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Heteroaryl estrogen receptor regulating agent and application thereof

A technology of estrogen receptors and modulators, applied in the field of medicine, can solve problems such as hot flashes and endometrial cancer, and achieve the effects of promoting regeneration or repair, prolonging shelf life, and enhancing sustained release

Inactive Publication Date: 2019-09-20
嘉兴市爵拓科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, clinically used tamoxifen and raloxifene can cause adverse reactions such as endometrial cancer and hot flashes

Method used

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  • Heteroaryl estrogen receptor regulating agent and application thereof
  • Heteroaryl estrogen receptor regulating agent and application thereof
  • Heteroaryl estrogen receptor regulating agent and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0071] According to the above scheme, the compound A with general formula (I) can be prepared, and its specific preparation steps are as follows:

[0072]1) Preparation of intermediate 1: Take 20 g of 4-hydroxyacetone and 100 g of anhydrous potassium carbonate and dissolve them in 20 times the amount of acetone, then add 22 g of low-level benzyl chloride to it, reflux for 24 hours, and evaporate the solvent acetone under reduced pressure , the residue was stirred with water, suction filtered and dried, and the obtained white solid was intermediate 1, m.p.101~102℃, ESI-MS: m / z241 ([M+H] + );

[0073] 2) Preparation of intermediate 2: Take 10 g of intermediate 1 and add it into a mixed solvent of 1,4-dioxane and anhydrous methanol, slowly add 7 g of liquid bromine dropwise, react at room temperature until the solution is transparent and clear, add water and stir for 1 h, Suction filtration and drying, the obtained white solid is Intermediate 2, m.p.74~75℃, ESI-MS: m / z 320 ([M+H...

Embodiment 2

[0084] According to the above scheme, the reddish-brown solid compound B with general formula (I) can be prepared, and the structural formula is as follows:

[0085] m.p.107~108℃, ESI-MS: m / z 560([M+H]+), 1H NMR(400MHz, CDCl3): δ7.48(d, J=7.6Hz, 1H), 7.22-7.16(m ,1H),7.13-7.06(m,1H),6.92(d,J=10.5Hz,2H),5.96(s,1H),5.51(s,1H),5.88(d,J=5.0Hz,1H) ,4.53(t,J=5.7Hz,1H),4.41(t,J=6.0Hz,1H),4.27(dd,J=4.0,11.3Hz,1H),4.14-4.07(m,1H),3.84- 3.80(m,1H,3.63(t,J=12.5Hz,2H),3.33-3.18(m,6H),2.93-2.78(m,2H),2.65-2.56(m,4H),1.75-1.67(m ,2H), 1.21-1.19(m,3H). Its infrared spectrum is shown in the attached figure 2 .

Embodiment 3

[0087] The preparation method of heteroaryl estrogen receptor modulator, its specific steps are as follows:

[0088] 1) Add alginate to sterile water containing 6 times the amount of propylene glycol, stir to form a uniformly mixed suspension, remove air bubbles to obtain a protective colloid, and the weight ratio of alginate to propylene glycol is 1:3.5;

[0089] 2) adding compound A into the protective colloid, stirring evenly to form a dispersion;

[0090] 3) Dissolve dodecylamine in an ethanol solution with a volume concentration of 75%, then add tetraethyl orthosilicate, calcium nitrate tetrahydrate and triethyl phosphate, and form an emulsion in a water bath for 120 minutes, then age for 18 hours, and wash the obtained Precipitate, freeze-dry the precipitate, and calcinate to obtain the microsphere carrier. The addition amount of tetraethyl orthosilicate is 2.5 times the weight of dodecylamine, and the addition amount of calcium nitrate tetrahydrate and triethyl phosphat...

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Abstract

The invention provides a compound as shown in a formula (I) and a heteroaryl estrogen receptor regulating agent including the same, belonging to the technical field of medicines. The heteroaryl estrogen receptor regulating agent further comprises a calcium phosphosilicate microsphere carrier, wherein the carrier includes silicon oxide, calcium oxide and phosphorus pentoxide in a weight ratio of 20: 4: 1, and the diameters of the microspheres are in a range of 300 to 1100 nm. The compound and the regulating agent provided by the invention can be used as estrogen receptor degrading agents, AKR1C3 inhibitors and bone resorption inhibitors for treating estrogen receptor related diseases or illnesses of patients and can be applied to the treatment of breast cancer, endometriosis and osteoporosis. The preparation method for the regulating agent can prolong the shelf life of the compound, increase the loading amount of a microsphere product, and enhance the stability and sustained release performance of the regulating agent; and the regulating agent provides a supersaturation amount of Ca<2+> in a biological fluid environment for binding to bone tissue nucleation sites so as to promote regeneration or repairing of bone tissue.

Description

technical field [0001] The invention belongs to the technical field of medicine, and in particular relates to a heteroaryl estrogen receptor modulator and its application. Background technique [0002] The estrogen receptor ("ER") is a ligand-activated transcriptional regulatory protein that mediates the induction of a variety of biological effects through its interaction with endogenous estrogens. Endogenous estrogens include 17β-estradiol and estrone. ER has been found to have two subtypes, ER-α and ER-β. After the ligand binds to the subtype, it exerts physiological effects with different tissue specificities. Estrogen and estrogen receptors are involved in many diseases or conditions such as breast cancer, lung cancer, ovarian cancer, colon cancer, prostate cancer, endometrial cancer, uterine cancer and other diseases or conditions. [0003] Estrogen is an important class of hormone compounds in the human body. When women enter menopause, the level of estrogen in the ...

Claims

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Application Information

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IPC IPC(8): C07D403/14C07D401/14A61P35/00A61P19/10A61P15/00A61K31/4439A61K31/506
CPCA61P15/00A61P19/10A61P35/00C07D401/14C07D403/14
Inventor 孟祥龙宋艳丽代素霞
Owner 嘉兴市爵拓科技有限公司
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