Certain 1,3,4-thiadiazole derivatives and anti-ulcer agent compr

Details Certain 1,3,4-thiadiazole derivatives and anti-ulcer agent compr Certain 1,3,4-thiadiazole derivatives and anti-ulcer agent compr

1990-07-30

1992-04-21

Rotman, Alan L.

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

546256, 546277, C07D40114, A61K 3144

Patent

active

051068591

DESCRIPTION:

BRIEF SUMMARY
TECHNICAL FIELD

The present invention relates to a novel 1,3,4-thiadiazole derivative and an anti-ulcer agent comprising this derivative as the active ingredient.


BACKGROUND ART

Recently, the number of patients suffering from digestive ulcers has increased and the development of an antacid, an anticholinergic agent, a histamine H.sub.2 receptor antagonist and the like has been promoted for the remedy of these ulcers. These agents, however, are not ideal medicines for a radical cure of these ulcers, and accordingly, the development of an agent having a greater anti-ulcer action is desired.


DISCLOSURE OF THE INVENTION

With a view to finding a substance having a better anti-ulcer action, the inventors synthesized many novel compounds and carried out screening, and as a result, found that effective compounds are present among 1,3,4-thiadiazole derivatives. We carried out further research based on this finding, and thus completed the present invention.
More specifically, in accordance with the present invention, there are provided a thiadiazole derivative represented by the following formula I, and an anti-ulcer agent comprising this derivative (hereinafter referred to as "compound of formula I") as the active ingredient: ##STR2## wherein when n is 0, m is 0, and when n is 1, m is 0 or 1.


BEST MODE OF CARRYING OUT THE INVENTION

The compound of formula I can be obtained, for example, by using 2-(3-pyridyl)-1,3,4-thiadiazoline-5-thione represented by the following formula II (hereinafter referred to as the "compound of formula II") as the starting compound and reacting this compound with ethyl 6-chloromethylnicotinate represented by the following formula III (hereinafter referred to as the "compound of formula III") to effect thioetherification: ##STR3##
The above reaction is particularly carried out in the presence of a base, and as specific examples of the base, there can be mentioned sodium hydroxide, sodium carbonate, potassium carbonate and potassium hydroxide. As the solvent, mixed solvents of water with a water-insoluble solvent such as benzene, chloroform, methylene chloride or toluene, and alcohols such as methanol and ethanol are preferably used.
The reaction time is preferably about 1 to about 30 hours. The reaction is sufficiently advanced at room temperature, but the reaction can be conducted under heating according to need.
After termination of the reaction, the reaction product can be purified by a customary purification process, for example, a recrystallization process using an appropriate solvent (such as methanol, ethanol or acetonitrile).
The obtained compound can be converted to an oxide by addition of a peroxide.
As specific examples of the peroxide, m-chloroperbenzoic acid, perbenzoic acid and sodium periodate can be used, and the reaction is completed within 15 minutes to 6 hours at -20.degree. to 40.degree. C. in an organic solvent such as chloroform or methylene chloride (if the starting compound is not dissolved, an alcohol, acetic acid or water can be appropriately used). After termination of the reaction, the reaction product can be purified by the above-mentioned process.
Furthermore, an oxide can be formed by using oxone, which is a composite of 2-KHSO.sub.5, KHSO.sub.4 and K.sub.2 SO.sub.4. In this case, the reaction is preferably carried out in the presence of an acid.
As specific examples of the solvent, there can be mentioned acetic acid/water, sulfuric acid/water, nitric acid/water and methanol/water. An acid such as methane-sulfonic acid can be added according to need. The reaction is completed with 15 minutes to 6 hours, and the reaction temperature is preferably -20.degree. C. to room temperature. After termination of the reaction, the reaction mixture is neutralized with an alkali and extracted with an organic solvent such as dichloromethane or chloroform, and the reaction product can be purified by a usual purification process (for example, by a recrystallization process or a column chromatography process using silica gel or the like).
The compounds of formula II

REFERENCES:
Ash et al., "2-Pyridine Aldoxines", Chemical Abstracts, vol. 72, No. 23, Abstract No. 121377y (Jun. 8, 1970), p. 337.
Kubota et al., "Synthesis of 1,3,4-Thiadiazole Derivatives. II. Synthesis of 1,3,4-Thiadiazoline-5-Thiones from Amidrazones and Carbon Disulfide", Chemical Abstracts, vol. 73, No. 19, Abstract No. 988/w (Nov. 9, 1970), p. 369.
Chemical Abstracts, vol. 112, No. 5, Jan. 29, 1990.
Chemical Abstracts, vol. 112, No. 17, Apr. 23, 1990.

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