JPS5811863B2 - 5-(4;-Chloro-N-butyl) - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a method for producing a novel 5-(4'-chloro-n-butyl)picolinic acid amide useful as a hypotensive agent represented by the following formula. Reactive derivatives at the carboxyl group of 4'-chloro-n-butyl) picolinic acid (
However, acid esters are excluded.

) and ammonia are reacted.
The present invention relates to a method for producing 4'-chloro-n-butyl)picolinic acid amide.

One of the inventors of the present invention, Penia, announced that alkylpicolinic acid inhibits dopamine β-hydroxylase and has a blood pressure lowering effect, and that fusaric acid; 5-n-butylpicolinic acid in particular shows a strong effect. (Chemical and Pharmaceutical Bulletin Vol. 17, 2377-238
0 p. 1969).

The present inventors conducted further research and confirmed that the efficacy of fusaric acid decreases when the terminal carbon of its side chain is oxidized in animals or humans.

Therefore, we thought that if one hydrogen atom at the terminal carbon was replaced with a halogen atom, it would not undergo in vivo oxidation, and 5-
Synthesize (4'-halogeno-n-butyl)picolinic acid,
When the degree of inhibition of dopamine β-hydroxylase was measured, results as expected were obtained (see JP-A-48-80572).

Subsequently, various studies were conducted to invent even better antihypertensive agents, and the result was a reactive derivative at the carboxyl group of 5-(4'-chloro-n-butyl)picolinic acid (however,
Excludes acid esters.

) was amidated with ammonia to give 5-(4'-chloro-n
-Butyl) picolinic acid amide has been found to be an excellent antihypertensive agent with fewer side effects than known picolinic acid derivatives.

The present invention was completed based on this knowledge.

For the amidation reaction in the present invention, well-known means for producing acid amides can be appropriately used.

That is, 5-(4'-chloro-n-butyl)picolinic acid halide obtained by halogenating 5-(4'-chloro-n-butyl)picric acid with a halogenating agent such as thionyl chloride or phosphorus pentachloride. , 5-( obtained by dehydrating 5-(4'-chloro-n-butyl)picolinic acid by a conventional method)
4'-chloro-n-butyl)picolinic anhydride, 5-(
A reactive derivative such as a mixed acid anhydride of 5-(4'-chloro-n-butyl)picolinic acid obtained from 4'-chloro-n-butyl)picolinic acid and, for example, a carbonic acid monoester is treated with aqueous ammonia or ammonia. The reaction can be carried out appropriately in a saturated organic solvent.

Examples of the halides of 5-(4'-chloro-n-butyl)picolinic acid mentioned above include chlorides, bromides, and iodides.

In addition, examples of mixed acid anhydrides include, for example, alkyl chlorocarbonate (
Examples include mixed acid anhydrides with methyl chlorocarbonate, ethyl chlorocarbonate, etc.).

Preferred organic solvents for ammonia include alcohol, toluene, and the like.

In addition, in order to amidate an acid halide to obtain the desired acid amide, the acid halide may be directly reacted with aqueous ammonia, but it is preferable to suspend or dissolve the acid halide in an inert solvent such as toluene. The solution was gradually added to the same inert solvent saturated with ammonia under ice cooling for about 1 hour.
The reaction is allowed to proceed for up to 3 hours with stirring, and after the reaction is completed, the desired acid amide can be obtained by distilling off the solvent.

In order to amidate acid anhydrides, the reaction and post-treatment may be carried out in substantially the same manner as in the case of mixed anhydrides.

5-(4'-chloro-n-butyl)picolinic acid amide obtained in the present invention is a new compound and has excellent effects as a hypotensive agent as described below.

The hypotensive effect of 5-(4'-chloro-n-butyl)picolinic acid amide was investigated using spontaneously hypertensive rats.
When compared with butylpicolinic acid (fusaric acid), 5-n-pentylpicolinic acid amide, and 5-(4'-chloro-n-butyl)picolinic acid, the degree of blood pressure reduction (%) is 50%.
■/kg oral administration of 5-(4'-chloro-n-butyl)
16% in picolinic acid amide, 24% in fusaric acid, 9% in 5-n-pentylpicolinic acid amide
%.

It was 35% in 5-(4'-chloro-n-butyl)picolinic acid.

The hypotensive degree of 5-(4'-chloro-n-butyl)picolinic acid amide is stronger than that of 5-n-pentylpicolinic acid amide, but 5-n-butylpicolinic acid and 5
It is slightly weaker than that of -(4'-chloro-n-butyl)picolinic acid.

However, the acute toxicity value (LD50) for oral administration in mice was 2000 μ/kg (95% confidence limit 1769 to 2260 mg/kg) for 5-(4'-chloro-n-butyl)picolinamide, and LD50 for fusaric acid. 230~(205~255■/kg), 5-(4
'-Chloro-n-butyl) picolinate is 470
mg (450-490 mg/kg).

That is, the acute toxicity value of 5-(4'-chloro-n-butyl)picolinic acid amide when administered orally is 1/8 that of fusaric acid.
7,5-(4'-chloro-n-butyl)picolinic acid 1
/4.35.

In addition, the acute toxicity value (LD50) after intraperitoneal administration was 5-(
450~(95% confidence limit 435~470/9) for 4'-chloro-n-butyl) picolinic acid amide
, for fusaric acid it is 125■ (112-132 mg
For 5-(4'-chloro-n-butyl)picolinic acid, it was 180 µ (171 to 193 µ/9).

That is, the acute toxicity value of 5-(4'-chloro-n-butyl)picolinic acid amide when administered intraperitoneally is 1/1 that of fusaric acid.
It was 1/2.5 of 3.6,5-(4'-chloro-n-butyl)picolinic acid.

These results are shown in Table 1.

Furthermore, as mentioned above, 5-(4'-chloro-n-butyl)picolinic acid amide has significantly lower toxicity than fusaric acid and 5-(4'-chloro-n-butyl)picolinic acid, so fusaric acid There was no gastric disorder observed with large doses.

That is, although the present compound is somewhat inferior to fusaric acid in terms of efficacy, it can be said to be an extremely useful antihypertensive agent because it has significantly fewer side effects and toxicity.

Hereinafter, the present invention will be specifically explained with reference to Examples.
1 Place 1 ml of thionyl chloride in an eggplant-shaped flask (equipped with a calcium chloride tube and a magnetic stirrer) and add 100 μl of 5-(4'-chloro-n-butyl)picolinic acid under ice cooling.

While cooling on ice, continue stirring on a magnetic Starcy for 3 hours.

Thereafter, excess thionyl chloride was distilled off under reduced pressure using a rotary evaporator to form a colorless oily 5-(4'-chloro-
The hydrochloride of n-butyl) picolinic acid chloride is obtained, and 2 ml of anhydrous toluene is added thereto, cooled on ice, and 5 ml of toluene saturated with ammonia is added dropwise.

After stirring overnight at room temperature, the toluene solution was washed with water, dried over Glauber's salt, and the toluene was distilled off under reduced pressure, leaving scaly crystals.

When this is recrystallized from methanol-water (2:5), colorless scaly crystals with a melting point of 119-120°C are obtained.

Yield 70n9 (71%) Example 2 2.12 g of 5-(4'-chloro-n-butyl)picolinic acid was dissolved in 15 ml of 1,2-dichloroethane, to which 1.2 g of ethyl chlorocarbonate was added. , further 1.2
After adding g of triethylamine dropwise, the mixture is heated under reflux for 4 hours.

Thereafter, 1,2-dichloroethane was distilled off, 20 ml of methanol was added to the residue (mixed anhydride), and 1 ml of methanol was added to the solution.
Add 0 ml of aqueous ammonia and heat under reflux for 5 hours.

After the reaction, the precipitated crystals were poured into 30 ml of ice water and filtered, air-dried, and recrystallized with methanol-water (2:5) to give colorless scale-like crystals with a melting point of 119-120°C of 1.65 (78%).
can get.

Claims (1)

[Claims] A 5-( characterized in that a reactive derivative at the carboxyl group of 15-(4'-chloro-n-butyl)picolinic acid (excluding acid ester) is reacted with ammonia.
A method for producing 4'-chloro-n-butyl)picolinic acid amide.