Imipenem derivant containing sulfonyl azetidine

An azetidine and aminosulfonyl technology, applied in the field of medicine, can solve the problems of inability to meet clinical needs, increased bacterial resistance and the like

Active Publication Date: 2010-02-17
XUANZHU BIOPHARMACEUTICAL CO LTD
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, due to the continuous increase of bacterial resistance due to e

Method used

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  • Imipenem derivant containing sulfonyl azetidine
  • Imipenem derivant containing sulfonyl azetidine
  • Imipenem derivant containing sulfonyl azetidine

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0123] Example 1 (4R, 5S, 6S)-3-[1-(azetidin-1-yl)sulfonyl-azetidin-3-yl]thio-6-[(1R)- 1-Hydroxyethyl Preparation of base]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid (compound 1)

[0124] Step 1 Preparation of 3-acetylthio-azetidine

[0125] In a dry reaction flask, add 6.9g (0.04mol) of 3-hydroxy-1-tert-butoxycarbonyl-azetidine and 9.2g (0.08mol) of potassium thioacetate, then add 20mL of DMF, stir and heat until dissolved Afterwards, keep the reaction for 12 hours, cool to room temperature, add 100 mL of water to dilute, extract with ethyl acetate, wash the organic phase with water, dry, and concentrate to obtain a yellow oil. Add 20 mL of dichloromethane to the oily substance, then add 10 mL of trifluoroacetic acid (TFA) dropwise at room temperature, stir overnight, TLC detects that the reaction is complete, concentrate, add 50 mL of dichloromethane to the residue, rotary evaporate to dryness, repeat several operations To remove the residual triflu...

Embodiment 2

[0137] Example 2 (4R, 5S, 6S)-3-[1-(aziridin-1-yl)sulfonyl-azetidin-3-yl]thio-6-[(1R)-1- Hydroxyethyl]-4-methyl Base-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid (Compound 2)

[0138] 1. With reference to step 1 in Example 1, 3-acetylthio-azetidine was prepared;

[0139] 2. Referring to step 2 in Example 1, 3-mercapto-1-(aziridin-1-yl)sulfonyl-azetidine was obtained;

[0140] 3. Refer to step 3 in Example 1 to prepare (4R, 5S, 6S)-3-[1-(aziridin-1-yl)sulfonyl-azetidin-3-yl]sulfanyl-6 -[(1R)-1-Hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate p-nitrobenzyl ester;

[0141] 4. Refer to step 4 in Example 1 to prepare compound 2.

[0142] Molecular formula: C 15 h 21 N 3 o 6 S 2 Molecular weight: 403.47 Mass spectrum (M+1): 404

[0143] Elemental Analysis: Found: C, 44.48%; H, 5.41%; N, 10.23%; S, 16.15%

[0144] Theoretical value: C, 44.65%; H, 5.25%; N, 10.41%; S, 15.89%

[0145] 1 H-NMR (δ / ppm, 300MHz, DMSO): 12.96 (1H, s), 4.96 ...

Embodiment 3

[0146] Example 3 (4R, 5S, 6S)-3-[1-(pyrrolidin-1-yl)sulfonyl-azetidin-3-yl]thio-6-[(1R)-1-hydroxy Ethyl]-4-methyl Preparation of yl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid (compound 3)

[0147] 1. With reference to step 1 in Example 1, 3-acetylthio-azetidine was prepared;

[0148] 2. Referring to step 2 in Example 1, 3-mercapto-1-(pyrrolidin-1-yl)sulfonyl-azetidine was obtained;

[0149] 3. Referring to step 3 in Example 1, (4R, 5S, 6S)-3-[1-(pyrrolidin-1-yl)sulfonyl-azetidin-3-yl]thio-6- [(1R)-1-Hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate p-nitrobenzyl ester;

[0150] 4. Refer to step 4 in Example 1 to prepare compound 3.

[0151] Molecular formula: C 17 h 25 N 3 o 6 S 2 Molecular weight: 431.53 Mass spectrum (M+1): 432

[0152] Elemental Analysis: Found: C, 47.16%; H, 6.01%; N, 9.58%; S, 14.98%

[0153] Theoretical value: C, 47.32%; H, 5.84%; N, 9.74%; S, 14.86%

[0154] 1H-NMR (δ / ppm, 300MHz, DMSO): 12.93 (1H, s),...

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Abstract

The invention belongs to the technical field of medicines, more particularly relates to imipenem derivant containing sulfonyl azetidine shown in a formula (I), acceptable salts in pharmacy, easily-hydrolyzed ester and a formula (II) of a midbody thereof, wherein R<1>, R<2>, R<3>, R<4> and R<5> are defined as a specification; and the invention also relates a preparation method of the compounds andthe midbody as well as the application of the compounds in the preparation of medicines for treating and/or preventing infectious diseases.

Description

1. Technical field [0001] The invention belongs to the technical field of medicine, and specifically relates to penem derivatives containing sulfonyl azetidine, pharmaceutically acceptable salts thereof, easily hydrolyzed esters and intermediates thereof, and methods for preparing these compounds and intermediates thereof , a pharmaceutical composition containing these compounds, and the use of these compounds in the preparation of medicines for treating and / or preventing infectious diseases. 2. Background technology [0002] Carbapenem antibiotics are a class of β-lactam antibiotics developed in the 1970s. It has attracted much attention because of its broad antibacterial spectrum, strong antibacterial activity, and stability to β-lactamase. Drugs of this type currently on the market include imipenem, meropenem, doripenem, biapenem, ertapenem, etc. Clinical studies include tipipenem, CS-023 and so on. [0003] Imipenem is the first carbapenem antibiotic on the market. It...

Claims

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Application Information

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IPC IPC(8): C07D477/20A61K31/407A61K31/4178A61K31/4155A61K31/454A61K31/541A61K31/5377A61K31/496A61P31/00C07D477/06
Inventor 谭晓娟郑立稳
Owner XUANZHU BIOPHARMACEUTICAL CO LTD
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