Amino-acid ester water-soluble derivative of (S)-ornidazole and application thereof

A technology of levornidazole and amino acid ester, which can be used in medical preparations containing active ingredients, drug combinations, organic active ingredients, etc., and can solve the problems of harsh storage conditions and poor stability.

Pending Publication Date: 2017-03-01
HC SYNTHETIC PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] However, the sodium salt, potassium salt, calcium salt and magnesium salt of previously disclosed levo-ornidazole phosphate, because of its poor stability, easily remove a part of sodium chloride at a temperature above 25 ° C to degrade and generate cyclized ester impurities , it needs to be stored at 2°C to 8°C during the long-term storage process, and the storage conditions are slightly harsh in practical applications

Method used

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  • Amino-acid ester water-soluble derivative of (S)-ornidazole and application thereof
  • Amino-acid ester water-soluble derivative of (S)-ornidazole and application thereof
  • Amino-acid ester water-soluble derivative of (S)-ornidazole and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0060] Example 1 ： Synthesis of (S)-3-chloro-1-(2-methyl-5-nitro-1H-imidazol-1-yl)propane-2-yl-2,6-diaminocaproic acid (Compound 1)

[0061] Under water bath conditions, N α -tert-butoxycarbonyl-N ε -tert-butoxycarbonyl-lysine (22mmol, 7.6g), N,N'-dicyclohexylcarbodiimide (4.4mmol, 0.91g), 4-dimethylaminopyridine (2.2mmol, 0.3g) , stirred and dissolved with anhydrous dichloromethane (30ml). Subsequently, levo-ornidazole (26 mmol, 5.7 g) was added and stirred overnight at room temperature. The insoluble solid was removed by filtration, and the filtrate was evaporated to dryness; ether was added to the residue, and insoluble impurities in the solution were removed by filtration. The filtrate was concentrated and quickly passed through the column with diethyl ether as the developing solvent to collect product fractions. Concentration under reduced pressure gave 3.7 g of the product; the yield of compound 1 was 64.9%.

[0062] ESI-MS m / z: 347 (M+1) +

Embodiment 2

[0063] Example 2 ： Synthesis of (S)-3-chloro-1-(2-methyl-5-nitro-1H-imidazol-1-yl)propane-2-yl-2-amino-5-guanidinovaleric acid (Compound 2)

[0064] Under water bath conditions, N α - tert-butoxycarbonyl-arginine hydrochloride (22mmol, 7.23g), N, N'-dicyclohexylcarbodiimide (4.4mmol, 0.91g), 4-dimethylaminopyridine (2.2mmol, 0.3g), stirred and dissolved with anhydrous dichloromethane (30ml). Subsequently, levo-ornidazole (26 mmol, 5.7 g) was added and stirred overnight at room temperature. The insoluble solid was removed by filtration, and the filtrate was evaporated to dryness; ether was added to the residue, and insoluble impurities in the solution were removed by filtration. The filtrate was concentrated and quickly passed through the column with diethyl ether as the developing solvent to collect product fractions. Concentration under reduced pressure gave 4.0 g of the product; the yield of compound 2 was 70.2%.

[0065] ESI-MS m / z: 389 (M+1) +

Embodiment 3

[0066] Example 3 ： (S)-3-Chloro-1-(2-methyl-5-nitro-1H-imidazol-1-yl)propan-2yl-2-amino-3-(4-imidazolyl)propionic acid (compound 3) Synthesis of

[0067] Under water bath conditions, N α -tert-butoxycarbonyl-Nim-trityl-histidine (22mmol, 7.6g), N,N'-dicyclohexylcarbodiimide (4.4mmol, 0.91g), 4-dimethylaminopyridine (2.2mmol, 0.3g), stirred and dissolved with anhydrous dichloromethane (30ml). Subsequently, levo-ornidazole (26 mmol, 5.7 g) was added and stirred overnight at room temperature. The insoluble solid was removed by filtration, and the filtrate was evaporated to dryness; ether was added to the residue, and insoluble impurities in the solution were removed by filtration. The filtrate was concentrated and quickly passed through the column with diethyl ether as the developing solvent to collect product fractions. Concentration under reduced pressure gave 4.2 g of the product; the yield of compound 3 was 73.6%.

[0068] ESI-MS m / z: 356 (M+1) +

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PUM

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Abstract

The invention relates to an amino-acid ester water-soluble derivative of (S)-ornidazole and application thereof. the amino-acid ester of (S)-ornidazole has a structure as shown in the formula (I), wherein R and (HnX)m are defined in the claims. The invention also relates to a preparation method of the compound as shown in the formula (I), pharmaceutical salt thereof, a pharmaceutical composition containing the compound and the pharmaceutical salt and application of the pharmaceutical composition used as a medicine, especially application of the pharmaceutical composition used for treatment of anaerobic infection or protozoan infection.

Description

technical field [0001] The present invention relates to amino acid ester water-soluble derivatives of L-ornidazole and their non-toxic pharmaceutically acceptable salts, their preparation methods, pharmaceutical compositions containing them and their use as medicines, especially for anaerobic infection or Treatment of protozoan infection. Background technique [0002] Ornidazole is a nitroimidazole derivative, which is a powerful drug against anaerobic infection and antiprotozoal infection. It is also developed after metronidazole with higher curative effect, shorter course of treatment, better tolerance and wider distribution in the body. The third generation of nitroimidazole derivatives. The antimicrobial effect of ornidazole is through the reduction of the nitro group in its molecule to an amino group in an oxygen-free environment or through the interaction with cell components in the form of free radicals, resulting in the death of microorganisms. [0003] Levo-ornida...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D233/94A61K31/4164A61P31/04A61P33/02
CPCC07D233/94
Inventor 陆华龙
Owner HC SYNTHETIC PHARMA CO LTD
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