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LHRH antagonist with low-histamine releasing function

A technology of sex hormones and uses, applied in the field of decapeptide derivatives, to achieve the effect of low histamine release side effects

Inactive Publication Date: 2013-03-27
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

[0006]Most drugs will cause side effects of histamine release more or less in the body, and the LHRH antagonists currently developed are because they can trigger excessive histamine release and thus can Lead to the occurrence of allergic reactions, so it has not been well applied clinically

Method used

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  • LHRH antagonist with low-histamine releasing function
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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0320] Example 1: Boc-p-CH 2 Synthesis of Cl-Phe

[0321] 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

[0322] Embodiment 2: Boc-Phe (NA B M) synthesis

[0323] Boc-p-CH 2 Cl-Phe (prepared by conventional methods in our laboratory) (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 Press, 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.

Embodiment 3

[0324] Example 3: Boc-p-NH 2 Synthesis of (PhOCO)-Phe

[0325] Boc-p-NH 2 -Phe (1.40g, 5mmol, synthesized according to the method described in the following references: Theobald, P., Porter J., Rivier C., et al, J.Med.Chem., 1991, 34, 2395-2402) placed In a 150mL round bottom flask, add 30mL of water and 9.8mL of 10% sodium carbonate aqueous solution to dissolve them, and then add 30mL of 1,4-dioxane. Phenoxycarbonyl chloride (0.63 mL, 5 mmol) was added under ice cooling. After reacting for 1 hour, 1,4-dioxane was spun off, and citric acid was acidified to acidity. It was extracted with ethyl acetate, and the ester layer was washed with water and saturated brine successively, and dried over anhydrous sodium sulfate. The ester layer was concentrated, 1.3 g of white crystals were obtained by column chromatography, and the yield was 65%. m.p.260°C (decomposition), TLC detection: chloroform:methanol:acetic acid (9:1:0.5), Rf=0.8.

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Abstract

The present invention provides decapeptide derivatives possessing LHRH receptor antagonizing activity, pituitary gonadotrophin secretion inhibiting effect, sex gland steroid hormone section inhibiting effect, and lower histamine releasing effect, their preparation processes, medicine compositions and uses in treating sex hormone related diseases, such as prostate carcinoma and diseases associated with anti-histamine or decreasing histamine release.

Description

technical field [0001] The present invention relates to decapeptide derivatives with LHRH receptor antagonistic activity and lower side effects of histamine release, the pharmaceutical composition containing them and the decapeptide derivatives are used for preparing and treating prostate cancer and other sex hormone-dependent related diseases use of the drug. [0002] Background technique [0003] 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: [0004] p-Glu-His-Trp-Ser-Tyr-Gly-Leu-Arg-Pro-Gly-NH 2 [0005] LHRH antagonists inhibit the rele...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07K7/23A61K38/10A61P15/08A61K38/095
CPCA61K38/08G01N33/76G01N2333/59A61P15/08A61P35/00A61P5/24A61K38/095
Inventor 刘克良周宁林凡程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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