4-(methoxycarbonyl)-4-(N- phenylpropionamido)- piperidine-1-substituted compound, preparation method and pharmaceutical application

A technology of phenylpropanamide and methoxycarbonyl, applied in the field of 4--4--piperidine-1-substituted compounds, which can solve the problem of low water solubility

Active Publication Date: 2012-07-25
WEST CHINA HOSPITAL SICHUAN UNIV
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, although propofol can produce better sedative effect when it is lower than the anesthetic concentration, it is currently used in the form of emulsion because of its low water solubility, and a large amount of fat emulsion is not suitable for the long-term treatment of postoperative patients. time administration

Method used

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  • 4-(methoxycarbonyl)-4-(N- phenylpropionamido)- piperidine-1-substituted compound, preparation method and pharmaceutical application
  • 4-(methoxycarbonyl)-4-(N- phenylpropionamido)- piperidine-1-substituted compound, preparation method and pharmaceutical application
  • 4-(methoxycarbonyl)-4-(N- phenylpropionamido)- piperidine-1-substituted compound, preparation method and pharmaceutical application

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0026] 2,6-Diisopropylphenol (IV) (9 mmol) was dissolved in THF (20 ml), 0 o C. Under the protection of nitrogen, 6 ml of tetrahydrofuran solution containing 21% potassium hexamethyldisilazide (KHMDS) was added dropwise. Reaction solution at 0 o Stir at C for 40 min, then add dropwise 5 ml of a tetrahydrofuran solution containing terminally brominated acid chloride (18 mmol). The reaction solution was stirred overnight at room temperature, then poured into a large amount of water, extracted with ethyl acetate, separated the organic layer, washed the organic layer once with brine, dried the organic layer with anhydrous sodium sulfate, filtered, evaporated the filtrate to dryness under reduced pressure, and the residue The product was purified by silica gel column chromatography (developing solvent: cyclohexane / ethyl acetate = 40:1) to obtain a yellow oil product intermediate (2,6-diisopropylphenol ω-bromocarboxylate or 2,6 - diisopropylphenol acrylate). Wherein when n=1, the...

Embodiment 2

[0041] Dissolve the compound of formula (Ⅴ) (RP-acid) (100 mg, 0.28 mmol) in 20 ml of acetone, add propofol chloromethyl ether (CAS: 22, 94 mg, 0.42 mmol), Cs 2 CO 3 (180 mg, 0.55 mmol). Reflux overnight after the completion of the reaction, cool the reaction solution to room temperature, filter, concentrate the filtrate, and purify the residue with preparative thin layer (developing solvent: cyclohexane / ethyl acetate = 1.5:1) to obtain the free base in the form of formula (I) Colorless oily product 100mg, yield 65%. The reaction process is as follows:

[0042] .

[0043] Product structure detection results:

[0044] 1 HNMR(δ)(CDCl 3 ): 0.928~0.976 (t, 3H), 1.183~1.206(2s,12H), 1.592~1.630(t,2H), 1.829~1.903 (q, 2H), 2.246~2.290 (d, 2H), 2.384~2.507 (m, 4H), 2.581~2.680 (m,4H), 3.257~3.303(m,2H), 5.526(s,2H), 7.092~7.123(t,3H), 7.263~7.415(m,5H).

[0045] Elemental analysis (instrument: Italian CARLO ERBA 1106 elemental analyzer): N (4.92%), C (69.21%), H (8.06%)...

Embodiment 3

[0047] The reaction process is as follows:

[0048] Under nitrogen protection, dissolve propofol chloroformate (0.6 ml, 0.34 mmol) in toluene, add triethylamine (52 mg, 0.52 mmol) (or pyridine 0.52 mmol), add formula (Ⅵ) compound (60 mg, 0.17 mmol) in dichloromethane solution 10 ml. The reaction was stirred overnight. After concentration, 23 mg of the free base yellow oily product in the form of formula (I) was obtained by thin layer preparation (developing solvent: cyclohexane / ethyl acetate = 1:1), with a yield of 24.5%. The reaction process is as follows:

[0049] .

[0050] Dissolve 23 mg of the free base product of formula (I) in 10 ml of anhydrous ether, and pass through dry hydrogen chloride gas at 0°C for 2 h, concentrate and filter to obtain 21 mg of its hydrochloride product as a white solid, with a yield of 84.9%.

[0051] The hydrochloride product structure detection result:

[0052] 1 HNMR(δ)(CD 3 OD): 0.831~0.868 (t, 3H), 1.078~1.095(2s,12H), 1.822~1...

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Abstract

The invention relates to a 4-(methoxycarbonyl)-4-(N- phenylpropionamido)- piperidine-1-substituted compound, a preparation method and pharmaceutical application. The compound is of a structure of free base in a formula (I) or corresponding hydrochloride (I'), wherein in the formula, n is an integral number in the range of 0 to 3 and R is a sulfonyl group or a substituent group with a propofol parent nucleus structure. The compound has excellent water-solubility and stability and can simultaneously have effects of alleviating pain and calming, is suitable for carrying out pain alleviation and calming on a postoperative monitored patient and is particularly beneficial for implementing the operation of the patient on a self-control drug delivery system and the operation of an anesthetist can be reduced. The basic method for preparing the compound comprises the following step that according to the property of the substituent group R, the 4-(methoxycarbonyl)-4-(N- phenylpropionamido)- piperidine-1-substituted compound can be formed by carrying out condensation on a compound with a remifentanil parent nucleus structure and a compound with a corresponding substituent group parent nucleus structure. The invention provides the 4-(methoxycarbonyl)-4-(N- phenylpropionamido)- piperidine-1-substituted compound.

Description

technical field [0001] The invention relates to a 4-(methoxycarbonyl)-4-(N-phenylpropanylamino)-piperidine-1-substituted compound, a preparation method and a pharmaceutical use thereof. Background technique [0002] Propofol (2,6-diisopropylphenol), whose structure is shown in formula (Ⅳ), is a widely used sedative drug for induction, maintenance and intensive care of general anesthesia in clinical practice. , fast metabolic inactivation, has been widely used in the medical field. The commonly used analgesic drug compatible with it in clinical practice is Remifentanil (Remifentanil, 3 [4 (methoxycarbonyl) - 4- (N-phenylpropanyl) 1 -piperidine] methyl propionate), also has the characteristics of rapid onset of action and fast metabolism. The combination of these two drugs can produce good analgesic and sedative effects, and the patient can recover quickly after stopping the drug. However, due to its rapid metabolism, anesthesiologists need to adjust the dosage of the two d...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D211/58A61K31/4468A61P23/00A61P25/04A61P25/20
CPCY02P20/55
Inventor 刘进张文胜杨俊
Owner WEST CHINA HOSPITAL SICHUAN UNIV
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