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(+)-Meptazinol diligand derivative and/or its salt and the prepn process

A technology of meptanol and methyl meptanol, which is applied in the directions of drug combinations, active ingredients of heterocyclic compounds, nervous system diseases, etc., can solve the problems such as the lack of dual ligand derivatives.

Inactive Publication Date: 2007-06-06
FUDAN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

So far, there are no research reports on the biligand derivatives of (+)-mebutamol at home and abroad.

Method used

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  • (+)-Meptazinol diligand derivative and/or its salt and the prepn process
  • (+)-Meptazinol diligand derivative and/or its salt and the prepn process
  • (+)-Meptazinol diligand derivative and/or its salt and the prepn process

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0026] Preparation of (+)-N-desmethylmeprotamol

[0027] (+)-Mebutamol (11.15g, 47.85mmol) was added to 700ml of chloroform, KHCO 3 (83.6g, 836mmol) and ethyl chloroformate (35ml, 347.9mmol). The reaction was refluxed for 2 hours. After the reaction solution was cooled, 500ml of water was added to make the KHCO 3 dissolved, the chloroform layer was separated, dried and concentrated, and the obtained yellow oil was dissolved in 830ml of methanol, and K 2 CO 3 (76.6g, 555mmol) dissolved in 830ml of water. React at room temperature for 1 hour. The methanol was distilled off, the pH was adjusted to ≈5 with hydrochloric acid, and extracted with 250ml×3 ether. The ether layers were combined, and the obtained oil (+)-N-ethoxycarbonyl-N-desmethylmeprotamol was added to 120 ml of 50% sulfuric acid and refluxed for 4 hours. Stop the reaction, cool in an ice-salt bath, add 150ml of chloroform, adjust the pH to 9 with ammonia water, and separate the liquids. The aqueous layer was ...

Embodiment 2

[0031] Preparation of N, N'-(1,2-ethyl)-bis-(+)-normaprotamol hydrochloride

[0032] (+)-N-desmethylmaprotamol (0.75g, 3.42mmol) was added to 6ml of acetonitrile, triethylamine (950μL, 6.84mmol), and 1,2-dibromoethane (148μL, 1.71mmol), The reaction was refluxed for 3 hours. After cooling, the reaction solution was concentrated to obtain 1.16 g of light yellow foam, and silica gel column chromatography obtained 0.55 g of N,N'-(1,2-ethyl)-bis-(+)-normaprotamol, with a yield of 69%.

[0033] N,N'-(1,2-ethyl)-bis-(+)-normaprotamol (0.55g, 1.19mmol) was dissolved in 10ml of anhydrous ether. Anhydrous HCl-ether solution was added dropwise to adjust the pH to ≈3, and a large number of light yellow solids were precipitated. Filtration, infrared drying to obtain N,N'-(1,2-ethyl)-bis-(+)-normeprotamol hydrochloride 0.58g, mp.156-160℃, [α] D =+23.29° (c=0.108, MeOH).

[0034] 1 HNMR (CDCl 3 ): δ7.19-7.15 (t, 1H, Ar-H, J=8), 6.89-6.82 (m, 2H, Ar-H), 6.72-6.69 (m, 1H, Ar-H), 6.4 (br...

Embodiment 3

[0037] Preparation of N, N'-(1,4-butyl)-bis-(+)-normaprotamol hydrochloride

[0038] Add (+)-N-desmethylmaprotamol (1.57g, 7.17mmol) to 15ml of anhydrous dichloromethane, cool in an ice-water bath, and add triethylamine (2ml, 14.38mmol). Succinoyl chloride (410 μL, 3.55 mmol) was diluted with 3 ml of anhydrous dichloromethane, and added dropwise to the reaction solution. The reaction stopped after 10 minutes. The reaction solution was washed with 2ml of water and 3ml of 1N HCl. The organic layer was dried. Filter and distill off the solvent to obtain a brown foam. Silica gel column chromatography yielded 1.35 g of N,N'-(1,4-succinoyl)-bis-(+)-N-desmethylmeprotamol with a yield of 73%.

[0039] LiAlH 4(0.52g, 13.68mmol) and 20ml of anhydrous tetrahydrofuran, stirred at room temperature. Dissolve N,N'-(1,4-succinoyl)-bis-(+)-N-desmethylmeprotamol (1.35g, 2.55mmol) in 35ml of anhydrous THF and add dropwise to the reaction solution . After the dropwise addition was complet...

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Abstract

The present invention relates to pharmaceutical technology, and is especially (+)-Meptazinol diligand derivative as shown in the structural general expression and / or its salt and the preparation process. The present invention modifies the structure of (+)-Meptazinol through eliminating its N-methyl radical and connecting two N's on the seven-membered rings of two (+)-N-nor Meptazinol with hydrocarbon chains in different lengths to obtain the (+)-Meptazinol diligand derivative. The pharmacological experiment shows that the (+)-Meptazinol diligand derivative possesses analgesic activity of different degree.

Description

technical field [0001] The invention belongs to the field of pharmacy, and relates to (+)-meprotamol biligand derivatives and salts, in particular to (+)-meprotamol biligand derivatives or / and salts thereof and Preparation. [0002] [0003] where n=2-7. Background technique [0004] Meptazinol, chemical name 3-(3-ethyl-hexahydro-1-methyl-1H-azepine-3-yl)phenol, is a partial agonist of opioid receptors, analgesic The effect is remarkable, and it is often used for moderate or severe pain caused by different reasons, such as clinically used for postoperative or postpartum analgesia. Its analgesic activity is equivalent to that of pentazocine, doperidine, dextropropoxyphene and paracetamol, but slightly weaker than morphine. Compared with other opioid analgesics, meprotamol has less side effects such as respiratory depression and withdrawal addiction. Meptidol hydrochloride was listed in 1986 under the trade name Meptid (Wyeth.UK) and Meptid (Ger) and Meptidol (Aust), wh...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D223/04A61K31/55A61P25/04
Inventor 仇缀百卢美艳谢琼盛韦郑优丽
Owner FUDAN UNIV
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