CN113620892B - Carboxyaminotriazole single crystal, preparation method, composition and application thereof - Google Patents

Carboxyaminotriazole single crystal, preparation method, composition and application thereof Download PDF

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CN113620892B
CN113620892B CN202111184575.XA CN202111184575A CN113620892B CN 113620892 B CN113620892 B CN 113620892B CN 202111184575 A CN202111184575 A CN 202111184575A CN 113620892 B CN113620892 B CN 113620892B
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carboxyamidotriazole
single crystal
test tubes
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CN113620892A (en
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寇玉辉
梅期红
刘诗雨
池研生
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Guangdong Yinzhu Medical Technology Co ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/04—1,2,3-Triazoles; Hydrogenated 1,2,3-triazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4192—1,2,3-Triazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C30—CRYSTAL GROWTH
    • C30B—SINGLE-CRYSTAL GROWTH; UNIDIRECTIONAL SOLIDIFICATION OF EUTECTIC MATERIAL OR UNIDIRECTIONAL DEMIXING OF EUTECTOID MATERIAL; REFINING BY ZONE-MELTING OF MATERIAL; PRODUCTION OF A HOMOGENEOUS POLYCRYSTALLINE MATERIAL WITH DEFINED STRUCTURE; SINGLE CRYSTALS OR HOMOGENEOUS POLYCRYSTALLINE MATERIAL WITH DEFINED STRUCTURE; AFTER-TREATMENT OF SINGLE CRYSTALS OR A HOMOGENEOUS POLYCRYSTALLINE MATERIAL WITH DEFINED STRUCTURE; APPARATUS THEREFOR
    • C30B29/00—Single crystals or homogeneous polycrystalline material with defined structure characterised by the material or by their shape
    • C30B29/54—Organic compounds
    • C—CHEMISTRY; METALLURGY
    • C30—CRYSTAL GROWTH
    • C30B—SINGLE-CRYSTAL GROWTH; UNIDIRECTIONAL SOLIDIFICATION OF EUTECTIC MATERIAL OR UNIDIRECTIONAL DEMIXING OF EUTECTOID MATERIAL; REFINING BY ZONE-MELTING OF MATERIAL; PRODUCTION OF A HOMOGENEOUS POLYCRYSTALLINE MATERIAL WITH DEFINED STRUCTURE; SINGLE CRYSTALS OR HOMOGENEOUS POLYCRYSTALLINE MATERIAL WITH DEFINED STRUCTURE; AFTER-TREATMENT OF SINGLE CRYSTALS OR A HOMOGENEOUS POLYCRYSTALLINE MATERIAL WITH DEFINED STRUCTURE; APPARATUS THEREFOR
    • C30B7/00—Single-crystal growth from solutions using solvents which are liquid at normal temperature, e.g. aqueous solutions
    • C30B7/02—Single-crystal growth from solutions using solvents which are liquid at normal temperature, e.g. aqueous solutions by evaporation of the solvent
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs

Abstract

The invention discloses a carboxyamidotriazole single crystal, a preparation method, a composition and an anti-tumor application, and the specific method comprises the following steps: dissolving carboxyamidotriazole in a benign solvent, magnetically stirring at normal temperature, filtering, adding the filtrate into a test tube, sealing, placing in a normal-temperature water bath, and standing for a period of time to obtain the carboxyamidotriazole single crystal. The carboxyamidotriazole single crystal prepared by the method has the technical effects of high purity and high stability. The carboxyamidotriazole single crystal is monoclinic; space group is P21C, crystal lattice: a =9.30028 (10) a, b =25.2228 (2) a, c =7.64354 (7) a; the included angles between the crystal planes α =90 °, β =100.1433 °, γ =90 °. Unit lattice area (V unit lattice) =1764.99 (3) A3The number of molecules (Z) in the unit cell is 4; density (D) of 1.598Mg/m3。

Description

Carboxyaminotriazole single crystal, preparation method, composition and application thereof
Technical Field
The invention relates to the technical field of biological medicines, in particular to a carboxyamidotriazole single crystal, a preparation method, a composition and application thereof.
Background
Carboxyamidazole (CAI) is a noncytotoxic antitumor drug. The chemical name is 5-amido-1- [3, 5-dichloro-4 (4-chlorobenzoyl chloride) benzyl ] -1H-1, 2, 3-triazole-4-benzamide, and the chemical structural formula is as follows:
Figure 809368DEST_PATH_IMAGE001
。
the current research shows that CAI has a good effect on various tumors, can inhibit the proliferation of endothelial cells and various tumor cell lines such as MDA-MB-231, OVCAR-3 and MCF-7, and can also inhibit the invasion of prostate cancer, bladder cancer, breast cancer, liver cancer, glioblastoma and the like.
Particularly aiming at the research of the carboxyamidotriazole for the advanced non-small cell lung cancer, a phase III clinical test is completed at present, and the safety and the effectiveness of the carboxyamidotriazole are proved. The applicant also carries out intensive research on a preparation method, a preparation and the like of the carboxyamidotriazole, and lays out related patents; but the patent and the literature aiming at the crystal form of the carboxyamidotriazole are not reported; the research on the crystal form of the drug and the solid representation thereof are significant in the pharmaceutical industry, because the difference of the three-dimensional structure of a plurality of complex and ordered aggregates formed by weak interaction of drug molecules leads to the change of the physicochemical properties of the drug. Different crystal forms of the same drug often have different biochemical properties, and have significant differences in the aspects of stability, solubility and the like. In addition, the crystal form of the medicine also has great influence on the absorption and the transportation of the medicine, thereby changing the bioavailability of the medicine and generating great influence on the curative effect.
Polymorphic forms of carboxyamidotriazole orotate have been claimed by artful therapy gmbh under the following patent application numbers: CN201080050000.2, which discloses polymorphs of carboxyamidotriazole orotate; however, compared with the carboxyamidotriazole, the orotate of the carboxyamidotriazole has changed various properties, and the preparation method of the crystal form has no reference significance. The current research on the crystal form of carboxyamidotriazole is close to the blank.
Disclosure of Invention
The invention aims to provide a carboxyamidotriazole single crystal which is high in purity and stable in properties.
The single crystal is a monoclinic system; space group P21/c, lattice: a =9.30028 (10) a, b =25.2228 (2) a, c =7.64354 (7) a; the included angles between the crystal planes α =90 °, β =100.1433 °, γ =90 °. Unit cell area (V)Unit cell）=1764.99（3）Å3The number of molecules (Z) in the unit cell is 4; density (D) of 1.598Mg/m3。
The invention also provides a preparation method of the carboxyamidotriazole single crystal, which comprises the following steps: dissolving carboxyamidotriazole in a benign solvent, magnetically stirring at normal temperature, filtering, adding the filtrate into a test tube, sealing, placing in a normal-temperature water bath, and standing for a period of time to obtain the carboxyamidotriazole single crystal.
Preferably, the benign solvent is tetrahydrofuran.
Preferably, the ratio of the benign solvent volume (mL) to the mass (g) of the carboxyamidotriazole is 10-50: 1.
more preferably, the ratio of the benign solvent volume (mL) to the mass (g) of the carboxyamidotriazole is 20-30: 1.
more preferably, the sealing is to seal the opening of the test tube by using a sealing film, and prick 1-2 holes by using a needle of a 10mL syringe. Besides the mode of pricking holes by using an injector, other technical means which are convenient for controlling the slow volatilization of the solvent can be adopted, and the method also belongs to the protection scope of the invention.
Preferably, the standing is carried out for 10-30 days, and the normal temperature is 22-27 ℃; the magnetic stirring time is 5-15 min.
Another objective of the present invention is to provide a pharmaceutical composition of carboxyamidotriazole single crystal, wherein the pharmaceutical composition is an oral preparation or an external preparation, and can be a soft capsule or a tablet, preferably a soft capsule. The specification of the carboxyamidotriazole single crystal in the soft capsule or tablet is 20-80mg, preferably 50 mg.
The invention also aims to provide the application of the carboxyamidotriazole single crystal in resisting malignant tumors, particularly the application in the aspects of lung cancer and colon cancer.
Drawings
FIG. 1 is a microscope observation image of carboxyamidotriazole single crystal.
FIG. 2 is a spatial structure diagram of carboxyamidotriazole single crystal.
FIG. 3 is a statistical chart of the CCK8 experiment.
Detailed Description
The present invention is specifically described below with reference to examples in order to facilitate understanding of the present invention by those skilled in the art. It should be particularly noted that the examples are given solely for the purpose of illustration and are not to be construed as limitations on the scope of the invention, as non-essential improvements and modifications to the invention may occur to those skilled in the art, which fall within the scope of the invention as defined by the appended claims. Meanwhile, the raw materials mentioned below are not specified in detail and are all commercial products; the process steps or preparation methods not mentioned in detail are all process steps or preparation methods known to the person skilled in the art.
Example 1
This example provides a method for preparing a single crystal of carboxyamidotriazole.
Adding 5g of carboxyamidotriazole solid into a 250mL single-mouth bottle at the ambient temperature of 26 ℃, adding 100mL of tetrahydrofuran, magnetically stirring at normal temperature for 10min, filtering, adding the filtrate into 10 test tubes, adding about 10mL of the filtrate into each test tube, pricking a small hole with a needle of a 10mL syringe after each test tube is sealed by a sealing film, placing 10 test tubes into a 1000mL beaker, adding 500mL of water into the beaker, standing for 15 days, growing single crystals from 10 tubes, standing for 7 days continuously, picking out the single crystals, and observing under a microscope, wherein the single crystals are shown in FIG. 1.
The resulting single crystal was analyzed by X-ray single crystal diffraction to obtain a crystallographic data table and a structural diagram as shown in fig. 2 (1 a =0.1 nm).
TABLE 1 Crystal data of carboxyamidotriazole single crystals
Figure 664192DEST_PATH_IMAGE002
。
Table 2 shows atomic coordinates (X10)4) And equivalent isotropic displacement parameter (A)2x103）
Figure 443929DEST_PATH_IMAGE004
。
TABLE 3 bond lengths and bond angles of bonding atoms
Figure 839138DEST_PATH_IMAGE006
Figure 89729DEST_PATH_IMAGE008
。
TABLE 4 anisotropy displacement factor index (A)2x103）
Figure 912191DEST_PATH_IMAGE010
。
Form of anisotropy displacement factor index: -2 pi [ h2 a* 2U11 + ... + 2 h k a* b* U12]Wherein a, b, c are unit lengths of reciprocal lattice; u shape11、U22 、U33 、U23 、U13And U12Is an anisotropic displacement parameter, also known as a temperature factor; h. k and l are diffraction indexes; parallel X-rays are emitted to a perfect monocrystal with proper size, and when the optical path difference meets the integral multiple of the conditional wavelength, diffraction is generated.
According to the three-dimensional laue equation:
a(cos α0 - cos α) = hλ
b(cos β0 - cos β) = kλ
c(cos γ0 - cos γ) = lλ
h. k and l are integers, and a group of h, k and l are called diffraction indexes and specify a specific diffraction direction.
Table 5 shows the coordinates of hydrogen atom (. times.10)4) And equivalent isotropic displacement parameter (A)2x103）
Figure 179225DEST_PATH_IMAGE011
。
TABLE 6 twist angle (°) of carboxyamidotriazole single crystal
Figure 315808DEST_PATH_IMAGE012
Figure 984687DEST_PATH_IMAGE013
Figure 978050DEST_PATH_IMAGE014
。
Table 7 shows the hydrogen bonds [ A and DEG ] of carboxyamidotriazole single crystal
Figure 670063DEST_PATH_IMAGE015
。
The symmetric transformation is used to generate equivalent atoms: #1 x, y, z +1 #2 x, -y +3/2, z +1/2 # 3-x +1, -y + l, -z +2 #4x, -y +3/2, z-1/2.
Example 2
This example provides a method for preparing a single crystal of carboxyamidotriazole.
Adding 5g of carboxyamidotriazole solid into a 250mL single-mouth bottle at the ambient temperature of 22 ℃, adding 150mL of tetrahydrofuran, magnetically stirring at normal temperature for 10min, filtering, adding the filtrate into 15 test tubes respectively, adding about 10mL of filtrate into each test tube, sealing all the test tubes with a sealing film, pricking a small hole with a needle of a 10mL syringe, placing 15 test tubes into a 1000mL beaker, adding 500mL of water into the beaker, standing for 18 days, growing single crystals in 15 test tubes, and standing for 7 days, wherein the single crystals in 15 test tubes are all single crystals.
Example 3
This example provides a method for preparing a single crystal of carboxyamidotriazole.
Adding 5g of carboxyamidotriazole solid into a 250mL single-mouth bottle at the ambient temperature of 27 ℃, adding 75mL of tetrahydrofuran, magnetically stirring at normal temperature for 15min, filtering, adding the filtrate into 5 test tubes respectively, adding about 15mL of filtrate into each test tube, sealing all the test tubes with a sealing film, pricking a small hole with a needle of a 10mL syringe, placing 5 test tubes into a 1000mL beaker, adding 500mL of water into the beaker, standing for 10 days, growing single crystals from 4 test tubes, continuously standing and observing, growing single crystals from all the test tubes on the 11 th day, and continuously standing for 6 days, wherein the single crystals are all in 5 test tubes.
Example 4
This example provides a method for preparing a single crystal of carboxyamidotriazole.
Adding 5g of carboxyamidotriazole solid into a 250mL single-mouth bottle at the ambient temperature of 25 ℃, adding 250mL of tetrahydrofuran, magnetically stirring at normal temperature for 5min, filtering, adding the filtrate into 20 test tubes respectively, adding about 10mL of filtrate into each test tube, sealing all the test tubes with a sealing film, pricking two small holes with a needle of a 10mL syringe, placing 20 test tubes into a 1000mL beaker, adding 500mL of water into the beaker, standing for 23 days, growing single crystals in 20 test tubes, and standing for 7 days, wherein the single crystals are all in 20 test tubes.
Example 5
This example provides a 50mg specification carboxyamidotriazole single crystal soft capsule, with the following contents:
carboxyaminotriazole monocrystal 100 parts
Polyethylene glycol 40090 parts
Vitamin E9.5 parts
And 75 parts of glycerol.
Melting the components of the capsule shell for preparing the soft capsule, preserving heat, and preparing the contents into medicinal liquid for later use; opening the conveyor, operating the equipment to adjust the thickness of the capsule shell to 0.70mm to keep the thickness of the capsule shell on the left and right sides consistent, extracting the heat-insulated glue solution and pressing into soft capsules, injecting and pelleting the liquid medicine, shaping, drying, washing and drying the pills.
Example 6
This example is a comparative test of the stability of carboxyamidotriazole single crystals with carboxyamidotriazole powder. Referring to the guiding principle of drug stability (9001 of the four-part general rule of the 2020 edition of Chinese pharmacopoeia) of the stability test of raw material drugs and preparations, the carboxyamidotriazole single crystal obtained in example 1 was placed at a temperature of 40 ℃. + -. 2 ℃ and a relative humidity of 75%. + -. 5%, and the changes of the indexes such as properties, content, related substances, drying weight loss and the like were examined. The data of 6 months of accelerated test shows that all indexes of the carboxyamidotriazole single crystal have no obvious change relative to 0 day, and the chemical stability is proved to be good.
Table 8 shows the results of stability tests of carboxyamidotriazole single crystal and carboxyamidotriazole powder
Figure DEST_PATH_IMAGE017
。
Example 7
This example is a CCK8 experiment in which carboxyamidotriazole single crystals inhibit the proliferation of HCT-8 cells, LLC cells and MCF-7 cells.
Respectively inoculating HCT-8 (human colon cancer cell), LLC (mouse derived Lewis lung cancer cell) and MCF-7 (human breast cancer cell) in 96-well microplate (3000-2Culturing in an incubator until 80% of cells are fused, and adding medicine for treatment; adding 100 μ L of carboxyamidotriazole single crystal solution with different concentrations (final concentration of 20, 10, 5, 1 and 0.1 μ g/mL) as a test group, and culturing a normal control group with 100 μ L of control solution; after 72 hours of incubation, 10. mu.L of CCK8 reagent was added, and after incubation at 37 ℃ for 4 hours, the absorbance of each well was measured using a microplate reader.
The results of the tests are shown in FIG. 3, IC of carboxyamidotriazole single crystals on different cells50The values are, LLC: 2.892 plus or minus 0.95 mu g/mL; HCT-8: 4.084 +/-0.89 mu g/mL; MCF-7: 0.854. + -. 1.05. mu.g/mL. The results show that the carboxyamidotriazole single crystal has growth inhibition effect on HCT-8, LLC and MCF-7, wherein the inhibition effect on human breast cancer MCF-7 cells is the best.
Comparative example 1
Adding 5g of carboxyamidotriazole solid into a 250mL single-mouth bottle at the ambient temperature of 26 ℃, adding 100mL of tetrahydrofuran, magnetically stirring at normal temperature for 10min, filtering, adding the filtrate into 10 test tubes respectively, adding 10mL of filtrate into each test tube, placing 10 test tubes in an open state, placing in a 1000mL beaker, adding 500mL of water into the beaker, and completely volatilizing the solvent in the open-state placed test tube in 4-6 days, wherein the crystallization fails.
Comparative example 2
At the temperature of 27 ℃, 5g of carboxyamidotriazole solid is added into a 25mL single-mouth bottle, 6mL of DMF is added, magnetic stirring is carried out at normal temperature for 10min, then filtration is carried out, the filtrate is respectively added into 5 test tubes, 1.2mL of filtrate is added into each test tube, all the test tubes are left to stand for 50 days at the open room temperature, and no single crystal grows out.
Comparative example 3
At the temperature of 28 ℃, 5g of carboxyamidotriazole solid is added into a 25mL single-mouth bottle, 5mL of DMSO is added, magnetic stirring is carried out at normal temperature for 10min, then filtration is carried out, the filtrate is respectively added into 5 test tubes, 1mL of filtrate is added into each test tube, all the test tubes are left to stand for 50 days in an open room temperature, and no single crystal grows out.
Comparative example 4
Adding 5g of carboxyamidotriazole solid into a 100mL single-mouth bottle at the ambient temperature of 26 ℃, adding 50mL of DMF (dimethyl formamide) and performing magnetic stirring at normal temperature for 10min, filtering, respectively adding the filtrate into 5 test tubes, adding about 10mL of filtrate into each test tube, slowly adding 0.2-1 mL of distilled water into the 5 test tubes along the wall of the test tube, placing the 5 test tubes in a 1000mL beaker after all the test tubes are open, adding 500mL of water into the beaker, standing for a period of time, observing whether crystals appear, and detecting the water temperature to be 18-25 ℃. After standing for 30 days, no single crystal is grown in all 5 test tubes.
Comparative example 5
Adding 5g of carboxyamidotriazole solid into a 100mL single-mouth bottle at the ambient temperature of 23 ℃, adding 50mL of DMF (dimethyl formamide) and performing magnetic stirring at normal temperature for 10min, filtering, adding the filtrate into 5 test tubes respectively, adding about 10mL of filtrate into each test tube, slowly adding 0.2-1 mL of petroleum ether into the 5 test tubes along the wall of the test tube, layering the solution, placing the 5 test tubes into a 1000mL beaker after all the test tubes are opened, adding 500mL of water into the beaker, standing for a period of time, observing whether crystals appear, and detecting that the water temperature is 18-27 ℃. Standing for 30 days, the solution in 5 test tubes is not layered any more, and no single crystal grows out of all 5 test tubes.
Comparative example 6
Adding 5g of carboxyamidotriazole solid into a 100mL single-mouth bottle at the ambient temperature of 26 ℃, adding 50mL of DMSO (dimethyl sulfoxide) and magnetically stirring at normal temperature for 10min, filtering, respectively adding the filtrate into 5 test tubes, adding about 10mL of filtrate into each test tube, slowly adding 0.2-1 mL of distilled water into the 5 test tubes along the wall of the test tube, placing the 5 test tubes in a 1000mL beaker after all the test tubes are open, adding 500mL of water into the beaker, standing for a period of time, observing whether crystals appear, and detecting the water temperature to be 20-25 ℃. After standing for 30 days, no single crystal is grown in all 5 test tubes.
Comparative example 7
Adding 5g of carboxyamidotriazole solid into a 100mL single-mouth bottle at the ambient temperature of 24 ℃, adding 50mL of DMSO (dimethyl sulfoxide) and magnetically stirring at normal temperature for 10min, filtering, respectively adding the filtrate into 5 test tubes, adding about 10mL of filtrate into each test tube, slowly adding 0.5-1.5 mL of petroleum ether into the 5 test tubes along the wall of the test tube, layering the solution, placing the 5 test tubes into a 1000mL beaker after all the test tubes are opened, adding 500mL of tap water into the beaker, standing for a period of time, observing whether crystals appear, and detecting that the water temperature is 19-27 ℃. Standing for 30 days, the solution in 5 test tubes is not layered any more, and no single crystal grows out of all 5 test tubes.
Comparative example 8
Adding 5g of carboxyamidotriazole solid into a 1000mL single-mouth bottle at the ambient temperature of 24 ℃, adding 400mL of ethanol, heating, adjusting the temperature of the solution to 75 ℃, magnetically stirring for 1h, filtering, adding the filtrate into 40 test tubes respectively, adding about 10mL of filtrate into each test tube, placing all the test tubes in a shade place for standing, and immediately precipitating white solid when the solution is slowly cooled to the room temperature, wherein the crystallization fails.
Comparative example 9
Adding 5g of carboxyamidotriazole solid into a 1000mL single-mouth bottle at the ambient temperature of 27 ℃, adding 600mL of ethyl acetate, heating, adjusting the temperature of the solution to 75 ℃, magnetically stirring for 1h, filtering, adding the filtrate into 40 test tubes, adding about 15mL of the filtrate into each test tube, placing all the test tubes in a shade place for standing, and immediately precipitating white solid after cooling to the room temperature, wherein the crystallization fails.
It should be understood that the above-mentioned embodiments of the present invention are only examples for clearly illustrating the technical solutions of the present invention, and are not intended to limit the specific embodiments of the present invention. Any modification, equivalent replacement, and improvement made within the spirit and principle of the present invention claims should be included in the protection scope of the present invention claims.

Claims (7)

1. The single crystal of carboxyamidotriazole is characterized by its crystal system, space group, lattice parameter, VUnit cellThe number of molecules in the unit cell and the density thereof are as follows:
Figure DEST_PATH_IMAGE001
。
2. a process for preparing carboxyamidotriazole single crystal as claimed in claim 1, wherein carboxyamidotriazole is dissolved in a benign solvent, magnetically stirred at room temperature and filtered, the filtrate is put into a test tube, sealed and placed in a water bath at room temperature, and left to stand for a while to obtain carboxyamidotriazole single crystal; the benign solvent is tetrahydrofuran, the sealing is to seal the opening of the test tube by adopting a sealing film, and prick 1-2 holes by using a needle of a 10mL syringe.
3. The method for preparing carboxyamidotriazole single crystal according to claim 2, wherein the mass ratio of benign solvent volume to carboxyamidotriazole is 10mL to 50 mL: 1g of the total weight of the composition.
4. The method for preparing carboxyamidotriazole single crystal according to claim 3, wherein the mass ratio of benign solvent volume to carboxyamidotriazole is 20mL to 30 mL: 1g of the total weight of the composition.
5. The method for preparing carboxyamidotriazole single crystal according to claim 2, wherein the standing time is 10 to 30 days, the normal temperature is 22 to 27 ℃, and the magnetic stirring time is 5 to 15 min.
6. A pharmaceutical composition comprising the carboxyamidotriazole single crystal of claim 1, and a pharmaceutically acceptable carrier.
7. Use of the carboxyamidotriazole single crystal of claim 1 for the preparation of a medicament for the treatment of malignant tumors selected from lung cancer, colon cancer, breast cancer.
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Publication number Priority date Publication date Assignee Title
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CN112358451A (en) * 2021-01-11 2021-02-12 广东银珠医药科技有限公司 Synthetic method of carboxyamidotriazole
CN112353778A (en) * 2021-01-11 2021-02-12 广东银珠医药科技有限公司 Carboxyaminetriazole soft capsule and preparation method thereof

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Publication number Priority date Publication date Assignee Title
EP0304221A2 (en) * 1987-08-20 1989-02-22 Merck & Co. Inc. 5-amino or substituted amino 1,2,3-triazoles useful as antiproliferative agents
CN102595904A (en) * 2009-09-04 2012-07-18 巧妙疗法股份有限公司 Novel compositions and processes for preparing 5-amino or substituted amino 1,2,3-triazoles and triazole orotate formulations
CN112358451A (en) * 2021-01-11 2021-02-12 广东银珠医药科技有限公司 Synthetic method of carboxyamidotriazole
CN112353778A (en) * 2021-01-11 2021-02-12 广东银珠医药科技有限公司 Carboxyaminetriazole soft capsule and preparation method thereof

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抗癌新药L-651582的合成;吴晓峰 等;《中国医药工业杂志》;20060310;第37卷(第3期);第147-149页 *

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