Imidazole derivatives

Details Imidazole derivatives Imidazole derivatives

1983-10-31

1986-04-08

Brust, Joseph Paul

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

546256, 546278, 548336, 548346, A61K 31415, C07D23360

Patent

active

045813698

DESCRIPTION:

BRIEF SUMMARY
TECHNICAL FIELD

This invention relates to novel imidazole derivatives and pharmaceutically acceptable acid addition salts thereof useful as pharmaceuticals, methods for preparing the same and pharmaceutical compositions containing such compound.


DISCLOSURE OF THE INVENTION

Imidazole derivatives of this invention are represented by the formula: ##STR2## wherein each of R.sup.1 and R.sup.4 is a hydrogen atom or a lower alkyl group; each of R.sup.2 and R.sup.3 is a hydrogen atom, a halogen atom, a hydroxyl group, a lower alkyl group, a lower alkoxy group, an aralkyloxy group, a nitro group or an amino group; A is --O--, --S--, --CH.dbd.CH-- or --CH.dbd.N--; Z is an aryl group, a thienyl group, a pyridyl group or a furyl group, in which definition these aromatic (heterocyclic) rings may have 1 to 3 substituents, each substituent being independently selected from a halogen atom, a lower alkyl group, a cyclic alkyl group, a lower alkoxy group, a hydroxy group, a carboxyl group, a lower alkoxycarbonyl group, a carboxy-lower-alkoxy group, a dilower-alkylamino-lower-alkoxy group and a nitro group.
In the above definitions, the lower alkyl group includes methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-butyl; the cyclic alkyl group includes cyclopropyl and cyclohexyl; the lower alkoxy group includes methoxy, ethoxy, propoxy, isopropoxy and butoxy; the aralkyloxy group includes benzyloxy and phenethyloxy; the lower alkoxycarbonyl group includes methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl and butoxycarbonyl; the carboxy-lower-alkoxy group includes carboxymethoxy, carboxyethoxy, carboxypropoxy and carboxybutoxy; the dilower-alkylamino-lower-alkoxy group includes dimethylaminomethoxy, dimethylaminoethoxy, dimethylaminopropoxy, dimethylaminobutoxy, diethylaminoethoxy, dipropylaminoethoxy and dibutylaminoethoxy; the halogen atom includes fluorine, chlorine, bromine and iodine; the aryl group includes phenyl and naphthyl.
According to this invention, the compounds of formula (I) can be prepared by the following methods, for example:


Method 1

This method comprises reacting a compound of the formula: ##STR3## wherein each symbol is as defined above, with an organometallic compound of the formula [a Grignard reagent (III) or an organolithium compound (IV)]: defined above.
This reaction is carried out in a non-aqueous solvent (e.g. ether, tetrahydrofuran, dioxane, benzene or toluene).


Method 2

This method, to be applied for the production of compounds of formula (I) wherein R.sup.4 is a hydrogen atom, comprises subjecting a compound of the formula: ##STR4## to reduction, wherein each symbol is as defined above.
As a reducing agent can be employed a conventional reagent having the ability to reduce a carbonyl group to the secondary alcohol.
This reaction is carried out by treating a suspension or a solution of the compound of formula (V) in a suitable solvent (e.g. water, methanol, ethanol, dioxane or a mixture thereof) with a complex metal hydride such as sodium borohydride at a temperature of from room temperature to the boiling point of the solvent employed, preferably from room temperature to 100.degree. C., for 1 to 24 hours. This reaction is also carried out by reducing the compound of formula (V) with a complex metal hydride such as lithium aluminum hydride or sodium bis-(2-methoxyethoxy)aluminum hydride in a suitable non-aqueous solvent (e.g. ether, tetrahydrofuran, dioxane or benzene) at a temperature from room temperature to the boiling point of the solvent employed.


Method 3

This method, to be applied for the production of compounds of formula (I) wherein R.sup.4 is a lower alkyl group, comprises reacting the above-mentioned compound of formula (V): ##STR5## wherein each symbol is as defined above, with a compound of the formula:
This reaction is carried out in a non-aqueous solvent (e.g. ether, tetrahydrofuran, dioxane, benzene or toluene).
The starting compounds of formula (V) can be prepared, for example, by the following Method A or Method B:


Method A



REFERENCES:
patent: 3657445 (1972-04-01), Buchel et al.
patent: 3813412 (1974-05-01), Gall et al.
patent: 3952006 (1976-04-01), Tahara et al.
patent: 3996238 (1976-12-01), Ilvespaa
patent: 4006243 (1977-02-01), Strehlke et al.
Noller, "Chemistry of Organic Compounds," (1965), pp. 224, 225, 236, 237; W. B. Saunders Co., Phila. & London.
Abstract of Japanese Patent Publication 89-369 (1975).
Chemical Abstracts 83-193312y (1975).
Chemical Abstracts 84-44045g (1976).

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