Thiophene carboxamides with ndm-1 inhibitory activity

Abstract

The invention provides a thiophene methanamide compound with a following general formula as shown in the specification, wherein R1 is selected from hydrogen, alkyl or halogen; and R2 is selected from C5-10 aralkyl, C5-10 aralkyl-C1-4 alkyl, 5-6 heterocyclic group, or 5-6 heterocyclic group-C1-4 alkyl, wherein the aralkyl or the heterocyclic group is un-substituted, or substituted by one or more groups selected from halogen, C1-4 alkyl, C1-4 alkoxy, or halogenated C1-4 alkyl. The compound is good in NDM-1 activity inhibition effect.

Description

technical field

[0001] The invention relates to the field of medicinal chemistry, in particular to thiophenecarboxamide compounds and their preparation methods and applications. Background technique

[0002] Antibiotics are a class of chemical substances produced by certain microorganisms in the course of life, which can inhibit or kill some other pathogenic microorganisms. It is also the main weapon for humans to resist bacterial infections. However, in August 2010, the famous medical journal "The Lancet" reported a case of resistance to all β-lactam antibiotics, insensitive to ciprofloxacin, and only sensitive to colistin. It carries a new type of metallo-beta-lactamase encoded by Klebsiella pneumoniae (Klebsiellapneumoniae), and this enzyme is named New Delhi metallo-beta-lactamase (NDM-1, New Delhimetallo-β-lactamase-1). This enzyme can exist in the DNA of Escherichia coli to make it widely resistant to drugs, and it is difficult for people to be cured or even die afte...

Examples

preparation example Construction

[0037] The starting materials used in the preparation of the compounds of the present invention are known, can be prepared according to known methods, or are commercially available.

[0038] Both intermediates and final products can be worked up and / or purified according to conventional methods, including pH adjustment, extraction, filtration, drying, concentration, chromatography, trituration, crystallization, and the like.

[0039] In addition, the compounds of the present invention can be prepared by various methods known in the art or variations on the methods described herein.

[0040] The following examples are only used to illustrate the present invention, and do not limit the present invention in any way.

Embodiment 1

[0041] The preparation of embodiment 1N-(4-bromo-3-fluorophenyl)-2-thiophenecarboxamide

[0042]

[0043] Put 2-thiophenecarboxylic acid (8mmol, 1.025g) into a 100ml flask, add thionyl chloride (28mmol, 3.331g), reflux for 30min, and evaporate the mixture under reduced pressure with a rotary evaporator (Shanghai Yarong) to remove thionyl chloride sulfone. Then the residue was placed in an ice bath, and 3-fluoro-4-bromoaniline (16 mmol, 3.04 g) and triethylamine (10 mmol, 1.012 g) dissolved in 15 ml of dichloromethane were slowly added to the residue, Reflux for 1h. with saturated NaHCO 3 Wash the reaction solution, separate the water phase until the pH of the water phase is approximately equal to 8, then wash the organic phase with 10ml of water, and wash it over anhydrous Na 2 SO 4 After drying and filtering, the filtrate was concentrated to dryness, and the residue was recrystallized from ethanol to obtain 2.08 g of the title compound with a yield of 87%. The compoun...

Embodiment 2

[0044] The preparation of embodiment 2N-(3-fluorobenzyl)-2-thiophene carboxamide

[0045]

[0046] Using 3-fluorobenzylamine instead of 3-fluoro-4-bromoaniline in Example 1, the same method as Example 1 was used to prepare this compound with a yield of 87%. The compound is a white powder, and its identification data are as follows: M.P.: 100.0-101.0°C; ESI-MSm / z: 236.22 ([M+H + ]); 1 HNMR (600MHz, CDCl 3 , δppm): 7.60 (s, 1H), 7.46 (s, 1H), 7.27-7.18 (m, 2H), 7.02 (m, 3H), 6.91 (m, 1H), 4.52 (s, 2H); 13 CNMR (150MHz, CDCl 3 ): 163.8, 162.1, 140.9, 138.7, 136.1, 135.6, 131.9, 130.2, 128.8, 127.7, 127.8, 114.4, 43.3.

technical field

[0001] The invention relates to the field of medicinal chemistry, in particular to thiophenecarboxamide compounds and their preparation methods and applications. Background technique

[0002] Antibiotics are a class of chemical substances produced by certain microorganisms in the course of life, which can inhibit or kill some other pathogenic microorganisms. It is also the main weapon for humans to resist bacterial infections. However, in August 2010, the famous medical journal "The Lancet" reported a case of resistance to all β-lactam antibiotics, insensitive to ciprofloxacin, and only sensitive to colistin. It carries a new type of metallo-beta-lactamase encoded by Klebsiella pneumoniae (Klebsiellapneumoniae), and this enzyme is named New Delhi metallo-beta-lactamase (NDM-1, New Delhimetallo-β-lactamase-1). This enzyme can exist in the DNA of Escherichia coli to make it widely resistant to drugs, and it is difficult for people to be cured or even die afte...

Examples

preparation example Construction

[0037] The starting materials used in the preparation of the compounds of the present invention are known, can be prepared according to known methods, or are commercially available.

[0038] Both intermediates and final products can be worked up and / or purified according to conventional methods, including pH adjustment, extraction, filtration, drying, concentration, chromatography, trituration, crystallization, and the like.

[0039] In addition, the compounds of the present invention can be prepared by various methods known in the art or variations on the methods described herein.

[0040] The following examples are only used to illustrate the present invention, and do not limit the present invention in any way.

Embodiment 1

[0041] The preparation of embodiment 1N-(4-bromo-3-fluorophenyl)-2-thiophenecarboxamide

[0042]

[0043] Put 2-thiophenecarboxylic acid (8mmol, 1.025g) into a 100ml flask, add thionyl chloride (28mmol, 3.331g), reflux for 30min, and evaporate the mixture under reduced pressure with a rotary evaporator (Shanghai Yarong) to remove thionyl chloride sulfone. Then the residue was placed in an ice bath, and 3-fluoro-4-bromoaniline (16 mmol, 3.04 g) and triethylamine (10 mmol, 1.012 g) dissolved in 15 ml of dichloromethane were slowly added to the residue, Reflux for 1h. with saturated NaHCO 3 Wash the reaction solution, separate the water phase until the pH of the water phase is approximately equal to 8, then wash the organic phase with 10ml of water, and wash it over anhydrous Na 2 SO 4 After drying and filtering, the filtrate was concentrated to dryness, and the residue was recrystallized from ethanol to obtain 2.08 g of the title compound with a yield of 87%. The compoun...

Embodiment 2

[0044] The preparation of embodiment 2N-(3-fluorobenzyl)-2-thiophene carboxamide

[0045]

[0046] Using 3-fluorobenzylamine instead of 3-fluoro-4-bromoaniline in Example 1, the same method as Example 1 was used to prepare this compound with a yield of 87%. The compound is a white powder, and its identification data are as follows: M.P.: 100.0-101.0°C; ESI-MSm / z: 236.22 ([M+H + ]); 1 HNMR (600MHz, CDCl 3 , δppm): 7.60 (s, 1H), 7.46 (s, 1H), 7.27-7.18 (m, 2H), 7.02 (m, 3H), 6.91 (m, 1H), 4.52 (s, 2H); 13 CNMR (150MHz, CDCl 3 ): 163.8, 162.1, 140.9, 138.7, 136.1, 135.6, 131.9, 130.2, 128.8, 127.7, 127.8, 114.4, 43.3.

Images