Novel LHRH antagonist

A CH2, R2N technology, applied in the field of decapeptide derivatives, can solve the problems of short half-life, limited application of LHRH antagonists, and high release of histamine, and achieve the effect of good antagonistic activity

Inactive Publication Date: 2007-10-03
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

Method used

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preparation example Construction

[0237] The preparation method of the compound of the present invention

[0238] The preparation of the compound of the present invention can adopt the solid-phase synthesis method, with MBHA resin as the carrier, Boc-protection strategy, DCC / HOBT or BOP / DIEA as the condensation reagent, HCl / dioxane as the deprotection reagent, after the reaction, the liquid HF cleaves decapeptide derivatives from MBHA resin. Boc-protected amino acids can be purchased from the market, or synthesized according to the methods in the Examples or methods known in the art. The compounds of the present invention may also be prepared by other methods known in the art.

[0239] In another aspect, the present invention also relates to intermediates useful in the preparation of the compounds of the present invention and processes for their preparation.

[0240] In one embodiment the invention relates to Boc-p-CH 2 Cl-Phe and its preparation method.

[0241] In another embodiment the invention relates...

Embodiment 1

[0258] Example 1: Boc-p-CH 2 Synthesis of Cl-Phe

[0259] Ac-Phe(p-CH 2 Cl)-Phe-OEt (prepared in this laboratory according to a conventional method, 5g, 17.6mmol) was refluxed in 40mL concentrated hydrochloric acid and 100mL dioxane for 10 hours, and then the hydrochloric acid and dioxane were evaporated to obtain a solid without separation and purification Add 50mL of methanol directly under the ice bath, adjust the pH to 9 with TEA, then add 35.2mmol (3.9mL), and then add 4.6g (Boc) 2 O (21.1 mmol), stirred at room temperature for 12 hours, spin off methanol, adjust the pH of the aqueous solution to acidic, extract with ethyl acetate, wash the ester layer twice with water, and dry over anhydrous sodium sulfate. The ester layer was concentrated, and the oil was recrystallized from ethyl acetate-petroleum ether after column chromatography to obtain 2.7 g of white crystals, with a total yield of 49.1%. TLC detection: chloroform:methanol:HOAc (20:1:0.5), Rf=0.6.

Embodiment 2

[0260] Embodiment 2: Boc-Phe (NA B M) synthesis

[0261] Boc-p-CH 2Cl-Phe (prepared as in Example 1) (1.75g, 5mmol) and dibenzyl iminodiacetate (1.88g, 6mmol, synthesized according to the method described in the following references: Huang Weide, Chen Changqing, Polypeptide Synthesis, Science Publishing Society, 1985, p47) was placed in a 100ml round bottom flask, and 50mL of ethanol was added to dissolve it. After adding TEA (1.69mL, 12mmol) in an ice bath, stir at room temperature for 72 hours, spin off 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 layer was dried over anhydrous sodium sulfate. The ester layer was concentrated, and the solid was recrystallized from ethyl acetate-petroleum ether to obtain 1.80 g of white crystals, with a yield of 61%. TLC detection: chloroform:methanol:HOAc (20:1:0.5), Rf=0.7.

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Abstract

The present invention relates to decapeptide derivatives with LHRH receptor antagonistic activity, the function of inhibiting pituitary gland secretion of gonadotropin and gonadal secretion of steroid hormones, their preparation method, their pharmaceutical composition and their role in the treatment of prostate cancer and Use for sex hormone dependence-related diseases related to reproduction.

Description

technical field [0001] The present invention relates to a decapeptide derivative with LHRH receptor antagonistic activity, a preparation method of unnatural amino acid, a pharmaceutical composition containing them and their use in treating prostate cancer and other sex hormone-dependent related diseases. 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 follows: [0003] p-Glu-His-Trp-Ser-Tyr-Gly-Leu-Arg-Pro-Gly-NH 2 [0004] Since the reduction of LH and FSH secretion can directly affect the functio...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07K7/06A61K38/08A61P5/24A61P35/00
Inventor 刘克良周宁张琪荣嫡吴萍韩寒张永祥周文霞程军平
Owner INST OF PHARMACOLOGY & TOXICOLOGY ACAD OF MILITARY MEDICAL SCI P L A
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