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

A technology of methoxyestradiol and analogues, which is applied in the field of medicine, can solve the problems of low water solubility, short half-life, and low solubility, and achieve the effects of simple preparation method, mild conditions, and high yield

Inactive Publication Date: 2014-05-07
ZHENGZHOU UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

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

Method used

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

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Effect test

Embodiment 1

[0023] In the specific implementation of the present invention, the 2-methoxyestradiol analog is a compound of the following structural formula (I):

[0024]

[0025] Among them, R 1It is a kind of hydrogen atom, methyl, ethyl and benzyl; R 2 Methyl, ethyl, vinyl, propyl, isopropyl, propenyl, allyl, butyl, isobutyl, tert-butyl, cyclopentyl, cyclohexane, chloromethyl, chloro Ethyl, chloropropyl, fluoromethyl, fluoroethyl, butyrate, crotonate, hydroxypropionate, phenyl, benzyl, chlorophenyl, fluorophenyl, tetrafluorophenyl, pyridyl and a kind of imidazolyl;

[0026] The compound of the general formula (I) can be one of the compounds of the following general formula:

[0027]

[0028]

[0029] The preparation method of the compound of the general formula (I), taking the I-3 compound and the I-7 compound as examples:

[0030] The preparation of A, Ⅰ-3 compound, the method is, under the condition of ice bath, add 0.48g (1.22mmol) 2-methoxy-3-benzyloxy-estra-1,3,5(10)-t...

Embodiment 2

[0034] In the specific implementation of the present invention, the 2-methoxyestradiol analog is a compound of the following structural formula (II):

[0035]

[0036] Among them, R 1 hydrogen atom, methyl, ethyl, benzyl, allyl, acetyl, propionyl, butyryl, chloroacetyl, chloropropionyl, chlorobutyryl, benzoyl, chlorobenzoyl, fluorobenzoyl One of acyl and furoyl;

[0037] The compound of the general formula (II) can be one of the compounds of the following general formula:

[0038]

[0039]

[0040] The preparation method of the compound of the general formula (II), taking compound II-4 and compound II-9 as examples:

[0041] A. The preparation of compound Ⅱ-4, the method is to add 169.8 μl (4.5 mmol) of anhydrous formic acid dropwise to 391.8 μl (4.5 mmol) of chlorosulfonyl isocyanate under ice bath, stir rapidly, and add to the system after 15 minutes Acetonitrile 6ml, stirred at room temperature for 7 hours; then slowly added 1.50g (3.8mmol) of 2-methoxy-3-benzyl...

Embodiment 3

[0046] In the specific implementation of the present invention, the 2-methoxyestradiol analog is a compound of the following structural formula (Ⅲ):

[0047]

[0048] Among them, R 1 It is one of hydrogen atom, methyl, ethyl, propyl, allyl, benzyl and aminosulfonyl; R 2 Methyl, ethyl, vinyl, propyl, isopropyl, propenyl, allyl, butyl, isobutyl, tert-butyl, cyclopentyl, cyclohexane, chloromethyl, chloro Ethyl, chloropropyl, fluoromethyl, fluoroethyl, butyrate, crotonate (e.g. fumarate, maleate), hydroxypropionate (e.g. tartaric acid, malate), phenyl, benzyl chlorophenyl, fluorophenyl, tetrafluorophenyl, pyridyl, imidazolyl, natural and unnatural amino acid residues (e.g. glycine, alanine, serine, threonine, valine, leucine , Isoleucine, Phenylalanine, Tyrosine, Cysteine, Methionine, Aspartic Acid, Asparagine, Glutamic Acid, Glutamine, Histidine, Lysine, Arginine , proline, hydroxyproline, tryptophan, β-alanine, γ-aminobutyric acid, ε-aminocaproic acid, ornithine, citrullin...

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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. ...

Claims

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Application Information

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IPC IPC(8): C07J1/00C07J41/00C07J43/00A61K31/565A61K31/58A61P35/00
Inventor 施秀芳张振中姚海峰孙帅军吴丹丹景飞路翔李鹏
Owner ZHENGZHOU UNIV
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