Five-membered heterocyclic dicarbonyl derivative and application thereof on multi-drug resistant bacteria

Abstract

The invention relates to the field of pharmaceutical chemistry, in particular to a five-membered heterocyclic dicarbonyl derivative (I) and application thereof on multi-drug resistant bacteria. Pharmacology experiments prove that the multi-drug resistant bacteria can be well inhibited through combined use of the compound in the invention and antibiotic.

Description

technical field

[0001] The invention relates to the field of medicinal chemistry, in particular to a class of five-membered heterocyclic biscarbonyl derivatives and their application in anti-multidrug-resistant bacteria. Background technique

[0002] Antibiotics are a class of antibacterial and microbial drugs that are widely used clinically and used in large quantities. Since penicillin was used clinically in 1940, it has played an important role in controlling and treating diseases. At present, there are many kinds of antibacterial and microbial drugs used clinically, but with the large number of antibiotics, they are widely used, especially in clinical irrational application, and even abused, which eventually leads to the emergence of a large number of drug-resistant bacteria. In particular, the recent emergence of NDM-1 super bacteria has attracted global attention and tension. Metallo-1, NDM-1) is famous, the gene produces a special β-lactamase, its activity requires t...

Examples

Embodiment 1

[0045] 4-Methyl-2-acetyl-5-propionyl-3-hydroxyfuran (CPU-ZH 003)

[0046]Add 9ml (0.1mol) of propionyl chloride, 8.8ml (0.1mol) of 1-hydroxy-2-butanone and 14g of potassium carbonate (0.1mol) into a 100ml three-necked flask, stir electromagnetically, and react under reflux at 80°C for 6 hours. Raise the reaction temperature to 110°C, slowly drop 8.5ml (0.1mol) of 2-oxopropionic acid into the reaction solution, and continue the reaction for 10 hours after the addition. Suction filtration, the reaction solution was concentrated under reduced pressure, and the remaining liquid was extracted with ethyl acetate. Concentrate and dry to obtain 10.56 g of solid, with a total yield of 53.86%.

[0047] Molecular formula: C 10 h 12 o 4 , molecular weight: 196.20

[0048] MS (EI) m / z 196.

[0049] 1 H-NMR (AV-500, δ, DMSO-d 6 ): 1.15(t, 3H); 1.92(s, 3H); 2.48(s, 3H); 3.75(q, 2H); 5.40(s, 1H)

Embodiment 2

[0051] 3-((1-H-1,2,4-triazolyl)methylene)-2-acetyl-3-hydroxy-pyrrolecarboxylic acid (CPU-ZH 008)

[0052] Add 11.6g (0.1mol) of sodium chloroacetate, 7.5ml (0.1mol) of 1-amino-2-propanone and 14g of potassium carbonate (0.1mol) into a 100ml three-necked flask, stir it electromagnetically, and reflux at 95°C for 6 hours , raise the reaction temperature to 110°C, slowly drop 15 g (0.1 mol) of 1-H-1,2,4-triazolyl-2-oxopropionic acid into the reaction liquid, react overnight, add concentrated hydrochloric acid to The pH of the solution was about 4.0. After suction filtration, the reaction solution was concentrated under reduced pressure, and the remaining liquid was extracted with a mixed organic solvent of ethyl acetate:chloroform=3:1. Concentrate and dry to obtain 18.14 g of solid, with a total yield of 71.13%.

[0053] Molecular formula: C 10 h 10 N 4 o 4 , molecular weight: 250.22

[0054] MS (EI) m / z 249 (M-1).

[0055] 1 H-NMR (AV-500, δ, DMSO-d 6 ):2.08(t,3H);5.02...

Embodiment 3

[0057] Dimethyl 3,4-dibenzyloxy-2,5-thiophenedicarboxylate (CPU-ZH 016)

[0058] Add 8ml (0.1mol) of acetyl chloride, 0.1mol of 1-mercapto-2-acetone, 200ml of DMF and 14g of potassium carbonate (0.1mol) into a 250ml three-necked flask, stir it electromagnetically, react at 40°C for 3 hours, and raise the reaction temperature To 85°C, 27 g (0.1 mol) of dibenzyl oxalate was slowly added to the reaction liquid, and the reaction was carried out for 5 hours. Suction filtration, the reaction solution was concentrated under reduced pressure, and the remaining liquid was extracted with chloroform. Concentrate and dry to obtain 20.14 g of solid, with a total yield of 53.02%.

[0059] Molecular formula: C 22 h 20 o 6 S, molecular weight: 412.47

[0060] MS(EI)m / z 435.1(M+23)

[0061] 1 H-NMR (AV-500, δ, DMSO-d 6 ): 3.00(s, 3H); 5.16(s, 2H); 7.24-7.41(m, 5H); 7.83(s, 2H)

technical field

[0001] The invention relates to the field of medicinal chemistry, in particular to a class of five-membered heterocyclic biscarbonyl derivatives and their application in anti-multidrug-resistant bacteria. Background technique

[0002] Antibiotics are a class of antibacterial and microbial drugs that are widely used clinically and used in large quantities. Since penicillin was used clinically in 1940, it has played an important role in controlling and treating diseases. At present, there are many kinds of antibacterial and microbial drugs used clinically, but with the large number of antibiotics, they are widely used, especially in clinical irrational application, and even abused, which eventually leads to the emergence of a large number of drug-resistant bacteria. In particular, the recent emergence of NDM-1 super bacteria has attracted global attention and tension. Metallo-1, NDM-1) is famous, the gene produces a special β-lactamase, its activity requires t...

Examples

Embodiment 1

[0045] 4-Methyl-2-acetyl-5-propionyl-3-hydroxyfuran (CPU-ZH 003)

[0046]Add 9ml (0.1mol) of propionyl chloride, 8.8ml (0.1mol) of 1-hydroxy-2-butanone and 14g of potassium carbonate (0.1mol) into a 100ml three-necked flask, stir electromagnetically, and react under reflux at 80°C for 6 hours. Raise the reaction temperature to 110°C, slowly drop 8.5ml (0.1mol) of 2-oxopropionic acid into the reaction solution, and continue the reaction for 10 hours after the addition. Suction filtration, the reaction solution was concentrated under reduced pressure, and the remaining liquid was extracted with ethyl acetate. Concentrate and dry to obtain 10.56 g of solid, with a total yield of 53.86%.

[0047] Molecular formula: C 10 h 12 o 4 , molecular weight: 196.20

[0048] MS (EI) m / z 196.

[0049] 1 H-NMR (AV-500, δ, DMSO-d 6 ): 1.15(t, 3H); 1.92(s, 3H); 2.48(s, 3H); 3.75(q, 2H); 5.40(s, 1H)

Embodiment 2

[0051] 3-((1-H-1,2,4-triazolyl)methylene)-2-acetyl-3-hydroxy-pyrrolecarboxylic acid (CPU-ZH 008)

[0052] Add 11.6g (0.1mol) of sodium chloroacetate, 7.5ml (0.1mol) of 1-amino-2-propanone and 14g of potassium carbonate (0.1mol) into a 100ml three-necked flask, stir it electromagnetically, and reflux at 95°C for 6 hours , raise the reaction temperature to 110°C, slowly drop 15 g (0.1 mol) of 1-H-1,2,4-triazolyl-2-oxopropionic acid into the reaction liquid, react overnight, add concentrated hydrochloric acid to The pH of the solution was about 4.0. After suction filtration, the reaction solution was concentrated under reduced pressure, and the remaining liquid was extracted with a mixed organic solvent of ethyl acetate:chloroform=3:1. Concentrate and dry to obtain 18.14 g of solid, with a total yield of 71.13%.

[0053] Molecular formula: C 10 h 10 N 4 o 4 , molecular weight: 250.22

[0054] MS (EI) m / z 249 (M-1).

[0055] 1 H-NMR (AV-500, δ, DMSO-d 6 ):2.08(t,3H);5.02...

Embodiment 3

[0057] Dimethyl 3,4-dibenzyloxy-2,5-thiophenedicarboxylate (CPU-ZH 016)

[0058] Add 8ml (0.1mol) of acetyl chloride, 0.1mol of 1-mercapto-2-acetone, 200ml of DMF and 14g of potassium carbonate (0.1mol) into a 250ml three-necked flask, stir it electromagnetically, react at 40°C for 3 hours, and raise the reaction temperature To 85°C, 27 g (0.1 mol) of dibenzyl oxalate was slowly added to the reaction liquid, and the reaction was carried out for 5 hours. Suction filtration, the reaction solution was concentrated under reduced pressure, and the remaining liquid was extracted with chloroform. Concentrate and dry to obtain 20.14 g of solid, with a total yield of 53.02%.

[0059] Molecular formula: C 22 h 20 o 6 S, molecular weight: 412.47

[0060] MS(EI)m / z 435.1(M+23)

[0061] 1 H-NMR (AV-500, δ, DMSO-d 6 ): 3.00(s, 3H); 5.16(s, 2H); 7.24-7.41(m, 5H); 7.83(s, 2H)

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