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Antagonist of luteinizing hormone releasing hormone (LHRH) containing hydantoin structure

A technology of stereoisomers and configurations, applied in the field of decapeptide derivatives, can solve the problems of limited application of LHRH antagonists, low bioavailability, short half-life, etc.

Inactive Publication Date: 2011-03-23
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

Method used

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  • Antagonist of luteinizing hormone releasing hormone (LHRH) containing hydantoin structure
  • Antagonist of luteinizing hormone releasing hormone (LHRH) containing hydantoin structure
  • Antagonist of luteinizing hormone releasing hormone (LHRH) containing hydantoin structure

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0305] Embodiment 1: the synthesis of compound 1

[0306] NHC-D-Phe 3 -Ser 4 -Mop 5 -D-Aph 6 (Diethyl-Cbm)-Leu 7 -Arg 8 -Pro 9 -D-Ala 10 -NH 2

[0307] With 63mg MBHA resin (0.04mmol) as the solid-phase carrier, BOP / DIEA as the condensing agent, according to the amino acid sequence of the compound, according to the standard Boc solid-phase peptide synthesis method (references: Huang Weide, Chen Changqing, Polypeptide Synthesis, Science Press , 1985) operation synthesis Boc-D-Nal 1 -D-Cpa 2 -D-Phe 3 -Ser 4 -Mop 5 -D-Aph 6 (Diethyl-Cbm)-Leu7 -Arg 8 -Pro 9 -D-Ala 10 -NH 2 - MBHA resin.

[0308] After Boc-D-Nal is connected to the peptide chain, use 4M HCl / Diox to remove the Boc at the N-terminus, neutralize, after washing, add 3 times excess CDI, react for 0.5h, wash off excess CDI with DCM, indene Test the condensation effect of triketone, if it is positive, react again until it is negative, add 10% DIEA / DCM, react at room temperature for 4 hours, wash the r...

Embodiment 2～48

[0310] Embodiment 2~48: the synthesis of compound 2~48

[0311] Compounds 2-48 were synthesized using a method similar to Example 1. The structures of compounds 2-48 are respectively referred to above. Various raw materials used in the synthesis of compounds 2-48 were purchased from Chengdu Chengnuo Technology Co., Ltd. and Nankai Synthetic Technology Co., Ltd., or synthesized by the inventors themselves.

[0312] The synthesis results are summarized in Table 1 below:

[0313] Table 1

[0314] Compound No.

[0315] 31～50

[0316] * "ESI-MS difference" means the absolute value of the difference between the theoretical value of ESI-MS and the measured value, ie: ESI-MS difference = |theoretical value-measured value|.

experiment example 1

[0317] Experimental Example 1: In vivo testosterone inhibition experiment in rats:

[0318] Before the experiment, the weight of the animals was weighed, and the blood was collected from the venous plexus behind the glass capillary bulb. After the serum was separated, the serum testosterone content was measured by chemiluminescence method. Randomly grouped according to the testosterone content and body weight, 4 animals in each group were injected subcutaneously with the compound to be tested in a one-time overdose. 1, 2, 4, 6, 8, 10, 12, 16, 20, and 24 hours after 500 μg, blood was collected from the retrobulbar venous plexus, centrifuged at 5000 rpm for 8 min, and the separated serum was analyzed by chemiluminescence (Access Immunoassay System, Beckman Coulter, USA). Chemiluminescence instrument) was used to measure serum testosterone levels. The results are shown in Table 2.

[0319] Table 2

[0320] Compound number a

Inhibition of testosterone action tim...

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Abstract

The invention relates to an antagonist of luteinizing hormone releasing hormone (LHRH) containing a hydantoin structure, and particularly relates to a decapeptide derivative which has LHRH receptor antagonism activity, can inhibit hypophysis from secreting gonadotropin and inhibit sexual gland from secreting steroid hormone and is shown in the formula (I): R-Xaa<3>-Ser-Saa <5>-Xaa<6>-Xaa<7>-Xaa<8>-Pro-D-Ala-B, wherein the definition of each symbol is in the specification. The invention also relates to a preparation method of compounds as shown in the formula (1), a pharmaceutical composition containing the compounds and applications of the compounds in preparing medicaments.

Description

technical field [0001] The present invention relates to decapeptide derivatives which have luteinizing hormone releasing hormone receptor antagonistic activity, have the function of inhibiting pituitary secretion of gonadotropin, and inhibition of gonadal secretion of steroid hormones, their preparation method, their pharmaceutical composition and their Use in the treatment of prostate cancer, endometrial cancer, sex hormone-dependent diseases related to reproduction, contraception, etc. Background technique [0002] Luteinizing hormone-releasing hormone (hereinafter referred to as LHRH) is one of the peptide hormones secreted by the hypothalamus. Its main function is to promote the synthesis of pituitary gland and release luteinizing hormone (LH) and follicle-stimulating hormone (FSH) to stimulate puberty. Development and regulation of reproduction, fertility, and sex hormone-related processes. LHRH consists of ten amino acid residues with an amide structure at the C-termi...

Claims

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Application Information

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IPC IPC(8): C07K7/06C07K1/107C07K1/06C07K1/04A61K38/08A61P5/04A61P5/08A61P5/28A61P5/32A61P5/36A61P5/24A61P35/00A61P15/16A61P15/18A61P29/00A61P37/08
CPCC07K7/23A61K31/4166C07D233/78A61K31/4174A61P5/04A61P5/06A61P5/08A61P5/24A61P5/26A61P5/28A61P5/30A61P5/32A61P5/34A61P5/36A61P15/16A61P15/18A61P29/00A61P35/00A61P37/08
Inventor 刘克良周宁高永清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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