Hormone releasing hormone receptor antagonists and uses thereof

A use, gonadal technology, applied in the direction of diseases, antineoplastic drugs, organic active ingredients, etc.

Active Publication Date: 2021-10-22
SHIJIAZHUANG YILING PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0010]Although meaningful research has been carried out in this field, there is still a need for effective small molecule GnRH receptor antagonists with more desirable drug properties

Method used

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  • Hormone releasing hormone receptor antagonists and uses thereof
  • Hormone releasing hormone receptor antagonists and uses thereof
  • Hormone releasing hormone receptor antagonists and uses thereof

Examples

Experimental program
Comparison scheme
Effect test

preparation example Construction

[0037] The second aspect of the present invention provides a method for preparing the compound provided by the first aspect of the present invention, comprising: hydrolyzing the compound of formula 1-12 to prepare the compound of formula I, and the reaction equation is as follows:

[0038]

[0039] In the preparation method provided by the present invention, the hydrolysis reaction can usually be carried out in the presence of a base. Those skilled in the art can select the appropriate type and amount of alkali for the above-mentioned hydrolysis reaction. For example, the alkali can be alkali metal hydroxide, etc., more specifically lithium hydroxide, etc., and for another example, the alkali The dosage relative to the compound of formula 1-12 is generally equal or in excess. Specifically, the molar ratio of the compound of formula 1-12 to the base can be 1:1.4-1.6.

[0040] In the preparation method provided by the present invention, the reaction can usually be carried out...

Embodiment 1

[0054] The concrete preparation route of compound G201 in the embodiment is as follows:

[0055]

[0056] Compound 1-1 (10 g, 72.4 mmol), pyridine (200 mL) and selenium dioxide (16 g, 144.8 mmol) were added into a three-neck flask. Under the protection of nitrogen, react at 100°C for 2 hours. After the reaction was completed, it was suction filtered, and the filtrate was spin-dried, then 1N hydrochloric acid was added, and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered with suction, and spin-dried to obtain off-white solid 1-2 (12 g).

[0057] Compound 1-2 (12 g, 71.4 mmol) and methanol (200 mL) were added into a three-neck flask. Thionyl chloride (17 g, 142.8 mmol) was added dropwise at 0° C. and stirred overnight at room temperature. After the reaction was completed, methanol was spin-dried, and saturated aqueous sodium bicarbonate solution was added, and extracted with ethyl acetate. The ...

Embodiment 2

[0069] Calcium flux detection:

[0070] FLIPR calcium flux assay kit (Calcium 4 assay kit) was used to measure intracellular calcium changes in recombinant human gonadotropin-releasing hormone receptor (GnRHR) stable cell line CHO-K1 / GNRHR / Gα15. GnRHR is a G protein-coupled receptor (GPCRs). GPCRs signal through the Gq pathway to release intracellular calcium. Therefore, detecting intracellular calcium release through the calcium ion-sensitive fluorescent probe can detect signal transduction through the Gq pathway. Functional changes of GnRHR. The experimental steps are as follows:

[0071] 1. Using F12+10% FBS medium, according to 10000cells / well, 20ul / well, cells were planted in 384-well plates (Corning, Cat#:3764), and cultured overnight (18h).

[0072] 2. Prepare probenecid stock solution (500mM) and Calcium 4 stock solution at a ratio of 1:100 to make dye working solution. Dilute the test product G201 and Elagolix (2mM in DMSO) with assay buffer: Take 5μl of 2mM stock ...

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PUM

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Abstract

The invention relates to a hormone releasing hormone receptor antagonists and uses thereof. The invention relates to the field of organic chemistry, in particular to a compound or pharmaceutically acceptable salt, isomer, prodrug, polymorphic substance or solvate thereof as well as a preparation method and application of same. The invention provides a compound or a pharmaceutically acceptable salt, an isomer, a prodrug, a polymorphic substance or a solvate thereof. The chemical structural formula of the compound is as shown in formula I in the specification. The compound provided by the invention is used as a GnRHR antagonist in a calcium flow detection experiment, the activity of the compound is equivalent to or better than that of Elagolix, and the compound has better pharmacokinetic characteristics.

Description

technical field [0001] The present invention relates to the field of organic chemistry, in particular to a compound or its pharmaceutically acceptable salt, isomer, prodrug, polymorph or solvate and its preparation method and use. Background technique [0002] Gonadotropin-releasing hormone (GnRH), also known as luteinizing hormone-releasing hormone (LHRH), is a decapeptide secreted by the hypothalamus. GnRH exerts biological effects by binding to its GnRH receptor located in the anterior pituitary gland, stimulating luteinizing hormone (LH) and follicle-stimulating hormone (FSH) biosynthesis and secretion. Under the synergistic effect of the two, the development of germ cells and the production and secretion of sex hormones in the ovary or testis are stimulated. [0003] Therapeutics targeting the GnRH receptor inhibit the function of the hypothalamic-pituitary-gonadal axis and have been widely used in the treatment of gonadal hormone-dependent diseases such as prostate ca...

Claims

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Application Information

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IPC IPC(8): C07D239/54A61P15/00A61P35/00A61P5/24A61P1/00A61P13/08A61P25/28A61P15/08A61P17/00A61P17/10A61P17/14A61K31/513
CPCC07D239/54A61P15/00A61P35/00A61P5/24A61P1/00A61P13/08A61P25/28A61P15/08A61P17/00A61P17/10A61P17/14A61K31/513A61P5/02A61P5/26
Inventor 刘国强刘伟王延东
Owner SHIJIAZHUANG YILING PHARMA
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