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Mercaptonicotinic acid compounds and preparation method thereof

A technology of mercaptonicotinic acid and compound, applied in the field of medicine, can solve problems such as activity improvement, cross-inhibition effect to be improved, etc.

Inactive Publication Date: 2013-08-28
SECOND MILITARY MEDICAL UNIV OF THE PEOPLES LIBERATION ARMY +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

These reported compounds have inhibitory effects on the toxin light chain in vitro, and some compounds also have inhibitory effects at the level of the whole toxin and animal models, but there is still room for improvement in activity
In addition, most of the compounds reported so far have toxin-specific inhibitory activity, but the cross-inhibition effect needs to be improved

Method used

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  • Mercaptonicotinic acid compounds and preparation method thereof
  • Mercaptonicotinic acid compounds and preparation method thereof
  • Mercaptonicotinic acid compounds and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0075] Embodiment 1, the synthesis of 2-(2-(5-chloro-2-methoxyanilino) acetylthio) sodium nicotinate (formula Ⅰ-1)

[0076]

[0077] (Formula Ⅰ-1)

[0078] Dissolve 3.14 g (0.02 mol) of 2-methoxy-5-chloroaniline in 30 ml of glacial acetic acid, add dropwise 2.5 g (0.02 mol) of chloroacetyl chloride, and stir overnight at room temperature. Then the reaction solution was poured into 50 ml of ice water, stirred for 1 hour, a solid was precipitated, filtered, washed with water, and dried to obtain a crude product.

[0079] Add the product from the previous step and 1.55 grams (0.01mol) of 2-mercaptonicotinic acid into 25 milliliters of THF and water mixed solution (volume ratio 1:1), cool to 0 degrees, add 1.6 grams of sodium hydroxide, stir the reaction, and raise the temperature After stirring overnight at room temperature, a large amount of solids precipitated, filtered, washed with water, and dried to obtain 3.55 g of off-white solids with a yield of 86%.

[0080] The res...

Embodiment 2

[0083] Embodiment 2, the synthesis of 2-(2-(5-chloro-2-methoxyanilino) acetylthio) nicotinic acid (formula Ⅰ-2)

[0084]

[0085] (Formula Ⅰ-2)

[0086] Put sodium 2-(2-(5-chloro-2-methoxyanilino)-2-acetylthio)nicotinate prepared in Example 1 in water, then adjust the pH value to 2 with 1M hydrochloric acid, and filter , washed with water, and dried to obtain a white solid with a yield of 97%.

[0087] The structure confirmation results are as follows: 1H-NMR (DMSO-d6): 13.56 (s, 1H), 9.75 (s, 1H), 8.69-8.70 (m, 1H), 8.29-8.30 (m, 1H), 8.19 (d, 1H),7.35-7.37(m,1H),7.01-7.08(m,2H),4.02(s,2H),3.79(s,3H).EI-MS:m / z:375.4[M+H]+ .

[0088] After identification, the obtained product is indeed the target compound formula Ⅰ-2.

Embodiment 3

[0089]Example 3, Synthesis of 2-(2-(5-chloro-2-methoxyanilino) acetylthio) potassium nicotinate (formula Ⅰ-3)

[0090]

[0091] (Formula Ⅰ-3)

[0092] Dissolve 3.14 g of 2-methoxy-5-chloroaniline in 30 ml of glacial acetic acid, add dropwise 2.5 g of chloroacetyl chloride, stir overnight at room temperature, then pour the reaction solution into 50 ml of ice water, stir for 1 hour, and precipitate a solid , filtered, washed with water, and dried to obtain a crude product.

[0093] Add the product from the previous step and 1.55 grams of 2-mercaptonicotinic acid into 25 milliliters of THF and water mixed solution (volume ratio 1:1), cool to 0 degrees, add 2.0 grams of potassium hydroxide, stir the reaction, warm up to room temperature, and stir Overnight, a large amount of solids precipitated, filtered, washed with water, and dried in vacuo to obtain 2.62 g of off-white solids with a yield of 67%.

[0094] The results of structural confirmation are as follows:

[0095] 1H-...

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Abstract

The invention belongs to the technical field of medicine, and provides substituted mercaptonicotinic acid compounds and a preparation method thereof. The structural general formula of the compounds is shown as formula I described in the specification, and the compounds comprise a pharmaceutically acceptable salt, ester and solvate. A substituted aniline compound is used as a raw material and reacted with chloroacetyl chloride or bromoacetyl chloride to generate amide, and then the amide is reacted with a mercapto-substituted nicotinic acid or isonicotinic acid compound to obtain the mercaptonicotinic acid compounds. The invention further provides an application of the compounds in a medicament.

Description

technical field [0001] The invention belongs to the technical field of medicine, and in particular relates to a class of mercaptonicotinic acid compounds and a preparation method thereof. Background technique [0002] Clostridium bacterial toxins include botulinum neurotoxin and tetanus toxin. Tetanus toxin is produced by Clostridium tetani in an anaerobic environment and can cause tetanus clinically. Clostridium Botulinum Neurotoxins (Clostridium Botulinum Neurotoxins, referred to as botulinum toxin) is a group of known most virulent proteins (including A-G types), mainly produced by Clostridium botulinum in an anaerobic environment. The median lethal dose for intravenous injection is about 1ng / kg, and the median lethal dose for inhalation is about 3ng / kg. Common botulinum toxin poisoning occurs mainly due to the consumption of contaminated food, wound infection toxin into the body, and the digestion of toxin precursors in the intestinal tract of infants to produce active...

Claims

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Application Information

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IPC IPC(8): C07D213/80C07D213/79C07D213/803A61K31/455A61P39/02A61P31/04
Inventor 张万年王慧缪震元李涛吴岳林王琴盛春泉罗森姚建忠刘雄
Owner SECOND MILITARY MEDICAL UNIV OF THE PEOPLES LIBERATION ARMY
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