Application of 3-mercaptopropionamides in inhibiting ndm-1 activity

Abstract

The invention provides 3-sulfydryl propanamide compound having a following general formula (I), a preparation method of the 3-sulfydryl propanamide compound and application of the 3-sulfydryl propanamide compound. R1 is hydrogen or C1-C4 alkyl, R2 is hydrogen or C1-C4 alkyl, and R3 is C1-C4 alkyl. The 3-sulfydryl propanamide compound has the good function for restraining new delhi metallo (NDM)-1 activity.

Description

technical field

[0001] The present invention relates to the field of pharmacy, in particular to 3-mercaptopropionamide compounds, their preparation method and application. Background technique

[0002] In the 1950s and 1960s, known as the "golden age" of antibiotics, about 7 million people died of infectious diseases worldwide every year, and this figure rose to 20 million by 1999. The main reason for the increase in the fatality rate is the difficulty in medication brought by drug-resistant bacteria.

[0003] At present, the problem of bacterial resistance has become very serious. In developed countries, 5% to 10% of hospitalized patients have one or more infections. There are about 2 million patients with nosocomial infection in the United States every year, 90,000 people die, and the economic loss reaches 4.5 billion to 5.7 billion US dollars. In developing countries, the risk of nosocomial infection is 2 to 20 times higher than in developed countries. The incidence r...

Examples

Embodiment 1

[0053] Example 1 3-mercapto-N-methoxy-N,2-dimethylpropionamide

[0054]

[0055] At room temperature (20°C-30°C), the compound 3-acetylsulfanyl-N-methoxy-N,2-dimethylpropanamide (100.15mg, 0.49mmol) obtained in Preparation 1 above was dissolved into 10ml of methanol, then added sodium bicarbonate (45.02mg, 0.54mmol), and reacted at room temperature (20°C to 30°C) for 8 hours, then spin-dried the methanol, dissolved the residue in water (15ml), and washed with petroleum ether (3*20ml) extraction, then the aqueous phase was adjusted to pH=6 with 5% aqueous citric acid solution, extracted with ethyl acetate (3*20ml), the ethyl acetate phases were combined, dried over anhydrous magnesium sulfate, filtered, Purified by silica gel column chromatography (petroleum ether: ethyl acetate = 15:1) to obtain 60.31 mg of the title compound with a yield of 75.84%. Its hydrogen spectrum data are as follows: 1 H-NMR (400MHz, CDCl 3 ): δppm 3.731(s, 3H), 3.138(q, 1H), 3.092(q, 1H), 2.730(...

Embodiment 2

[0056] Example 2 3-mercapto-N-methoxy-2-methylpropionamide

[0057]

[0058] At room temperature (20°C to 30°C), the compound 3-acetylsulfanyl-N-methoxy-2-methylpropionamide (100.02 mg, 0.52 mmol) obtained in Preparation 2 above was dissolved in 10 ml of methanol , then add sodium bicarbonate (87.85mg, 1.05mmol), react at room temperature for 4 hours, then spin dry methanol, dissolve the residue in 15ml water, extract with petroleum ether (3*20ml), and then use 5% KHSO 4The aqueous solution was adjusted to pH = 6, extracted with ethyl acetate (3*20ml), the ethyl acetate phase was combined, dried over anhydrous magnesium sulfate, filtered, and subjected to silica gel column chromatography (petroleum ether: ethyl acetate = 15:1) Purification afforded 61.12 mg of the title compound with a yield of 78.33%. Its hydrogen spectrum data are as follows: 1 H-NMR (600MHz, CDCl 3 ): δppm8.372(s, 1H), 3.801(s, 3H), 2.879(m, 1H), 2.568(d, 1H), 2.290(t, 1H), 1.593(s, 1H), 1.272(d, 3H...

Embodiment 3

[0059] Embodiment 3 (S)-3-mercapto-N-methoxy-N,2-dimethylpropionamide

[0060]

[0061] At room temperature (20°C~30°C), the compound (S)-3-acetylsulfanyl-N-methoxy-N,2-dimethylpropanamide (100.08mg, 0.49 mmol) was dissolved in 10ml of methanol, then sodium bicarbonate (45.02mg, 0.54mmol) was added, reacted at room temperature for 8 hours, then the methanol was spin-dried, the residue was dissolved in 15ml of water, and extracted with petroleum ether (3*20ml) Impurities, then the aqueous phase was adjusted to pH=6 with 5% aqueous citric acid solution, extracted with ethyl acetate (3*20ml), the ethyl acetate phases were combined, dried over anhydrous magnesium sulfate, filtered, and the filtrate was spin-dried, 48.32 mg of the title compound were obtained, yield 60.76%. Its hydrogen spectrum data are as follows: 1 H-NMR (400MHz, CDCl 3 ): δppm 3.741(s, 3H), 3.211(s, 3H), 3.074(t, 1H), 2.884(q, 1H), 2.433(m, 1H), 1.532(s, 1H), 1.196(d, 3H ).

technical field

[0001] The present invention relates to the field of pharmacy, in particular to 3-mercaptopropionamide compounds, their preparation method and application. Background technique

[0002] In the 1950s and 1960s, known as the "golden age" of antibiotics, about 7 million people died of infectious diseases worldwide every year, and this figure rose to 20 million by 1999. The main reason for the increase in the fatality rate is the difficulty in medication brought by drug-resistant bacteria.

[0003] At present, the problem of bacterial resistance has become very serious. In developed countries, 5% to 10% of hospitalized patients have one or more infections. There are about 2 million patients with nosocomial infection in the United States every year, 90,000 people die, and the economic loss reaches 4.5 billion to 5.7 billion US dollars. In developing countries, the risk of nosocomial infection is 2 to 20 times higher than in developed countries. The incidence r...

Examples

Embodiment 1

[0053] Example 1 3-mercapto-N-methoxy-N,2-dimethylpropionamide

[0054]

[0055] At room temperature (20°C-30°C), the compound 3-acetylsulfanyl-N-methoxy-N,2-dimethylpropanamide (100.15mg, 0.49mmol) obtained in Preparation 1 above was dissolved into 10ml of methanol, then added sodium bicarbonate (45.02mg, 0.54mmol), and reacted at room temperature (20°C to 30°C) for 8 hours, then spin-dried the methanol, dissolved the residue in water (15ml), and washed with petroleum ether (3*20ml) extraction, then the aqueous phase was adjusted to pH=6 with 5% aqueous citric acid solution, extracted with ethyl acetate (3*20ml), the ethyl acetate phases were combined, dried over anhydrous magnesium sulfate, filtered, Purified by silica gel column chromatography (petroleum ether: ethyl acetate = 15:1) to obtain 60.31 mg of the title compound with a yield of 75.84%. Its hydrogen spectrum data are as follows: 1 H-NMR (400MHz, CDCl 3 ): δppm 3.731(s, 3H), 3.138(q, 1H), 3.092(q, 1H), 2.730(...

Embodiment 2

[0056] Example 2 3-mercapto-N-methoxy-2-methylpropionamide

[0057]

[0058] At room temperature (20°C to 30°C), the compound 3-acetylsulfanyl-N-methoxy-2-methylpropionamide (100.02 mg, 0.52 mmol) obtained in Preparation 2 above was dissolved in 10 ml of methanol , then add sodium bicarbonate (87.85mg, 1.05mmol), react at room temperature for 4 hours, then spin dry methanol, dissolve the residue in 15ml water, extract with petroleum ether (3*20ml), and then use 5% KHSO 4The aqueous solution was adjusted to pH = 6, extracted with ethyl acetate (3*20ml), the ethyl acetate phase was combined, dried over anhydrous magnesium sulfate, filtered, and subjected to silica gel column chromatography (petroleum ether: ethyl acetate = 15:1) Purification afforded 61.12 mg of the title compound with a yield of 78.33%. Its hydrogen spectrum data are as follows: 1 H-NMR (600MHz, CDCl 3 ): δppm8.372(s, 1H), 3.801(s, 3H), 2.879(m, 1H), 2.568(d, 1H), 2.290(t, 1H), 1.593(s, 1H), 1.272(d, 3H...

Embodiment 3

[0059] Embodiment 3 (S)-3-mercapto-N-methoxy-N,2-dimethylpropionamide

[0060]

[0061] At room temperature (20°C~30°C), the compound (S)-3-acetylsulfanyl-N-methoxy-N,2-dimethylpropanamide (100.08mg, 0.49 mmol) was dissolved in 10ml of methanol, then sodium bicarbonate (45.02mg, 0.54mmol) was added, reacted at room temperature for 8 hours, then the methanol was spin-dried, the residue was dissolved in 15ml of water, and extracted with petroleum ether (3*20ml) Impurities, then the aqueous phase was adjusted to pH=6 with 5% aqueous citric acid solution, extracted with ethyl acetate (3*20ml), the ethyl acetate phases were combined, dried over anhydrous magnesium sulfate, filtered, and the filtrate was spin-dried, 48.32 mg of the title compound were obtained, yield 60.76%. Its hydrogen spectrum data are as follows: 1 H-NMR (400MHz, CDCl 3 ): δppm 3.741(s, 3H), 3.211(s, 3H), 3.074(t, 1H), 2.884(q, 1H), 2.433(m, 1H), 1.532(s, 1H), 1.196(d, 3H ).

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