JPS5830309B2 - 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 5-(dithiocarbamoylmethyl)picolinic acid halide, 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.

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 invention can be achieved by reacting 5-(dithiocarbamoylmethyl)picolinic acid halide with ammonia or lower alkyl amines.

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

The 5-(dithiocarbamoylmethyl)picolinic acid halide used in the present invention is produced by reacting 5-(dithiocarbamoylmethyl)picolinic acid or a salt thereof with a halogenating agent.

Examples of the halogenating agent include thionyl chloride, phosphorus pentachloride,
Preferred are phosphorus chloride, phosphorus oxychloride, sulfuryl, chloride, etc. When using thionyl chloride and phosphorus oxychloride,
The acid chloride can be removed without solvent, but usually
This reaction is carried out in an inert solvent such as chloroform, dichloromethane, benzene, toluene, cyclohexane, acetone, methyl ethyl ketone, ether, dioxane, tetrahydrofuran, pyridine, n-hexane, etc.
This is done by dissolving dithiocarbamoylmethyl)picolinic acid.

The inert solvent is mixed with 5-(dithiocarbamoylmethyl)picolinic acid or its salt at a ratio of 0.5 to 500 times the volume.

The halogenating agent is blended with 5-(dithiocarbamoylmethyl)picolinic acid or its salt in a proportion of 1 to 500 equivalents, preferably 1 to 10 equivalents.

The reaction temperature is -30 to 200°C, preferably -10 to 200°C.
The temperature is 100°C.

The reaction product contains 5-(dithiocarbamoylmethyl)picolinic acid halide, which is separated and
It may be used in the next reaction, either as a solution in the solvent or with an appropriate solvent added thereto.

Note that unreacted halogenating agent may be removed in advance or inactivated by neutralization, decomposition, etc., but since it will be inactivated by reacting with ammonia or lower alkylamine used in the next reaction, It has the characteristic that the reaction agent can be used in the next reaction without being separated.

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 di0picolinic acid halide) 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 ec-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, ethylacetite, dioxane, tetrahydrofuran, dimethylformamide, acetonitrile, cyclohexane water, etc. are used.

If acid is produced in this reaction, sodium hydroxide,
A neutralizing agent such as calcium hydroxide, sodium bicarbonate, or sodium carbonate may be used, but ammonia or lower alkylamine itself serves as a neutralizing agent.

The reaction between 5-(dithiocarbamoylmethyl)picolinic acid halide and ammonia or lower alkylamine is carried out in 1 to 10 equivalents in anhydrous conditions, but in aqueous conditions, a large excess of the latter is used to fully react the former with 5-( It is desirable to convert it to dithiocarbamoylmethyl)picolinic acid amide, and usually 10 to 500 equivalents of the latter are used.

The reaction temperature is -30 to 200°C, preferably 0 to 100°C.
It is 0C.

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, the drug was administered to mice (DD strain).
Administer intraperitoneally to administer rich feed, viruscoxon (
(Litchfied & Wil coxon)
method (J, Pharm, 969'9-113.194
9) to determine LD5o (dose at which 50% of deaths occurred)
was calculated.

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.

Closed. 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 reduction in blood pressure was observed unless given in relatively large doses. Ta.

Taking dimethyldithiocarbamylpicolinite as an example,
For DOCa salt hypertensive rats, ED5o is 150
mp/ky (oral), 100 mp/ky (transperitoneal), and in normotensive rats, ED.

The dose was 850 μ/kg (oral) and 600 μ/kg (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 amide 1.0 g of 5-(N,N-dimethyldithiocarbamoylmethyl)picolinic acid was dissolved in 3 ml of thionyl chloride in chloroform solution (13 mL of hot water). Reflux was performed on the bath for 15 minutes.

The reaction mixture was evaporated under reduced pressure, and the oily residue was dissolved in 20 r of chloroform.
10 ml of 28-polymer ammonia water was added to the solution while stirring vigorously under water cooling, and the mixture was stirred for 1 hour.

The precipitate was filtered and recrystallized from 80φ aqueous methanol to obtain 5(N,N-dimethyldithiocarbamoylmethyl)picolinic acid amide as colorless needles with a melting point of 192 to 194°C.

Elemental analysis value (fo)HN as C1oH13ON3S
S 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)picolinic acid methylamide Acid obtained from 5-(N,N-dimethyldithiocarbamoylmethyl)picolinic acid 1.09 by a method similar to Example 1 A chloroform solution of chloride is reacted with 10 ml of 30% methylamine water, and the chloroform layer is separated, washed with water, dried, and then chloroform is evaporated under reduced pressure.

When the residual aroma was recrystallized from ethanol, 5-(N,N
-dimethyldithiocarbamoylmethyl)picolinic acid methylamide was obtained as colorless needles with a melting point of 129-131°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 5-(N,N-dimethyldithiocarbamoylmethyl)picolinic acid ethylamide 5-(N,N-dimethyldithiocarbamoylmethyl)picolinic acid 1.0. ! A chloroform solution of the acid chloride obtained from ;' was reacted with 10 ml of 35-modified methylamine water in the same manner as in Example 2, and recrystallized from isopropyl ether. ) Picolinate cotylamide has a melting point of 8.
Obtained as colorless hairy needle crystals at 7-88°C.

Cl2H17oN3s2 and teno elemental analysis value (rice cake) C Calculated value 50.86 Experimental value 50.84 6.05 5.95 14.83 14.92 22.63 22.51

Claims (1)

[Claims] 1. A method for producing 5-(dithiocarbamoylmethyl)picolinic acid amide, which comprises reacting 15-(dithiocarbamoylmethyl 9-picolinic acid halide with ammonia or a lower alkylamine).