CN111410677A - 2-methoxy estramustine and derivatives, preparation method and application thereof - Google Patents
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Abstract
The invention discloses 2-methoxy estramustine and derivatives thereof, and the structural formula of the 2-methoxy estramustine and the derivatives thereof is shown in formulas 1-4. The 2-methoxyestramustine takes 2-methoxyestradiol as a carrier, an alkylating agent (nitrogen mustard) is connected through carbamate to form a dual-functional drug molecular compound, the whole molecule is taken as an antimitotic agent, and after the carbamate is metabolized and hydrolyzed in vivo, the metabolite-mediated released 2-methoxyestradiol can still continuously play an antitumor role. Derivatives of 2-methoxyestramustine can be used as prodrugs of 2-methoxyestradiol. The invention also discloses a preparation method of the 2-methoxy estramustine and the derivatives thereof, and the preparation method can prepare the 2-methoxy estramustine and the derivatives thereof with higher yield. The invention also discloses application of the 2-methoxy estramustine and the derivatives thereof in medicaments for treating tumors or multiple myeloma.
Description
Technical Field
The invention relates to the technical field of organic synthesis, in particular to a novel compound 2-methoxy estramustine and derivatives, a preparation method and application thereof.
Background
At present, with the improvement of medical level, the tumor treatment also makes great progress, the life cycle of tumor patients is obviously prolonged, the life quality is obviously improved, and the invention and the clinical application of various high-efficiency anticancer and antitumor drugs are mainly benefited. However, some tumor drugs used in clinical practice at present are accompanied by some side effects and adverse reactions while achieving significant curative effects, thereby causing great pain to patients and seriously affecting the quality of life of patients.
At present, the development and research on nitrogen mustard antineoplastic compounds are focused on modifying the structural part of a carrier, mainly through designing nitrogen mustard drugs with targeting carriers to reduce the toxic and side effects, estramustine sodium phosphate is also called estramustine phosphate and is clinically used for treating prostatic cancer, estramustine phosphate is taken as a carrier, nitrogen mustard (an alkylating agent) and estradiol-17- β -phosphate (hormone) are connected through carbamate, the whole molecule of the estramustine phosphate is an antimitotic agent, after the carbamate is hydrolyzed, estrogen released by mediation of metabolites plays a role of anti-gonadotropin, estramustine can specifically introduce the drugs into prostate tissues through steroid receptors to generate cytotoxic effect and hormone effect, and the purpose of damaging cancer cells is achieved.
Tumor growth and metastasis depend on the nutrition and oxygen supply of blood vessels, so cutting off tumor angiogenesis is one of the main directions for seeking antitumor drugs at present. 2-methoxyestradiol (5) is a neovascular inhibitor which enters phase I-III clinical research and is proved to be effective in treating various solid tumors, particularly breast cancer, prostatic cancer, multiple myeloma and the like. Because 2-methoxyestradiol is an endogenous active metabolite of a human body and shows low toxicity clinically, the development prospect of 2-methoxyestradiol as a novel tumor chemotherapeutic drug has great advantages.
Disclosure of Invention
The invention aims to overcome the defects of the prior art and provides 2-methoxy estramustine and derivatives, a preparation method and application thereof.
In order to achieve the purpose, the invention adopts the technical scheme that:
the structural formula of the 2-methoxy estramustine and the derivatives thereof is shown as the formula 1-4:
wherein R is amino acid residue, can be L-amino acid, such as glycine, alanine, histidine and other common amino acids, HY is hydrochloric acid, sulfuric acid, phosphoric acid, tartaric acid, malic acid or p-toluenesulfonic acid, and n is 2 or 3, when n is 2 or 3, the corresponding organic dibasic acid sodium salt is different, such as succinic acid, glutaric acid.
The invention also aims to provide a preparation method of the 2-methoxy estramustine and the derivatives thereof,
the synthetic routes of the compounds represented by formula 1 and formula 2 are as follows:
the preparation method of the compound shown in the formula 1 comprises the following steps:
dissolving the compound shown in the formula 5 in dichloromethane, adding triethylamine and 4-dimethylaminopyridine, and uniformly stirring; dissolving N, N-bis (2-chloroethyl) carbamoyl chloride in dichloromethane, dropwise adding the dichloromethane into the reaction solution, stirring for reaction for 0.4-0.6 hour, then moving the reaction solution to a water bath with the temperature of 38-42 ℃, keeping the temperature for reaction till the reaction is complete, stopping the reaction, cooling the reaction solution to room temperature, adding distilled water, adjusting the pH of the reaction solution to be 5-6 by using a hydrochloric acid solution under stirring, extracting to obtain an organic phase, and removing the solvent by reduced pressure distillation to obtain the compound shown in the formula 1; wherein the molar ratio of the compound shown in the formula 5 to the triethylamine to the 4-dimethylaminopyridine to the N, N-bis (2-chloroethyl) carbamoyl chloride is as follows: 1 (1.8-2.2), (0.08-0.12), (1.2-1.8);
the preparation method of the compound shown in the formula 2 comprises the following steps:
(1) dropping phosphorus oxychloride into pyridine at 4-6 ℃, and uniformly stirring to obtain a pyridine solution of phosphorus oxychloride; dissolving the compound shown in the formula 1 in pyridine, dropwise adding the pyridine solution into a pyridine solution of phosphorus oxychloride, after the reaction is completed, pouring the reaction solution into an ice-water mixture, adding a hydrochloric acid solution to adjust the pH value to be 2-3, filtering, taking filter residue, drying, dissolving the filter residue in ethyl acetate, adding ethanol, dropwise adding distilled water until the generated turbidity does not disappear, adding a small amount of ethyl acetate to redissolve, continuously stirring, filtering, taking the filter residue, and drying to obtain the compound shown in the formula 6; wherein the mol ratio of the compound shown in the formula 1 to the phosphorus oxychloride is as follows: 1: 4-6
(2) Adding anhydrous methanol into the compound shown in the formula 6, dissolving, and cooling to 0-5 ℃ to obtain a methanol solution of the compound shown in the formula 6; dissolving metal sodium in absolute methanol, and cooling to 5-8 ℃ to obtain a methanol solution of sodium methoxide; dropwise adding a methanol solution of sodium methoxide into a methanol solution of a compound shown in a formula 6, stirring and reacting for 8-15 minutes at 0-5 ℃, adding anhydrous ether at 0-5 ℃, filtering, taking filter residues, washing the filter residues with the anhydrous ether, and drying to obtain a compound shown in a formula 2; wherein, the mol ratio of the compound shown in the formula 6 to the metallic sodium is as follows: 1: 1.1-1.3;
the synthetic route of the compound represented by formula 3 is as follows:
the preparation method of the compound shown in the formula 3 comprises the following steps:
dissolving the compound shown in the formula 1 in dichloromethane, adding triethylamine, stirring uniformly, slowly adding glycyl chloride hydrochloride, stirring until the reaction is complete, adding distilled water, taking an organic phase, washing with inclusion sodium chloride, drying with anhydrous sodium sulfate, distilling under reduced pressure to remove part of a solvent, dropwise adding a HY 1, 4-dioxane solution, stirring, filtering, and taking filter residues to obtain the compound shown in the formula 3; wherein the compound shown in the formula 1, triethylamine, glycinyl chloride hydrochloride and HY have the following molar ratio: 1, (2.5-3.5): (1.2-1.8): 3-5;
the synthetic route of the compound represented by formula 4 is as follows:
the preparation method of the compound shown in the formula 4 comprises the following steps:
dissolving the compound shown in the formula 1 in dichloromethane, adding triethylamine and 4-dimethylaminopyridine, and uniformly stirring; dissolving succinic anhydride or glutaric anhydride in dichloromethane, dropwise adding the succinic anhydride or glutaric anhydride into the reaction solution, stirring until the reaction is complete, stopping the reaction, cooling the reaction solution to room temperature, adding distilled water, adjusting the pH of the reaction solution to be 5-6 by using a hydrochloric acid solution under stirring, extracting to obtain an organic phase, washing, removing the solvent to obtain a solid, dissolving the solid in methanol and water, adding sodium bicarbonate, stirring, distilling under reduced pressure to remove the solvent to obtain a solid, and recrystallizing ethanol and diethyl ether to obtain a compound shown in a formula 4; wherein, the mole ratio of the compound shown in the formula 1, triethylamine, 4-dimethylamino pyridine and succinic anhydride or glutaric anhydride is as follows: 1: (1.8-2.2): (0.08-0.12): (1-1.2).
The invention also aims to provide application of the 2-methoxy estramustine and the derivatives thereof in preparing antitumor drugs.
Preferably, the tumor is prostate cancer, breast cancer or colon cancer.
The invention also aims to provide application of the 2-methoxy estramustine and the derivatives thereof in preparing medicines for treating multiple myeloma.
The invention has the beneficial effects that: the invention provides a novel compound 2-methoxy estramustine and derivatives thereof. The inventor discovers through research that the 2-methoxyestramustine (the compound shown in the formula 1) takes 2-methoxyestradiol as a carrier, an alkylating agent (nitrogen mustard) is connected through carbamate to form a dual-functional drug molecular compound, and the whole molecule is taken as a mitosis inhibitor, so that the 2-methoxyestramustine compound can play a role in tumor cytotoxicity caused by the nitrogen mustard and can play an anti-tumor role of 2-methoxyestradiol released by metabolite mediation. Since 2-methoxyestradiol is an endogenous substance, it has fewer adverse side effects than estradiol, a metabolite of estramustine. The derivative of 2-methoxyestramustine (the compound shown in the formula 2-4) can be used as a prodrug of 2-methoxyestradiol, and aims to improve the water solubility of the compound and further improve the bioavailability. The prodrug is metabolized and hydrolyzed by various active esterases or phosphatases in vivo to release active 2-methoxy estramustine (the compound shown in the formula 1), enters the blood circulation system of a human body and reaches target cells, thereby playing the same anti-tumor role as 2-methoxy estramustine. The invention also provides a preparation method of the 2-methoxy estramustine and the derivatives thereof, and the preparation method can prepare the 2-methoxy estramustine and the derivatives thereof with higher yield. The invention also provides application of the 2-methoxy estramustine and the derivatives thereof in medicaments for treating tumors or multiple myeloma.
Detailed Description
To better illustrate the objects, aspects and advantages of the present invention, the present invention will be further described with reference to specific examples.
Examples
The synthetic routes of the compounds represented by formula 1 and formula 2 are as follows:
the preparation method of the compound shown in the formula 1 comprises the following steps:
dissolving 0.906g (3.0mmol) of 2-methoxy-1, 3,5(10) -triene-3, 17 β -estradiol (5) in 30.0m L dichloromethane, adding 0.606g (6.0mmol) of triethylamine and 0.037g (0.3mmol) of 4-dimethylaminopyridine/DMAP, stirring at room temperature for 10 minutes, dissolving 0.918g (4.5mmol) of N, N-bis (2-chloroethyl) carbamoyl chloride in 5.0m L dichloromethane, slowly adding dropwise to the reaction solution, stirring for 0.5 hour, moving the reaction solution to a water bath at 40 ℃ for 2 hours, detecting by T L C that the reaction is complete, stopping the reaction, cooling the reaction solution to room temperature, adding 50.0m L of distilled water, adjusting the pH of the reaction solution to 5-6 with 10% hydrochloric acid solution under stirring, demixing, separating an organic layer, distilling the dichloromethane (20.82 m) to extract a white compound (19.4 m H) with a concentration of dichloromethane, a white crystal of 1.4H, 1.4, 18 m, 18H, 2m, 18H, 18 m 3H, 18 m 32 m H, 18 m H7H 4H 7m, 18H 7H 4H 7H 4H 7m, 18H 7H 4H 7H 4H 7H 4H 7H 4H 7H 4H 7H 4H 7.
The preparation method of the compound shown in the formula 2 comprises the following steps:
(1) weighing 20.0m L pyridine, cooling to 5 ℃, slowly dropwise adding 0.92m L (10.0mmol) phosphorus oxychloride into the reaction solution, stirring for 30 minutes continuously after dropwise addition is completed within 5 minutes, dissolving 0.940g (2.0mmol) of compound (1) into 5.0m L pyridine, slowly dropwise adding the mixture into the reaction solution, dropwise adding the mixture into the reaction solution for 5 minutes, keeping the temperature for reaction for 0.5 hour continuously, monitoring that the reaction is complete by T L C, stopping the reaction, slowly pouring the reaction solution into 100.0m L crushed ice under stirring, adjusting the pH value of the reaction solution to be between 2 and 3 by using 36% concentrated hydrochloric acid solution, continuously stirring for 10 minutes with a large amount of precipitate in the reaction solution with addition of hydrochloric acid solution, carrying out suction filtration, washing the filter cake to be neutral by using distilled water, drying to obtain a crude compound (shown in formula 14), dissolving the crude compound (shown in formula L) ethyl acetate in 9.0m L, adding 3.0m L ethanol, adding a small amount of distilled water until a small amount of precipitate is obtained, stirring, gradually adding a small amount of pure compound (20.4 m H) in the reaction solution, stirring, 4m H) in the reaction solution, drying the reaction solution (20.4 m H) to obtain a crude compound (1.4 m H4 m), drying the pure H4 m, 2m H4 m, 2m H4 m,2H 4m, 2m H4 m, 4m, 4m, 4 m;
(2) weighing 0.55g (1.0mmol) of a compound (shown in formula 6), adding 10.0m L anhydrous methanol, stirring at room temperature for complete dissolution, transferring the reaction liquid to an ice bath, cooling to 0-5 ℃ to obtain a methanol solution of the compound shown in formula 6, adding 0.0276g (1.20mmol) of metallic sodium into 2.0m L anhydrous methanol, completely dissolving the metallic sodium into the methanol, cooling to 5-8 ℃ to obtain a methanol solution of sodium methoxide, slowly dripping the methanol solution of sodium methoxide into the methanol solution of the compound shown in formula 6 within 1 minute, continuously stirring the reaction liquid at 0-5 ℃ for 10 minutes, dripping 20.0m L0-5 ℃ of anhydrous ether into the reaction liquid, wherein a large amount of precipitate is precipitated in the reaction liquid, performing suction filtration, washing a filter cake with the anhydrous ether, and performing vacuum drying to obtain 0.42g of the compound (shown in formula 2), wherein the yield is 70.6%. Ms (m/z): 595.2; NMR (400MHz, 6.86, 62H, 1H, 4H, 3, 4H, 3.4, 3, 4, 3.4H 3, 4, 3, 2, 3, 4, 3, 2, 3, 2, 3, 2, 3, 2, 3, 2, 3.
The synthetic route of the compound represented by formula 3 is as follows:
the preparation method of the compound shown in the formula 3 comprises the following steps:
dissolving 0.470g (1.0mmol) of 2-methoxyestramustine (the compound shown in the formula 1) in 20.0M L dichloromethane, adding 0.303g (3.0mmol) of triethylamine, stirring at room temperature for 10 minutes, slowly adding 0.195g (1.5mmol) of glycinyl chloride hydrochloride in small portions into the reaction solution, after 10 minutes, continuing to stir for 2 hours, detecting that the reaction is complete by T L C, stopping the reaction, adding 50.0M L of distilled water, taking an organic layer after layering, washing a saturated sodium chloride solution (20.0M L× 3), drying anhydrous sodium sulfate, distilling under reduced pressure to remove a half solvent, dropwise adding 4M HCl 1, 4-dioxane solution 1.0M L, after stirring for 30 minutes, taking a large amount of white precipitate, stopping the reaction, performing suction filtration, washing a filter cake with dichloromethane (5.0M L× 3), and drying in vacuum to obtain 0.49g of a white crystal (the compound shown in the formula 3), 80.0.0M/3), DMSO (3), 2.4M, 4H 2S, 1.4H 2S, 10-10H 2S, 4.4H 26, 10-10M, 1.7H 2S, 10-H2S, 4-10-H2H 26, L, 4-H2M, 10-H, L, 4-H3, L, 4-H3H, 4-H3, L, 4-H3, 4-4H 3H.
The synthetic route of the compound represented by formula 4 is as follows:
dissolving 0.470g (1.0mmol) of 2-methoxyestramustine (compound shown in formula 1) in 20.0m L dichloromethane, adding 0.202g (2.0mmol) of triethylamine and 0.012g (0.1mmol) of 4-dimethylaminopyridine/DMAP, stirring at room temperature for 10 minutes, dissolving 0.110g (1.1mmol) of succinic anhydride in 5.0m L dichloromethane, slowly adding dropwise to the reaction solution, stirring within 3 minutes, continuing stirring for 5 hours, detecting by T L C that the reaction is complete, stopping the reaction, cooling the reaction solution to room temperature, adding 50.0m L of distilled water, adjusting the pH of the reaction solution to 5-6 with 10% hydrochloric acid solution under stirring, standing for layering, separating an organic layer, extracting the aqueous layer with dichloromethane (10.0m L× 3), combining the organic layers, washing with saturated common salt (20.0m L ×), distilling under reduced pressure to remove the solvent to obtain a solid, distilling the solid with 10.0m 670.63 m of methanol and 2H, extracting the aqueous layer with dichloromethane (10.0.0.0 m L×), dissolving the solid with dichloromethane (1.4H 3H) to 2H 4, adding the compound shown in 20.7.7.4H 8 m H8, stirring, adding the solvent to 2H 4H 2H 4H 2H 4H 2H 4H 3H 2H 4H 3H 4H 2H 4H 3H 4H 3H 4H 3H 5, adding the total weight of 20.7H 4H 2H 4.
Synthesis of the control Compound estramustine
The synthetic route is as follows:
dissolving 4.00g (14.7mmol) of 1,3,5(10) -triene-3, 17 β -estradiol (compound shown in formula 14) in 150.0m L dichloromethane, adding 2.97g (29.4mmol) of triethylamine and 0.19g (1.5mmol) of 4-dimethylaminopyridine/DMAP, stirring for 10 minutes at room temperature, dissolving 4.51g (22.1mmol) of N, N-bis (2-chloroethyl) carbamoyl chloride in 50.0m L dichloromethane, slowly adding dropwise into the reaction solution, stirring for 1 hour within 30 minutes, continuing to react for 1 hour, then moving the reaction solution to a water bath at 40 ℃ for 3 hours, detecting that the reaction is complete by T L C, stopping the reaction, cooling the reaction solution to normal temperature, adding 50.0m L of distilled water, adjusting the pH of the reaction solution to 5-6 with 10% of hydrochloric acid solution under stirring, standing for layering, separating an organic layer, extracting an aqueous layer with dichloromethane (50.0m 466), extracting a white compound (19.7.26.7 m H, 18 m) with dichloromethane (1.18 m H26.18H, 18 m H26.18 m H, 18 m H26H 6H 19H 6H 19H 6H 18H 6H 7H 6H 7H 6H 7H.
The antitumor activities of the compounds represented by the formulas 1, 5 and 15 were tested, wherein the structural formulas of the compounds represented by the formulas 1, 5 and 15 are as follows, the compound represented by the formula 5 was purchased from the market, multiple myeloma cell lines (L P1, RPMI8226, OCI-MCY5), breast cancer cell line (MDA-MB-435), colon cancer cell line (HCT-116) and prostate cancer cell line (L NCaP) were purchased from the market, and the antitumor activities of the compounds represented by the formulas 1, 5 and 15 were measured using MTS kit (CellTiter 96 AQ)ueousOne solvationagent; promega Corporation, Madison, WI, USA) tested the results obtained.
Experimental procedure 50.0 microliter of cells was 2 × 104One well was seeded in a 96 well plate at 2 replicates per concentration 50.0 microliters of media containing different concentrations of the test compound (DMSO concentration less than 0.1%) were added to the wells and incubated at 37 ℃ for 72 hours, 15 microliters of media containing MTS (0.5mg/m L) were added and placed in the incubator for 4 hours, absorbance at 570nm or 490nm was measured using a multiwell plate microplate reader, inhibition of cell growth was calculated as the ratio of absorbance of the sample to the control, inhibition of each compoundThe experiment was repeated at least 5 times and the IC was finally calculated50Values, as shown in tables 1 and 2.
1. The data for the inhibition activity of multiple myeloma cell lines are shown in table 1:
TABLE 1
2. The data of the inhibition activity experiment on breast cancer, colon cancer and prostate cancer cell lines are shown in table 2:
TABLE 2
EPI
Is a product of American Pharmacia. Molecular weight: 579.98
As can be seen from tables 1 and 2, 2-methoxyestramustine (compound represented by formula 1) has high inhibitory activity on multiple myeloma, breast cancer, colon cancer and prostate cancer cell lines.
Finally, it should be noted that the above embodiments are only used for illustrating the technical solutions of the present invention and not for limiting the protection scope of the present invention, and although the present invention is described in detail with reference to the preferred embodiments, it should be understood by those skilled in the art that modifications or equivalent substitutions can be made on the technical solutions of the present invention without departing from the spirit and scope of the technical solutions of the present invention.
Claims (5)
1.2-methoxy estramustine and derivatives thereof, which are characterized in that the structural formula is shown as formulas 1-4:
wherein R is an amino acid residue; HY is hydrochloric acid, sulfuric acid, phosphoric acid, tartaric acid, malic acid or p-toluenesulfonic acid; n is 2 or 3.
2. The process for the preparation of 2-methoxyestramustine and derivatives thereof according to claim 1, wherein the starting materials are selected from the group consisting of,
the synthetic routes of the compounds represented by formula 1 and formula 2 are as follows:
the preparation method of the compound shown in the formula 1 comprises the following steps:
dissolving the compound shown in the formula 5 in dichloromethane, adding triethylamine and 4-dimethylaminopyridine, and uniformly stirring; dissolving N, N-bis (2-chloroethyl) carbamoyl chloride in dichloromethane, dropwise adding the dichloromethane into the reaction solution, stirring for reaction for 0.4-0.6 hour, then moving the reaction solution to a water bath with the temperature of 38-42 ℃, keeping the temperature for reaction till the reaction is complete, stopping the reaction, cooling the reaction solution to room temperature, adding distilled water, adjusting the pH of the reaction solution to be 5-6 by using a hydrochloric acid solution under stirring, extracting to obtain an organic phase, and removing the solvent by reduced pressure distillation to obtain the compound shown in the formula 1; wherein the molar ratio of the compound shown in the formula 5 to the triethylamine to the 4-dimethylaminopyridine to the N, N-bis (2-chloroethyl) carbamoyl chloride is as follows: 1 (1.8-2.2), (0.08-0.12), (1.2-1.8);
the preparation method of the compound shown in the formula 2 comprises the following steps:
(1) dropping phosphorus oxychloride into pyridine at 4-6 ℃, and uniformly stirring to obtain a pyridine solution of phosphorus oxychloride; dissolving the compound shown in the formula 1 in pyridine, dropwise adding the pyridine solution into a pyridine solution of phosphorus oxychloride, after the reaction is completed, pouring the reaction solution into an ice-water mixture, adding a hydrochloric acid solution to adjust the pH value to be 2-3, filtering, taking filter residue, drying, dissolving the filter residue in ethyl acetate, adding ethanol, dropwise adding distilled water until the generated turbidity does not disappear, adding a small amount of ethyl acetate to redissolve, continuously stirring, filtering, taking the filter residue, and drying to obtain the compound shown in the formula 6; wherein the mol ratio of the compound shown in the formula 1 to the phosphorus oxychloride is as follows: 1: 4-6
(2) Adding anhydrous methanol into the compound shown in the formula 6, dissolving, and cooling to 0-5 ℃ to obtain a methanol solution of the compound shown in the formula 6; dissolving metal sodium in absolute methanol, and cooling to 5-8 ℃ to obtain a methanol solution of sodium methoxide; dropwise adding a methanol solution of sodium methoxide into a methanol solution of a compound shown in a formula 6, stirring and reacting for 8-15 minutes at 0-5 ℃, adding anhydrous ether at 0-5 ℃, filtering, taking filter residues, washing the filter residues with the anhydrous ether, and drying to obtain a compound shown in a formula 2; wherein, the mol ratio of the compound shown in the formula 6 to the metallic sodium is as follows: 1: 1.1-1.3;
the synthetic route of the compound represented by formula 3 is as follows:
the preparation method of the compound shown in the formula 3 comprises the following steps:
dissolving the compound shown in the formula 1 in dichloromethane, adding triethylamine, stirring uniformly, slowly adding glycyl chloride hydrochloride, stirring until the reaction is complete, adding distilled water, taking an organic phase, washing with inclusion sodium chloride, drying with anhydrous sodium sulfate, distilling under reduced pressure to remove part of a solvent, dropwise adding a HY 1, 4-dioxane solution, stirring, filtering, and taking filter residues to obtain the compound shown in the formula 3; wherein the compound shown in the formula 1, triethylamine, glycinyl chloride hydrochloride and HY have the following molar ratio: 1, (2.5-3.5): (1.2-1.8): 3-5;
the synthetic route of the compound represented by formula 4 is as follows:
the preparation method of the compound shown in the formula 4 comprises the following steps:
dissolving the compound shown in the formula 1 in dichloromethane, adding triethylamine and 4-dimethylaminopyridine, and uniformly stirring; dissolving succinic anhydride or glutaric anhydride in dichloromethane, dropwise adding the succinic anhydride or glutaric anhydride into the reaction solution, stirring until the reaction is complete, stopping the reaction, cooling the reaction solution to room temperature, adding distilled water, adjusting the pH of the reaction solution to be 5-6 by using a hydrochloric acid solution under stirring, extracting to obtain an organic phase, washing, removing the solvent to obtain a solid, dissolving the solid in methanol and water, adding sodium bicarbonate, stirring, distilling under reduced pressure to remove the solvent to obtain a solid, and recrystallizing ethanol and diethyl ether to obtain a compound shown in a formula 4; wherein, the mole ratio of the compound shown in the formula 1, triethylamine, 4-dimethylamino pyridine and succinic anhydride or glutaric anhydride is as follows: 1: (1.8-2.2): (0.08-0.12): (1-1.2).
3. The use of 2-methoxyestramustine or a derivative thereof according to claim 1 for the preparation of an anti-tumor medicament.
4. The use of claim 3, wherein the tumor is prostate cancer, breast cancer or colon cancer.
5. The use of 2-methoxyestramustine or a derivative thereof according to claim 1 for the preparation of a medicament for the treatment of multiple myeloma.
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| CN112979744A (en) * | 2021-02-18 | 2021-06-18 | 齐齐哈尔医学院 | Diosgenin mosaic nitrogen mustard derivative with anti-tumor activity and preparation method and application thereof |
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| CN112979744A (en) * | 2021-02-18 | 2021-06-18 | 齐齐哈尔医学院 | Diosgenin mosaic nitrogen mustard derivative with anti-tumor activity and preparation method and application thereof |
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