MXPA99010609A - Use of 1-ar(alk)yl-imidazolin-2-one for treating anxiety and stress conditions - Google Patents

Abstract

The invention relates to the use of 1-ar(alk)yl-imidazolin-2-ones of general formula (I) or their pharmaceutically acceptable salts for treating anxiety and stress conditions. 1-(4-chlorophenyl)4-morpholino-imidazolin-2-one serves as an example.

Description

EMPLOYMENT OF l-AR (ALQU) IL-IMIDAZOLIN-2-ONAS FOR THE TREATMENT OF ANXIETY AND TENSION STATUSES Description of the invention The invention relates to the use of 1-ar (alkyl) -imidazolin-2-ones- of the general formula I or its pharmaceutically acceptable salts, for the treatment of anxiety and tension states. The compounds of the general formula I wherein X = means hydrogen, C1-C4-alkyl, C? -C4-alkoxy, trifluoromethyl, halogen R1 or R2 = mean C? -C-alkyl, cycloalkyl, heteroalkyl or. R1 and R2 together mean an alkylene group with 2-6 carbon atoms in which a CH2 group may be substituted by oxygen, nitrogen or sulfur, and the amount of the CH2 groups is either 0 (1-aryl-imidazolin- 2-onas) or 1 (l-aralkyl-imidazolin-2-ones) are described in the German patent application 195 32 668.7. The pharmacological results show that the compounds of the general formula I are suitable for the treatment of various epileptic diseases. Even today it is impossible to satisfactorily treat in all cases the states of anxiety and tension of diverse origin and manifestation. Since about 1960, benzodiazepine derivatives are mainly used for the treatment of anxiety and tension states. Substances with such a profile usually have a calming and impulse-attenuating effect. In the short term these drugs are of great help, but already in therapeutic dosages there are side effects such as sedation, drowsiness and a reduced capacity for reaction. Due to sedation, a negative influence of mental processes may ensue. In part, ataxia and coordination disorders can be observed that influence (negatively) efficiency. In the case of permanent use, these benzodiazepine compounds generate habit effects, which is known as tolerance. The effectiveness of the preparation is reduced and it is necessary to increase the dose. A psychic and even more physical dependency can develop. That is why there are complicated deprivation phenomena when trying to stop taking them. As the most important representatives of the anxiolytics introduced in the market, the active substances diazepam, clonazepam and medazepam can be mentioned. To obtain anxiolytic activity of diazepam, plasma concentrations of 300 to 400 mg / ml are required. However, at these same concentrations there are also the mentioned secondary effects, such as sedation and psychomotor disorders that manifest themselves in diurnal sedation, drowsiness as well as an inhibition of the capacity of concentration and reaction. Due to the high half-life of diazepam and clonazepam, there are strong "crude" effects, which also go hand in hand with somnolence, deterioration of intellectual and motor capacity, as well as longer reaction intervals. The anxiolytic activity of clonazepam is disguised by the sedative or hypnotic effect. Also the high doses of medazepam go together with hypnotic phenomena and muscle relaxation. All three drugs increase the effect of many drugs with central activity, and alcohol. In this, effects can be presented that it is almost impossible to foresee when administering the individual substances. To date, it has not been possible to achieve a satisfactory therapeutic standard in the case of longer anxiety states. At present, an effect that exceeds the duration of the therapy, of the anxiety-resolving drugs, is not sufficiently guaranteed. Therefore, the task of the present invention is to provide for the treatment of various states of anxiety and tension, drugs that have a wide therapeutic range. Surprisingly it was discovered in animal experiments that the compounds of the general formula I possess significant anxiolytic activity without sedative side effects. Pharmacological investigations The purpose of the investigations with the compounds of the general formula I is to evaluate the possible influence in models for the investigation of the activity against states of anxiety. For this purpose the animals were exposed to various conflicting situations and an exemplary influx was measured by the compound 1- (4-chlorophenyl) -4-morpholino-imidazolin-2-one (Example 1) . Investigation of inhibition of anxiety in the Vogel conflict trial In this model rats are deprived for a certain period of time of access to water. After this period the free access to drinking water is again allowed, but nevertheless it is coupled to a slight electrical stimulus. For the animals the conflict of accepting the electrical stimulus or refraining from drinking arises. The reactions to such conflicting situations are similar to the sequels of anxiety in the human being. Evasion reactions occur which can be suppressed by the substances of anxiolytic activity. As a measure of the anxiolytic effect, the number of current discharges tolerated by the animals treated with the substance is evaluated, as compared to the control group treated with vehicle. The results of the test that were obtained according to table 1 are represented in graphic form in figure 1.

Table 1 Anxiolytic activity of the substances in the Vogel conflict rats test ± SEM; *? < 0.05, ** p < 0.01 Table 1 For the compound according to example 1, an anxiolytic activity was already observed from 3 mg / kg p.o. which does not increase with an increase in dose to 10 mg / kg p.o. After increasing the dose to 30 mg / kg p.o. An increase in activity could be measured. The equiefective doses of diazepam and clonazepam are 1 to 3 mg / kg p.o and 1 mg / kg p.o. For the medazepam, no activity could be verified in the dosage range of 0.3 to 3 mg / kg p.o. Untreated animals drink considerably less, which means that they suffer more anxiety than animals treated with anxiety-inhibiting substances. The compound according to example 1 increases the amount of electrical stimuli tolerated significantly from the oral dose of 3 mg / kg. This effect documents the good anxiolytic activity of the compounds of the general formula I. It is therefore expected that the compounds of the general formula I cause an inhibition of anxiety, in particular in conflictive situations. Investigation of the inhibition of anxiety in the elevated labyrinth In this model the rats are introduced in an elevated system of corridors with open and closed branches (Peílow, S., Chopin, P., File SE, Briley, M.: Validation of open: closed arm entries in an elevated plus-maze aa measure of anxiety in rats J. of Neuroscience Methods 14: 149-167, 1985; Hogg, S .: A review of the validity and variability of the elevated plus-maze as an animal model of anxiety, Pharmacology Biochemistry and Behavior: 21-30, 1996). Untreated animals tend mostly to closed corridors. The inhibition of anxiety is measured based on the number of entries to the open branches and the time of permanence in the branches opened percentage with respect to the totality of the entries or the total residence time. The treatments with the compounds of the general formula 1 increase percentage of the entrances and the time of permanence in the open branches, as can be seen from figure 2. The proportion of entrances to the open branches and the residence time in the branches. open branches is significantly increased after intraperitoneal application of 10 and 30 mg / kg of the compound according to example 1. The compounds of the general formula I show a large separation between the anxiolytic activity and the sedative effects in the pharmacological experiment. It can be seen from FIG. 3 that, for example, the compound according to Example 1 has considerably less sedation than the comparative substance diazepam. The central sedative activity of the compounds of the general formula I was investigated in mice. The animals were given an amount of alcohol that does not cause lateral decubitus of the mice. It was investigated to what extent the hypnotic effect of the alcohol is increased and side decubitus can be induced in the animals by additional administration of the compounds of the general formula I. The exemplary dosages of the compound according to example 1 amount to 15 to 66 times of the anxiolytically active dose induce only an increase in the effect of alcohol, weak and independent of the dose. In comparison, diazepam and clonazepam were investigated in the anxiolytically active dosage range. For both standard compounds, a strong increase in the effect of alcohol on the dose function could be measured (Figure 3). The compounds of the general formula I also show a very reduced neurotoxicity compared to the comparative substances diazepam and clonazepam. The minimum neurotoxic dose of the compound according to example 1 was determined with 998 mg / kg p.o. in the rotating rod test.

The therapeutic index calculated as a quotient of the minimum neurotoxic dose in the rotating rod test and the anxiolytically active dose is very high with the value of 333 and is indicative of a wide therapeutic range, as can be seen in figure 4. The therapeutic range as an important pharmacological characteristic is a measure of safety between therapeutic activity and toxic activity. That is why it was all the more surprising that the compounds of the general formula I showed a substantially greater therapeutic range compared to substances of anxiolytic activity that exist in the market. Thus, the treatment of patients suffering from anxiety and tension states, in particular for a longer period of time, is markedly improved. The compounds of the general formula I as well as their pharmaceutically acceptable salts can be converted in a known manner into pharmaceutical formulations such as tablets, capsules, dragees, granules, emulsions, suspensions or solutions. The usual pharmaceutical carriers and auxiliaries can be used to prepare these preparations. In this the daily dose should preferably be 3-30 mg / day.

Claims (2)

1. Use of compounds of the general formula I wherein X = means hydrogen, C? -C4-alkyl, C? -C-alkoxy, trifluoromethyl, halogen R1 or R2 = mean C? -C4-alkyl, cycloalkyl, heteroalkyl or R1 and R2 together mean an alkylene group with
2. 2-6 carbon atoms in which a CH2 group may be substituted by oxygen, nitrogen or sulfur, and the amount of the CH2 groups is either 0 (1-aryl-imidazolin-2-ones) or 1 (1) -aralkyl-imidazolin-2-ones), as well as their pharmaceutically acceptable salts to produce a medicament for the treatment of anxiety and tension states. Use of the compounds of the general formula I according to claim 1 for the treatment of anxiety conditions conditioned by conflicts. A drug with anxiolytic activity containing at least one compound of the general formula I or its pharmaceutically acceptable salts, and optionally vehicles and auxiliary substances.