JPS6018652B2 - Pyridine derivative - Google Patents

Description

[Detailed description of the invention] This invention relates to a novel pyridine conductor.

This pyridine derivative is particularly useful against lesions caused by toxins or pathogens, especially at the liver level*, and against agents that cause liver damage and blood circulation disorders in general, and against atherosclerotic or inflammatory lesions. , exhibiting protective activity. The compound provided by this invention is represented by the following formula.

The compounds provided by this invention also include compounds (
1) with physiologically acceptable inorganic acids (e.g., hydrochloride, sulfate, etc.) or acid addition salts with organic acids (e.g., fumarate, citrate, pamate, etc.). .

The method for producing compound XI) of the present invention includes halogenated N-(
Q-penzoylthiopropionyl)glycine (b) 2
, 6-dihydroxymethylpyridine (m).

Compound (m) is known, and compound (0) is Z, which can be produced by a known conventional method.

The following examples are intended to explain the invention in more detail and are not meant to limit the invention.

Example Z 'a} N-(Q-penzoylthiopropionyl) chloride
) Preparation of Glycine Thionyl chloride (10 min.) was added under concentration to N-(Q-benzoylthiopropionyl)glycine suspended in benzene (25M).

The reaction mixture was kept at room temperature until all the solids were dissolved.
The resulting yellow solution was evaporated in vacuo, taken up in benzene and evaporated again until all remaining thionyl chloride was removed. The residual oil was dissolved in 15' of anhydrous chloroform. 'b} Preparation of bis-2,6[N-(Q-penzoylthiopropionyl)glycyloxymethyl]pyridine To the solution obtained in the above 'all process and kept at 1000, under a nitrogen atmosphere, To the solution, 2,6-dihydroxymethylpyridine (1.3 hours) dissolved in anhydrous pyridine (10 hours) was added.

The addition was carried out in such a way that the temperature of 0°C was not exceeded. Once the addition was complete, the reaction mixture was allowed to stand at room temperature for 4 hours;
The solvent was then evaporated under nitrogen atmosphere. The residue was then treated with saturated sodium carbonate solution and extracted repeatedly with chloroform. The extract was dried over Na2S04 and then concentrated to 25'. This solution was subjected to column chromatography (silica gel, 150 yen). Chloroform was used as the brood solution. The main fraction, which consists of the desired 2,6-dihydroxymethylpyridine diester and contains some impurities, is again short-circuited with silica gel. It was subjected to ram chromatography and then dissolved in chloroform. The product had a melting point of 86° C. and exhibited spectroscopic (1.R. and N.MR) and elemental analysis values consistent with the structure of formula (1) above. Compounds of formula (1) have antivenom, hepatoprotective and antiatherosclerotic activity and are therefore particularly useful for therapeutic purposes.

The following is intended to detail the results of toxicological and pharmacological tests performed with compounds of formula (1).

1. Toxicology test product had almost no curative properties.

Studies have shown that the oral LD50 of this compound in rats and mice was 1.459 and 1.75, respectively. Oral LD50 in guinea pigs is 1.05.
It was evening. Intraperitoneal LD50 of mouse is 9/k of 625
It was 9.

The chronic toxicity of this compound was also mostly favorable. At a dose of 200 9/kg, this compound was well tolerated when administered orally daily for two months to rats. There were no changes in the body weight of the experimental animals in the blood picture, axemia, or urine excretion tests.

There were also no changes in histological examination at the level of major organs.

Evening 2 Pharmacology Test 'a} Antitoxin protective activity against heavy metal-induced poisoning Compound of formula 0) against experimental poisoning 0 induced by administration of mercuric chloride or sodium ethylmercury thiosalicylate to mice We evaluated the protection shown by

When the compound of formula (1) is previously administered intraperitoneally in an amount of 200 females/kg, mercury chloride of 20/k9 or 100/9
Almost 100% of the animals treated with intraperitoneal administration of sodium ethylmercury thiosalicylate of /k9 were protected by almost 100%.

This compound is 50 part 9/k9 copper sulfate or 200 part 9
A dose of 250 x9/kg had the same protective effect against death induced in mice by intraperitoneal administration of copper phosphate at 250/k9/kg. 0 'b} Protective effect against experimental poisoning induced by carbon tetrachloride (CC14) in rats.
) induces rapid changes in hepatic metabolism, usually evidenced by substantial lipid infiltration of this organ.

According to experiments, the compound of formula (1) was added to 100 or 200 m
When administered intraperitoneally or orally in a dose of o/k9, a 10% concentration solution of CC14 in olive oil prevented the infiltration at the liver level induced by oral administration of 10 cc/k9.

'C} Protective effect against experimental intoxication induced by ethionine. 200 of the compound of this invention for 8 days
was inhibited by oral administration of 9/k9.

{d) Protective action formula against hyperbaric oxygen-induced intoxication (
Oral administration of 9/kg of Compound 300 of 1) prevented the onset of dehydration and death in mice placed in a hyperbaric chamber with an oxygen pressure of 4 atm.

{e} Protective effect against vascular lesions induced by 8-aminopropionitrile. It was suppressed by administering 4% of the compound of formula (1) for a period of 4%.

This vascular lesion was hardly observed by microscopic observation of animals treated with the compound of formula 1. [f}
Anti-atherosclerotic effect Rabbits were fed with the compound of formula (1) at 20 t/k9 per day and a hypercholesterinemia-inducing diet (1% cholesterol in the diet) for one feeding period. When given simultaneously, hypercholesterinemia and atherosclerotic lesion formation at the aortic and arterial levels were prevented.

Hawk) Anti-inflammatory lysine effect The inflammatory effect of kallidin was reduced by administration of the compound of formula (1).

When 200 to 400 9/k9 compounds are administered orally,
Injection of 0.5 Kallidin solution prevented the induced edema of the rat's paws.

(A) Effect on platelet aggregation Platelet aggregation induced by ADP (adenosine diphosphate) was suppressed in the presence of the compound of formula (1) both in vivo and in vitro.

In view of its anti-hypercholesterinemia and anti-inflammatory activity, the compound of formula (1) is useful in the treatment and prevention of reactive or metabolic hepatic lesions and the treatment and treatment of atherosclerosis in humans. It is useful in prophylaxis and in the treatment of all diseases requiring the administration of sulfur.

The compounds may be administered orally, parenterally, intraorally or locally.

For these various administrations, the active ingredient may be formulated with suitable excipients or excipients into tablets, capsules, suppositories, or ointments. Each unit dose is 0.1-1
It is good to include active ingredients in the evening.

Examples of pharmaceutical formulations containing compounds of formula (1) are given below,
It is not limited only to these.

{a' Tablets or capsules containing 0.25 g of active ingredient in a suitable excipient; b' Injectable solution containing 0.1 g of active ingredient per 1 cc of a suitable solvent; c' 0.25 g of active ingredient in a suppository base; Suppositories containing 5 active ingredients 10% in a suitable saucepan
The amount that can be administered in a particular ointment containing the active ingredient will vary according to the particular application.

Claims (1)

[Claims] 1 Bis-2,6-[N-(α-benzoylthiopropionyl)glycyloxymethyl]pyridine or its inorganic or organic compound represented by the following formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ Acid addition salts with acids.