2-methoxy-estradiol analogue and preparation method and application thereof

Abstract

The invention relates to a 2-methoxy-estradiol analogue and a preparation method and application thereof, aiming to solve the problem of preparation of the 2-methoxy-estradiol analogue and realize the application of the 2-methoxy-estradiol analogue to preparation of anti-tumor medicaments. The method comprises the following steps: dissolving 2-methoxy-3-benzyloxy-estradiol-1,3,5-(10)-triene-17beta-alcohol or 17beta-amine serving as a raw material into an organic solvent; in the presence of Lewis alkali, carrying out an acylation reaction on the raw materials and a compound (1) to obtain a 2-methoxy-3-benzyloxy-estradiol-1,3,5-(10)-triene-17beta-ester or 17beta-amide compound (2); carrying out a catalytic hydrogenation to obtain a compound (3); carrying out an acylation reaction or a hydrocarbylation reaction to obtain a compound, namely, the 2-methoxy-estradiol analogue (4), wherein a reaction formula is shown in the specifications. The preparation method of the 2-methoxy-estradiol analogue has the advantages of easiness, mild conditions and high yield, and can be effectively applied to development of anti-tumor medicaments.

Description

technical field [0001] The invention relates to medicine, in particular to a 2-methoxyestradiol analogue and its preparation method and application. Background technique [0002] In the 1970s, in the study of estrogen metabolism, the endogenous metabolite 2-methoxyestradiol (2-methoxyestradiol, 2-ME) of estradiol was discovered, which is the cytochrome P450s in the body. Oxidase and catechol-O-methyltransferase (COMT), resulting in ordered hydroxylation and methylation of estradiol. 2-methoxyestradiol exists in the urine and blood of normal people, and it is reported that the plasma content of 2-methoxyestradiol in men and non-pregnant women is relatively low (10-35 pg·ml respectively -1 and 18~138pg·ml -1 ), and the content in the plasma of pregnant women is relatively high (up to 216-10690pg·ml -1 ) (Dubey R.K. et al. Trends Endocrinol Metab. 2009,20(80):374-379). Studies have found that 2ME has a broad-spectrum anti-tumor effect, and the treatment is well tolerated. ...

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Problems solved by technology

[0003] However, there are still some problems that need to be solved urgently for 2-ME to be widely used in clinic: (1) 2-ME is a concentration-time-dependent antitumor drug, and its solubility in water is extremely low (approximately 1.669 μg· ml -1 , The lipid-water partition coefficient is about 2.86 (Guo Xinhong et al., Journal of Zhengzhou University (Medical Edition), 2010, 45(1): 141-143)) (2) There is no correlation between oral absorption and dosage, and it is easy to rapidly hydroxy in the body Biological changes such as dehydrogenation and dehydrogenation produce inactive metabolites, resulting in a short half-life (about 20 minutes), low bioavailability, and extremely low oral blood and tissue drug concentrations (less than 100ng·ml -1 ), which cannot satisfy the time-dose-dependent pharmacological action characteristics of the drug itself (James J, et al.Invest New Drugs, 2007,25:41-48)

The disadvantages of 2-ME, such as low water solubility, large oral dose, irregular absorption, short half-life, first-pass effect and low bioavailability, limit the clinical application of 2-ME.

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