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Acyl chloride and sulfonyl chloride derivant, and uses thereof

A compound and acetamide technology, applied in the field of acyl chloride and sulfonyl chloride isoxazoline derivatives and their preparation, can solve the problems of difficult clinical treatment, bacterial resistance and the like

Inactive Publication Date: 2010-12-22
TIANJIN INSTITUTE OF PHARMA RESEARCH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0002] In recent years, various types of antibiotics and antibacterial agents have developed rapidly, such as: methicillin-resistant Staphylococcus aureus (MRSA), methicillin-resistant Staphylococcus epidermidis (MRSE), penicillin-resistant Streptococcus pneumoniae (PRSP), The emergence of multidrug-resistant tuberculosis, especially vancomycin-resistant enterococci (VRE), has caused great difficulties in clinical treatment
[0003] Oxazolidinone antibacterial drugs are a new type of chemical fully synthetic antibacterial drugs. The representative of this class of drugs is linezolid approved by the US FDA in 2000. It is effective in the treatment of multi-drug resistant Gram-positive bacteria and Mycobacterium tuberculosis Infection shows a good effect. However, after several years of clinical use, there have been reports of drug-resistant bacteria. Therefore, people will continue to face the problem of bacterial drug resistance and need to develop new antibacterial drugs.

Method used

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  • Acyl chloride and sulfonyl chloride derivant, and uses thereof
  • Acyl chloride and sulfonyl chloride derivant, and uses thereof
  • Acyl chloride and sulfonyl chloride derivant, and uses thereof

Examples

Experimental program
Comparison scheme
Effect test

preparation example Construction

[0071] Reference example 1 (preparation of compound 6)

[0072]

[0073] Using 3,4-difluorobenzaldehyde as the starting material, react with hydroxylamine hydrochloride under strong alkaline conditions to generate 3,4-difluorobenzoxime, and then react with N-chlorosuccinimide to generate 3,4 - Chloride of difluorobenzoxime, followed by cyclization with allyl acetamide to generate (±)-N-5-(acetamidomethyl)-3-(3,4-difluorophenyl)isoxazoline , after reacting with anhydrous piperazine to generate (±)-N-[[3-[3-fluoro-4-(1-piperazinyl)phenyl]-4,5-dihydro-5-isoxazolyl ]methyl]acetamide (compound 6). m.p.160.2-161.3℃, HPLC99.7%, 1 H-NMR (DMSO-d 6 , 400MHz) δ: 8.11-8.08 (1H, t, NH), 7.377-7.337 (2H, m, ArH), 7.057-7.013 (1H, t, ArH), 4.722-4.650 (1H, m, CH), 3.458 -3.349(1H, m), 3.239-3.210(2H, t), 3.089-3.029(1H, m), 2.982-2.959(4H, t), 2.833-2.822(4H, d), 2.494-2.458(1H, t), 1.085 (3H, s).

Embodiment 1

[0075] (±)-N-[[3-[3-fluoro-4-[4-(p-fluorophenylacetyl)-1-piperazinyl]phenyl]-4,5-dihydro-5-isoxazole Base] methyl] acetamide (compound I-1)

[0076]

[0077] In a 100ml three-necked round-bottomed flask, add 3.7g of compound 6, 40ml of chloroform, and 5g of anhydrous potassium carbonate, cool in an ice bath to -5°C, and add 2.1g of p-fluorophenylacetyl chloride in portions under stirring, keeping The temperature is below 15°C. After the addition, it was raised to room temperature, reacted for about 30 minutes, and then slowly raised to reflux, reacted for about 2.5 hours, and was monitored by TLC to complete the reaction. Add 50ml of water to wash, separate the organic layer, dry over anhydrous sodium sulfate, and distill under reduced pressure to obtain 3.97g of white solid (I-1), Rf=0.48 (developing solvent: dichloromethane / anhydrous methanol (v:v)= 19:1), m.p.196.6-197.8°C, HPLC 98.4%.

Embodiment 2-8

[0079] Referring to the operation of Example 1, the difference is that an acid chloride compound with a different structure is used instead of p-fluorophenylacetyl chloride in Example 1, and reacted with compound 6 to obtain the following compound of formula I.

[0080]

[0081]

[0082] The physical and chemical constants of the obtained general formula I compound are as follows:

[0083] I-2: white solid, yield 52.8%. m.p.197.8-198.6°C, Rf=0.74 (developing solvent: dichloromethane / anhydrous methanol (v:v)=19:1), HPLC 98.8%.

[0084] I-3: white solid, yield 57.2%. m.p.199.81-200.9°C, Rf=0.52 (developing solvent: dichloromethane / anhydrous methanol (v:v)=19:1), HPLC 98.3%.

[0085] I-4: Pale yellow solid, yield 72.6%. m.p.143.2-144.9°C, Rf=0.55 (developing solvent: dichloromethane / anhydrous methanol (v:v)=19:1), HPLC 99.1%.

[0086] I-5: white solid, yield 74.1%. m.p.185.9-186.9°C, Rf=0.65 (developing solvent: dichloromethane / anhydrous methanol (v:v)=19:1), HPLC 98.6%....

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Abstract

The invention belongs to an infection related medical field, providing acyl chloride and sulfonyl chloride ixazoline derivatives provided with structures of a general formula (I) and a pharmaceutically acceptable salt for the derivatives: wherein, R1 in the formula equals to aryl, which comprises C3-C6 heterocyclic radical of sulfur, oxygen and nitrogen atom, aryl and heterocyclic radical (comprising C3-C6 heterocyclic radical of sulfur, oxygen and nitrogen atom); the aryl singly or multiply substituted by halogen, oxhydryl, carboxyl, azyl, nitryl, nitrile grouping, C1-C6 alkoxy, C1-C6 dialkylamino, C3-C6 naphthene base, C3-C6 heterocyclic radical, aryl, substituted aryl and other radicals, comprises C3-C6 heterocyclic radical of sulfur, oxygen, nitrogen atom, aryl and heterocyclic radical (C3-C6 heterocyclic radical of sulfur, oxygen and nitrogen atom); wherein, the definitions of R2, R3, and R4 are the same as described in the specification. A compound and the pharmaceutically acceptable slat as medicine, in particular to the function as antibacterial medicine are provided either.

Description

technical field [0001] The invention belongs to the field of infection-related medicines, and more specifically, relates to a new class of isoxazoline derivatives with antibacterial activity such as acid chlorides and sulfonyl chlorides and their preparation methods, pharmaceutical compositions containing them, and antibacterial drugs. the use of. Background technique [0002] In recent years, various types of antibiotics and antibacterial agents have developed rapidly, such as: methicillin-resistant Staphylococcus aureus (MRSA), methicillin-resistant Staphylococcus epidermidis (MRSE), penicillin-resistant Streptococcus pneumoniae (PRSP), The emergence of multidrug-resistant Mycobacterium tuberculosis, especially vancomycin-resistant enterococci (VRE), has brought great difficulties to clinical treatment. [0003] Oxazolidinone antibacterial drugs are a new type of chemical fully synthetic antibacterial drugs. The representative of this class of drugs is linezolid approved ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D261/04A61K31/496A61P31/04C07D413/10
Inventor 刘默刘登科刘颖徐为人张士俊张存彦王玉丽刘巍成碟汤立达
Owner TIANJIN INSTITUTE OF PHARMA RESEARCH