Liver-targeted platinum-based anticancer drug and its synthesis method
A compound and derivative technology, applied in the field of liver-targeted platinum cancer drugs and their synthesis, can solve the problems of destroying the chemical structure of bile acid, affecting the recognition of bile acid by liver tissue, reducing the liver-targeting properties of compounds, etc. High cancer activity, major clinical application prospects, good liver targeting effect
Active Publication Date: 2016-05-25
KUNMING INST OF PRECIOUS METALS +1
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Problems solved by technology
The 3-position keto group on dehydrocholic acid introduces a more complex group, which will destroy the original chemical structure of cholic acid, affect the recognition of cholic acid by liver tissue, and reduce the liver targeting of the compound
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[0047] (1) Synthetic method of liver targeting platinum anticancer drug of the present invention
[0048] a) Preparation of 3-TsO-1,1-diethyl cyclobutanedicarboxylate (2)
[0049] Under nitrogen protection, take 5.1g (0.024mol) diethyl 3-hydroxy-1,1-cyclobutanedicarboxylate, 9.6g (0.094mol, 4eq.) triethylamine (Et 3 N), 0.58g (0.0047mol, 20%eq.) of 4-dimethylaminopyridine (DMAP) was added to 10mL of dichloromethane, dissolved after stirring, and 9.0g (0.047mol, 2eq.) of p-toluenesulfonyl chloride (TsCl ) and 10 mL of dichloromethane were mixed and added dropwise in an ice bath. After the addition was complete, the mixture was stirred overnight at room temperature, and the reaction was monitored by TLC to complete. Developing agent: petroleum ether: ethyl acetate = 4:1, R f =0.4, column chromatographic separation (petroleum ether: ethyl acetate = 6:1) yielded 8.2 g of the product, with a yield of 94%.
[0050] b) Preparation of diethyl 3-azido-1,1-cyclobutanedicarboxylate (3...
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The invention discloses a liver-targeting platinum anticancer drug and a synthetic method thereof, and relates to the liver-targeting platinum anticancer drug which uses cholic acid and derivatives thereof as carrier molecules, and the synthetic method thereof. According to the invention, ammonia / amine ligand (A2) of the liver-targeting platinum anticancer drug comprises 2NH3, 1R,2R-diaminocyclohexane, 1,2-bis(aminomethyl)cyclobutane, (4S,5S)-4,5-(aminomethyl)-2-isopropyl-1,3-dioxolane, cholic acid, deoxycholic acid, hyodeoxycholic acid, ursodeoxycholic acid and chenodeoxycholic acid (RCOOH). The cholic acid and derivatives thereof are conjugated with 1,1-cyclobutane dicarboxylic radicals through amide bonds to form compounds with a structure as described in the specification. The compounds have the characteristics of high anticancer activity and strong liver-targeting property and can be applied as the anticancer drug to hepatic artery infusion or hepatic artery intervention embolization therapy for liver cancer; the structural formula of the compounds is described in the specification.
Description
technical field [0001] The invention relates to a class of liver-targeting platinum carcinoid drugs using cholic acid and its derivatives as carrier molecules and a synthesis method thereof, belonging to the field of biopharmaceuticals. Background technique [0002] According to the "World Cancer Report" released by the World Health Organization in 2014, liver cancer is one of the most common malignant tumors in China. 80% of the world's liver cancer patients are in my country, and the number of deaths caused by it reaches 130,000 every year, ranking first in cancer mortality. second only to lung cancer. Surgery is the most effective way to treat early liver cancer, but chemotherapy is an important option for patients who cannot accept surgery and patients with advanced stages, and platinum-based anticancer drugs [1] (mainly cisplatin, carboplatin, oxaliplatin, see structural formula 1) is one of the few effective drugs for liver cancer, used for hepatic arterial infusion ch...
Claims
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IPC IPC(8): C07J51/00C07F15/00A61K31/575A61K31/282A61P35/00
CPCC07F15/0093C07J51/00
Inventor 刘伟平楼丽广姜婧侯树谦叶青松常桥稳
Owner KUNMING INST OF PRECIOUS METALS