CZ296188B6 - 1-Ar(alk)yl-imidazolin-2-one for treating anxiety and stress conditions - Google Patents

Abstract

The present invention relates to the use of 1-ar(alk)yl-imidazolin-2-ones of the general formula I, in which the substituents and variables have specific meaning and their pharmaceutically acceptable salts for preparing a medicament intended for the treatment of anxiety and stress conditions. 1-(4-chlorophenyl)4-morpholino-imidazolin-2-one serves as an example.

Description

The invention relates to the use of certain 1-ar (alk) ylimidazolin-2-ones or their pharmaceutically acceptable salts for the manufacture of a medicament for the treatment of anxiety and tension states.

BACKGROUND OF THE INVENTION

Compounds of formula (I)

(I) wherein n is 0 or 1, m is 0, 1, 2, 3, 4 or 5,

X represents a hydrogen atom, a (C1-C4) alkyl group, a (C1-C4) alkoxy group, a trifluoromethyl group or a halogen atom,

R ¹ and R ² are C 1 -C 4 alkyl, cycloalkyl or heteroalkyl, or

R ¹ and R ² together represent an alkyl group having 2 to 6 carbon atoms, one methylene group being replaced by an oxygen, nitrogen or sulfur atom and the number of methylene groups being either 0, in the case of 1-arylimidazolin-2-one, or 1, in the case of 1-aralkylimidazolin-2-one, they are described in German Patent Application No. 195 32 668.

The pharmacological results show that the compounds of formula I are suitable for the treatment of states of fear and tension.

Even today, states of fear and tension cannot be satisfactorily treated in all cases for various reasons and to varying degrees. Since about 1960, benzodiazepine derivatives have been used to treat fear and tension. Substances with such a profile have a generally calming and dampening effect. These drugs work well in the short term, but side effects such as sedation and somnolence as well as decreased responsiveness are already seen at therapeutic doses.

By calming down, mental processes can be adversely affected. In part, ataxia and coordination disorders that affect performance can be observed. With continued use, these benzodiazepine compounds lead to addictive effects and so-called tolerance. The efficacy of the composition is reduced and the dose must be increased. Mental and physical dependence may develop. Therefore, complicated withdrawal phenomena occur during withdrawal tests.

Diazepam, clonazepam and medazepam are mentioned as the most prominent representatives of the marketed anxiolytics.

-1 CZ 296188 B6

A plasma concentration of 300 to 400 mg / ml is required to achieve the anxiolytic effect of diazepam. At the same concentrations, however, these side effects, such as sedation and psychomotor disturbances, occur, which manifest themselves in calming daytime, sleepiness, as well as limited attention and responsiveness. Due to the high half-life of clonazepam, there are strong hangovers, which are also associated with somnolence, impaired intellectual and motor performance, as well as prolonged reaction times. The anxiolytic action of clonazepam is covered by a sedative or hypnotic effect. Also, high doses of medazepam are associated with hypnotic and muscular relaxation phenomena.

All three drugs enhance the effect of numerous centrally acting drugs and alcohol. There may be phenomena that are hardly noticeable when the individual substances are administered.

To date, satisfactory therapeutic standards have not been achieved in longer anxiety states. Also, the therapy of sustained action of drugs, releasing anxiety feeling is not sufficiently ensured.

SUMMARY OF THE INVENTION It is an object of the present invention to provide a medicament for the treatment of a variety of anxiety and tension states with a wide therapeutic range.

SUMMARY OF THE INVENTION

It is an object of the present invention to use compounds of formula I

where n is 0 or 1, m is 0, 1, 2, 3, 4 or 5,

X represents a hydrogen atom, a (C1-C4) alkyl group, a (C1-C4) alkoxy group, a trifluromethyl group or a halogen atom,

R ¹ and R ² are C 1 -C 4 alkyl, cycloalkyl or heteroalkyl, or

R ¹ and R ² together represent an alkylene group having 2 to 6 carbon atoms, one methylene group being replaced by an oxygen, nitrogen or sulfur atom and the number of methylene groups being either 0, in the case of 1-arylimidazolin-2-one, or 1, in the case of 1-arylalkylimidazoline-

2-one, and pharmaceutically acceptable salts thereof for the manufacture of a medicament for the treatment of anxiety and tension states.

A preferred embodiment of the present invention is the use of the compounds of formula I for the manufacture of a medicament for the treatment of conflict-related anxiety states.

Surprisingly, it has been found that the compounds of formula (I) exhibit significant anxiolytic activity in animal experiments, without any sedative effects.

-2GB 296188 B6

Fear states are equivalent to anxiety states and both terms may be used interchangeably within the scope of the present invention.

Pharmacological tests

The aim of the tests of the compounds of the formula I is to eliminate possible influences in the models for testing the effects of anxiety. To this end, the animals are exposed to various conflict situations and the effect on, for example, the compound 1- (4-chlorophenyl) -4-morpholinoimidazolin-2-one (Example 1) is measured.

Fear suppression test in Vogel's conflict test

In this test model, rats are prevented from accessing drinking water for some time. After this period, access to drinking water is released, but associated with slight electrical irritation. There is a conflict in animals whether to undergo electronic irritation or to refrain from drinking.

Responses to such conflict situations resemble subsequent manifestations of fear in humans. There are rejection phenomena which can be suppressed by anxiolytically acting substances. The number of tolerated current shocks of the animals treated with the substance was evaluated as a measure of the anxiolytic effect compared to the vehicle-treated control group. The results of the experiment according to Table I are shown graphically in FIG. 1.

Table 1

Anxiolytic action of substances in rats subjected to Vogel conflict test x ± standard deviation * p <0.05, ** p <0.01

Substance mg / kg p.o. Impulses Altered pulse count vs. control,% Control - 51.4 ± 7.73 Example 1 1.0 61.3 ± 8.72 19.3 3.0 83.2 ± 7.19 ** 61.9 10.0 80.1 ± 9.23 ** 55.8 - 39.6 ± 7.2 Control 30.0 126.0 ± 15.70 ** 218.0 Control - 62.3 ± 7.07 Diazepam 0.1 58.4 ± 6.47 -6.3 0.3 70.9 ± 6.85 13.8 1.0 92.1 ± 3.22 ** 47.8 3.0 104.4 ± 11.90 ** 67.6 Control - 63.9 ± 6.63 Clonazepam 0.1 77.7 ± 8.54 21.6 0.3 81.8 ± 7.81 28.0 1.0 110.3 ± 13.50 * 72.6 Control - 54.6 ± 7.89 Medazepam 0.3 54.8 ± 8.85 0.4 1.0 71.3 ± 10.00 30.6 3.0 42.7 ± 4.54 -21.8

The compound of Example 1 has been shown to have an anxiolytic effect from as low as 3 mg / kg p.o., which is increased to 10 mg / kg p.o. no longer increases.

After increasing the dose to 30 mg / kg p.o. potentiation was measured. Doses of diazepam and clonazepam with the same effect are 1 to 3 mg / kg p.o. and 1 mg / kg p.o. Medazepam was not possible at doses ranging from 0.3 to 3 mg / kg p.o. demonstrate no effect.

Untreated animals drink significantly less, which means they are more timid than animals that have been treated with anti-fear agents. The compound of Example 1 significantly increased the number of tolerated electrical shocks from 3 mg / kg orally. This phenomenon demonstrates a good anxiolytic effect of the compounds of formula (1).

It can therefore be expected that the compound of formula (I) has an effect of suppressing fear, especially in conflict situations.

Test of suppressing fear in a state of increased confusion

In this model, rats are embedded in an elevated open and closed shoulder disease system (S. Pellow, P. Chopin, SE Filé, M. Briley: Validation of open: closed arm entries in an elevated plus — maze as a measure of anxiety in J. of Neuroscience Methods 14, (149-167) 1985; S. Hogg, A review of the validity and variability of elevated plus-maze as an animal model of anxiety Pharmacology Biochemistry and Behavior, pp. 21-30 (1996) Untreated animals strive to enter more into closed diseases, fear suppression is measured by the number of entrances to open corridors and the dwell time in the open arms as a percentage of the total number of entrances or the total dwell time. in the open arms as shown in FIG. 2.

The proportion of open arms entrances and dwell time in open arms is significantly increased following intraperitoneal administration of the compound of Example 1 at a dose of 10 to 30 mg / kg.

The compounds of formula I show a strong separation of anxiolytic effect and sedation phenomena in a pharmacological experiment.

Figure 3 shows that, for example, the compound of Example 1 exhibits substantially less sedation compared to diazepam as a comparator.

The central sedative activity of the compounds of formula I is investigated in mice. Animals are given an amount of alcohol that does not cause the mice to lay on their sides. It is tested to what extent the hypnotic effect of the alcohol intensifies and whether the additional dose of the compounds of formula I can cause the animals to lie sideways. For example, dosing of the compound of Example 1, which is 15 to 66 times the anxiolytically acting dose, produces only a minor and dose independent enhancement of the effect of the alcohol. In contrast, diazepam and clonazepam were studied in the anxiolytically effective dose range. For both standard compounds, a strong dose-dependent potentiation of the effect of alcohol could be measured (Fig. 3).

Compounds of formula I also show very low neurotoxicity compared to diazepam and clonazepam as comparators.

The minimum neurotoxic dose of the compound of Example 1 is determined by a stick rotation test of 998 mg / kg p.o.

The therapeutic index, calculated as the ratio of the minimum neorotoxic dose in the rod rotation test and the anxiolytically effective dose, is very high at 333 and indicates a large therapeutic width as seen in Figure 4.

The therapeutic width of a substance, as an important pharmacological variable, is a measure of safety between therapeutic and toxic effects.

Therefore, it is all the more surprising that the compounds of the formula I exhibit a significantly higher therapeutic width compared to the anxiolytically active active compounds. In particular, long-term treatment of patients with fear and tension conditions is also significantly improved.

-4GB 296188 B6

The compounds of the formula I as well as their pharmaceutically usable salts can be converted in a known manner into pharmaceutical compositions such as tablets, capsules, dragees, granules, emulsions, suspensions or solutions.

Conventional carriers and excipients may be used to prepare such compositions. The daily dose should preferably be 3 to 30 mg per day.

Claims (2)

Use of compounds of formula I (I) wherein n is 0 or 1, m is 0, 1, 2, 3, 4 or 5, X represents a hydrogen atom, a (C1-C4) alkyl group, a (C1-C4) alkoxy group, a trifluoromethyl group or a halogen atom, R ¹ and R ² are C 1 -C 4 alkyl, cycloalkyl or heteroalkyl, or R ¹ and R ² together represent an alkylene group having 2 to 6 carbon atoms, one methylene group being replaced by an oxygen, nitrogen or sulfur atom and the number of methylene groups being either 0, in the case of 1-arylimidazolin-2-one, or 1, in the case of 1-aralkylimidazol-2-one, as well as pharmaceutically acceptable salts thereof for the manufacture of a medicament for the treatment of anxiety and tension states. Use of compounds of formula I according to claim 1 for the manufacture of a medicament for the treatment of conflict-related anxiety states. 4 drawings -5GB 296188 B6 Increase the number of pulses above the control value (%) Compound i Diazepam Vogel conflict test Explanatory notes: control = 0%, * p <0.05, ** p <0.01, *** p <0.001 significant compared to control group, Student's t-test Giant. 1 -6GB 296188 B6 Compound I mg / kg ί · Ρ · Entry into open arms EZZZ / 3 Delay in open arms Explanatory notes: * p <0.05, ** p <0.01 compared to the control group, Student's t-test Increased confusion Giant. 2 Number of animals laying sideways (%) 0.3 0.06 100 ALIGN! 0.67 0.12 200Compound i · 1.33 Diazepam O 0.24 Clonazepam ^Δ mg / kg po Sedative effects Giant. 3 -8EN 296188 B6 mg / kg p.o. 400 -j / 80 70 60 50 40 30 20 10 Compound I Diazepam Clonazepam Neurotoxicity Therapeutic breadth Giant. 4 End of document