KR20010012884A - Use of 1-ar(alk)ylimidazolin-2-one for treating anxiety and stress conditions - Google Patents

Abstract

The present invention relates to the use of 1-ar (alk) imidazolin-2-one of formula (I) or a pharmaceutically acceptable salt thereof in the treatment of anxiety and stress conditions. 1- (4-chlorophenyl) -4-morpholino-2-imidazolin-2-one can be mentioned.

Description

Use of 1-ar (alk) ylimidazolin-2-one for treating anxiety and stress conditions}

The present invention relates to the use of 1-ar (alk) imidazolin-2-one of formula (I) or a pharmaceutically acceptable salt thereof in the treatment of anxiety and nervous conditions.

Compounds of formula (I) are described in German Patent Application No. 195 32 668.7.

In the above formula,

X is hydrogen, C ₁ -C ₄ -alkyl, C ₁ -C ₄ -alkoxy, trifluoromethyl or halogen,

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

R ¹ and R ² together are an alkylene group of 2 to 6 carbon atoms in which one -CH ₂ -group may be substituted with oxygen, nitrogen or sulfur,

n (number of CH ₂ groups) is 0 (1-aryl-imidazolin-2-one) or 1 (1-aralkylimidazolin-2-one),

m is 0, 1, 2, 3, 4 or 5.

As can be seen from the pharmacological results, the compounds of formula (I) are suitable for the treatment of various types of interstitial disorders.

To date, anxiety and tension conditions of different causes and intensities cannot be satisfactorily treated in all cases. Since about 1960, benzodiazepines derivatives have been used as important substances for the treatment of anxiety and tension conditions. In general, materials with such a profile exhibit sedative and excitatory-weakening effects. In the short term, these agents are quite beneficial, but side effects such as sedation, drowsiness, and reduced responsiveness occur at therapeutic doses.

There may be negative effects on psychological effects of sedation. In part, ataxia and coordination disorders can be observed, which can affect functional capacity. In continuous use, these benzodiazopepine compounds will cause addictive effects, the so-called resistance. As the efficacy of these agents decreases, the dosage should be increased. Psychological dependence, of course, will increase physiological dependence. Thus, complex withdrawal will occur when attempting to discontinue dosing.

The most important representative anxiolytic agents on the market are the active compounds diazepam, clonazepam and medazepam. In order to achieve the anxiolytic action of diazepam, a plasma concentration of 300 to 400 mg / ml is required. However, at such concentrations, side effects such as daytime sedation, drowsiness, and a number of motor disturbances and sedation that are evident in limited attention and responsiveness also occur. Because of the high half-life of diazepam and clonazepam, serious "side effects" can result, which is also associated with drowsiness, impairment of intellectual and motor skills, and delay in response time. The anxiety relief action of clonazepam can be hidden by sedation or hypnosis. In addition, high doses of medazepam are associated with hypnotic, muscle-relaxation phenomena.

All three agents increase the action of various centrally active agents and alcohols. In this case, a nearly detectable effect may occur after the administration of each substance.

In the case of relatively long-standing anxiety, no satisfactory therapeutic criteria have been achieved. At present, the treatment-sustaining action of the anxiety relief agent is also not adequately guaranteed.

Accordingly, it is an object of the present invention to provide a medicament for treating different anxiety and nervous conditions, with a great range of treatments.

Surprisingly, it has now been found that the compounds of formula (I) exhibit significant anxiety relief without involving a soothing effect in animal experiments.

Pharmacological investigation

The purpose of investigating the compounds of formula (I) is to assess the possible effects in models for investigating the action on anxiety. For this purpose, the animals are exposed to different conflict situations and the effect by, for example, compound 1- (4-chlorophenyl) -4-morpholinimidazolin-2-one (Example 1) is measured.

Investigation of Anxiety Suppression in the Vogel Conflict Test

In this model, the rats do not have continuous access to the drink for a period of time. After this period, the drink is freely accessible, but connects a weak electrical stimulus to the drink. The animal's conflict is either accepting electrical stimulation or staying without a drink.

The response to this type of conflict situation is similar to secondary anxiety in humans. An avoidance reaction occurs that can be inhibited by anxiolytics. As a measure of anxiolytic action, the resistance values of the current pulses of animals treated with the material are calculated by comparison with the vehicle-treated control group. The experimental results obtained as in Table 1 are shown graphically in FIG. 1.

Anxiety Relieving Effects of Substances in the Vogel Conflict Test in Rats (X ± SEM; * p <0.05, ** p <0.01) matter mg / kg (oral administration) Impulse % Changed Impulse Values for Control Control Example 1 Control - 51.4 ± 7.73 One 61.3 ± 8.72 19.3 3 83.2 ± 7.19 ** 61.9 10 80.1 ± 9.23 ** 55.8 - 39.6 ± 7.20 30 126.0 ± 15.7 ** 218.0 Control diazepam - 62.3 ± 7.07 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 ± 11.9 ** 67.6 Control clonazepam - 63.9 ± 6.63 0.1 77.7 ± 8.54 21.6 0.3 81.8 ± 7.81 28.0 1.0 110.3 ± 13.5 * 72.6 Control medazepam - 54.6 ± 7.89 0.3 54.8 ± 8.85 0.4 1.0 71.3 ± 10.0 30.6 3.0 42.7 ± 4.54 -21.8

In the case of the compound as in Example 1, oral administration of 3 mg / kg can be detected anxiety relief, but this does not increase even if the oral dose is increased to 10 mg / kg. After increasing the oral dose to 30 mg / kg, the action can be measured to be elevated. Equally effective amounts for oral administration of diazepam and clonazepam are 1 to 3 mg / kg and 1 mg / kg, respectively.

In the case of medazepam, no action can be detected in the oral dosage range of 0.3 to 3 mg / kg.

Untreated animals drink much less water, which means that they are more anxious than animals treated with anxiety-inhibiting substances. 3 mg / kg oral administration of a compound as in Example 1 significantly increases the resistance value of electrical stimulation. From these effects, it can be confirmed that the excellent anxiety alleviating effect of the compound of formula (I).

Thus, it can be expected that the compounds of formula I will inhibit anxiety, particularly in conflict situations.

Investigation of anxiety suppression in expensive maze

For this model, rats are placed in an elevated passage system with open and closed armrests. Pellow, S., Chopin, P., File SE, Briley, M .: Validation of open: closed arms entries in an elevated plus-maze as a measure of arm entries in an elevated plus-maze as a 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 repeatedly select closed passages. Anxiety suppression is measured as a percentage of total entry and total stay time by the number of entries into the open armrest passage and the time of stay in the open armrest passage. When treated with a compound of formula (I), as can be seen from FIG. 2, the percentage of entry and stay into the open armrest passage increases. After intraperitoneal administration of 10 or 30 mg / kg of the compound as in Example 1, the ratio of entry into and open stay in the open armrest passage increased significantly.

In pharmacological experiments, the compounds of formula I show a clear separation between anxiolytic and sedative effects. As is apparent from FIG. 3, for example, the compound as in Example 1 shows a significantly lower soothing effect compared to the comparative substance, dazepam.

Central sedation of compounds of formula (I) is investigated in mice. The animals are administered with an amount of alcohol that does not allow the mouse to lie on its side. The degree of elevation of the hypnotic effect of alcohol may be checked and the compound of formula I may be further administered to allow the mouse to lie on its side. For example, a dose of a compound, such as in Example 1, 15-66 times the anxiolytic dose, causes only a low, non-dosage-dependent rise in alcohol action. In contrast, diazepam and clonazepam are investigated within the range of anxiolytic doses. For both standard compounds, a strong, dose-dependent rise in alcohol action can be measured (FIG. 3).

Compounds of formula I have very low neurotoxicity compared to the comparative compounds diazepam and clonazepam.

The minimum neurotoxic dose of the compound as in Example 1 was determined to be 998 mg / kg (oral administration) in a rotorod test.

The therapeutic index, calculated as the quotient of the minimum neurotoxic dose and the anxiolytic dose in the swivel test, is a very high value of 333, indicating a significant therapeutic range, as can be seen from FIG.

The therapeutic range of a substance in the case of an important pharmacologically characteristic amount is a measure of the safety between the therapeutic and toxic effects. Thus, it is surprising that the compounds of formula (I) have a significantly higher therapeutic range than commercially available anxiety activating substances. As a result, in particular, the treatment of patients with anxiety and tension over a relatively long period of time is significantly improved.

The compounds of formula (I) and pharmaceutically acceptable salts thereof can be converted into pharmaceutical formulations such as tablets, capsules, refining tablets, granules, emulsions, suspensions or solutions by known methods. Conventional pharmaceutical excipients and auxiliaries can be used to prepare these formulations. In this case, the daily dose should preferably be 3 to 30 mg / day.

Claims (3)

Use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of anxiety and tension. Formula I In the above formula, X is hydrogen, C ₁ -C ₄ -alkyl, C ₁ -C ₄ -alkoxy, trifluoromethyl or halogen, R ¹ and R ² are C ₁ -C ₄ -alkyl, cycloalkyl or heteroalkyl, or R ¹ and R ² together are an alkylene group of 2 to 6 carbon atoms in which one -CH ₂ -group may be substituted with oxygen, nitrogen or sulfur, n (number of CH ₂ groups) is 0 (1-aryl-imidazolin-2-one) or 1 (1-aralkylimidazolin-2-one), m is 0, 1, 2, 3, 4 or 5. The use of a compound of formula I according to claim 1 in the treatment of conflict-associated anxiety conditions. A medicament exhibiting an anxiolytic action comprising at least one compound of formula (I) or a pharmaceutically acceptable salt thereof, and optionally an excipient and / or adjuvant.