JPS63101361A - Antianxiety composition containing dioxopiperidine derivative - Google Patents

Abstract

(57) [Abstract] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention provides the use of species 3-phenyl-3 as anxiolytic agents.
-Aminoalkyl-4-methyl-2,6-thioxobiperidine. In particular, the present invention provides the use of said dioxopiperidines in the manufacture of anxiolytic drugs, low unit dose compositions comprising said dioxopiperidines, and the use of said dioxopiperidines to treat anxiety disorders. This provides a method to do so.

The most widely prescribed anxiolytics are benzothiacebin agonists, such as diazepam, and these drugs are known to be effective by reacting with benzothiacebin receptors.

Although such drugs have virtually no side effects when used in low doses, their anxiolytic efficacy is often insufficient. Increasing the dose to the usual effective dose often causes side effects such as dizziness and sedation. Also, this level of dosage may cause memory impairment. Moreover, tolerance to the effects of such doses usually develops within four months of chronic use, and the risk of addiction/addiction is great for many patients.

Benzothiazepine agonists are generally gamma-aminobutyric acid (
It is believed that it exerts its anxiolytic effects by increasing the binding function of penzothiazepine receptors to GAB 8) receptors/chloride channels. Additionally, although benzothiazepine inverse agonists are known to reduce the alteration of serotonin (5-hydroxytryptamine i 5HT), the significance of this reduction was not previously known. It was.

However, surprisingly, some 3-phenyl-3-
It has been discovered that aminoalkyl-4-methyl-2,6-dioxopiperidine (defined below) has strong anxiolytic effects.

British Patent No. 1455687 (as well as Australian Patent No. 480855 and Belgian Patent No. 808958)
3-phenyl-3-aminoalkyl-4- and/or methyl 5-
2.6-dioxopiperidine derivatives have central nervous system activity,
In particular, it has been disclosed that it has antidepressant effects. Among the above compounds, mention may be made of compounds represented by the following formula.

However, in this formula, varnish represents hydrogen or C,-C4 alkyl; R3 is
Represents hydrogen or C, -C4 alkyl; R4 is C, -C
, represents alkyl; R6 and R6 each represent hydrogen or methyl; 8 represents C, -C, alkylene; m is 0 to 3; Y is hydroxyl, C, -C, Alkoxy, C, -C
, alkyl, C, -C, hydroxyalkyl, halogen or trifluoromethyl.

The dosages specified for administration of the compound include:
unit dose per unit to 100
When using a pharmaceutical composition containing 0 mg (yo, 0.1
to 100 mg/kg.

Also, in U.S. Pat. No. 4,4461.771 (In formula A, R1 represents hydrogen; R3 and R4 each represent methyl or ethyl; R5 is methyl; R6 represents hydrogen; represents ethylene or propylene; m is 1 or 2; Y is in each meta position,
Compounds that are hydroxy or auto-02 alkoxy, respectively, appear to reduce the activity of tryptophan hydroxylase in vitro by blocking the depolarization-inducing activity of that enzyme in the brainstem, thus reducing the potential for stressful disorders. It is disclosed that it may be used in the prophylactic treatment of migraine.The dosage specified for such treatment is 0.1 kg per unit dose.
When using a pharmaceutical composition that normally contains 1 to 100 m87 kg, 0.01 to 10 m87 kg,
In particular, it is 0.1 to 3 m87 kg. Then, more recently, at least one compound of formula A (i.e. 3-(3'-methoxy-phenyl)-3-(3''-N
, N-dimethylaminopropyl)-4,4-dimethyl-
2,6-Sioxopiperidine; CN 29791 also produced by exposing brainstem slices to metabolic inhibitors, ie methylxanthines, in vitro or by culturing supernatant preparations of the enzyme under phosphorylating conditions. It has been reported that the activation of tributophane hydrocylase induced by
r, M, C, etc., Biochem, Pharma-
col, vol. 35, p. 1521-6 (1986)),
However, it has also been reported that 80N 2979 has no significant effect on unactivated enzymes in vitro (Boadle-Biber,
M, C0, etc., supra).

Furthermore, recently, itris patent No. 2181346A -
), in formula A, R1 represents hydrogen; R3 and R4 each represent methyl or (yonityl); A represents ethylene or propylene; m (yo1 or 2); and Y is each in the meta position. , respectively hydroxy (yoC, -C,
It has been disclosed that compounds representing alcoquines may be expected to reduce the turnover of 5-hydroxytryptamine (5HT) due to inhibition of the activity of tributophane pidolokylase. Such compounds have anxiolytic effects, antagonize the anxiogenic effects of benzothiazepine inverse agonists, and reduce chronically abnormally high brain concentrations of 5HT or its metabolite 5-hydroxy-indoleacetic acid. It is also reported to have antibacterial and antiviral effects.

British Patent No. 21813468 was replaced by British Patent Application No. 8522455 (
(filed on 911/1985), No. 8603909 (19
It was published following British Patent Application No. 8621577, which was filed claiming infringement based on Patent Application No. 8603910 (also filed February 17, 1986). Originally, such disclosed compounds had virtually no effect on penzothiazepine receptors, and therefore had no anxiety-411 effect (although it is unclear, they could induce penzothiazepine receptors by some pharmacological mechanism). It was thought to act to enhance the anxiolytic effect of the zevin receptor.The anxiolytic effect of such a compound was first disclosed in British Patent Application No. 86215.
It was in No. 77. At that time, such compounds appeared to be active in the range from 0.1 to 20 mg, especially from 0.5 to 10 mg, and therefore as pharmaceutical compositions from 10 to 500 mg, especially from 10 to 10 mg.
Compositions containing from 100 mg to 100 mg were proposed. However, surprisingly here,
These compounds can be used at much lower doses, i.e. nonagram/
It was found to be active at doses of up to 1 kg.

According to the first aspect of the present invention, a compound represented by the following formula (1) or a pharmacologically acceptable salt thereof is used as a medicament for treating anxiety. It can be used for construction.

In the formula; 艮 represents hydrogen or C, -C, alkyl; n is 1
or 2; R2 represents hydrogen or methyl. However, when n is 2, R2 is hydrogen; R3 represents hydrogen or C,-C2 alkyl; R4 is
C, -C2 alkyl; R6 and R6 each represent hydrogen or methyl; m(
y, 0 to 3; and each Y is in the meta or;
-02Hydroxyalkyl, halogen or (matrifluor) represents unromethyl.However, hydroxy and alkoxy are never in the para position.

In a second aspect, the present invention comprises administering to a patient with an anxiety disorder an anxiolytically effective amount of a compound represented by formula I below, or a pharmacologically acceptable salt thereof. ,
It provides a method for treating people with disabilities.

In the formula: Ro represents hydrogen or C, -C, alkyl; n is 1
or 2; R2i, t represents hydrogen or methyl. However, when n is 2, R2 is hydrogen; R3+, hydrogen or (yC, -C2 represents alkyl; R4
represents C, -C2alkyl; R5 and R6 each represent hydrogen or methyl; m is 0 to 3; and each Y is in the meta or para position, and each represents hydroxy, C , -C2 alkoxy, C, -C2 alkyl, C1-
02 and represents droxyalkyl, halogen or trifluoromethyl. However, droxy and alkoxy are never in the para position.

According to a third aspect of the invention, a compound of the following formula (I) or a pharmacologically acceptable salt thereof, together with a pharmacologically acceptable diluent or carrier, is added at 10 -7 % per unit dosage.
Unit doses of pharmaceutical compositions containing from 10-' mg to 10-' mg are provided.

In the formula: R8 represents hydrogen or C,-C4 alkyl; n is 1
or 2; R, + represents hydrogen or methyl. However, when n is 2, R2 is hydrogen; R3 is hydrogen or C, -C2 alkyl; R4 is C, -C2 alkyl; R6 and R6 are each hydrogen or methyl m is 0 to 3; and each Y is in the meta or para position and represents hydroxy, C, -C2 alkoxy, C, -C, alkyl, C1-
Represents C2 hydroxyalkyl, halogen or trifluoromethyl. However, hydroxy and alkoxy are never in the para position.

Compounds of formula I can be prepared in the manner disclosed in GB 1455687. These compounds exist as optical isomers and can be used as racemates or as individual (·) or (−) isomers. Currently, the (−) isomer is preferred. .

As mentioned above, compounds of formula I have anxiolytic effects and therefore can be used in the treatment of anxiety disorders. This 1
At least some of these compounds are ten orders of magnitude (105) more potent than diazepam, with effective single dose ranges on the order of a million times (e.g. 105) more potent than diazepam.
-4 to 102 mg/kg). These compounds exhibit dose-related anxiolytic effects and do not produce sedation even at high doses (10'' mg/kg).

Compounds of formula (1) can be administered in a variety of ways to achieve the desired anxiolytic effect.

Such compounds can be administered to treated patients either internally or parenterally. Although oral administration may be the preferred route in some circumstances, injection, especially subcutaneous or intravenous injection, may also be preferred in some circumstances.

The dosage of the compound is not constant, but may be any anxiolytically effective amount. Depending on the patient and the method of administration, the dosage of the compound can vary within a wide range, with a dosage of 10-7 per patient's body weight per unit dosage.
10"mg7kg1 usually (10"mg7kg1)
02mg/kg, especially 10-3 to 102mg/kg
It can be. A unit dose of such compounds may be, for example, about 10-1 mg to 500 mg of the compound, usually 1
0-4 to 102 mg, especially 104 to 10” m
It may also contain gold, for example,
It may be administered once.

“unit dosage form B”
The term rm) is used herein to mean a single or multiple dosage form containing a fixed amount of the active ingredient mixed with or in combination with a diluent or carrier. It is used for. In addition, the above-mentioned constant amount:, ? , a predetermined unit of - for a single therapeutic dose is the amount required.

In the case of multi-dose forms such as tablets and tablets, such a predetermined unit may be a fraction of the multi-dose form, such as a 5 ml (spoonful) of liquid. It will be half to a quarter of a scored tablet.

The compound represented by formula (2) has virtually no effect on penzothiazepine receptor. The ability of selected compounds of formula 1 to displace flunitrasepam diluted from penzothiazepine receptors was determined and the results are summarized in Table 1 below.

*7-chloro-1,3-dihydro-1-methyl-5-
F22-2H-1,4-benzodeacevin-2-one The compound represented by the general formula I has one or two meta positions and moc+-C2 alkyl, Cl-02 hydroquine alkyl, halogen; It has a phenyl group substituted with fluoromethyl, or more preferably with hydroxy or C,-C,alkoxy. Moreover, instead of:
The phenyl group may be substituted at the rose position with the above-mentioned atomic group group other than hydroxy and alkoxy. It is presently preferred that such substituent is anddoxy or especially methoxy. Also, if one or both meta positions are substituted and there are two substituents (
It is preferred that such substituents are the same.

The amino group of the compound of formula (1) may be secondary or tertiary having a methyl or ethyl group on its nitrogen atom. Dimethylamino is preferred for the time being.

The amino group may be optionally substituted with a divalent ethylene (i.e. n.1) or trimethylene (i.e. n.2) group - a methyl group on one carbon atom but not on the adjacent ring. - is bonded to the piperidine ring via -. For the time being, unsubstituted trimethylene is preferred.

The piperidine ring of the compound represented by formula r is substituted with a methyl group at the 4-position, and optionally;
or further substituted at the 5-position by one or two methyl groups. Currently preferred is the presence of a further methyl group in the 4- or 5-position, especially in the 4-position.

Although the endocyclic nitrogen atom of the piperidine ring may be substituted with a C, -C, alkyl group, it is presently preferred that the nitrogen atom is unsubstituted.

The C, -C2 alkyl group or alkyl moiety (methyl or ethyl, with methyl currently preferred) as described herein, can also be a substituent on the nitrogen atom of the piperidine ring. It may be straight chain or branched, but at present it is straight chain n-
Propyl or n-butyl groups are preferred. The halogen substituent on the phenyl ring may be chlorine, bromine or fluorine, although chlorine is currently preferred.

Presently preferred compounds of formula I are:
It is a compound represented by ^ or a pharmacologically acceptable salt thereof.

In the formula: n is 1 or 2; R2 represents hydrogen or methyl. However, when n is 2 (R2 is hydrogen; R5 represents hydrogen or C, -C, alkyl) R4 is
C, -C2 alkyl; R and R6 each represent hydrogen or methyl; and Y and Y2 each represent hydrogen, hydroxy or C, -
Represents C2 alkoxy.

A currently particularly preferred compound of formula r^ is a compound of formula IB below or a pharmacologically acceptable salt thereof.

In the formula: n: 1 or 2; R, / and R4 each represent C, -C, alkyl; R5 and R6 each represent hydrogen or methyl; 1
/, / represents hydroxy or C, -C, alkoxy; and Y2' represents hydrogen, hydroxy or C, -C, alkyl.

Examples of compounds of formula IC include the following compounds.

3-(3'-methquintuunyl)-3-(2'-N, N
-dimethylaminoethyl)-4,4-dimethyl-2,6
-dioxopiperidine 3-(3'-methoxytuunyl)-3-(3' -N,
N-dimethylaminopropyl)-4,4-dimethyl-2
,6-dioxopiperidine (8GN 2979); 3-(3'-methoxytuunyl)-3-(2'-N,
N-diethylaminoethyl)-4,4-dimethyl-2,
6-thioxopiperidine; 3-(3'-methoxytuunyl)-3-(3"-N,N
-diethylaminopropyl)-4,4-dimethyl-2,
6-thioxopiperidine; 3-(3'-hydroxytuunyl)-3-(2' -N
, N-dimethylaminoethyl)-4,4-di,methyl-2,6-sioxopiperidine; 3-(3'-hydroxytuunyl)-3-(3'-N,
N-dimethylaminopropyl)-4,4-dimethyl-2
,6-thioxopiperidine; 3-(3'-methoxytuunyl)-3-(2' -N,
N-dimethylamineethyl)-4,5-dimethyl-2,
6-diosopiveridine (8GN 2939).

3-(3'-methoxytuunyl)-3-(3N-N,N
-dimethylaminopropyl)-4,5-dimethyl-2,
6-dioxopiperidine (8GN 3181); 3-(3'-nitoxyfuunyl)-3-(3'-N,
N-dimethylaminopropyl)-4,4-dimethyl-2
,6-thioxobiberidine; 3-(3'-nitoxyfuunyl)-3-(3'-N,
N-diethylaminopropyl)-4,4-dimethyl-2
,6-thioxopiperidine; 3-(3',5'-dimethoxytuunyl l-3-(3'
-N,N-dimethylaminoprobilto4,4-dimethyl-2,6-dioxopiperidine (AGN 3222)
.

3-(3',5'-dimethoxytuunyl)-3-(2
'-N,N-dimethylaminoethyl)-4,4-dimethyl-2,6-sioxopiperidine;3-(3',5'-dimethoxytuunyl)-3-(3'
-N,N-dimethylaminopropyl)-4,5-dimethyl-2,6-sioxopiperidine;
-N,N-dimethylaminoethyl)-4,5-dimethyl-2,6-sioxobiperidine; Examples of other compounds of formula I include substituent.

3-phenyl-3-(2'-N,N-dimethylaminoethyl)4-methyl-2,6-thioxopiperidine; 3-
Phenyl-3-(2'-N,N-dimethylaminoethyl)4.4-dimethyl-2,6-thioxobiperidine; 3
-phenyl-3-(2'-N,N-dimethylaminoethyl)4,5-dimethyl-2,6-thioxobiberidine;
3-phenyl-3-(3'-N,N-dimethylaminopropyl)-4,4-dimethyl-2,6-thioxopiperidine;3-(4'-chlorophenyl)-3-,(3'
-N,N-dimethylamitub;pil)-4,4-dimethyl-2,6-dioxopiperidine= and 3-phenyl-3-(2'-N-methylaminoethyl)
-4,4-dimethyl-2,6-dioxopiperidine.

The compounds of formula I may be administered in free salt form, as alkali metal or alkaline earth metal salts or as pharmacologically acceptable acid addition salts.

However, alkali metal or alkaline earth metal salts are usually
Provided that it cannot be combined with acid addition salts except in layer-forming formulations. Representative acid addition salt forms include, for example, organic acid salt forms such as maleate and methanesulfonate, and mineral acid salt forms such as Tomaruba hydrochloride and perchlorate.

Pharmaceutical formulations, which are the forms in which the active compounds of the invention are usually used, are prepared in a manner known per se in the pharmaceutical industry and are usually prepared by incorporating at least one active compound of the formula I into a pharmacologically active compound. In preparing such formulations, the active compound is usually mixed with a suitable carrier or diluent. or (diluted with a diluent, or capsules, chassier,
Enclose or encapsulate in cash, paper, or other containers. A carrier or diluent is a solid, semi-solid or liquid material that serves as a vehicle, excipient or medium for the active compound. Suitable carriers or diluents are known per se.

Such formulations may be made available orally or parenterally and may be administered to the patient in the form of tablets, capsules, dragees, suppositories, syrups, suspensions, and the like.

Such formulations may be in sustained release or sustained release form).

Apart from the active ingredients, such compositions may also contain pharmaceutically inert organic or inorganic auxiliaries, optionally granules, binders, lubricants, dispersants, wetting agents and preservatives. In addition, such pharmaceutical compositions may contain coloring agents, flavoring agents and sweetening agents.Auxiliary agents for preparing tablets include, for example, calcium carbonate, lactose, microcrystalline Cellulose, mannitol or talc may be used. Starch, alginic acid or microcrystalline cellulose may be used as a granulating agent or disintegrating agent. Starch, polyvinyl vinyl chloride or gelatin may be used as a binding agent. Also, magnesium stearate, stearic acid, co-idal silica or talc may be used as a lubricant.

Tablet formulations may or may not be coated, the purpose of such coatings being to delay disintegration and absorption in the gastrointestinal tract. Suitable dispersants for preparing liquid dosage forms include, for example, methylcellulose and sodium alginate. Capsule formulations are
The active ingredient may be contained by itself or together with an inert solid diluent such as calcium phosphate, l-res9-ti, lactose or mannitol.

The invention is illustrated in the following non-limiting examples.

Example 1 Tablet Formulation Tablets are prepared in a conventional manner, each tablet having the following composition: mg/tablet (a) GN 2979 base to compound 1 (b
) Lactose 51.5 (C) Dried corn starch 45 (d) Magnesium stearate 1.5 Example 2 Suppository formulation mg/tablet (a) Compound AGN 2979 HCI
10(b) Theobroma oil (cocoa butter) 990 This compound (a) is powdered, passed through a sieve (BS No. 100) and formulated with theobroma oil at 45°C to obtain a smooth uniform dispersion. This liquid mixture is thoroughly stirred and poured into a mold having a nominal capacity of IC to produce a suppository.

Example 3 Tablet formulation (a) GN 2979 base to compound 10 m
g (b) Wheat starch 7 g (C) Lactose 20 g (d) Magnesium stearate 1 g This mixture is compressed into tablets to obtain 1000 tablets of 138 mg each.

Example 4 Granules Prescription Granules - Glare (at compound 8 he N 2979) 1c1 10
mg(b) corn starch 45 m
g (C) Liquid glucose 7 mg top granules are mixed with active ingredient (a) and starch, then liquid glucose is added and kneaded well to form a plastic mass, from which granules are cut and shaped. do.

Example 5 Gelatin capsule formulation (a) Compound 8GN 29798C12,5 mg (b) per capsule
Talc 70 mg Capsules are prepared by passing the dry powder of active ingredient (a) and powdered talc in the above proportions through a fine mesh sieve and then mixing them. Net fill per capsule in hard gelatin capsules 72.
Fill as 5 mg.

Example 6 Male Albino BK-mice weighing 25-30 g, which had never been used in laboratory animal experiments, were used in all experiments. Ten mice were usually housed in each cage, with access to food and water. They were given free access.Lights off at 8,200 am and exposed at 8,200 pm.

Anxiolytic test The device used to detect changes in anxiety was an open-lid box (81 x 36 cm) with three sides painted black.
x 27cm high) consists of 1, dim red light (1x
The box was illuminated with 60 mm and separated from the rest of the box, which was painted white and brightly illuminated by a 100 mm light source mounted 17 cm above the box. These areas could be freely accessed through an opening measuring 7.5 x 7.5 cm provided at the floor level in the center of the partition. Mark the floor with a straight line and mark 9.
It was divided into cm squares. Testing was conducted in a quiet, darkened room illuminated using only red lights. The animals were then placed in a dark container and transferred from the dark holding room to the testing room.

Animals receiving drug or vehicle injections were placed individually in the center of a white area and their behavior was observed for 5 minutes using a remote-controlled video recording device. Four behavioral parameters were noted every minute; namely, the number of exploratory hindstands in the white and black areas, the number of dividing line crossings in the white and black areas, and the number of exploratory rear stances in the white and black areas,
: Conventional times between black and white areas and time spent in white and black areas. The experimenter was blinded to the drug treatment during the experiment and was only informed of the code after the analysis was completed.

Experimental Design Animals were used in treatment groups of 5 animals, and vehicle control studies were conducted on each day of testing.

Results were analyzed using single-factor analysis of variance, followed by Dunnett's test when appropriate, to compare drug-treated groups with controls.

Drug (±) AGN 2979 was prepared by dissolving it in distilled water,
A solution prepared by dissolving diazepam (manufactured by Roche) in a minimum amount of polyethylene glycol (2! J breath) was made up to a predetermined volume with distilled water. Various doses (expressed as base) were administered by intraperitoneal injection (diazepam) or subcutaneous injection (8GN2979) in a volume of 1 ml, 7100 g body weight as a 60 minute pretreatment.

The results are shown in Figures 1.2 and 3 attached hereto and discussed under breath.

FIG. 1 shows the changes in hindlimb standing behavior and separation line separation (locomotion) within the white and black areas of the box that were observed when diazepam was administered intraperitoneally. C shows the response of vehicle-treated control animals. In addition, n
-5, but for C it is n-15, S, Eo
M and s are 11.6X or less. A significant increase in response is expressed as *P less than or equal to 0.001, and a significant decrease is expressed as +P less than or equal to 0.05 and -P less than or equal to o, ooi (one-u+ay A#OV8 and Dun
net's t test).

FIG. 2 depicts the changes in IL% m (locomotion) within the white and black areas of the box when Rudder N 2979 was administered subcutaneously in the dorsal neck. C shows the response of a vehicle-treated control animal. In addition, n = = 5, but when lying on C, n = 1
5, and S, E, M, and sba were 7.3%.

A significant increase in response indicates *P 0. It is expressed as below QOIJu, and a significant decrease is expressed as *P below 0.05JJ and -
P is expressed as 0.001 or less (one-u+ay A
NOVA and Dunnett's t test).

FIG. 3 depicts the change in time spent by mice exploring the black area of the box when 8GN 2979 was administered subcutaneously in the dorsal neck. C. Responses of vehicle-treated control animals are shown.

Note that n = 5, but for C, n = 15,
S, E, M, s for the original data is 6.6
It is less than or equal to z. A significant increase in the time spent within the black region is represented by
t test).

Within the general observational testing context, vehicle-treated animals exhibited distinctive behavioral patterns that could be summarized as breathing.

(1) The time spent in each area of the test area is approximately equal to 1.

(2) The passing speed between the two areas is 8.3±0.17
It was on the order of 5 minutes.

(3) Walking movement in the white area (33,7 ± 3.075 minutes) and crossing the dividing line in the black area (53,5 ± 4.975 minutes)
minutes) is significant.

(4) Standing on hind legs in black area (49,7±3.275
minutes) is the frequency of this behavior within the white area (22,1±1.
575 minutes).

These data indicate that under the test conditions, the test animals showed a significant preference for activity within the black area of the test area, likely induced by the repellent properties of the brightly illuminated white painted area. It would be something like that. Intuitively, this finding might have been expected given the nocturnal nature of the experimental animal species used. The preference for black areas is most clearly demonstrated on measures of locomotion and rear stance.

A detailed initial study showed that the responses of vehicle-treated animals were not significantly different from the responses previously induced in untreated control animals (P = 0.05).
．． 1 above). Therefore, only the responses obtained from vehicle-treated animals are shown as control data.

Diazepam-induced exploratory behavior changesDiazepam (0,125-5,0 mg/kg) increased hind-leg standing (2- to 4-fold) and crossing the dividing line in the white area.1. When the dose was lowered to 0.063 mg/kg, there was no effect and the response characteristics (all or none) were reduced.
) has become clear. Dose 10 mg/kg
When raised to , sedation occurred and hind-leg stance and separation line crossing decreased.

The increase in hind-leg standing and dividing line crossing within the white area reflected the decrease in such behavior within the black area (Figure 1).

8 GN 29 to variation of exploratory behavior by GN 2979
79 is effective as diazepam in increasing standing and line-crossing behavior afterward in the white region, and as seen in the case of diazepam, such changes are effective in increasing laterally in the dark region. There was a correlation with a decrease in step-standing and partition line crossing behaviors (Figure 2). Noteworthy features of the inner workings of AGN 2979 include (a) its unusually high potency (0,00001
-100,0 mg/kg), (b) the dose range over which a response is obtained is unusually wide (dose of 10,000,000 (i
os)) and (c)
The effects of 8GN 2979 vary depending on the dose, which is in contrast to the all-or-none response of diazepam. Furthermore, mice treated with 8GN 2979 (aged 3 years old) significantly decreased the time spent within the black area (Figure 3); importantly, 8GN 297
9 effects were achieved without sedation.

Example 7 Separate groups of mice were given 0.1 mg/kg or 10
The method of Example 6 was repeated, except that mg/kg (±)8GN 2979 dissolved in distilled water was tested at 0.5.1.2.4 and 6 hours after subcutaneous administration.

Results were analyzed using single-factor analysis of variance according to Dunnett's method to compare drug-treated animals to vehicle-treated control animals. The results of this experiment are shown in the accompanying Figures 4 and 5 and discussed below.

1 in Figure 4, 8GN at 0.1 mg/kg in the posterior neck.
The figure shows changes in standing behavior and crossing the partition line (walking movement) after the white and black areas that were observed when 2979 was administered subcutaneously. C shows the response of vehicle-treated control animals. 8, n=5, and S , E
,M,s! As shown. Significant increase in response behavior: expressed as *P of 0.05 or less, **P of 0.01 or less, -P of o, ooi or less,
In addition, the significant decrease is 0.0 as ++P of 0.01 breath.
Expressed as -P less than or equal to 01 (expressed as less than or equal to 0.001 (one-u+ay ANQν^-Dunnet
T's t test (Koyoro).

Figure 5 shows 10 mg/kg of 8GN2 applied to the back of the neck.
979 is a diagram corresponding to FIG. 4 when subcutaneously injected.

The anxiety 4Im effect of 8GN 2979 is characterized by an increase in hindlimb stance and slow gait within the white area of the test box, which mice normally dislike, and a corresponding decrease in behavior within the black area. , 0゜1 mg/kg
This was observed to occur within 30 minutes after administration of AGN 2979. However, the maximum effect can be achieved within 1 hour.
It was not realized. This anxiolytic effect persisted until the next administration, but returned to the comparative reference value 6 hours later (FIG. 4). 8GN 2979 at 10 mg/kg
A similar course (in terms of onset and persistence) occurred when the drug was administered.
Anxiety 5IJ was recorded, but using such dosages
The N effect was more clearly established at 30 minutes than at lower dosages, and its maximum effect was well sustained over 4 hours. However, as was observed with the lower doses, the anxiolytic effect was no longer detectable after 6 hours.

Example 8 Body M225-275 g, male Sprague-Da
Wley rats were housed in groups of 5, and 8.00
The lights were kept on a 12 hour light/dark cycle. The test was carried out in a brightly lit room between 13.00 and 18.00.

The device used to detect changes in social interaction was made of opaque white Perspex (Perspex-TM)
), open-lid box (45 x 320 m x 2
It consisted of a 15 x 16 cm area marked on the floor. Two native rats were removed from a separate storage box and placed in a test box (with 100 W bright color illumination from 170 m above) and their behavior was observed for 10 minutes using a remote-controlled video recording device. Social interactions between two animals involve
It is measured by measuring (in seconds) the movements of sniffing, crawling under or climbing on the partner, blooming the partner, probing the genitals of the partner, and following the partner. Decided. Additionally, exploratory locomotion was measured as the number of times a line drawn on the floor of the test box was crossed.

The experimental design involved using rats in groups of six (ie, three pairs). (±)8GN 2979 was prepared in distilled water, and diazepam (Roche) was dissolved in a minimum amount of polyethylene glycol (25%) and made up to volume in distilled water. Dosage is expressed as base;
A volume of 1 ml/kg body weight was administered intraperitoneally as a 40 minute pretreatment.

The results are shown in the accompanying Figures 6 and 7 and discussed below.

Figure 6 shows that diazepam affects social interaction (number of seconds per 10 minutes) and exploratory locomotion (number of line crossings per 10 minutes) of rats placed in pairs in observation boxes. This shows the impact it has. Note that n=6, S, E
, M and s are as predetermined. Significant increases in social interaction are expressed as *P less than or equal to 0.001 (
one-uay ANOV^-by Dunnett's t test). ° indicates sedation.

Figure 7 shows the effect of ACrN2 on social interaction (number of seconds per 10 minutes) and exploratory locomotion (number of line crossings per 10 minutes) of rats housed in pairs in an observation box.
Showing the influence of 979. Note that n = 6, S, E
, M and s are as predetermined. A significant increase in social interaction is expressed as zero P less than or equal to 0.01 and as -P less than or equal to 0.001 (one-u+ay AN○
V8-by Dunnett's t test).

Example 9 The procedure of Example 6 was repeated with the following differences.

a) Dosage Range Determination Experimental mice were administered oral dosages of (±)8 GN 2979 as follows: 0.0001.0.001.0.1.1.0.10.0
．． 100 mg/kgP, 0. The test was conducted 90 minutes after administration.

b) Duration of action experiment 35 mice were treated with (±)^ON of ioo mg/kg.
2979 was administered at P, O, (bore), and studies were conducted on groups of 5 mice at the times indicated below after administration.

Comparison of three vehicle administrations for 1.2.4.6.10.16.22 hours! ! The ¥ group was examined at fixed intervals throughout the experiment.

AGi42979 was prepared by dissolving it in distilled water, and the dosage was expressed as a base, but it was administered by force through a tube in an amount of 2 ml/kg body weight.

The results are shown in the attached Figures 8 and 9 and discussed below.

FIG. 8 shows changes in hind leg standing behavior and partition line cutting (walking movement) in the white and black areas of the box. C
indicates the response of vehicle-treated control animals. Note that n = 5 for each animal group. Significant increases in response behavior are expressed as ◆P below 0.01 and as -P below 0.001U (one-u
+ay ANOV^-Dunnett's t test)
.

FIG. 9 shows changes in rear leg standing behavior and partition line crossing (walking movement) in the white and black areas of the box. C
indicates the response of vehicle-treated control animals. Note that n = 5, with 1 animal in each animal group. Significant increases in response behavior are expressed as ◆P less than or equal to 0.001. Significant decreases are expressed as xP under o, o1g and as -P under o, ooxa (on
e-+l1ay ANOV^-by Dunnett's t test).

General Observations Under this test condition, vehicle-treated control animals exhibited a unique behavioral pattern.

Its characteristics can be summarized as follows: (1) The time spent within each region of the test area is approximately equal.

(2) The movement speed between the two areas is 8.3=0.17
It is 5m1n.

(3) Walking movement in the white area (38,4 ± 3.875 m
1n) and the partition line crossing in the black area (51,2±5.3
75m1n) is significant.

(4) Compared to the frequency of hind-leg standing behavior in the white area (2
This behavior increases significantly in the black region (50.7 ± 2.775 m1n).
.

The anxiolytic effect of 8GN 2979 is characterized by an increase in hindlimb stance and locomotion within the white area of the test box, which mice normally dislike, and a corresponding decrease in behavior within the black area. , was observed at the lowest 'v) dose (0.0001 mg/kg p,

,). This effect (1.0-10.Omg/kg p
, o, was found to be near-maximal and dose-dependent.

was recognized. After administration of 100 mg/kg p,o, the anxiolytic effect was found to occur 1 hour after administration. The effect was maximal 1 hour after administration and remained at this level for at least 10 hours. The anxiolytic effect, although still significantly greater, began to decline at 16 hours and returned to the comparative reference value at 22 hours post-dose.

Example 10 The method of Example 6 was repeated to add diazepam (2°5 and 10 mg/kg) and (±) 〇N 2979 (0,
The effect of abruptly discontinuing long-term treatment at 1 and 10 mg/kg) was determined. The experimental outline plan was written below.

1. Diazepam 10 mg/kg was administered acutely, intraperitoneally twice per day for 7 days. Although such doses of diacebam (1) are the lowest doses that cause sedation problems in acute procedures, tolerance to the drug also develops rapidly in long-term treatments, and therefore such doses are It was selected as the highest dose that could be administered over a long period of time to maintain a good anxiety-reducing effect without causing anxiety.
It was included in this study only for the purpose of comparing k4 agonistic responses.

Animals were subjected to a withdrawal test that was terminated 8 hours after the last treatment with diazepam (ie, 8 hours after the second dose on day 7). The effects of diazepam were evaluated 45 minutes after treatment, and animals were submitted to the study after the second dose on day 7 to determine the effects of long-term treatment with diazepam.

2. The above general schedule was repeated using 2.5 mg/kg of diazepam and 0.1 and 10 mg/kg of 8GN 2979. To confirm that discontinuing AGN 2979 did not result in lingering problems later, separate groups of mice were used to administer the last dose of AGN 2979 at 8 hours, 24 hours, 48 hours, 96 hours, and 144 hours after administration. The impact on potential discontinuation was assessed at time and 10 days.

The results are shown in the attached FIGS. 10 to 13 and discussed below.

Figure 10 shows the anxiety profile when 2.5 mg/kg diazepam was administered acutely or chronically (2.5 mg/kg intraperitoneally twice a day, tested on day 7). Figure 2 shows the so-called effects and the effects of discontinuation measured at 8,48 and 96 hours after administration of the last dose of diazepam.

C shows the sponse of control animals treated with vehicle administration either by single injection of vehicle or by administration of Bi (P on 0, C05,1) twice daily for 7 days. In addition, although n-6, S, E, M, and s are 12.4
It is below X. *-P is 0.001 or less (D
unnett's t test).

Figure 11 shows 10. o Anxiolytic effects of mg/kg diazepam when administered acutely or chronically (10,0 mg Ag administered twice daily in the recovery cavity, tested on day 7!! r: ) and the last dose of diazepam administered The effect of discontinuation measured at 8.48 and 96 hours is shown. C is
Responses of control animals treated with vehicle after a single injection of vehicle or vehicle administered twice daily for 7 days (PA on 0, os, 1) are shown.

Although n = 6, S, E, M, and s are 12.
2Z or less.

*◆P is 0.01 or less, -P is 0.001 or less (Dunnett's t test). . The mark represents sedation.

Figure 12 shows the anxiolytic effect of AGN 2979 administered acutely or chronically at 0.1 mg/kg (8 GN 2979 administered twice daily, tested on the 7th FFi day) and the final effects of AGN 2979. 8. After administering Yoro.
Represents the effect of discontinuation measured at 48 and 96 hours (
P is 0.05 or more).

n=6, and S, E, M, and s are 11.7 dollars or less.

*◆P is less than 0.001 (Dunnett's t
test).

Figure 13 shows the anxiolytic effects of 8GN 2979 administered acutely or chronically (10 mg/kg twice daily, tested on day 7) and the effects of 8GN 2979. 8. After administering the last dose of 2979.
Represents the effects of discontinuation measured after 48 and 96 hours. C1, single injection of vehicle or 7
Responses of vehicle-treated control animals treated with vehicle twice daily are shown (P greater than or equal to 0.05). Although n=6, S, E, M, sba,
12.17 or less. *◆P is 0.001 or less (Du
nnett's t test).

Acute treatment with 2.5 mg/kg intracavitary diacepam produced an anxiolytic response in the mouse test method, a phenomenon characterized by the presence of a white, brightly illuminated test box. Aversion to the area was reduced (standing on hind legs and crossing the dividing line within the white area were significantly increased). This increase in behavioral responses within white areas was reflected by a decrease in behavior within black areas (Figure 10).
. These anxiolytic effects of diazepam were associated with longer latencies for entry into the black area of the test box as well as a decreased proportion of time spent in the dark area. In this regard, the traversal behavior between the two regions of the test box was significantly altered by drug treatment, as reported in other experiments ().

The anxiolytic effect of diazepam administered intraperitoneally at 2.5 mg/kg was maintained in pseudochronic treatment (Figure 10). However, when the treatment was discontinued, a clear anxiety-generating phenomenon emerged, characterized by a shortened latency for the test box to enter the black area, and an increase in rear-leg standing and separation line crossing within the black area. This resulted in an increase in the amount of time spent in the black area as well as an increase in the amount of time spent in the black area. This anxiety-producing phenomenon became evident within 8 hours after the last treatment with diazepam and persisted for 48 hours (Figure 10).
.

Similar data were obtained with a higher dose of diazepam, 10 mg/kg intraperitoneally. The main differences between high and low doses during diazepam treatment are: (1) sedation at higher doses - this became evident during acute treatment (tolerance to this sedation was
When the treatment was continued, it appeared within 3 days) and (2)
) The anxiolytic phenomenon caused by discontinuation of administration persisted more clearly for 48 hours after discontinuation of treatment (Figure 11).

The anxiolytic effect of HachiGN 2979 is 0.1 mg/
kg (Figure 12) and 10 mg/kg (Figure 13) during acute treatment; however, no sedation was observed. The essence of the anxiolytic effect of GN 2979 is
Like diazepam, there is a reduction in the latency to enter the black area of the test box, an increase in exploratory behavior within the white area (increased hind-leg stance and separation line configuration), and At the same time, there was a corresponding decrease in behavior within the black area (reduced post-control standing and separation line breaks), which correlated with a decrease in the proportion of time spent in the black area during the 5-min test. was there.

The anxiolytic effect of GN 2979 was maintained with twice daily treatment. However, there was a significant difference from the findings with diazepam (i.e., abrupt discontinuation of treatment with 80N 2979 did not result in a reduction in anxiety production).

In fact, to the contrary, the anxiolytic effect of 0.1 mg
It was evident 8 hours after the last dose of /kg GN 2979 and 48 hours after the last dose of 10 mg/kg GN 2979 (Figures 12 and 13).

Although this anxiolytic effect gradually decreased over the next 48 hours, careful observation using a separate group of animals (the animals were not adapted to the test environment) showed that the anxiolytic phenomenon was due to 8GN 2979. Continued after discontinuing treatmentb
) does not occur after treatment is discontinued.
It was found that it did not appear at any time for 0 days. This markedly different response of mice after discontinuing coagulant treatment with diazepam and AGN 2979 is evident when using the same experimental protocol.

Example 11 Laboratory-reared male marmoset (Callithrix jack) weighing between 350 and 400 g.
The animals were housed individually and fed ad libitum.
primate diet s.

D, S, Ltd., Es5ex). 1
Once a day, the marmosenotes were also fed a combination of fruit and brown bread or malt bread. The breeding room is 25 degrees Celsius and humidity 5.
5% and kept on a 12 hour light/dark (red lighting) cycle with lights on at 7.00am (dawn and dusk h/'4J).

Testing was carried out between 13.30 and 15.30 in the normal rearing room (to prevent unnecessary disturbance of behavior by transfer to new room or cage). The breeding room in which the marmosenotes were housed individually for this research was 76 cm high, 50 cm wide, and 60 cm deep.
It was cm. “Anxiety” was triggered by a human H2 subject standing 0.6 m in front of the breeding cage. Changes in behavior were observed over a 10-minute period (2 consecutive minutes of recordings were taken for each behavioral response) by the observer as well as by another independent observer and by video recordings taken throughout the duration of the human threat. Recorded by. The behavioral scales selected for this study were (,
) Percentage of time spent at the front of the cage in the face of human threat; There were a number of aggressive body postures that could be seen, such as staring and flattening the tufts of hair on the ears.

The results are shown in Figures 14 and 15 and discussed below.

Figure 14 shows 1, percentage of time spent in front of the cage when faced with threat from a human standing 0.6m in front of the cage.
Anxiety of diazepam in ermocet is expressed by an increase in the number of positions and a decrease in the number of positions.
= 6, and S, E, M, and s are as shown or 1
2.22 or less, and *◆P:yo0.001 or less (one-toay ANI) V8-Dunnet
L test of t! 9!1 Koyoru)・.

Figure 15 shows that AGN 2979 relaxation in marmosets is represented by an increase in the percentage of time spent admiring in front of the cage and a decrease in the number of postures when faced with the threat of a human standing 0.6 m in front of the cage. Show action.

n=6, and S , E , M , and s are as shown, and *・P(yoO,0OIU (one-ma
y ANOV^-by testing Dunnett's).

Diazepam is available in doses of 0.1 and 0.025 mg/
AGN 2979 was also administered at 0°00001.0.0001.0.001 and 1 mg/kg on a monthly basis.

Marmots treated with noacebam showed behavioral changes characteristic of treatment with anxiolytic agents.

That is, by spending more time directly facing the experimenter and in front of the cage, the animals had less time to react to human threats and direct their aggressive posture toward the experimenter.
(decreased number of postures). Diazepam is 0.01 and 0.01.
It was effective and active in reducing anxiety in marmosets at a subcutaneous dose of 0.025 mg/kg (Figure 14).
.

Similar to diazepam, 8GN 2979 was also found to exhibit anxiolytic effects in marmosets as evidenced by a decrease in the number of postures and an increase in the percentage of time spent in front of the cage. Marmosets +r treated with AGN 2979, generally not afraid of the experimenter, spent significantly more time hopping back and forth between the front of the cage and the cage perch than the control animals.

Such behavior generally reflects play behavior and thus artificially reduces the amount of time spent at the front of the cage. From the data obtained in this way,
Signs that AGN 2979 is less effective than diazepam in marmosets as an anxiolytic: 1 - 1 - GN 2979 is even more potent than diazepam.

Marmosets have been shown to be particularly sensitive to the sedative effects of diazepam, and therefore
It was difficult to develop behavioral measures for animals treated with diazepam doses above mg/kgU. However, no sedation was observed after treatment with AGN 2979.

Example 12 The method of Example 6 was repeated with (0.0 of -118 GN 2979)
1.0.01.1 and 10 mg/'tg in 1 m17
It was repeated intracavitally as a 45 minute pretreatment in an amount of 100 g body weight.

The results are shown in the attached Figure 16 and discussed below.

FIG. 16 shows changes in the rear four standing positions and the crossing of the partition line (walking movement) in the white and black areas of the box. C is
Responses of vehicle-treated control animals are shown. Although n=5, S + E + Toma.

S: Yo display:) Temero. Significant increase in response activity::,
*P is expressed as 0.001, and a significant decrease is expressed as ・P less than or equal to 0°001 (one-u+ay ANO
VA-Dunnettc7).

When administered intracavitally using a 45-minute pretreatment time, the eight-gone isomer of GN 2979 (doses ranging from 0.01 to 10 mg/kg produced significant anxiety relief). It has been found that such an anxiety-reducing effect results in an increase in dividing line crossing and rear standing in the white and black areas, and a corresponding decrease in behavior within the black area. This was the characteristic (Fig. 16).

(-) Anxiety warming effect of 8GN 2979:':, also associated with a reduction in the latency for the movement of the test box from the white area to the black area (the normal control value is )na',)l, ranged from 12 seconds, but was delayed to 16 to 59 seconds for all doses of (-)8 GN 2979. P was less than 0.01;
AGN 2979 (all doses) decreased by 19-39z. However, such decreases were most pronounced at higher (and higher) doses.

It was also associated with P (which was less than 0.001).

These results indicate that (-)8GN 2979 is more potent as an anxiety-fighting agent than (Yo(◆)8GN 2979).

[Brief explanation of the drawing]

The figures are graphs showing the results of the animal experiments in Examples 6 to 12, and in each figure except FIG. 7, C is a control. Figures 1 and 2 show the changes in the number of hind-leg standing behavior (Rears) and dividing line crossing (CrO3sing) in mice treated with diazepam intraperitoneally and AGN2979 subcutaneously as a 60-minute pretreatment, respectively. show. Third
The figure shows the change in time spent in the black area by mice treated with AGN2979. Figure 4 (0.1 mg/ka
Fig. 5 shows the changes in the number of times of hind leg standing (F+) and dividing line crossing in the white and black areas of mice to which 80N2979 was subcutaneously administered.
FIG. 4 is a diagram corresponding to FIG. 4 when 979 is administered subcutaneously. Figure 6 shows the effects of diazepam on social interaction (seconds per 10 minutes) and exploratory walking behavior (number of dividing line crossings per 10 minutes) in paired rats; FIG. 6 is a diagram corresponding to FIG. 6 when ΔGN2979 is administered. Figure 8 shows the changes in hindlimb standing behavior and the number of dividing line crossings in the white and black areas when AGN2979 was orally administered to mice, and Figure 9 shows the change in GN2979 to mice.
The change in the above frequency with the passage of time after administration of 9-diameter B is shown. Figure 10 shows that 2.5 ma/kg of diazepam was administered acutely (Δcnte) or chronically (Chroni) to mice.
c) shows the anxiolytic effect when administered intraperitoneally and the influence of discontinuation measured after administration of post-R suspension. 11th
The figure shows diazepam at 10+no/ka, and the figure 12 shows 0.1
m9/kg AGN2979, Figure 13 is 1011
1 (+/Each first when administering Niri's AGN2979
It is a figure corresponding to figure 0. Figure 14 shows the anxiolytic effect of diazepam on marmosets 1~. When a person standing in front of the breeding cage threatens, administration of diazepam increases the amount of time the marmoset spends in front of the cage.
This is indicated by a decrease in aggressive posture. Figure 15 shows the first result when AGN2979 was administered.
Figures corresponding to Figure 4 are not shown. FIG. 16 shows the changes in the number of times of standing on the hind legs and crossing the dividing line in the white and black areas when ΔGN2979 was intraperitoneally administered to mice as a 45-minute pretreatment.

Claims (1)

[Claims] 1. A compound represented by the following formula I or a pharmacologically acceptable salt thereof together with a pharmacologically acceptable diluent or carrier at a dosage of 10 to 10 per unit dose. ^-^1m
A pharmaceutical composition in unit dosage form comprising an amount of g. ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (I) In the formula: R_1 represents hydrogen or C_1-C_4 alkyl; n
is 1 or 2; R_2 represents hydrogen or methyl. However, when n is 2, R_3 is hydrogen; R_3 represents hydrogen or C_1-C_2 alkyl; R
_4 represents C_1-C_2 alkyl; R_5 and R
_6 each represents hydrogen or methyl; m is 0 to 3; and each Y is in the meta or para position, and each represents hydroxy, C_1-C_2 alkoxy, C_1-C_2 alkyl, C_1-C_2 hydroxyalkyl , represents halogen or trifluoromethyl. However, hydroxy and alkoxy are never in the para position. 2. An anxiolytic agent comprising a compound represented by the following formula I or a pharmacologically acceptable salt thereof. ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (I) In the formula: R_1 represents hydrogen or C_1-C_4 alkyl; n
is 1 or 2; R_2 represents hydrogen or methyl. However, when n is 2, R_2 is hydrogen; R_3 represents hydrogen or C_1-C_2 alkyl; R
_4 represents C_1-C_2 alkyl; R_5 and R
_6 each represents hydrogen or methyl; m is 0 to 3; and each Y is in the meta or para position, and each represents hydroxy, C_1-C_2 alkoxy, C_1-C_2 alkyl, C_1-C_2 hydroxyalkyl , represents halogen or trifluoromethyl. However, hydroxy and alkoxy are never in the para position. 3. An anxiolytic agent according to claim 2, wherein the drug is in unit dosage form and contains 10^-^7 to 10^-^1 mg of the compound represented by formula 1.