Aromatization enzyme inhibitor

An aromatase and inhibitor technology, applied in the field of enzyme inhibitors, can solve the problems of lowering aldosterone level, no better curative effect than tamoxifen, poor selectivity, etc., and achieve the effect of reducing activity

Inactive Publication Date: 2013-05-01
TIANJIN UNIV OF SCI & TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0013] Aminoglutethimide, the first-generation aromatase inhibitor, was initially used clinically as an antiepileptic drug, and was used for advanced hormone-dependent breast cancer in the 1960s. At the same time, it also widely affects the metabolism of other steroid hormones, and the metabolism of adrenal cortex hormones is also affected. When using this drug, glucocorticoids must be supplemented
[0014] The second-generation aromatase inhibitor, Lentaron, is in the form of intramuscular injection. The drug has good selectivity and does not affect the metabolism of other steroid hormones in the body. It does not need to be supplemented with glucocorticoids, but its curative effect is not good It is based on tamoxifen, and it is an intramuscular injection preparation, which is inconvenient to apply
Fadrozole lowers aldosterone levels, limiting its application dose to 90% inhibitory efficacy, and other second-generation aromatase inhibitors have not been approved for clinical use

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0051] Synthesis and aromatase inhibitory activity of methyl o-(2-ethyl-4-methylimidazol-1-methyl)phenylacetate

[0052] (1) Preparation of 2-chloromethylphenylacetic acid methyl ester

[0053] Prepared according to U.S. Patent 6048998, take isochromone (15g, 0.099mol) and dissolve it in (30.2g, 0.9mol) methanol solution, put the reaction bottle in an ice-water bath, and add chlorination dropwise at -5°C-0°C Sulfoxide (25g, 0.21mol); After the dropwise addition, be warmed up to room temperature and stirred for two hours; After the reaction, adjust the pH>6 with 10% potassium carbonate solution, extract the organic layer with methanol (75ml×3 times), and use Distill the water solution (100ml×3 times), dry over night with anhydrous magnesium sulfate, and concentrate with a rotary evaporator to obtain a colorless oily liquid, the product 2-chloromethylphenylacetic acid methyl ester 16.9g, the yield is 85%, the reaction formula is as follows :

[0054]

[0055] Its HNMR analy...

Embodiment 2

[0082] (1) Preparation of o-(2-ethyl-4-methylimidazolium-1-methyl)phenylacetic acid

[0083] Take the prepared o-(2-ethyl-4-methylimidazol-1-methyl)methyl phenylacetate 2.7g (10mmol) in a 100ml flask, add 10ml ethanol and 20ml 5% NaOH aqueous solution and reflux for 10h under stirring conditions Afterwards, use 6M hydrochloric acid to neutralize to partial acidity, evaporate the water to dryness under reduced pressure, extract twice with methanol after cooling, combine the methanol solution, evaporate the methanol under reduced pressure to obtain a light yellow oil, and obtain a light yellow crystal after cooling. O-(2-ethyl-4-methylimidazol-1-methyl)phenylacetic acid, the reaction formula is as follows:

[0084]

[0085] Its HNMR analysis see image 3 , where 1H NMR (CDCl 3 , ppm, 400MHz) δ1.20(t, 3H), 2.07(s, 3H), 2.53(m, 2H), 3.30(s, 3H), 3.50(s, 2H), 5.02(s, 2H), 6.60 (s, 1H), 7.22 (m, 4H) MS: m / z = 259.31 (M+H) + , elemental analysis: C 69.25; H 7.12; N 10.91.

[...

Embodiment 3

[0089] Synthesis and Aromatase Inhibitory Activity of Methyl O-(4-Formic Acid Ethylimidazol-1-Methyl) Phenylacetate

[0090] (1) Synthesis of o-(4-formic acid ethyl imidazole-1-methyl) methyl phenylacetate

[0091] Dissolve ethyl imidazole-4-carboxylate (5g, 35.68mmol) in 150ml of chloroform, add methyl 2-chloroethylphenylacetate (8.0g, 40.27mmol) under stirring, stir for 30min, then raise the temperature until reflux for 3h . Cool to room temperature, pour into distilled water, add 100ml of ethyl acetate, separate the layers and extract the organic layer (2×100ml). Dry over anhydrous magnesium sulfate overnight, and concentrate. Purification by column chromatography, eluting with ethyl acetate / petroleum ether (1:3), gave methyl o-(4-ethyl imidazole-1-methyl)phenylacetate as a white oily product with a yield of 73%. The reaction formula is as follows:

[0092]

[0093] Its HNMR analysis see Figure 4 ,in,

[0094] 1H NMR (CDCl 3 , ppm, relative to TMS, 400MHz) δ1.36(...

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Abstract

The invention relates to a series of aromatization enzyme inhibitors. In a structural formula, R1, R2 and R3 can be selected from -H, CH3-, CH3CH2-, CH3CH2CH2-, -Cl, -Br, -F, -OH, HOCH2CH2-, -COOH or ester of -COOH respectively; R4 is -H or alkyl; and n is 1, 2, 3, 4 or 5 and 1-benzyl carbazole. A series of ortho-methyl phenyl carboxylic acid compounds and derivatives thereof are synthesized by changing certain terminal structures of an ortho-methyl phenyl carboxylic acid compound, and a benzyl 1-benzyl carbazole compound is synthesized by taking carbazole as a raw material. These compounds have good inhibiting effects on aromatization enzymes. As proved by testing, the highest aromatization enzyme inhibiting activity of the inhibitor is 0.7 mug / mL, which is higher than that of aminoglutethimide (7.7 mug / mL) serving as a first generation aromatization enzyme inhibitor.

Description

technical field [0001] The invention belongs to the field of enzyme inhibitors, in particular to an aromatase inhibitor. Background technique [0002] 1. Structure and function of aromatase [0003] Aromatase (CYP19) belongs to the cytochrome P450 superfamily and is an enzyme protein composed of 503 amino acids. It is widely present in normal tissues and organs such as ovary, placenta, testis, brain, fat, bone, etc. Endoplasmic reticulum membrane, and tightly combined with the membrane, highly expressed in placenta and ovarian follicular granulosa cells, and also expressed at low levels in non-glandular tissues such as subcutaneous fat, muscle, liver, brain, normal breast stroma and breast cancer . Eighty percent of estrogen receptor (ER)-positive postmenopausal breast cancer patients have aromatase activity in tumor tissue. The active center of aromatase also has an iron-containing porphyrin ring (heme prosthetic group), which plays a decisive role in the catalytic activ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): A61K31/4174A61K31/403A61P35/00A61P5/32C07D233/56C07D233/90C07D209/86
Inventor 戴玉杰马忠俊王强张同存张黎明魏树梅
Owner TIANJIN UNIV OF SCI & TECH
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