Imidazole derivatives

Details Imidazole derivatives Imidazole derivatives

1988-04-11

1990-08-28

Gerstl, Robert

Organic compounds -- part of the class 532-570 series

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

548343, C07D23390, C07D41304

Patent

active

049526987

DESCRIPTION:

BRIEF SUMMARY
The invention relates to new CNS active imidazole derivatives of general formula I ##STR3## wherein
R.sup.1 represents hydrogen or halogen in the o-, m- or p-position, and the halogen can occur once or repeatedly in the phenyl radical,
R.sup.4 represents ##STR4## with R.sup.6 and R.sup.9 representing hydrogen or a straight or branched alkyl group with 1 to 6 carbon atoms, R.sup.7 and R.sup.8 are the same or different and represent hydrogen or a straight or branched alkyl group with 1 to 6 carbon atoms or R.sup.7 and R.sup.8 together with the nitrogen atom represent a saturated heterocyclic five-membered or six-membered ring optionally containing another heteroatom, and
R.sup.5 represents hydrogen, an alkyl group with 1 to 6 carbon atoms or an alkoxyalkyl grop with 1 to 6 carbon atoms.
By halogen is understood fluorine, chlorine, bromine or iodine, with fluorine and chlorine being preferred.
By alkyl is meant in each case a straight or branched alkyl grop with 1 to 6 carbon atoms, for example, the methyl, ethyl, propyl, isopropyl, butyl, pentyl and hexyl group. C.sub.1-4 alkoxy C.sub.1-4 alkyl, especially C.sub.1-4 alkoxymethyl is to be regarded as preferred embodiment for R.sup.5 in the meaning of alkoxyalkyl.
If R.sup.7 and R.sup.8 together with the nitrogen atom represent a saturated heterocyclic five-membered or six-membered ring optionally containing another heteroatom, ##STR5## for example, stands for pyrrolidine, piperidine, morpholine or piperazine.
It is known that certain sites in the central nervous system of vertebrates exhibit a high specific affinity for the binding of 1,4- and 1,5-benzodiazepines (Squires, R. F. and Braestrup, C., Nature (London) 266 (1977) 734). These sites are called benzodiazepine receptors.
It has been found that the substituted imidazole derivatives according to the invention, although they differ greatly from benzodiazepines in their chemical structure, surprisingly exhibit a great affinity and specificity for binding on the benzodiazepine receptors and at the same time only slight toxicity.
Thus, the compounds according to the invention can, for example, have agonistic, inversely agonistic and antagonistic effects on the known properties of benzodiazepines. Benzodiazepines, for example, exhibit anticonvulsive, anxiolytic and muscle-relaxing as well as sedating effects.
A disadvantage of the benzodiazepines is the relatively broad activity spectrum with slight selectivity.
Therefore, as before there exists a need for well tolerated substances with dissociated CNS effectiveness.
The compounds according to the invention on the basis of their biological effectiveness appear to be suitable as psychopharmaceuticals for human medicine. They can be formulated for psychopharmaceutical preparations, for example, for oral and parenteral application.
As formulation auxiliary agents physiologically tolerable organic and inorganic vehicles, which are inert toward the compounds according to the invention, are suitable.
As vehicles there can be mentioned, for example, water, salt solutions, alcohols, polyethylene glycols, polyhydroxyethoxylated castor oil, gelatins, lactose, amylose, magnesium stearate, talc, silicic acid, fatty acid mono- and di-glycerides, pentaerythritol fatty acid ester, hydroxymethylcellulose and polyvinyl pyrrolidone.
The pharmaceutical preparations can be sterilized and/or mixed with auxiliary agents, such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, buffering agents and dyes.
For parenteral application especially injection solutions or suspensions, particularly aqueous solutions of the active compounds in polyhydroxyethoxylated castor oil are suitable. Surfactant auxiliary agents such as salts of bile acids or animal or vegetable phospholipids, but also mixtures of them as well as liposomes and their components can also be used as vehicles.
Especially tablets, dragees or capsules with talc and/or a hydrocarbon vehicle or binder, such as, for example, lactose, corn or potato starch are suitable for oral application. The application ca

REFERENCES:
patent: 4292431 (1981-09-01), Kim
patent: 4755213 (1988-07-01), Schmierer
patent: 4780539 (1988-10-01), Watjen
Chemical Abstracts Registry No. 18075-64-4 (1978).
Goderol, J. Med. Chem. 8, 220 (1965).
Ktritzky Comprehensive Heterocyclic Chemistry vol. 5, p. 468 (1952).

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