Betulinic acid analogue and preparation method and application thereof
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A technology of betulinic acid and betulinamide, applied in the field of medicine, can solve the problems of poor water solubility, anti-tumor activity to be improved, and low bioavailability
Inactive Publication Date: 2011-07-06
TIANJIN HANKANG PHARMA BIOTECH
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[0007] The existing research results show that the natural product betulinic acid has biological activities such as anti-HIV and anti-tumor activity, and has a new structure and a novel mechanism of action. It has a wide range of natural sources and mature semi-synthetic methods. Although betulinic acid has poor water solubility, Low bioavailability and other issues, it is still an excellent lead for anti-HIV and anti-tumor drugs
Through the structural modification of betulinic acid, some betulinic acid derivatives have been synthesized, their activity has been tested, and some research results have been obtained, but the antitumor activity still needs to be improved, and there are still problems such as strong hydrophobicity, poor absorption, and low bioavailability. Due to these problems, no such compounds have entered the clinical research stage for many years, which requires in-depth research to continue to find better anti-tumor drugs
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example 1
[0160] Example 1: 3-deoxy-3-oxo-betulinic acid (3-nitrate) propyl ester (HK-101)
[0161] a. Add 18.2g of 3-deoxy-3-oxo-betulinic acid (compound A) and 250ml of anhydrous methanol to the reaction flask, slowly add 2.2g of sodium methoxide under stirring, and keep warm for 1.5 hours at room temperature. Then the solvent was evaporated under reduced pressure and dried to obtain off-white sodium salt. The sodium salt can be used in the next step without purification.
[0162] b. In the reaction flask, add 9.5g of 3-deoxy-3-oxo-sodium betulinate, 100ml of dimethylformamide (DMF), and add 6.3g of 1,3-bromochloropropane dropwise under stirring, within 30 minutes After the dropwise addition was completed, the reaction was maintained at 40° C. for 18 hours. Stop the reaction, filter to remove the generated sodium bromide. DMF was evaporated under reduced pressure, 85ml of dichloromethane was added, and the insoluble matter was removed by filtration. Dichloromethane was evaporated ...
Embodiment 2
[0169] Example 2: 3-deoxy-3-oxo-betulinic acid (4-nitrate) butyl ester (HK-102)
[0170] According to the preparation method and process provided in Example 1, the 3-deoxy-3-oxo-betulinic acid (4-bromo) butyl ester obtained in Example 1 (b) is replaced in Example 1 (c) 3-Deoxy-3-oxo-betulinic acid (3-chloro)propyl ester, you can get 3-deoxy-3-oxo-betulinic acid (4-nitrate) butyl ester (HK-102) . HPLC: 99.18%, ESI-MS: 594.4 (M+Na).
Embodiment 3
[0171] Example 3: 3-deoxy-3-oxo-betulinic acid (6-nitrate) hexyl ester (HK-103)
[0172] According to the preparation method and process provided in Example 1, the 3-deoxy-3-oxo-betulinic acid (6-chloro) butylhexyl ester obtained in Example 1 (b) is replaced in Example 1 (c). 3-deoxy-3-oxo-betulinic acid (3-chloro)propyl ester, 3-deoxy-3-oxo-betulinic acid (6-nitrate) hexyl ester (HK-103), HPLC: 99.26%, ESI-MS: 622.4 (M+Na).
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Abstract
The invention relates to the field of antineoplastic medicines and provides a betulinic acid analogue with the structure shown in figure (1) or solvate thereof. The definition of R1, R2, X and n is inThe invention relates to the field of antineoplastic medicines and provides a betulinic acid analogue with the structure shown in figure (1) or solvate thereof. The definition of R1, R2, X and n is inthe specification. The invention also provides the a preparation method of the betulinic acid analogue with the structure shown in figure (1) or the solvate thereof, and the applications of pharmaceu the specification. The invention also provides the a preparation method of the betulinic acid analogue with the structure shown in figure (1) or the solvate thereof, and the applications of pharmaceutical compositions containing the betulinic acid analogue or the solvate thereof and medicines using the betulinic acid analogue or the solvate thereof as the effective constituent for preparing antintical compositions containing the betulinic acid analogue or the solvate thereof and medicines using the betulinic acid analogue or the solvate thereof as the effective constituent for preparing antineoplastic medicines for treating pulmonary cancer, prostatic cancer, colon cancer, leukemia, mammary cancer, liver cancer, gastric cancer, pancreatic cancer, malignant neuroglioma, cerebral tumor, andeoplastic medicines for treating pulmonary cancer, prostatic cancer, colon cancer, leukemia, mammary cancer, liver cancer, gastric cancer, pancreatic cancer, malignant neuroglioma, cerebral tumor, andthe like. the like.
Description
technical field [0001] The present invention belongs to the technical field of medicine, more specifically, relates to a class of betulinic acid analogues obtained by chemical synthesis, a preparation method of these betulinic acid analogues, a pharmaceutical composition containing these betulinic acid analogues and these betulinic acid analogues. Drugs are used for anti-tumor purposes. Background technique [0002] Malignant tumor is a disease that seriously threatens human health, and its mortality rate ranks second among all diseases, second only to cardiovascular and cerebrovascular diseases. Due to changes in living environment and living habits, under the influence of adverse environment and some unfavorable factors, the incidence of tumors is increasing year by year. Among the 6 billion people in the world, about 8 million new cancer patients are added every year, and more than 6 million people die of cancer, almost every 6 seconds. One cancer patient dies. Accordin...
Claims
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