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Novel semisynthetic macrolide antibiotics of the azalide series

A macrocyclic lactone and semi-synthetic technology, applied in the direction of carbohydrate active ingredients, antibacterial drugs, drug combinations, etc., can solve undisclosed problems

Inactive Publication Date: 2006-01-25
PLIVA ISTRAZIVACKI INST D O O
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] According to the known and established prior art, 9-deoxy-9-dihydro-9a-aza-9a-homoerythromycin A and 5-O-desosamino-9-deoxy-9 have not been disclosed -Dihydro-9a-aza-9a-N″-substituted 9a-N-(N′-carbamoyl-γ-aminopropyl), 9a-N-(N′- Thiocarbamoyl-γ-aminopropyl), 9a-N-[N′-(β-cyanoethyl)-N′-carbamoyl-γ-aminopropyl] and 9a-N-[N '-(β-cyanoethyl)-N'-thiocarbamoyl-γ-aminopropyl] derivatives, their pharmaceutically acceptable addition salts with inorganic or organic acids, their preparation methods, and medicaments Preparation method and application of preparation

Method used

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  • Novel semisynthetic macrolide antibiotics of the azalide series
  • Novel semisynthetic macrolide antibiotics of the azalide series
  • Novel semisynthetic macrolide antibiotics of the azalide series

Examples

Experimental program
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Effect test

Embodiment 1

[0027] 9-Deoxy-9-dihydro-9a-N-(N′-isopropylcarbamoyl-γ-aminopropyl)-9a-aza-9a-homoerythromycin A

[0028] 1.0g (1.26mmol) 9-deoxy-9-dihydro-9a-aza-9a-(γ-aminopropyl)-9a-homoerythromycin A and 0.1g (1.3mmol) isopropyl isocyanate A mixture of the ester in 10 mL of anhydrous toluene was stirred at room temperature for 30 minutes to complete the reaction. The crystals of the crude product were filtered and chromatographed on a silica gel column using the solvent system dichloromethane:methanol:ammonia=90:9:1.5 to obtain pure 9-deoxy-9-dihydro-9a-N-(N' -Isopropylcarbamoyl-γ-aminopropyl)-9a-aza-9a-homoerythromycin A.

[0029] MS (ES + )m / z=877.

Embodiment 2

[0031] 9-Deoxy-9-dihydro-9a-N-[N'-(1-naphthyl)carbamoyl-γ-aminopropyl]-9a-aza-9a-homoerythromycin A

[0032] 1.0g (1.26mmol) 9-deoxy-9-dihydro-9a-aza-9a-(γ-aminopropyl)-9a-homoerythromycin A and 0.22g (1.26mmol) 1-naphthyl isocyanate The mixture in 10 ml of anhydrous toluene was stirred at room temperature for 30 minutes to complete the reaction. The crystals of the crude product were filtered and chromatographed on a silica gel column using the solvent system dichloromethane:methanol:ammonia=90:9:1.5 to obtain pure 9-deoxy-9-dihydro-9a-N-[N' -(1-Naphthyl)carbamoyl-γ-aminopropyl]-9a-aza-9a-homoerythromycin A.

[0033] MS (ES + )m / z=961.

Embodiment 3

[0035] 9-Deoxy-9-dihydro-9a-N-(N′-benzylcarbamoyl-γ-aminopropyl)-9a-aza-9a-homoerythromycin A

[0036] 1.0g (1.26mmol) 9-deoxy-9-dihydro-9a-aza-9a-(γ-aminopropyl)-9a-homoerythromycin A and 0.17g (1.3mmol) benzyl isocyanate The mixture in 10 ml of anhydrous toluene was stirred at room temperature for 30 minutes to complete the reaction. The crystals of the crude product were filtered and chromatographed on a silica gel column using the solvent system dichloromethane:methanol:ammonia=90:9:1.5 to obtain pure 9-deoxy-9-dihydro-9a-N-(N' -Benzylcarbamoyl-γ-aminopropyl)-9a-aza-9a-homoerythromycin A.

[0037] MS (ES + )m / z=925.

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Abstract

The invention relates to N''-substituted 9a-N-(N'-carbamoyl-gamma-aminopropyl), 9a-N-(N'-thiocarbamoyl-gamma-aminopropyl), 9a-N-[N'-((beta-cyanoethyl)-N'-carbamoyl-gamma-aminopropyl) and 9a-N-[N'-((beta-cyanoethyl)-N'-thiocarbamoyl-gamma-aminopropyl) derivatives of 9-deoxo-9-dihydro-9a-aza-9a-homoerithromycin A and 5-0-desosaminyl-9-deoxo-9-dihydro-9a-aza-9a-homoerithronolide A, novel semisynthetic macrolide antibiotics of the azalide series, of the general formula 1, wherein R represents H or cladinosyl moiety, R<1> represents H or (beta-cyanoethyl moiety, R<2> represents isopropyl, 1-naphtyl, 2-naphtyl, benzyl, 2-(trifluoromethyl)phenyl, 3-phenylpropyl, beta-phenylethyl, ethoxycarbonylmethyl, 1-(1-naphtyl)ethyl, 3,4,5-trimethoxyphenyl and 2,4-dichlorophenyl group, and X represents 0 and S, and their acceptable addition salts thereof with inorganic or organic acids, to the process for preparation of their pharmaceutical compositions as well as the use their compositions in the treatment of bacterial infections.

Description

technical field [0001] The present invention relates to 9-deoxy-9-dihydro-9a-aza-9a-homoerythromycin A and 5-O-desosamino-9-deoxy-9-dihydro-9a-aza-9a- N″-substituted 9a-N-(N′-carbamoyl-γ-aminopropyl), 9a-N-(N′-thiocarbamoyl-γ-aminopropyl) of homoerythromycin A ), 9a-N-[N'-(β-cyanoethyl)-N'-carbamoyl-γ-aminopropyl] and 9a-N-[N'-(β-cyanoethyl)- N'-thiocarbamoyl-γ-aminopropyl] derivatives, they are the macrolide antibiotics of the new semi-synthetic nitrogen heterocyclic lactone series with antibacterial activity of general formula 1, [0002] [0003] Among them, R represents H or claridine glycosyl group, R 1 Represents H or β-cyanoethyl, R 2 Represents isopropyl, 1-naphthyl, 2-naphthyl, benzyl, 2-(trifluoromethyl)phenyl, 3-phenylpropyl, β-phenylethyl, ethoxycarbonylmethyl, 1-(1-naphthyl)ethyl, 3,4,5-trimethoxyphenyl and 2,4-dichlorophenyl, and X represents O or S, [0004] It relates to a pharmaceutically acceptable addition salt thereof with an inorganic or organic ac...

Claims

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Application Information

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IPC IPC(8): C07H17/00A61K31/70A61P31/04C07H17/08
CPCC07H17/00A61P31/00A61P31/04C07H17/08A61K31/70
Inventor N·库云季奇M·布克维奇卡加斯奇K·布拉耶萨
Owner PLIVA ISTRAZIVACKI INST D O O