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Carbonic acid diester water-soluble derivant of amino acid and propofol, and application of carbonic acid diester water-soluble derivant of amino acid and propofol

A technology of amino acids and derivatives, which is applied in the field of water-soluble derivatives of carbonate diesters of amino acids and propofol and their uses, and can solve problems such as unfavorable drug safety

Active Publication Date: 2012-08-01
CHENGDU YIPING MEDICAL SCI & TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] However, fospropofol will release a molecule of formaldehyde during the metabolism in the body (Europ.JPharm.Sci.2008, 31:110-117), so it is relatively unfavorable in terms of drug safety.

Method used

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  • Carbonic acid diester water-soluble derivant of amino acid and propofol, and application of carbonic acid diester water-soluble derivant of amino acid and propofol
  • Carbonic acid diester water-soluble derivant of amino acid and propofol, and application of carbonic acid diester water-soluble derivant of amino acid and propofol
  • Carbonic acid diester water-soluble derivant of amino acid and propofol, and application of carbonic acid diester water-soluble derivant of amino acid and propofol

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0071] Synthesis of 2-L-lysine-(2,6-diisopropyl-phenyl-)carbonic anhydride dihydrochloride (compound 1)

[0072]

[0073] Compound 1

[0074] Under water bath conditions, propofol (2.6mmol, 0.46g) was added to anhydrous dichloromethane (30ml), cooled to -5°C, triphosgene (0.9mmol, 0.27g) was added, and under temperature control, dropwise Add triethylamine (2.6 mmol, 0.26 g), slowly warm up to room temperature, and stir for 1 hour. then add N α -tert-butoxycarbonyl-N ε -tert-butoxycarbonyl-lysine (2.2mmol, 0.76g), triethylamine (2.2mmol, 0.22g), stirred overnight at room temperature. The reaction was monitored by HPLC until the raw material was completely reacted. Concentrate, add 4M HCl / dioxane solution (20ml), stir and react at room temperature for 1h. The solvent was evaporated under reduced pressure, the insoluble matter was washed by adding n-hexane, and filtered to obtain a white solid, which was recrystallized from ether / n-hexane to obtain 0.61 g of compound 1 ...

Embodiment 2

[0079] Synthesis of 2-L-arginine-(2,6-diisopropyl-phenyl-)carbonic anhydride dihydrochloride (compound 2)

[0080]

[0081] Compound 2

[0082] Synthetic method with reference to embodiment 1, with N α - tert-butoxycarbonyl-arginine hydrochloride replaces N α tert-butoxycarbonyl-N ε - tert-butoxycarbonyl-lysine. Compound 2 was obtained with a yield of 60.1%.

[0083] ESI-MS m / z: 379 (M+1 + ).

[0084] 1 H NMR (D 2 O)δ0.98(d,12H,-C H 3 ), 1.6-1.7 (m, 2H, CH 2 -C H 2 -CH 2 - δ NH-), 1.8-2.0 (m, 1H, C H), 2.2-2.2 (m, 1H, C H ), 2.99(t, 2H, C H 2 -CH 2 -CH 2 - δ NH-), 3.2-3.3 (m, 2H, CH 2 -C H 2 -δNH-), 4.41 (dd, 1H, C H - α NH 2 ), 7.1-7.3 (m, 3H, Ar H ).

[0085] Elemental analysis: calculated value C, 50.56; H, 7.15; N, 12.41; found value 50.39; H, 7.11; N.12.50

Embodiment 3

[0087] Synthesis of 2-glycine-(2,6-diisopropyl-phenyl-)carbonic anhydride hydrochloride (compound 3)

[0088]

[0089] Compound 3

[0090] Synthetic method with reference to embodiment 1, with N α tert-butoxycarbonyl-glycine replaces N α tert-butoxycarbonyl-N ε - tert-butoxycarbonyl-lysine. Compound 3 was obtained with a yield of 58.3%.

[0091] ESI-MS m / z: 280 (M+1 + ).

[0092] 1 H NMR (D 2 O)δ0.99(d,12H,-C H 3 ), 1.8-2.0 (m, 1H, C H ), 2.2-2.2 (m, 1H, C H ), 4.39 (dd, 1H, C H - α NH 2 ), 7.1-7.3 (m, 3H, Ar H ).

[0093] Elemental analysis: calculated value C, 57.05; H, 7.02; N, 4.44; found value 57.21; H, 7.09; N.4.29.

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Abstract

The invention relates to a carbonic acid diester water-soluble derivant of amino acid and propofol, and application of the carbonic acid diester water-soluble derivant of amino acid and propofol. The amino acid carbonic acid diester of propofol has the structure which is shown as a formula (1), wherein R is shown in the specifications; and the invention also discloses a preparation method for the compound with the formula (I), pharmaceutical salt of the compound, a medical composition of the compound and the pharmaceutical salt of the compound, and application of the compound used as a dope.

Description

technical field [0001] The present invention relates to water-soluble derivatives of carbonic acid diester of amino acid and propofol and their non-toxic pharmaceutically acceptable salts, their preparation method, their pharmaceutical composition and their use 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 the characteristics of fast onset and quick recovery, and no accumulation , has been widely used clinically. However, due to its poor water solubility, it is mainly used clinically in fat emulsion. The emulsion of propofol has poor physical stability, and it is easy to cause pain at the injection site and inflammatory reaction during clinical use, and it is difficult to be compatible with other preparations. [0003] [0004] Propofol Chemical Structure [0005] In December 2008, the U.S. FDA approved a water-soluble derivativ...

Claims

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Application Information

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IPC IPC(8): C07C229/26C07C227/18C07C279/14C07C277/08A61K31/265A61P25/20A61P23/00
Inventor 不公告发明人
Owner CHENGDU YIPING MEDICAL SCI & TECH
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