JPS5812256B2 - Medications for treating stomach ulcers, etc. - Google Patents

Description

Detailed Description of the Invention This invention provides 2-(p-chlorophenyl)-3-(aminocarbonylmethyl)-imidazo[1.21a,l-pyridine or its organic or inorganic acid, represented by the formula: Relates to the use of salt in the treatment of duodenal ulcers, duodenitis and gastritis.

The compound of formula (I) is a compound belonging to the imidazo[1,2-a]pyridine family, which is known to have an anti-inflammatory effect (J, Med. Chem, 1
Volume 2 (1969) 122 pages and GB-PS1076
089).

This invention has confirmed that the compound of formula (I), as the only compound in this group, has a surprising anti-ulcer effect in the gastrointestinal tract.

This effect is extremely important therapeutically and has never been observed before.

The subject of the invention is a 2-(p-chlorophenyl)-3-(aminocarbonylmethyl)-imidazo[
1.2-a] This invention relates to a pharmaceutical having an anti-ulcer effect that is composed of pyridine or its salt with an acid, or contains this compound or its salt as an active substance.

The compound of formula (I) is designated by the following code As. Let's call it 809.

The object of this invention is to use S,8
09 also relates to the use of its salts.

"Using" refers to the entire process of manufacturing, purifying, formulating, and/or placing in a container suitable for administration into a medicament that can be administered.

Compound 8.809 was fairly well tolerated in tests conducted on various animals to determine acute toxicity.

The results are shown in Table IK, for example:
The DL5o value when administered orally is 6000 in mice.
1n9/yu, and in latte it is 6000~/yu or more.

and daily oral doses of 50, 100 and 300mg/
In a long-term toxicity test using Latch (200 animals), a type of Spragdolle, the drug showed suitable tolerability over a test period of 6 months or more, and no significant abnormalities in biological functions were observed.

For beagles (18 dogs), test period of 6 months or more 2
Oral administration of 5 mg/kg also showed suitable tolerability.

The particular pharmacological effect of the compounds of the invention is that, when administered orally or intraperitoneally, 50 to 100
It showed a significant protective effect at an average dose of mg/kg, and in this case, the experimental gastric ulcers were caused by which drugs, such as indomethacin, phenylbutazone, acetylsalicylic acid, etc., and also by stress ulcers, ulcers due to pyloric ligation, and duodenal compression. It does not matter whether the cause is neurological, such as an ulcer, or a mixed cause.

The results of the two surveys are explained below.

The first study involved rats treated with an ulcer-inducing dose of indomethatin (see Table ■), and the second study stressed rats by arresting locomotion at low temperatures (Table ■). Regarding.

Excellent protective effects were also obtained for compound 8.809 against polymyxin B-induced hemorrhagic gastric ulceration and indomethacin-induced intestinal ulceration.

In another study on rats, S,809 was found to exhibit excellent antagonistic effects against gastric hyperacidity induced by pylorus ligation (see Table ■).

The products of the invention, which have shown general antagonistic effects in tests within tests and which have good cholinergic effects, have been shown to reduce the mucoprotein content of gastric scrapings that occur during various experimentally induced gastric pains.
counter (see table ■).

This allows us to conclude that the protective effect of the compounds of this invention on the stomach is a result of the mucosal effects exerted on the gastric wall (eg, the effect of enhancing mucus production from gastric mucosal cells).

At the doses used to demonstrate anti-ulcer effect, various tests such as mortality with procaine in combination with sodium bisulfite in mice, local blisters with chloroform in LATCH and rabbits, and Blashen in mice, etc. In local and small-bleb tests, bradykinin produced significant vascular anti-diffusion and anti-osmosis effects, that is, enhanced capillary resistance.

The anti-inflammatory, analgesic and antipyretic effects described in the above publications of the compounds of this invention occur essentially at higher doses.

At such high doses (200~/kg and above), a significant delay in gastrointestinal transit occurs in the case of lattes.

In humans, S,809 is extremely well tolerated.

When 200 to 400 doses are orally administered three times daily for 3 to 4 weeks or more, a remarkable regenerative effect occurs on duodenal ulcers.

In patients who are particularly sensitive to the gastric secondary effects of anti-inflammatory drugs, the products of the invention exert an excellent protective effect on the mucous membranes.

As mentioned above, 8.809 has therapeutic indications for duodenal ulcer, duodenitis, gastritis, etc.

Tables I to V are listed below.

Compound S. 809 can be administered as is.

They are preferably administered in the form of salts of organic acids, such as citric acid, maleic acid, malic acid, tartaric acid, malonic acid, etc., or of inorganic acids, such as hydrobromic acid, phosphoric acid, sulfuric acid, etc.

A few of these salts are known (J.Med.C
hem. 12 (1969) p. 122).

The following example illustrates a novel salt preparation process.

Example 1 2-(p-chlorophenyl)-3-(aminocarbonylmethyl)-imidazo[1,2-a]pyridine-citrate 4.2 r (0.2 mol) of citric acid was heated for 15 minutes.
Dissolve in a mixture of 0d ethanol and 50ml methanol.

The clear solution was mixed with 5.7 g (0.02 mol) of 2-(p-chlorophenyl)-3-(aminocarbonylmethyl)-imidazo(1.2-a)pyridine as the free base (as described in the literature cited at the beginning). method) and dissolve under heating.

After cooling to room temperature, the solution is mixed with 350 ml of diethyl ethyl.

The precipitated crude salt is filtered, washed on the filter with ether and recrystallized from 50 ml of pure methanol.

Thus 5g of pure salt Melting point 169-170℃ (uncorrected)
I can be hatched.

C21H2oCIN308 (477.86)C
H CI N Calculated value: 52.78 4.22 7.42 8.
79 experimental value: 52.67 4.25 7.31
8.58 Example 2 2-(p-chlorophenyl)-3-(aminocarbonylmethyl)-imidazo[1.2-a]pyridine-hydrobromide3. 2-(p-chlorophenyl)-3-(aminocarbonylmethyl)-imidazo[1.22a]pyridine (prepared according to the literature mentioned in the introduction) as the free base of Of (0.0 1 mol) at 95% Heat the mixture in ethanol while stirring to completely dissolve the compound.

Add this solution to 3. Mix with QwLl 47% hydrobromic acid.

The salt precipitated when the solution was cooled was filtered, washed with diethyl ether, and recrystallized from 150 WLl of pure alcohol.

Analytically pure product (melting point 236-238°C (uncorrected))
I can be hatched.

C, 5H13 BvCIN30 (3 6 6.6
5) CHN Calculated value 49.14 3.57 11.46 Experimental value 49.30 3.44 11.26 S,809 can be administered, for example, as a capsule tablet or sugar-coated tablet.

Next, the composition for making tablets will be illustrated.

(1) Gelatin capsule 2-(p-chlorophenyl)-3-330■ (aminocarbonylmethyl)-imidazo[1,2-a]pyridine-polyvinylpyrrolitone citrate 1omg Talc 5mg Magnesium stearate 5mg (2)
Tablet 2-(p-chlorophenyl)-3-330 da(aminocarbonylmethyl)-imidazo[1.27a), pyridine-citrate lactose, corn starch, 450 mg gum labia, Merck, magnesium stearate.

(3) Sugar-coated tablet 2-(p-chlorophenyl)-3-250~(aminocarbonylmethyl)-imidazo[1,2-a]pyridine-hydrobromide Starch, gum arabic, stearic acid 500mg Magnesium, talc, TiQ2 , CaCO3, kaolin, and sugar pigment.

Claims (1)

[Scope of Claims] 1 Formula: 2-(p-chlorophenyl)-3-(aminocarbonylmethyl)-imidazo[1.2-a)-pyridine or its salt with an organic or inorganic acid An anti-ulcer composition comprising: