JPS5830310B2 - 5- (dithiocarbamoylmethyl) picoline sanamide - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a novel method for producing 5-(dithiocarbamoylmethyl)picolinic acid amide.

The present inventors have previously demonstrated that 5-(dithiocarbamoylmethyl)picolinic acid and its derivatives are effective for dopamine-β
- It was found that it significantly inhibits hydroxylase and has a good antihypertensive effect.

As a result of further research, it has been found that 5-(dithiocarbamoylmethyl)picolinic acid amides have the above-mentioned effects, have extremely low side effects such as gastric and intestinal disorders, and exhibit particularly useful medical effects.

The present inventors used the previously invented ester of 5-(dithiocarbamoylmethyl)picolinic acid as a starting material to obtain 5-
As a result of research into a method for producing (dithiocarmoylmethyl)picolinic acid amide, the present invention was completed.

The purpose of the present invention is to develop a novel 5-molecule that has few side effects and is medically useful.
- Provided is a method for producing (dithiocarbamoylmethyl)picolinic acid amide.

The object of the present invention is achieved by reacting 5-(dithiocarbamoylmethyl)picolinate with ammonia or lower alkyneamines.

The reaction of the present invention preferably involves reacting ammonia or a lower alkylamine in an alcoholic solution of 5-(dithiocarbamoylmethyl)picolinic acid ester.

5-(dithiocarbamoylmethyl)picolinic acid ester used in the reaction of the present invention is obtained by reacting alcohol or alkyl halide with 5-(dithiocarbamoylmethyl)picolinic acid, a salt thereof, or an acid chloride thereof. be able to.

In particular, an alcoholic solution of the ester can be easily prepared by dissolving 5-(dithiocarbamoylmethyl)picolinic acid in alcohol in the presence of a dehydrating agent such as thionyl chloride, hydrogen chloride, sulfuric acid, or P-toluenesulfonic acid. Obtainable.

The alcohol used in this reaction is preferably methanol,
It is preferable to use a solution such as ethanol, propatool, butanol, cyclohexanol, phenol, substituted phenol, etc., and it is particularly preferable to use methanol or ethanol.

5-(dithiocarbamoylmethyl)picolinic acid, or
The ratio of alcohol to acid halide is 1 to 5
00 equivalents and alcohol can be used as a solvent.

Note that a suitable inert solvent other than alcohol can be used.

The reaction temperature is -30 to 1508C, and when esterifying with an alcohol and a dehydrating agent, heating is preferably carried out under reflux.

The reaction product can be used in the next reaction as it is in its solvent solution or with the addition of a suitable solvent.

Note that the acidic substance used as a dehydrating agent may be removed by evaporation or neutralized in advance, but since it will be neutralized by ammonia or lower alkylamine used in the next reaction, it cannot be used as is for the next reaction. There are features that allow it.

The salt of 5-(dithiocarbamoylmethyl)picolinic acid is dissolved in a suitable solvent such as alcohol, acetone, tetrahydrofuran, benzene, chloroform, dichloromethane,
The ester can be obtained by dissolving it in dimethylformamide, ethyl acetate, etc. and allowing an alkyl halide to act thereon.

Preferred alkyl halides used in this case include methyl iodide, ethyl iodide, and l)-bromophenacetyl bromide.

Note that other alkyl halides can be used, but since alkyl halides are expensive, they are economically disadvantageous compared to the esterification method described above.

This reaction is completed in a short time at low temperature.

It is economically preferable to use an equivalent amount or a slight excess of the alkyl halide.This reactive product solution can also be used as it is in the next reaction.

In addition, 5-(dithiocarbamoylmethyl)picolinic acid,
Or, by reacting the salt with a halide such as thionyl chloride, phosphorus pentachloride, phosphorus trichloride, phosphorus oxychloride, sulfuryl, or chloride, the acid chloride is obtained, and this is reacted with an alcohol to obtain the ester. can be manufactured.

When using thionyl chloride or phosphorus oxychloride, without solvent,
Although the acid chloride can be obtained, this reaction is usually carried out in an inert solvent, i.e. chloroform, dichloromethane,
This is carried out by dissolving 5-(dithiocarbamoylmethyl)picolinic acid in benzene, toluene, cyclohexane, acetone, methyl ethyl ketone, ether, dioxane, tetrahydrofuran, pyridine, n-hexane, or the like.

After this reaction, the alcohol is added to form its ester.

5-(dithiocarbamoylmethyl)picolinic acid amide can be prepared by introducing ammonia or a lower alkylamine into a solvent solution of the above-mentioned 5-(dithiocarbamoylmethyl)picolinic acid ester in a gaseous state, adding it as a liquid, or adding it as a solution. It can be produced by adding it in a state.

For the reaction with 5-(dithiocarbamoylmethyl)picolinic acid halide, ammonia or methylamine, ethylamine, dimethylamine, diethylamine, n-propylamine, isopropylamine, n-butylamine,
Lower alkylamines such as 5ec-butylamine and t-butylamine are used.

When using these ammonia or lower alkyl amines as a solvent solution, alcohols, acetone, methyl ethyl ketone, chloroform, dichloromethane, benzene, toluene, ethylacetite, dioxane, tetrahydrofuran, dimethylformamide, acetonitrile, cyclohexane, etc. are used.

Moreover, water can be used depending on the case.

The amount of ammonia or lower alkylamine is usually
As a large excess equivalent, 5-(dithiocarbamoylmethyl)
It is desirable to fully convert the picolinate ester to its amide.

Usually 1 to 10 equivalents are used.

5-(dithiocarbamoylmethyl)picolinic acid amide produced by the method of the present invention can be obtained as a pure product by separation and purification methods such as extraction, distribution, recrystallization, and chromatography.

The antihypertensive effect and toxicity of 5-(dithiocarbamoylmethyl)picolinic acid amide obtained by the method of the present invention were investigated and the results were as shown in Table 1.

Toxicity test and efficacy test For the purpose of determining acute toxicity, drugs were administered orally and intraperitoneally to mice (DD strain), and rich-fed and Wilcoxon were administered to mice (DD strain).
) method (J, Pharm9699-113, 194
9) was used to calculate the LD50 (dose at which 50% of the patients died).

The effectiveness was determined by examining the blood pressure lowering effect.

Different doses of the drug were administered to three types of rats: normotensive rats, spontaneously hypertensive rats, and DOCa salt-treated hypertensive rats. The amount of drug that lowered blood pressure by 20% or more was defined as ED5o.

Table 1 shows that various derivatives were significantly effective in mice and spontaneously hypertensive rats, DOCa salt hypertensive rats were the next most effective, and in normotensive rats, no blood pressure reduction was observed unless given in comparatively large doses. I couldn't.

Taking dimethyldithiocarbamylpicotonite as an example,
For DOCa salt hypertensive rats, ED5o is 150
7 Q/kg (oral), 100 ■/Iy (transperitoneal), and in normotensive rats, ED, o is 850 m1? /′
kg (oral), 600 Takumi/ToP (transplantation cavity).

This fact indicates that this drug is specifically effective in lowering blood pressure in patients with hypertension.

When administered to normal males, a drop in blood pressure was observed after a single dose of 500 μg, and no side effects such as a hypotensive effect were observed even when 5 g was administered.

Example 1 5-(N,N-dimethyldithiocarbamoylmethyl)picolinic acid methyl ester 170TLl of methanol was added to 17g of 5-(N,N-dimethyldithiocarbamoylmethyl)picolinic acid, and -5
While cooling to 0.degree. C. and stirring, 15 ml of thionyl chloride was added dropwise over 30 minutes.

Subsequently, the reaction was stirred at 0 to 5°C for 30 minutes and at room temperature overnight, and then refluxed for 3 hours.

After 4 hours, 5 TL of concentrated sulfuric acid was added, and the mixture was further heated under reflux for 7 hours.

The reaction mixture was evaporated under reduced pressure, the residual aroma was dissolved in 50 TL of water, 50 ml of chloroform was added, and the mixture was neutralized with sodium hydrogen carbonate while stirring, and the chloroform layer was separated.

The aqueous layer was extracted with chloroform.

The chloroform layers were combined, washed with water, dried, and the solvent was distilled off.
If recrystallized from carbon tetrachloride, 5-(N.

N-dimethyldithiocarbamoylmethyl)picolinate methyl ester 17.1.9 (95.5% yield) was obtained as colorless needles with a melting point of 95-96°C.

Elemental analysis value (%) H as CH25CN(CH3)2 H3O2C C11H1402N2S2
NS Calculated value 48.87 5.22 10.36 23.
72 experimental value 48.77 5.02 10.37 24
．． 015-(N,N-dimethyldithiocarbamoylmethyl)picolinic acid amide 1.0 g of 5-(N,N-dimethyldithiocarbamoylmethyl)picolinate methyl ester was dissolved in 10 Tll of methanol containing 10% ammonia and reacted overnight at room temperature. Ta.

The precipitate was collected by filtration and recrystallized from 80 Da aqueous methanol to give 5-(N,N-dimethyldithiocarbamoylmethyl)picolinic acid amide 0.9 (Bi' (yield 95.3).
) was obtained as colorless needle crystals with a melting point of 192-194°C.

HNS Calculated value 47.04 5.13 16.46 25.
11 Experimental value 47.01 4.99 16.48 2
5.18 Example 2 5-(N,N-dimethyldithiocarbamoylmethyl)picolinate methylamide 5-(N,N-dimethyldithiocarbamoylmethyl)picolinate methyl ester1. Og with 10% methylamine-containing methanol 10m71! and reacted overnight at room temperature.

When the solvent was evaporated under reduced pressure and the residue was recrystallized from ethanol, 5-(N) was obtained.

0.9 g (90% yield) of N-dimethyldithiocarbamoylmethyl)picolinic acid methylamide had a melting point of 129-1
Obtained as colorless needles at 31°C.

HNS calculated value 49.07 5.61 15.60 23.
80 experimental value 48.74 5.49 15.61 2
3.87 Example 3 5-(N,N-dimethyldithiocarbamoylmethyl)picolinate ethylamide 1.0 g of 5-(N,N-dimethyldithiocarbamoylmethyl)picolinate methyl ester was dissolved in methanol 107711 containing 10% ethylamine, The reaction was allowed to proceed overnight at room temperature.

When the solvent was evaporated under reduced pressure and the residue was recrystallized from isopropyl ether, 1.03 g (yield: 98 strips) of 5-(N,N-dimethyldithiocarbamoylmethyl)picolinic acid ethylamide was obtained as colorless needles with a melting point of 87-88°C. Obtained as solid crystals.

HNS

Claims (1)

[Claims] 1 5-(dithiocarbamoylmethyl)picolinic acid, its salt, or its acid halide with alcohol or
A method for producing 5-(dithiocarbamoylmethyl)picolinic acid amide, which comprises reacting with an alkyl halide to form an ester thereof, and reacting the ester with ammonia or a lower alkylamine.