4-chloro-2-phenylimidazole-5-acetic acid derivatives and use as

Details 4-chloro-2-phenylimidazole-5-acetic acid derivatives and use as 4-chloro-2-phenylimidazole-5-acetic acid derivatives and use as

1983-05-17

1986-04-15

Jiles, Henry R.

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

548337, C07D23366, A61K 31415

Patent

active

045828474

DESCRIPTION:

BRIEF SUMMARY
DESCRIPTION

1. Technical Field
This invention relates to novel imidazole derivatives having excellent pharmacological actions.
2. Background Art
There are known various imidazole derivatives having diuretic and antihypertensive actions but none of the derivatives so far reported have been clinically satisfactory.
The extensive research undertaken by the present inventors resulted in the successful preparation of imidazole derivatives possessing desirable diuretic and antihypertensive actions and, consequently, in the development of this invenion.


DISCLOSURE OF THE INVENTION

This invention relates to novel imidazole derivatives having excellent pharmacological actions. More particularly, this invention provides compounds of the formula ##STR2## wherein R is lower alkyl and salts thereof, which have angiotensin II-antagonizing, diuretic and antihypertensive activities and are of use as diuretics and antihypertensives.
Referring to the formula (I), lower alkyl R is preferably of 1 to 3 carbon atoms, such as methyl, ethyl, propyl, i-propyl, etc.
The above-mentioned compound (I) can be produced for example by (A) deprotecting a compound of the formula ##STR3## wherein R is lower alkyl and R.sup.1 is a protective group, or, alternatively, by (B) hydrolyzing a compound of the formula ##STR4## wherein R is as defined above.
Referring to the above formula (II), the protective group R.sup.1 may for example be lower (C.sub.1-3) alkyl or a benzyl group which may be substituted (by 1 to 3 C.sub.1-3 alkyl, C.sub.1-3 alkoxy or/and other groups). The method of deprotection is optional only if it is capable of replacing R.sup.1 with a hydrogen atom, e.g. solvolysis, hydrogenolysis or a suitable dealkylation reaction.
When R.sup.1 is lower alkyl, there may be mentioned such procedures as 1) heating in the presence of an aqueous hydrogen halide, 2) reaction with trimethylsilyl iodide and subsequent treatment with water, 3) reaction with boron tribromide and subsequent treatment with water and 4) reaction in the copresence of a Lewis acid and a sulfur-containing compound followed by treatment with water, for instance.
In process 1), 1 to 10 hours of heating in 20 to 60% hydrobromic acid at 50.degree. to 150.degree. C. is desirable. In process 2), II is preferably reacted with 1 to 5 equivalents of trimethylsilyl iodide in a solvent such as acetonitrile at 50.degree. to 90.degree. C. for 10 to 50 hours and, then, water is added. In process 3), II is reacted with 1 to 2 equivalents of boron tribromide in a solvent such as dichloromethane at 10.degree. to 30.degree. C. for 1 to 10 hours, followed by treatment with water. In process 4), II is preferably reacted with 3 to 5 equivalents of a Lewis acid and 3 to 30 equivalents of a sulfur-containing compound in a solvent such as dichloromethane at 0.degree. to 30.degree. C. for 1 to 20 hours, followed by treatment with water. The Lewis acid mentioned above is preferably aluminum chloride, ferric chloride or the like, and the sulfur-containing compound is preferably 1,3-ethanedithiol, thiophenol, thioglycolic acid, dimethyl disulfide, diethyl disulfide or the like.
When R.sup.1 is said benzyl group which may be substituted; there may be employed the process comprising heating (II) in trifluoroacetic acid for 10 minutes to 1 hour or the catalytic reduction reaction in hydrogen gas streams in the presence of a suitable catalyst such as palladium, Raney nickel or the like.
The hydrolysis of said compound (III) is conducted advantageously in the presence of an alkali or an acid. The alkali is preferably a metal hydroxide such as sodium hydroxide, potassium hydroxide, etc., while the acid is preferably a mineral acid such as hydrochloric acid, sulfuric acid, hydrobromic acid, etc. The solvent is preferably aqueous alcohol. Generally, this reaction is preferably conducted at 50.degree. to 100.degree. C. for 2 to 10 hours.
The resulting compound (I) can be easily isolated by the conventional separation procedure such as aqueous dilution, extraction, neutralization, recrystallization, et

REFERENCES:
patent: 4207324 (1980-06-01), Matsumura et al.
H. Karppanen et al., Agents and Actions, 9, 84-85 (1979).
M. H. Maxwell, Advances in Nephrology, 8, 297-319 (1979).

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