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LHRH antagonist with long-acting low-histamine release side effect

A CH2, R1O technology, applied in the field of decapeptide derivatives, can solve the problems of short half-life, low bioavailability, and high release of histamine, and achieve good antagonistic activity, low side effects of histamine release, and long in vivo action time.

Inactive Publication Date: 2013-04-24
INST OF PHARMACOLOGY & TOXICOLOGY ACAD OF MILITARY MEDICAL SCI P L A
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] Although there are many LHRH antagonists developed at present, as a peptide drug, most of them still have low bioavailability, short half-life in vivo, and high release of histamine, which limit the clinical application of LHRH antagonists. Applications
In addition, similar to other peptide drugs, LHRH antagonist drugs are also difficult to absorb through oral administration
As far as we know, currently marketed LHRH antagonist drugs are administered by non-oral route

Method used

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  • LHRH antagonist with long-acting low-histamine release side effect
  • LHRH antagonist with long-acting low-histamine release side effect
  • LHRH antagonist with long-acting low-histamine release side effect

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0388]Example 1: N, N-(dibenzyloxycarbonylmethyl)-aminoacetic acid [NTA B ]Synthesis

[0389] Dibenzyl iminodiacetate (28.8mmol, 9g) and bromoacetic acid (14.4mmol, 2.0g) were placed in a 100ml round bottom flask, and 50mL of ethanol was added to dissolve it. After adding TEA (10mL, 72mmol) in an ice bath, stir at room temperature for 72 hours, spin off the ethanol, adjust the pH of the aqueous solution to alkaline, wash with ether and then adjust the pH of the aqueous phase to acidic, extract with ethyl acetate, wash twice with water, and the ester layer Dry over anhydrous sodium sulfate. The ester layer was concentrated, and the oil was subjected to column chromatography to obtain 2 g of the oil, with a yield of 44.4%. TLC detection: chloroform:methanol:HOAc (20:1:0.5), Rf=0.3.

Embodiment 2

[0390] Embodiment 2: the synthesis of N-tert-butoxycarbonyl-imine-diacetic acid

[0391] 8.6g (65.6mmol) amino diacetic acid, add 80mL water, 40mL 2N NaOH, 80mL dioxane. Control pH=9, add dropwise 17.2g (Boc) 2 O (78.7 mmol, dissolved in 30 mL of dioxane). During the reaction process, the pH was kept at 9. After 12 hours, the dioxane was removed under reduced pressure. The aqueous phase was extracted with ether, acidified to pH 3 with citric acid, extracted 3 times with ethyl acetate and 3 times with chloroform, and then dried. Filtration and concentration gave 10.5 g of white solid. Yield 69.1%, Rf=0.56 (n-butanol:acetic acid:water, 3:1:1), m.p.: 123-126°C.

Embodiment 3

[0392] Example 3: Synthesis of N-tert-butoxycarbonyl-imine-diacetyl tert-butylamine

[0393] 13g (56.3mmol) of N-tert-butoxycarbonyl-imine-diacetic acid was dissolved in 180mL of anhydrous tetrahydrofuran, and 24.77mL of N-methylmorpholine was added dropwise at -15°C, followed by 29.3mL (225.2mmol) of chlorine After 3 minutes of tert-butyl formate, 24.77 mL (225.2 mmol) of tert-butylamine was added dropwise. After 3 hours, it was detected by TLC that the raw materials had been reacted. The tetrahydrofuran was spun off, dissolved in ethyl acetate, and the insoluble matter was filtered off. The ester layer was washed with sodium bicarbonate, water, citric acid, and saturated brine, and dried over anhydrous sodium sulfate. Concentrate under reduced pressure, add petroleum ether for crystallization. 13.51 g of a white solid was obtained, with a yield of 70.0%. Rf = 0.54 (chloroform:methanol:acetic acid, 20:1:0.5), m.p.: 139-141°C.

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Abstract

The invention relates to a decapeptide derivative with LHRH receptor antagonism activity and actions of restricting a pituitarium to secrete gonadotrophins and restricting a gonad to secrete steroid hormones, a preparation method thereof, a medicine composition containing the decapeptide derivative and the application of the medicine composition on treating prostatic cancer, endometrial cancer, interrelated sex hormone dependence diseases relative to reproduction, contraception, and the like.

Description

technical field [0001] The present invention relates to decapeptide derivatives with LHRH receptor antagonistic activity, the function of inhibiting pituitary secretion of gonadotropin, and inhibition of gonadal secretion of steroid hormones, the preparation method thereof, the pharmaceutical composition containing them and their effects in the treatment of prostate cancer, Use in endometrial cancer, sex hormone-dependent diseases related to reproduction, contraception, etc. Background technique [0002] LHRH (luteinizing hormone releasing hormone) is one of the peptide hormones secreted by the hypothalamus, its main function is to promote the pituitary gland to synthesize and release luteinizing hormone (LH) and follicle stimulating hormone (FSH), stimulate puberty development and regulate reproduction , reproductive and sex hormone-related processes. LHRH consists of ten amino acid residues with an amide structure at the C-terminus. The primary structure of LHRH is as fo...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07K7/06C07K1/04C07K1/06A61K38/08A61P35/00A61P15/16A61P15/18A61P29/00A61P5/24A61P37/00
CPCY02P20/55
Inventor 刘克良周宁高永清荣嫡付慧君林凡程张文录周文霞张永祥程军平
Owner INST OF PHARMACOLOGY & TOXICOLOGY ACAD OF MILITARY MEDICAL SCI P L A
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