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Water-soluble amino-acid ester derivative of propofol

A technology of amino acid esters and derivatives, which can be used in drug combinations, anesthetics, organic chemistry, etc., and can solve problems such as difficult to use, easy to grow bacteria, poor physical stability of emulsions, etc.

Inactive Publication Date: 2010-11-10
BEIJING MEIBEITA DRUG RES
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] The emulsion of propofol has poor physical stability, which can easily cause pain at the injection site, easy to grow bacteria, and is not easy to use with other injection drugs

Method used

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  • Water-soluble amino-acid ester derivative of propofol
  • Water-soluble amino-acid ester derivative of propofol
  • Water-soluble amino-acid ester derivative of propofol

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 12

[0024] Example 12-(L-glycyloxymethyloxy)-1,3-diisopropyl-benzene hydrochloride (I 1 ) preparation

[0025]

[0026] 1. Synthesis of 12-chloromethyloxy-1,3-diisopropyl-benzene

[0027] Dissolve 30.0g propofol in 500ml dry tetrahydrofuran under N 2 12g of sodium hydroxide and 380g of bromochloromethane were added under protection. The reaction was stirred at 64°C for 3 hours, cooled to room temperature, filtered, and the filtrate was evaporated to dryness under reduced pressure to obtain 31 g of 2-chloromethyloxy-1,3-diisopropyl-benzene. Proton NMR spectrum δ (ppm, CDCl3): 7.21-7.08 (m, 3H); 5.76 (s, 2H); 3.36 (m, 2H); 1.21 (d, 12H). 1.22-(L-glycyloxymethyloxy)-1,3-diisopropyl-benzene hydrochloride (I 1 )Synthesis

[0028] in N 2 Under protection, add 2.1g N-Boc-L-glycine, 1.7ml milliliter triethylamine, 1.2g 2-chloromethyloxy-1,3-diisopropyl-benzene to 30ml acetonitrile, stir at 60°C Reacted for 10 hours, after cooling, the solid was filtered off, the filtrate was con...

Embodiment 2

[0030] Example 22-(L-alanyloxymethyloxy)-1,3-diisopropyl-benzene hydrochloride (I 2 ) preparation

[0031]

[0032] With reference to the method of Example 1.2, replace N-Boc-L-glycine with N-Boc-L-alanine and react with 2-chloromethyloxy-1,3-diisopropyl-benzene to obtain 2-( N-Boc-L-alanyloxymethyloxy)-1,3-diisopropyl-benzene. Proton NMR spectrum δ (ppm, CDCl3): 7.20-7.09 (m, 3H); 5.48 (s, 2H); 4.31 (q, 1H); 3.35 (m, 2H); 1.60 (d, 3H); 1.40 ( s, 9H); 1.22 (d, 12H).

[0033] Deprotection of 2-(N-Boc-L-alanyloxymethyloxy)-1,3-diisopropyl-benzene with hydrogen chloride affords I 2 . Proton NMR spectrum δ (ppm, DMSO-d6): 8.25 (br s, 2H); 7.22-7.11 (m, 3H); 5.46 (s, 2H); 4.35 (q, 1H); 3.38 (m, 2H) ; 1.62(d, 3H); 1.22(d, 12H).

Embodiment 32

[0034] Example 32-(L-valyloxymethyloxy)-1,3-diisopropyl-benzene hydrochloride (I 3 ) preparation

[0035]

[0036] With reference to the method of Example 1.2, replace N-Boc-L-glycine with N-Boc-L-valine and react with 2-chloromethyloxy-1,3-diisopropyl-benzene to obtain 2-( N-Boc-L-valyloxymethyloxy)-1,3-diisopropyl-benzene. Proton NMR spectrum δ (ppm, CDCl3): 7.20-7.09 (m, 3H); 5.44 (s, 2H); 4.28 (d, 1H); 3.35 (m, 2H); 2.36 (m, 1H); 1.40 ( s, 9H); 1.22 (d, 12H); 1.06 (d, 6H).

[0037] Deprotection of 2-(N-Boc-L-valyloxymethyloxy)-1,3-diisopropyl-benzene with hydrogen chloride affords I 3 . Proton NMR spectrum δ (ppm, DMSO-d6): 8.23 ​​(br s, 2H); 7.15-7.04 (m, 3H); 5.43 (s, 2H); 4.23 (d, 1H); 3.31 (m, 2H) ; 2.32 (m, 1H); 1.19 (d, 12H); 0.96 (d, 6H).

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Abstract

The invention relates to a water-soluble amino-acid ester derivative of propofol shown in a formula (I), nontoxic pharmaceutically-acceptable salts thereof, a pharmaceutical composition which contains the compound and is used as an active ingredient, and the application of the compound and the pharmaceutical composition as narcotic drugs, wherein R1 is an alkyl of H or C1-C3, and R2 is a lateral chain of L-amino acid of hydrogen, methyl, isopropyl, isobutyl, 2-methyl-propyl or benzyl, and the like.

Description

technical field [0001] The present invention relates to novel derivatives of amino acid esters of propofol and their non-toxic pharmaceutically acceptable salts, as well as pharmaceutical compositions containing these compounds as active ingredients, and the use of the compounds and pharmaceutical compositions as anesthetics . Background technique [0002] Propofol (chemical name: 2,6-diisopropylphenol, also known as propofol), is a quick-acting, short-acting systemic intravenous anesthetic, with fast onset, fast and complete recovery, and no accumulation. It is widely used clinically for the induction and maintenance of general anesthesia. However, due to the poor water solubility of propofol, it can only be used clinically in the form of emulsion. [0003] [0004] Propofol [0005] The emulsion of propofol has poor physical stability, which can easily cause pain at the injection site, easy to grow bacteria, and is not easy to be used together with other injection me...

Claims

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Application Information

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IPC IPC(8): C07C229/08C07C229/36A61K31/223A61K31/216A61P23/00
Inventor 杨美英王建民
Owner BEIJING MEIBEITA DRUG RES
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