51mL of aqueous solution of 15g (165.6 mmol) of sodium chlorite and 17.7g (128.3 mmol) of sodium dihydrogen phosphate monohydrate; stirring for 10 min and removing ice bath; slowly heating to room temperature, reacting for 1 hour, evaporating off volatile matters, diluting the residue with water, adding 1N hydrochloric acid, and acidifying until the pH value is 3; extracting with dichloromethane for 2 times, drying with anhydrous sodium sulfate, concentrating, and performing column chromatography to obtain disulfiram carboxylic acid;
Figure FSA0000176604180000033
(6) the compound with the structural formula VI is prepared by the following method;
dissolving 3.46g (10.6 mmol) of disulfiram carboxylic acid in 200mL of anhydrous dichloromethane, and sequentially adding 0.75mL (12.6 mmol) of anhydrous ethanol, 1.29g (10.6 mmol) of DMAP and 2.18g (10.6 mmol) of DCC; filtering insoluble substances after the mixture is kept at room temperature overnight, concentrating the filtrate, and directly performing column chromatography to obtain the disulfiram ethyl carboxylate.
Figure FSA0000176604180000034
3. Use of a compound according to claim 1 for the preparation of a medicament for the treatment of tumors.
4. A compound selected from the group consisting of:
a compound of formula VII;
Figure FSA0000176604180000041
a compound of formula VIII;
Figure FSA0000176604180000042
a compound of formula IX.
Figure FSA0000176604180000043
5. A process for the preparation of a compound according to claim 4, wherein:
(7) a compound of formula VII is prepared as follows:
dissolving 0.2mmol of diethylamine in 2mL of methanol, sequentially adding 0.5mmol of carbon disulfide and 0.5mL of ammonia water, stirring at room temperature for 1 hour, adding 0.2mmol of N-ethylglycine, continuously stirring for 1 hour, slowly dropwise adding a methanol solution of 0.2mmol of copper chloride, stirring for 20 minutes, and evaporating to dryness to obtain [ (N-carboxymethyl) ethylamino thiocarbamic acid mercapto ] diethylamino thiocarbamic acid mercapto copper (II);
Figure FSA0000176604180000044
(8) a compound of formula VIII is prepared as follows:
dissolving 0.2mmol of diethylamine in 2mL of methanol, sequentially adding 0.5mmol of carbon disulfide and 0.5mL of ammonia water, stirring at room temperature for 1 hour, adding 0.2mmol of N-hydroxyethyl ethylamine, continuously stirring for 1 hour, slowly dropwise adding 0.2mmol of copper chloride in methanol, stirring for 20 minutes, and evaporating to dryness to obtain [ (N-hydroxyethyl) ethylamino thiocarbamate mercapto ] diethylamino thiocarbamate mercaptocopper (II);
Figure FSA0000176604180000051
(9) a compound of formula IX is prepared as follows:
dissolving 0.4mmol of N-hydroxyethyl ethylamine in 2mL of methanol, sequentially adding 0.5mmol of carbon disulfide and 0.5mL of ammonia water, stirring at room temperature for 1 hour, slowly dropwise adding a methanol solution of 0.2mmol of copper chloride, stirring for 20 minutes, and evaporating to dryness to obtain bis [ (N-hydroxymethyl) ethylamino thiocarbamic acid mercapto ] copper (II).
Figure FSA0000176604180000052
6. Use of a compound according to claim 4 for the preparation of a medicament for the treatment of tumors.
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