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Short-acting sedative hypnotic agents for anesthesia and sedation

A compound and alkyl technology, which is applied in the direction of anesthetics, active ingredients of esters, medical preparations containing active ingredients, etc., can solve problems such as short recovery time

Inactive Publication Date: 2005-06-01
THERAVANCE BIOPHARMA R&D IP LLC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Thus, although propanidil offers a shorter and more predictable recovery time than propofol, it has not been widely accepted as an injectable anesthetic

Method used

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  • Short-acting sedative hypnotic agents for anesthesia and sedation
  • Short-acting sedative hypnotic agents for anesthesia and sedation
  • Short-acting sedative hypnotic agents for anesthesia and sedation

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0130] Example 1. Compound 1: [4-[(N,N-diethylcarbamoyl)methoxy]-3-ethoxyphenyl]propyl acetate

[0131]

[0132] In a 50 mL round bottom flask equipped with a magnetic stir bar, propyl 3-ethoxy-4-hydroxyphenylacetate (800 mg, 3.4 mmol, 1.0 equiv.) was dissolved in anhydrous acetone (20 mL). To this solution was added K 2 CO 3 (705 mg, 5.1 mmol, 1.5 equiv.), followed by 2-chloro-N,N-diethylacetamide (0.55 mL, 4.0 mmol, 1.2 equiv., Aldrich). With vigorous stirring, the suspension was heated to reflux and maintained at this condition for 15 hours. After cooling to room temperature, the reaction mixture was filtered through folded filter paper, and the solvent of the remaining solution was removed under reduced pressure. The oily product was purified by column chromatography (SiO 2 , 50% EtOAc / Hexane) to afford 630 mg (53% of theory) of a colorless oil with a purity of 99.6% by HPLC.

[0133] TLC (Silica, 50% EtOAc / Hexane) Rf 0.25; 1 H NMR (CDCl 3 , 300MHz): d 0.90 (3H, ...

Embodiment 2

[0152] Example 2. Compound 2: [4-[(N,N-diethylcarbamoyl)methoxy]-3-ethoxyphenyl]ethyl acetate

[0153]

[0154] Utilize the technique similar to that described in Example 1, except that ethanol is used to replace 1-propanol in the synthesis of the intermediate, generate the intermediate of formula (IIa), wherein R 1 = ethyl, R 4 =Propyl, the title compound was obtained in 81% yield as a colorless oil with a purity of 96% as determined by HPLC.

[0155] TLC (Silica, 50% EtOAc / Hexane) Rf 0.25; 1 H NMR (CDCl 3 , 300MHz): d 1.13-1.22 (6H, m, N-ethyl CH 3 ), 1.25 (3H, t, ethyl ester CH 3 ), 1.43 (3H, t, ethoxy CH 3 ), 3.38-3.45 (4H, m, N-ethyl CH 2 ), 3.52 (2H, s, OCH 2 CO), 4.05-4.17 (4H, m, 2xOCH 2 ), 4.71 (2H, s, ArCH 2 CO), 6.78-6.91 (3H, m, ArH). m / z: [M+H + ]C 18 h 27 NO 5 The calculated value is 338.20; the measured value is 338.

Embodiment 3

[0156] Example 3. Compound 3: [4-[(N,N-diethylcarbamoyl)methoxy]-3-ethoxyphenyl]acetate isopropyl ester

[0157]

[0158] Utilize the technique similar to that described in Example 1, except replacing 1-propanol with isopropanol in the synthesis of the intermediate, generate the intermediate of formula (IIa), wherein R 1 = ethyl, R 4 =Isopropyl, the title compound was obtained in a yield of 63% as a colorless oil with a purity of 99% as determined by HPLC.

[0159] TLC (Silica, 50% EtOAc / Hexane) Rf 0.25; 1 H NMR (CDCl, 300MHz): d 1.06-1.19 (6H, m, N-ethyl CH 3 ), 1.14 and 1.16 (2×3H, 2s, isopropyl ester CH 3 ), 1.36 (3H, t, ethoxy CH 3 ), 3.30-3.36 (4H, m, N-ethyl CH 2 ), 3.42 (2H, s, OCH 2 CO), 3.98-4.03 (2H, m, OCH 2 ), 4.64 (2H, s, ArCH 2 CO), 4.90-4.98 (1H, m, CH), 6.71-6.84 (3H, m, ArH). m / z: [M+H + ]C 19 h 29 NO 5 The calculated value is 352.22; the measured value is 352.

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PUM

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Abstract

The invention provides compounds compositions and methods useful for inducing or maintaining general anesthesia or sedation in mammals.

Description

technical field [0001] The present invention relates to novel substituted phenylacetate compounds useful as short-acting sedative-hypnotics for anesthesia and sedation. The invention also relates to pharmaceutical compositions comprising such compounds; methods of using such compounds to induce or maintain anesthesia or sedation; and intermediates for the preparation of such compounds. Background technique [0002] Propofol, 2,6-diisopropylphenol (Diprivan(R) Injectable Emulsion, AstraZeneca) is an injectable anesthetic with hypnotic properties. It can be used to induce and maintain general anesthesia and sedation. Although propofol is a widely used anesthetic, its usefulness is limited by its long and unpredictable duration of action after infusion. This unpredictable duration of action results in irregular and often prolonged recovery times for patients, which are undesirable. [0003] Propanidil, [4-[(N,N-diethylcarbamoyl)methoxy]-3-methoxyphenyl]propyl acetate, is ano...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/216A61P23/00C07C69/734C07C69/736C07C235/20C07D229/02
CPCA61K31/216A61K31/24C07C69/734C07C235/20A61P23/00A61P25/20C07C219/14
Inventor T·E·詹金斯S·阿克斯特J·博尔顿
Owner THERAVANCE BIOPHARMA R&D IP LLC
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