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Monocyclic lactam compound and applications thereof

A compound and solvate technology, applied in the field of medicinal chemistry, can solve the problems of weak activity and restricted use of Pseudomonas and Acinetobacter

Active Publication Date: 2020-05-19
NANJING SANHOME PHARMACEUTICAL CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although they are not easily hydrolyzed by MBLs, their clinical use is also limited due to their weak activity against Pseudomonas and Acinetobacter

Method used

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  • Monocyclic lactam compound and applications thereof
  • Monocyclic lactam compound and applications thereof
  • Monocyclic lactam compound and applications thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0129] Example 1: (S)-3-((Z)-2-(((S)-2-(4-((1-(3-aminopropyl)-2-(azetidine-3 -ylmethyl)-1H-pyrazol-2-onium-4-yl)carbamoyl)phenoxy)-1-carboxyethoxy)imino)-2-(2-aminothiazol-4-yl )acetamido)-2,2-dimethyl-4-oxoazetidine-1-yl sulfate

[0130]

[0131] Step 1: Preparation of tert-butyl (R)-(1,3-dihydroxy-3-methylbutan-2-yl)carbamate

[0132]

[0133] Under nitrogen protection, (tert-butoxycarbonyl)-D-serine methyl ester (70g, 0.32mol) was dissolved in tetrahydrofuran (2L), at -78°C, methylmagnesium bromide (500mL, 0.166mol, 3.0M) was added, After the addition, the temperature was raised to room temperature, and the reaction was carried out at room temperature for 2 hours. After the reaction was monitored by thin layer chromatography, saturated aqueous ammonium chloride solution was added to quench the reaction. Ethyl acetate was added for extraction, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrat...

Embodiment 2

[0197] Example 2: (S)-3-((Z)-2-(((S)-2-(4-(1-(3-aminopropyl)-2-(azetidine-3- ylmethyl)-1H-pyrazole-2-onium-4-carboxamido)phenoxy)-1-carboxyethoxy)imino)-2-(2-aminothiazol-4-yl)acetamide yl)-2,2-dimethyl-4-oxoazetidine-1-yl sulfate

[0198]

[0199] Step 1: Preparation of (R)-tert-butyl 3-(4-nitrophenoxy)-2-hydroxypropionate

[0200]

[0201] The preparation method is the same as the preparation method of steps 12-14 in Example 1, except that p-bromophenol is replaced by p-nitrophenol to obtain the title compound.

[0202] Step 2: Preparation of (R)-tert-butyl 3-(4-aminophenoxy)-2-hydroxypropanoate

[0203]

[0204] In a 100mL single-necked flask, (R)-tert-butyl 3-(4-bromophenoxy)-2-hydroxypropionate (3.1 g, 11 mmol) was dissolved in methanol (85 mL), and 10% wet palladium on carbon ( 320 mg), replaced by hydrogen 3 times, and stirred at room temperature for 6 h. After the reaction was completed, suction filtration, the filtrate was spin-dried to make sand, and the...

Embodiment 3

[0214]Example 3: (3S)-3-((Z)-2-(((1S)-2-(4-(2-(3-aminopropoxy)-2,3-dihydro-1H-pyridine azolo[1,2-a]pyrazol-4-onium-6-yl)phenoxy)-1-carboxyethoxy)imino)-2-(2-aminothiazol-4-yl)acetamide yl)-2,2-dimethyl-4-oxoazetidine-1-yl sulfate

[0215]

[0216] Step 1: Preparation of 6-bromo-2-hydroxy-2,3-dihydro-1H-pyrazolo[1,2-a]pyrazol-4-bromonium

[0217]

[0218] In a 100 mL single-neck flask, 4-bromopyrazole (2.94 g, 20 mmol) and epibromopropane (2.74 g, 20 mmol) were dissolved in DMF (30 mL), and heated and stirred at 100° C. overnight. After the reaction, most of the N,N-dimethylformamide was removed by rotation, methyl tert-butyl ether was added, and a yellow-white solid was precipitated; the title product was obtained by suction filtration and drying. ESI-MS m / z: 204.1[M] + .

[0219] Step 2: 6-Bromo-2-(3-((tert-butoxycarbonyl)amino)propoxy)-2,3-dihydro-1H-pyrazolo[1,2-a]pyrazol-4- Preparation of Onium

[0220]

[0221] In a 100 mL three-necked flask, dissolve 6-bro...

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Abstract

The invention belongs to the field of medical chemistry, and relates to a class of monocyclic lactam compounds and applications thereof, and particularly provides a compound represented by a formula (I) or an isomer, a pharmaceutically acceptable salt, a solvate, a crystal or a prodrug thereof, and a preparation method thereof, pharmaceutical compositions containing the compounds, and applicationsof the compounds or the compositions in treatment of bacterial infection. The compound provided by the invention has excellent antibacterial activity and is hopeful to become a therapeutic agent forbacterial infection.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, in particular to a class of monocyclic lactam compounds or isomers, pharmaceutically acceptable salts, solvates, crystals or prodrugs, their preparation methods and pharmaceutical compositions containing these compounds and Use of these compounds or compositions for the treatment of bacterial infections. Background technique [0002] The discovery and use of antibiotics, as one of the greatest medical achievements of the 20th century, saved countless lives. But in the past few decades, the emergence of drug-resistant bacteria is seriously threatening the safety of people's lives. [0003] Beta-lactam antibiotics are one of the most commonly used antibiotics, and their resistance is gradually emerging. In most Gram-negative bacteria, resistance to β-lactam antibiotics is driven primarily by β-lactamases, which hydrolyze β-lactams and lead to antibiotic inactivation. There are four β-lactamase...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D417/14C07D487/04C07D471/04A61P31/04A61K31/427A61K31/4439A61K31/437A61K31/4709
CPCC07D417/14C07D487/04C07D471/04A61P31/04A61K31/427A61K31/4439A61K31/496A61K31/4725A61K31/551Y02A50/30A61K2300/00
Inventor 王勇赵立文王亚洲全旭王小伟张晓平吕坤志林泽琦张健许涛常玉杰
Owner NANJING SANHOME PHARMACEUTICAL CO LTD