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Endomorphin analog and its preparing method

A technology of endomorphin and analogues, which is applied in the field of new compounds and their preparation methods and pharmacological efficacy, can solve the problems of restricting the application of analgesics, restricting applications, difficulties, etc., and achieves good application prospects and high analgesic specificity , the effect of reliable technical support

Inactive Publication Date: 2008-01-23
LANZHOU UNIVERSITY
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  • Abstract
  • Description
  • Claims
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AI Technical Summary

Problems solved by technology

[0007] However, due to the flexible molecular structure of endomorphins, they can have different conformations required for molecular recognition of various receptors, including binding to different subtypes of receptors, so that their selectivity is low, and some side effects are produced in clinical treatment. For example, endomorphin can significantly reduce the systemic arterial pressure and heart rate of experimental animals in a dose-dependent manner to experimental animals such as rabbits, cats, mice, and rats, thus limiting its application as an analgesic
At the same time, as an opioid, endomorphin also has the inherent weakness of opioids. If it has a certain degree of addiction, it also increases difficulties for clinical use.
Moreover, endomorphin also has the weaknesses of peptide drug molecules, such as easy metabolism, poor resistance to enzymolysis, short half-life of action, etc., which limit its application.

Method used

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  • Endomorphin analog and its preparing method
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  • Endomorphin analog and its preparing method

Examples

Experimental program
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Embodiment 1

[0036] Embodiment 1: compound c (Tyr-D-Pro-Phe-Gly-NHCH (CH 3 ) Ph, the synthesis of tyrosyl-D type-prolylphenylalanylglycyl-L-α-methylbenzylamine)

[0037] Compound i (Z-GIy, N-benzyloxycarbonylglycine) was dissolved in anhydrous DCM (adding anhydrous DMF to aid dissolution), ice-bathed, and L-(-)α- Methylbenzylamine, and then ice-bathed for 10min, then added DCC dissolved in pre-cooled dichloromethane (DCM) with a molar ratio of 1.5 times relative to compound i, and after stirring in an ice bath for 30min, added 0.5 times molar ratio relative to compound i After 30min, return to room temperature and react for 40h, filter off DCU, concentrate the filtrate under reduced pressure to remove solvent, dissolve in ethyl acetate, then wash with dilute hydrochloric acid, saturated NaHCO 3 , NaCl solution, and dried over anhydrous sodium sulfate. The crude product was recrystallized with EA / PE (1:2, v / v) to obtain compound ii (Z-Gly-NHCH(CH 3 )Ph): yield = 86.7%; mass spectrum (EI-...

Embodiment 2

[0044] Embodiment 2: compound a (Tyr-Pro-Phe-GIy-NHCH (CH 3 ) Ph, the synthesis of tyrosylprolylphenylalanylglycyl-L-α-methylbenzylamine)

[0045] Compound viii (Phe-Gly-NHCH(CH 3) Ph) structure and synthesis process are the same as in Example 1.

[0046] Dissolve equimolar amounts of Z-Tyr and HOSu in anhydrous THF, and slowly drop into the pre-cooled THF solution in which an equal amount of DCC was dissolved under cooling at 0°C with sufficient stirring, and then react at room temperature overnight. Suction filtration to obtain Z-Tyr-OSu solution. Stir, then use NaHCO with 1.5 times molar ratio of L-Pro relative to Z-Tyr 3 After the solution was dissolved, it was added dropwise into the Z-Tyr-OSu solution and reacted at room temperature for about 2 days. After the reaction was finished, 6 mol / L HCl was slowly added dropwise until the pH of the solution was 2. It was then concentrated under reduced pressure to remove THF, extracted with ethyl acetate, washed with acid, t...

Embodiment 3

[0049] Embodiment 3; Compound d(Tyr-D-Pro-Phe-Ala-NHCH(CH 3 ) Ph, the synthesis of tyrosyl-D type-prolylphenylalanylalanyl-L-α-methylbenzylamine)

[0050] The synthesis of compound vii (Z-Tyr-D-Pro) in Example 3 is shown in Example 1: Compound xii (Phe-Ala-NHCH(CH 3 )Ph) synthetic process and concrete operation and embodiment 1 compound viii (Phe-Gly-NHCH(CH 3 ) Ph) is similar, but the raw material compound I (Z-Gly) in Example 1 is changed to compound xiii (Z-Ala, N-benzyloxycarbonylalanine) to react to obtain compound xii (Phe-Ala-NHCH (CH 3 )Ph).

[0051] Dissolve equimolar amounts of compound vii (Z-Tyr-D-Pro) and HOBt in anhydrous DCM / DMF mixed solvent, and slowly drop into the pre-cooled DCM solution in which equimolar amounts of DCC were dissolved under ice-salt bath cooling and stirring , After reacting at room temperature for 12h, filter off DCU to obtain Z-Tyr-D-Pro-OBt solution. Ice-salt bath, stirring, adding compound xii (Phe-Ala-NHCH(CH 3 )Ph), react in an ...

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Abstract

The four kinds of endomorphin analogs with analgetic effect with the shown structures are prepared with Z-Tyr-Pro-OH or Z-Tyr-D-Pro-OH as I segment and Z-Phe-Ala-NHCH (CH3)Ph or Z-Phe-Gly-NHCH(CH3)Ph as the II segment and through segment condensation process. The preparation process has minimum protection on amino acid; DCC / DMAP synthesis of material Z- Ala-NHCH (CH3) Ph and Z- Gly-NHCH(CH3)Ph; DCC / HOSu synthesis of segments and DCC / HOBt synthesis between segments with DCC / HOBt coupling agent; crystal separating purification of intermediate product; and common silicon gel column chromatography for purifying final product. Serial experiments show that these endomorphin analogs are polypeptide precursor with excellent analgetic activity and may be further developed into analgetic polypeptide medicine for research and clinical application.

Description

technical field [0001] The present invention relates to a class of novel compounds and their preparation methods and pharmacological effects, in particular to a class of endomorphin-2 analogues and their preparation methods and analgesic activity, and are applied in the pharmaceutical and chemical industries. Background technique [0002] Endomorphins (EMs) are divided into endomorphin-1 (endomorphin-1, EM-1, Tyr-Pro-Trp-Phe-NH 2 ) and endomorphin-2 (endomorphin-2, EM-2, Tyr-Pro-Phe-Phe-NH 2 ), which is an endogenous agonist of mu-opioid receptor (MOR), has a very high affinity and selectivity for MOR, and has a wide range of physiological and pharmacological effects, especially potent analgesic effects. [0003] The amino acid composition and structure of endomorphin are shown in the following formula: [0004] [0005] As bioactive peptides with potent analgesic effects, endomorphins have unique advantages over the non-peptide analgesic drug morphine. A large number ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07K5/10C07K1/22A61P25/04
Inventor 王锐张启军冯云
Owner LANZHOU UNIVERSITY
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