Endomorphin-1 analogs, synthesis thereof and application of endomorphin-1 analogs in preparation of analgesic medicines

Abstract

The invention synthesizes four novel endomorphin-1 analogs, and belongs to the technical field of biochemistry. The endomorphin-1 analogs are prepared by performing N-end guanidyl formation at the first-position Tyr of endomorphin-1, replacing the second-position Pro by D-Ala, replacing the third-position Trp by Gly, and replacing the fourth-position Phe by Trp or performing para-position chlorination and fluorination modification or no modification on a benzene ring of Phe. The synthesized endomorphin-1 analogs are subjected to a series of physiological and pharmacological activity identification such as radio-ligand receptor binding assays, isolated organ bioactivity identification experiments, isolated enzymolysis stability experiments, analgesic tests with water bath and medicine tolerance experiments, show high affinity activity, high enzymolysis stability and high analgesic activity, and hardly cause tolerance. Therefore, the four novel endomorphin-1 analogs can be used for preparing clinical analgesic medicines.

Description

technical field

[0001] The invention belongs to the technical field of biochemistry, and relates to a new class of endomorphin-1 analogues and their synthesis; the invention also relates to the application of the endomorphin-1 analogues in the preparation of analgesic drugs. Background technique

[0002] The so-called pain in modern medicine is a complex physiological and psychological activity, and it is one of the most common clinical symptoms. It includes the pain sensation caused by noxious stimuli acting on the body and the body's pain response to noxious stimuli. Long-term pain brings pain and anxiety to patients, and severe pain can also cause insomnia or other biological dysfunction, affecting the quality of life of patients. Therefore, the research and development of pain drugs has always been a global hotspot and difficulty. Opioids play an irreplaceable role in relieving severe pain due to their strong analgesic effect. However, they are often accompanied by ma...

Examples

Embodiment 1

[0121] Example 1: Synthesis of Analogue [GAGS]-EM-1

[0122] (1) Synthesis of monobenzyloxycarbonylamidinopyrazole

[0123] 0.73g (5mmol) compound amidinopyrazole hydrochloride joins in the mixed solution of equal volume dichloromethane (DCM) and dimethylformamide (DMF), adds triethylamine (10mmol), under ice bath slowly Add 845ul (6mmol) benzyloxycarbonyl chloride dropwise, react in ice bath for 30 minutes, and react at room temperature for 1.5 hours. After the reaction was complete, the DCM was concentrated under reduced pressure, a large amount of ethyl acetate was added to dissolve the residue, extracted three times with 5% citric acid aqueous solution and saturated NaCl aqueous solution, dried over anhydrous sodium sulfate, and concentrated. The crude product was crystallized from ethyl acetate / petroleum ether (1:4, v / v) to obtain 1.127 g of monobenzyloxycarbonylamidinopyrazole as white crystals. The yield was 92%. ESI-MS m / z=245[M+H] + .

[0124] (2) Synthesis of bi...

Embodiment 2

[0140] Example 2: Synthesis of Analogue [GAGP]-EM-1

[0141] (1) Synthesis of monobenzyloxycarbonylamidinopyrazole

[0142] With embodiment 1 step (1)

[0143] (2) Synthesis of bisbenzyloxycarbonylamidinopyrazole

[0144] With embodiment 1 step (2)

[0145] (3)Cbz 2 -Synthesis of Amidino-Tyr-D-Ala-OH

[0146] With embodiment 1 step (3)

[0147] (4)Cbz 2 -Amidino-Tyr-D-AIa-GIy-Phe(4-Cl)-NH 2 Synthesis

[0148] 0.562g (1mmol) of Cbz 2 - Amidino-Tyr-D-AIa-OH and 0.126g (1.1mmol) of HOSU were dissolved in THF and stirred at 0-5°C for 10 minutes; then 0.227g (1.1mmol) of DCC was added and Stir for 20 minutes, then stir the reaction at room temperature for 6 hours to give Cbz 2 -Activated ester solution of Amidino-Tyr-D-AIa-OH i.e. Cbz 2 - Amidino-Tyr-D-AIa-OSU solution.

[0149] 0.374g (1.1mmol) of Boc-Gly-Phe(4-Cl)-NH 2 Dissolve in 2ml of ethyl acetate, add 0.5ml of concentrated hydrochloric acid at 0-5°C, react for 30 minutes; then react at room temperature for 2 hou...

Embodiment 3

[0157] Example 3: Synthesis of Analogue [GAGF]-EM-1

[0158] (1) Synthesis of monobenzyloxycarbonylamidinopyrazole

[0159] With embodiment 1 step (1)

[0160] (2) Synthesis of bisbenzyloxycarbonylamidinopyrazole

[0161] With embodiment 1 step (2)

[0162] (3)Cbz 2 -Synthesis of Amidino-Tyr-D-Ala-OH

[0163] With embodiment 1 step (3)

[0164] (4)Cbz 2 -Amidino-Tyr-D-AIa-GIy-Phe(4-F)-NH 2 Synthesis

[0165] 0.562g (1mmol) of Cbz 2 - Amidino-Tyr-D-AIa-OH and 0.126g (1.1mmol) of HOSU were dissolved in THF and stirred at 0-5°C for 10 minutes; then 0.227g (1.1mmol) of DCC was added and Stir for 20 minutes, then stir the reaction at room temperature for 6 hours to give Cbz 2 -Activated ester solution of Amidino-Tyr-D-AIa-OH i.e. Cbz 2 - Amidino-Tyr-D-AIa-OSU solution.

[0166] 0.374g (1.1mmol) of Boc-Gly-Phe(4-F)-NH 2 Dissolve in 2ml ethyl acetate, add 0.5ml concentrated hydrochloric acid at 0-5°C, react for 30 minutes; then react at room temperature for 2 hours, conc...

technical field

[0001] The invention belongs to the technical field of biochemistry, and relates to a new class of endomorphin-1 analogues and their synthesis; the invention also relates to the application of the endomorphin-1 analogues in the preparation of analgesic drugs. Background technique

[0002] The so-called pain in modern medicine is a complex physiological and psychological activity, and it is one of the most common clinical symptoms. It includes the pain sensation caused by noxious stimuli acting on the body and the body's pain response to noxious stimuli. Long-term pain brings pain and anxiety to patients, and severe pain can also cause insomnia or other biological dysfunction, affecting the quality of life of patients. Therefore, the research and development of pain drugs has always been a global hotspot and difficulty. Opioids play an irreplaceable role in relieving severe pain due to their strong analgesic effect. However, they are often accompanied by ma...

Examples

Embodiment 1

[0121] Example 1: Synthesis of Analogue [GAGS]-EM-1

[0122] (1) Synthesis of monobenzyloxycarbonylamidinopyrazole

[0123] 0.73g (5mmol) compound amidinopyrazole hydrochloride joins in the mixed solution of equal volume dichloromethane (DCM) and dimethylformamide (DMF), adds triethylamine (10mmol), under ice bath slowly Add 845ul (6mmol) benzyloxycarbonyl chloride dropwise, react in ice bath for 30 minutes, and react at room temperature for 1.5 hours. After the reaction was complete, the DCM was concentrated under reduced pressure, a large amount of ethyl acetate was added to dissolve the residue, extracted three times with 5% citric acid aqueous solution and saturated NaCl aqueous solution, dried over anhydrous sodium sulfate, and concentrated. The crude product was crystallized from ethyl acetate / petroleum ether (1:4, v / v) to obtain 1.127 g of monobenzyloxycarbonylamidinopyrazole as white crystals. The yield was 92%. ESI-MS m / z=245[M+H] + .

[0124] (2) Synthesis of bi...

Embodiment 2

[0140] Example 2: Synthesis of Analogue [GAGP]-EM-1

[0141] (1) Synthesis of monobenzyloxycarbonylamidinopyrazole

[0142] With embodiment 1 step (1)

[0143] (2) Synthesis of bisbenzyloxycarbonylamidinopyrazole

[0144] With embodiment 1 step (2)

[0145] (3)Cbz 2 -Synthesis of Amidino-Tyr-D-Ala-OH

[0146] With embodiment 1 step (3)

[0147] (4)Cbz 2 -Amidino-Tyr-D-AIa-GIy-Phe(4-Cl)-NH 2 Synthesis

[0148] 0.562g (1mmol) of Cbz 2 - Amidino-Tyr-D-AIa-OH and 0.126g (1.1mmol) of HOSU were dissolved in THF and stirred at 0-5°C for 10 minutes; then 0.227g (1.1mmol) of DCC was added and Stir for 20 minutes, then stir the reaction at room temperature for 6 hours to give Cbz 2 -Activated ester solution of Amidino-Tyr-D-AIa-OH i.e. Cbz 2 - Amidino-Tyr-D-AIa-OSU solution.

[0149] 0.374g (1.1mmol) of Boc-Gly-Phe(4-Cl)-NH 2 Dissolve in 2ml of ethyl acetate, add 0.5ml of concentrated hydrochloric acid at 0-5°C, react for 30 minutes; then react at room temperature for 2 hou...

Embodiment 3

[0157] Example 3: Synthesis of Analogue [GAGF]-EM-1

[0158] (1) Synthesis of monobenzyloxycarbonylamidinopyrazole

[0159] With embodiment 1 step (1)

[0160] (2) Synthesis of bisbenzyloxycarbonylamidinopyrazole

[0161] With embodiment 1 step (2)

[0162] (3)Cbz 2 -Synthesis of Amidino-Tyr-D-Ala-OH

[0163] With embodiment 1 step (3)

[0164] (4)Cbz 2 -Amidino-Tyr-D-AIa-GIy-Phe(4-F)-NH 2 Synthesis

[0165] 0.562g (1mmol) of Cbz 2 - Amidino-Tyr-D-AIa-OH and 0.126g (1.1mmol) of HOSU were dissolved in THF and stirred at 0-5°C for 10 minutes; then 0.227g (1.1mmol) of DCC was added and Stir for 20 minutes, then stir the reaction at room temperature for 6 hours to give Cbz 2 -Activated ester solution of Amidino-Tyr-D-AIa-OH i.e. Cbz 2 - Amidino-Tyr-D-AIa-OSU solution.

[0166] 0.374g (1.1mmol) of Boc-Gly-Phe(4-F)-NH 2 Dissolve in 2ml ethyl acetate, add 0.5ml concentrated hydrochloric acid at 0-5°C, react for 30 minutes; then react at room temperature for 2 hours, conc...

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