JPS5830311B2 - 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 medicinal effects.

The present inventors used 5-(dithiocarbamoylmethyl)picolinic acid anhydride, which was invented earlier, as a starting material.
As a result of research into a method for producing dithiocarbamoylmethyl)picolinic acid amide, the present invention was completed.

An object of the present invention is to provide a novel method for producing 5-(dithiocarbamoylmethyl)picolinic acid amide, which has fewer side effects, fewer medical effects, and is medically useful.

The object of the present invention can be achieved by reacting 5-(dithiocarbamoylmethyl)picolinic anhydride with ammonia or a lower alkylamine.

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

5-(dithiocarbamoylmethyl) used in the present invention
Picolinic anhydride is produced by reacting 5-(dithiocarbamoylmethyl)picolinic acid or a salt thereof with an acid halide or an alkyl chloroformate, preferably in a solvent solution.

Suitable acid halides include aliphatic halides such as acetyl chloride, pentyl chloride, and isovaleryl chloride, aromatic acid halides such as benzoyl chloride, and the like.

Suitable alkyl chloroformates include inbutyl chloroformate, benzyl chloroformate, and the like.

This reaction is preferably carried out in an inert solvent.

Inert solvents include chloroform, dichloromethane,
Benzene, toluene, cyclohexane, acetone, ethyl acetate, dioxane, tetrahydrofuran, dimethylformamide and the like are preferred.

The reaction temperature of this reaction is -30 to 100°C, preferably -11°C.
The temperature is 0 to 30°C.

The amount of acid halide or alkyl dichloroformate used is 1 to 500 equivalents relative to 5-(dithiocarbamoylmethyl)picolinic acid.

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.
If unreacted acid halide or alkyl chloroformate remains, it can be used in the next reaction after being reacted with a lower fatty acid such as acetic acid to form an inert compound.

Incidentally, by-products such as acids produced by the reaction may be neutralized in advance, but since they are neutralized by ammonia or lower alkyl amines used in the next reaction,
It has the characteristic that it can be used as is for the next reaction.

Usually, 5-(dithiocarbamoylmethyl)picolinic acid is dissolved in an inert solvent such as chloroform together with a neutralizing agent such as triethylamine, and an alkyl chloroformate is added dropwise to carry out the reaction. ) 5-(dithiocarbamoylmethyl)picolinic acid amide can be obtained in high yield by forming picolinic acid mixed anhydride and reacting this with ammonia or a lower alkylamine under cooling.

Thus, a production process without anhydride separation has significant advantages.

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 anhydride in a gaseous state or by adding it as a liquid.
Alternatively, it can be produced by adding it in a solution 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, acetone, methyl ethyl ketone, chloroform, dichloromethane, benzene, toluene, ethyl acetite, dioxane, tetrahydrofuran, dimethylformamide, acetonitrile, cyclohexane, etc. are used.

The amount of ammonia or lower alkylamine is usually
It is desirable to convert sufficient excess equivalents of 5-(dithiocarbamoylmethyl)picolinic anhydride to its amide.

Usually 1 to 10 equivalents are used.

The reaction temperature is -30 to 200°C, preferably 20 to 50°C.
It is ℃.

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 the drugs were administered to mice (DD strain) using rich feed and Wilcoxon.
) method (J, Pharm 9699-113.194
9) was used to calculate the LD5(1 (50% mortality)).

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. ED, the amount of drug that has decreased by 20% or more compared to blood pressure.

And so. Table 1 shows that various derivatives were significantly effective in mice and spontaneously hypertensive rats, with DOCa salt hypertensive rats being the next most effective, and no reduction in blood pressure was observed in normotensive rats unless given in relatively large doses.

Taking dimethyldithiocarbamylpicolinite as an example,
For DOCa salt hypertensive rats, ED, o is 150
7 V/kg (oral), 9 to 100 V/kg (transperitoneal), and ED in normotensive rats.

is 8507nfl/9 (oral), 6007”&M(
(transperitoneal).

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 other than a drop in blood pressure** were observed even when 5 g was administered.

Example 1 5-(N,N-dimethyldithiocarbamoylmethyl)picolinic acid 1.0 g of 5-(N,N-dimethyldithiocarbamoylmethyl)picolinic acid and 0.56 ml of triethylamine were dissolved in 20 rnl of chloroform, and Add 0.531 nl of inbutyl chloroformate under cooling, and incubate at 5°C for 3 hours.
The reaction was carried out for 0 minutes.

Ammonolysis was carried out by blowing dry ammonia gas into the reaction solution while cooling it to 5°C.

-After standing overnight, the precipitate was collected and recrystallized from so% aqueous methanol; 5-(N,N-dimethyldithiocarbamoylmethyl)picolinic acid amide had a melting point of 192-19
Obtained as colorless needles at 4°C.

HNS Calculated value 47.04 5.13 16.46 25.
11 Experimental value 47.01 4.99 16.48 25
．． 18 Example 2 5-(N,N-dimethyldithiocarbamoylmethyl)picolinic acid methylamide Mixed acid prepared from 1.0 g of 5-(N,N-dimethyldithiocarbamoylmethyl)picolinic acid by a method similar to Example 1. Amitylysis was carried out by inhaling dry methylamine gas into an oloroform solution of the anhydride.

When the reaction solution was evaporated under reduced pressure and the residue was recrystallized from ethanol, 5-(N,N-dimethyldithiocarbamoylmethyl)picolinate methylamide was obtained as colorless crystals with a melting point of 129 to 131°C.

HNS Calculated value 49.04 5.61 15.60 23.
80 experimental value 48.74 5.49 15.61 2
3.87 Example 3 By the same method as in Example 1, 5-(N,N dimethyldithiocarbamoylmethyl)picolinic acid 1,Q,! li'
Amitylysis was carried out by inhaling dry ethylamine gas into a chloroform solution of mixed acid anhydride prepared from.

When the reaction solution was evaporated under reduced pressure and the residue was recrystallized from isopropyl ether, 5-(N,N-dimethyldithiocarbamoylmethyl)picolinic acid ethylamide was obtained with a melting point of 87-88.
Obtained as colorless hairy needles at ℃.

HNS

Claims (1)

[Claims] A method for producing 5-(dithiocarbamoylmethyl)picolinic acid amide, which comprises reacting 15-(dithiocarbamoylmethyl)picolinic anhydride with ammonia or a lower alkylamine.