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Luteinizing hormone-releasing hormone (LHRH) antagonist derivative, preparation method of LHRH antagonist derivative and application of LHRH antagonist derivative

A solvate and physiological technology, applied in the fields of chemistry and medicine, can solve problems such as easy gel formation, short half-life, and limited application of LHRH antagonists

Inactive Publication Date: 2012-09-19
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 kind of peptide drugs, most of them still have the disadvantages of low bioavailability, short half-life in vivo, high release of histamine, poor water solubility, and high The concentration is easy to form a gel, which is not conducive to injection administration, which limits the clinical application of LHRH antagonists
Similar to other peptide drugs, LHRH antagonist drugs are also poorly absorbed orally
As far as we know, currently marketed LHRH antagonist drugs are administered by non-oral route

Method used

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  • Luteinizing hormone-releasing hormone (LHRH) antagonist derivative, preparation method of LHRH antagonist derivative and application of LHRH antagonist derivative
  • Luteinizing hormone-releasing hormone (LHRH) antagonist derivative, preparation method of LHRH antagonist derivative and application of LHRH antagonist derivative
  • Luteinizing hormone-releasing hormone (LHRH) antagonist derivative, preparation method of LHRH antagonist derivative and application of LHRH antagonist derivative

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0168] Embodiment 1: the synthesis of Boc-Aph(Bet)-OH:

[0169] Reference method (Gao Yongqing, Zhou Ning, Lu Yujian, Shi Weiguo, Cheng Maosheng, Liu Keliang, Indirect introduction of aromatic nitro-p-aminophenylalanine in ammonium formate catalytic transfer hydrogenation reduction peptide chain, Chemical Journal of Chinese Universities, 2010, 31 (4), 718-722.) Synthesis of N α -tert-butoxycarbonyl-4-(phenoxycarbonyl)aminophenylalanine methyl ester [Boc-Aph-OMe]

[0170] 5.88g (20mmol) of Boc-Aph-OMe was dissolved in 50ml of DCM, 6.9ml (40mmol) of DIEA was added, and 3.44g (20mmol) of freshly prepared betaine acid chloride hydrochloride was added in batches. After the disappearance of the raw material was detected by TLC, a small amount of water was added, extracted with ethyl acetate, washed with saturated sodium chloride, and dried over anhydrous sodium sulfate. filter. Concentrate and perform silica gel column chromatography. 4.26 g of [Boc-Aph(Bet)-OMe] was obtained as...

Embodiment 2

[0172] Embodiment 2: the synthesis of Boc-Aph(DHE-Cbm)-OH:

[0173] Reference method ( Zhou Ning , Fu Huijun, Rong Yi, Cheng Maosheng, Liu Keliang, Design, Synthesis and Application of Unnatural Amino Acids Containing Complexing Functional Groups in Bioactive Peptides, Chemical Journal of Chinese Universities, 2007, 28(4): 668-671. ) to synthesize N α - tert-butoxycarbonyl-4-(phenoxycarbonyl)aminophenylalanine [Boc-Aph(PhOCO)-OH] and N,N-diethylbenzyl ether-imine hydrochloride (NDOB)

[0174] Add 4.00g (10mmol) Boc-Aph(PhOCO)-OH, 1.4ml (200mmol) pyridine, and 10ml methanol into a 50ml round bottom flask. After the raw materials are dissolved, add 32.2g (100mmol) NDOB. After TLC detects that the raw materials disappear, depressurize Evaporate to dryness and adjust pH to 3 with dilute hydrochloric acid, extract with ethyl acetate, wash with saturated sodium chloride, and dry over anhydrous sodium sulfate. Filter and evaporate to dryness. Silica gel column chromatography gav...

Embodiment 3

[0175] Embodiment 3: the synthesis of decapeptide derivatives

[0176] With 1g of MBHA resin (0.96mmol) as the solid phase carrier, DCC / HOBt 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), first synthesized Leu 7 -Ilys(Cbz)[or Arg(Tos)] 8 -Pro 9 -D-Ala 10 - MBHA resin.

[0177] A: Synthesis of compound 69: Connect the remaining amino acids in sequence according to the standard Boc strategy, put the above peptide resin into the reactor of the HF cutter, add 1.0mL of anisole, and vacuum the system of the HF cutter after installation , cooled the reactor with liquid nitrogen, transferred to about 10 mL of liquid HF, and reacted at 0°C for 40 minutes. Use an oil pump to pump out HF, remove the reactor, add frozen anhydrous ether to precipitate a solid, and then transfer the suspension to a fun...

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Abstract

The invention belongs to the field of medicine and chemistry and particularly relates to a luteinizing hormone-releasing hormone (LHRH) antagonist derivative which is represented as formula (I), a preparation method of the LHRH antagonist derivative and application for preparation of drugs curing related sex hormone diseases or contraceptives. The invention also relates to a stereoisomeride of the LHRH antagonist derivative which is represented as the formula (I), a solvate of the LHRH antagonist derivative which is represented as the formula (I), or physio-toxicity-free salt of the LHRH antagonist derivative which is represented as the formula (I) and a pharmaceutical composition which contains compounds such as the LHRH antagonist derivative, the stereoisomeride, the solvate or the salt. An LHRH antagonist is modified with a water soluble group and a water soluble vitamin structure, the obtained LHRH antagonist derivative can maintain the activity of original antagonists, has low histamine-releasing activity and is beneficial to the clinic application and the water solubility is increased. The formula (I) is R-D-NAI-D-Cpa-D-Aaa3-Ser-Aaa5-Aaa6-Leu-Aaa8-Pro-D-Ala-B.

Description

technical field [0001] The invention belongs to the fields of medicine and chemistry, and in particular relates to LHRH antagonist derivatives, their preparation method and their application in the preparation of medicines for treating sex hormone-related diseases or contraception. 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] LHRH antagonists inhibit the release of LH by blocking the action of LHRH, so they can be used for the treatment of sex hor...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K7/06C07K1/107C07D495/04C07D339/04C07D213/81C07D239/557C07C237/22C07C233/22C07C279/14C07K5/068A61K38/08A61P5/04A61P5/08A61P5/24A61P5/32A61P5/36A61P13/08A61P15/14A61P15/00A61P15/18A61P35/00
CPCC07K7/23C07K14/72A61K38/00A61P5/04A61P5/08A61P5/24A61P5/32A61P5/36A61P13/08A61P15/00A61P15/14A61P15/18A61P35/00
Inventor 刘克良周宁吕玉健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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