JPS6058911B2 - Isonicotinic acid hydrazide derivative and method for producing the same - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention is based on the general formula δHN:CH center (I) [wherein R is substituted with a lower dialkylamino group, an alicyclic amino group, a morpholino group, or a lower alkyl group, which may or may not be substituted with a hydroxyl group. The present invention relates to a novel isonicotinic acid hydrazide derivative represented by the following formula (representing a piperazino group) and a method for producing the same.

The novel isonicotinic acid hydrazide derivatives of the present invention have strong antibacterial activity against pathogenic bacteria, particularly Mycobacterium tuberculosis, and are useful for the treatment of tuberculosis.

The novel compound (1) of the present invention can be produced by the method shown below.

[However, in the formula, R has the same meaning as defined above, and x represents a halogen] That is, according to the method for producing the new compound of the present invention, o-formylbenzenesulfonyl halide (■) and a hydroxyl group are substituted. Compound (■) is obtained by reacting with a secondary amine from the group of lower dialkylamines, alicyclic amines, morpholine, and piperazines substituted or unsubstituted with lower alkyl groups, and then compound (■) is converted into isonicotinic acid hydrazide. The novel isonicotinic acid hydrazide derivative (1) can be obtained by reacting with

The o-formylbenzenesulfonyl halide (■) used as a starting material in the method for producing the compound of the present invention is a known compound, for example, Canadian Journal of Chemistry, No. 4, p. 943, 1971.
It is listed in the year etc. As X in formula (■), F, . C
1, Br and I may be mentioned. Further, the secondary amines of the present invention include the following compounds. A compound can be used.

(1) Lower dialkylamine substituted or unsubstituted with a hydroxyl group, where the lower alkyl group has 1 to 8 carbon atoms.
The following alkyl groups can be mentioned. Specific examples of the above amines include dimethylamine, diethylamine, dipro-
Examples include biruamine, dibutylamine, dioctylamine, diethanolamine, and dipropanolamine. (2) Alicyclic amines, specifically pyrrolidine, piperidine and the like. (3) Morpholine. (4) Piperazine substituted or unsubstituted with a lower alkyl group, where the lower alkyl group has 1 to 1 carbon atoms.
8 alkyl groups may be mentioned. Specific examples of the piperazines mentioned above include piperazine, N-methylpiperazine, N-ethylpiperazine, N-propylpiperazine,
N-butylpiperazine, N-hexylpiperazine, N-
Octylpiperazine and the like can be mentioned. For the reaction between 0-formylbenzenesulfonyl halide (■) and secondary amines, 1 mol or more of the secondary amine is used per 1 mol of o-formylbenzenesulfonyl halide (■).

The reaction is usually carried out at a temperature of about -10 to 30°C, preferably about -10 to 5°C. The reaction solvent is not particularly limited as long as it does not participate in this reaction, but examples include chloroform, dichloromethane, dichloroethane,
Preferably, aprotic polar solvents such as nitromethane, dioxane, etc. are used. The reaction is usually carried out in the presence of a de-hydrogenating agent, but it can be substituted by adding an excess of secondary amines as raw materials. The dehydrohalogenating agents used include triethylamine, trimethylamine,
A tertiary amine such as pyridine or picoline is used, and usually 1 mole or more is used per mole of o-formylbenzenesulfonyl halide (■), but pyridine, picoline, etc. can also be used as a solvent. The reaction time is usually between about 1 and 1 C@. The reaction between the reaction intermediate (■) and isonicotinic acid hydrazide is usually carried out after isolation of the intermediate (■), but it can also be carried out without isolation.

When the reaction is continued without isolating the intermediate, a protic polar solvent such as methanol or ethanol is appropriately added in consideration of the solubility of isonicotinic acid hydrazide. Although the reaction usually proceeds satisfactorily at room temperature, the reaction time can be shortened by heating. The solvent is not particularly limited as long as it does not participate in the reaction, but examples include water, alcohols such as methanol and ethanol, ethers such as diethyl ether and dioxane, halogenated hydrocarbons such as chloroform, dichloromethane and dichloroethane, or pyridine. , and amines such as picoline. Usually, it is preferable to use a protic polar solvent such as methanol or ethanol. Intermediate (■)
About 1-2.5 isonicotinic acid hydrazide per mole
Preferably, the reaction is carried out using moles. The compound of the present invention can be easily purified by conventionally known methods such as recrystallization and column chromatography.

The isonicotinic acid hydrazide derivative (1) thus obtained has an antituberculous action and is a compound useful as an antituberculous agent. The in vitro minimum inhibitory concentration of 2-dimethylsulfamoylbenzalisonicotinyl hydrazone, one of the novel compounds of the present invention, against Mycobacterium tuberculosis H37R strain was determined using a dejuboalbumin liquid medium. The result (after 3 weeks of incubation at 37°C) was 0.04μGlmt, which is a strong antibacterial agent that exceeds the value of isonicotinic acid hydrazide as a control drug, 0.05py1mL, while acute toxicity using mice According to the test results, the LD5O value of 2-dimethylsulfamoylbenzalisonicotinylhydralazone is 1007m9
1k9, which had a low toxicity of about 114 compared to the LD5O value of isonicotinic acid hydrazide, which was used as a control, of 251Tn91k9. As described above, the novel isonicotinic acid hydrazide derivative of the present invention has significantly lower toxicity and superior antibacterial activity than conventional isonicotinic acid hydrazide, and is a new and useful compound.

The present invention will be specifically explained below with reference to Examples.

Example 1 0-formylbenzenesulfonyl chloride 6f1 (0
．． 03 mol) was dissolved in 60 ml of dichloromethane, and 4.1 (0.03 mol) of triethylamine was added dropwise while cooling with ice water.

Next, methylpiperazine 3y (0.03 mol) was added, and after stirring for 1 hour, the reaction solution was concentrated under reduced pressure. The residue is dissolved in a chloroform-ethanol mixture, passed through a silica gel column, and the eluate is fractionated and concentrated under reduced pressure. Residue 5.49 (0.
02 mol) of isonicotinic acid hydrazide was dissolved in 30 ml of ethanol. 02 mol) and stirred at room temperature for 3 hours. The reaction solution was concentrated under reduced pressure, the residue was dissolved in ethyl acetate, ether was added, and the precipitate was collected. This precipitate was recrystallized from ethyl acetate-ether to obtain crystals of 2-(4-methyl-1-piperazinylsulfonyl)benzalisonicotinyl hydrazone 5.
．． 2y (yield 44.8%) is obtained. Melting point 176.5~1
785C elemental analysis Cl8H2lN, Calculated value (%) as O3S: C55.8O; H5.46; Nl8. O
8 Actual value (%): C55.87; H5.54: Nl7.
93 Example 2 0-formylbenzenesulfonyl chloride 10.2y
(0.05 mol) was dissolved in 90 ml of dichloromethane,
7 ml of triethylamine under cooling with ice water (a). 05) to k
Drip.

Then, excess dimethylamine gas is introduced into the solution, and 3
After stirring for an hour, the reaction solution was concentrated under reduced pressure. The residue was dissolved in a chloroform-ethanol (20:1) mixture, passed through a silica gel column, and the eluate was collected in 7 fractions and concentrated under reduced pressure.

The residue 9y (0.042 mol) was dissolved in 100 ml of ethanol, and 5.8y (0.04 mol) of isonicotinic acid hydrazide was dissolved in 100 ml of ethanol.
3 mol) and stirred at room temperature for 1 turbidity. The resulting precipitate was taken off the coast and recrystallized from chloroform-ethanol to obtain 11.69 crystals of 2-dimethylsulfamoylbenzalisonicotinylhydrazine (yield: 69.8%). Melting point 214-216.5. C elemental analysis Cl5Hl6N
Calculated value (%) as 4O3S: C54.2O; H4.85; N16.8
6 Actual value (%): C54.35; H4.89; Nl6.
49 Example 3 0-formylbenzenesulfonyl chloride 4.3y (
0.02 mol) of dichloromethane 4077! Dissolve triethylamine in 377 liters of water and cool with ice water. Add L (0.02 mol) dropwise.

Then diisopropylamine 2.1y (0.02 mol)
was added and stirred at room temperature for 8 hours, then concentrated under reduced pressure. Dissolve the residue in chloroform, pass through a silica gel column, collect the eluate, and concentrate under reduced pressure.

Residue 29 was mixed with 32 ml of ethanol and 9.6 T of chloroform.
isonicotinic acid hydrazide dissolved in a mixture of nt.
y (0.0076 mol) and stirred at room temperature for 8 hours.

The reaction solution was concentrated under reduced pressure, and the residue was recrystallized from ethanol.
-Crystals 2.4f (yield 30%) of diisopropylsulfamoylbenzalisonicotinyl hydrazone are obtained. Melting point 183-186℃ Elemental analysis Calculated value (%) as Cl9H24N4O3S: C58.74; H6.23; Nl4.4
2 Actual value (%): C58.77; H6.4l; Nl4.
39 Example 4 0-formylbenzenesulfonyl chloride 4.3y (
0.02 mol) was dissolved in 40 ml of dichloromethane, and 3 ml (0.02 mol) of triethylamine was added dropwise while cooling with ice water.

Next, 2.2y (0.02 mol) of diethanolamine was added and the mixture was stirred at room temperature for 8 hours, and then concentrated under reduced pressure. The residue was dissolved in 50 ml of a chloroform-ethanol (5:1) mixture, passed through a silica gel column, and the eluate was fractionated and concentrated under reduced pressure. Residue 2.6 was dissolved in 50 ml of ethanol and 1.32' (0.0096 mol) of isonicotinic acid hydrazide was dissolved.
and stirred at room temperature for 8 hours.

The reaction solution was concentrated under reduced pressure, and the residue was recrystallized from ethanol.
-Diethanol Sulfamoyl benzalisonicotinyl hydrazone crystals 2.9y (yield 36.9%) are obtained.
Melting point 169-170℃ Elemental analysis Cl7H2ON4O5S
Calculated value (%): C52. O3; H5. l4;Nl4.2
8 Actual value (%): C52. l6; H5.37; Nl4.
l2 Example 5 0-formylbenzenesulfonyl chloride 4.3f (
0.02 mol) was dissolved in 40 ml of dichloromethane, and 3 ml of triethylamine (a) was added under cooling with ice water. 02 mol) was added dropwise.

Next, 1.85 f (0.02 mol) of morpholine was added and the mixture was stirred at room temperature for 8 hours and then concentrated under reduced pressure. 3.7y of the residue was dissolved in a mixed solvent of 74ml of ethanol and 12ml of chloroform, and 2y of isonicotinic acid hydrazide (0.015ml) was dissolved in a mixed solvent of 74ml of ethanol and 12ml of chloroform.
mol) and stirred at room temperature for 2 hours.

Claims (1)

[Claims] 1. General formula ▲ Numerical formulas, chemical formulas, tables, etc. ▼ (I) [In the formula, R is a lower dialkylamino group, an alicyclic amino group, a morpholino group, or a lower alkyl group substituted with or without a hydroxyl group. an isonicotinic acid hydrazide derivative having a substituted or unsubstituted piperazino group. 2 o-formylbenzenesulfonyl halide and a lower dialkylamine substituted or not substituted with a hydroxyl group,
a second selected from the group of alicyclic amines, morpholine and piperazines substituted or unsubstituted with lower alkyl groups;
The general formula is characterized by the reaction of isonicotinic acid hydrazide with the reaction product obtained by reacting with a class amine ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (I)
[In the formula, R represents a lower dialkylamino group, an alicyclic amino group, a morpholino group, or a piperazino group substituted or unsubstituted with a lower alkyl group].