JPS63215678A - Antianxiety n-(1-azabicyclo(2,2,2)-3-octyl) benzamide and thiobenzamide - Google Patents

Abstract

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

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to certain N-(3-quinuclidinyl)benzamides and thiobenzamides, namely N-(3-quinuclidinyl)- Benzamide translation, thiobenzamide,
Otherwise, N-(1-azabicyclo(2e2s2
)-3-octyl)-benzamide and thiobenzamide. The compounds useful in the present invention have not only been shown to have general anxiolytic activity, but also to reduce anxiety caused by withdrawal of ingested substances such as alcohol, hemp (such as cocaine), and nicotine. It has been recognized that it is effective in the treatment of.

The 1,000-nucleidine homolog of sulpiride is i(nim -F'armatsevt, Z)r,
10 t JFh 11 e 56
-60 (1976); C, A, 85: 15
Mikhlina as reported in 5489r
, manufactured and researched by E, E, Q, compound =
5-aminosulfonyl-N-(l-7zabicyclo[2
,2,2]-3-octyl)-2-meth. The compound named above has a Soviet patent S
It was reported in U-A-414261 that it was effective for neuroleptic U1.

4-amino-N-(1-azabicyclo(2,2゜2)-
The synthesis of 3-octyl)benzamide and N-(1-azabicyclo(2,2,2)-3-octyl)benzamide was described by Khim-Farmatsevt, Zh.

7, 20-24 (1974); C, A, 79
, 146458a, the latter by Khim, Geter
osikl, Soedim, Akad, Nau
k.

Latv, 88R243-9 (1966); C,
A, 65: Mikhlina, E at 2220b.
, E. et al. These compounds were reported to have hypotensive, anesthetic, and ganglion stimulating/blocking effects.

4-Amino-N-(1-azabicyclo[2°2.2)-3-octyl)-3 from 4-amino-3-chloro-5-trifluoromethylbenzoic acid chloride and 3-aminoquinuclidine Synthesis of -chloro-5-trifluoromethylbenzamide is described in DE-A-2548968; C, A, 8
7, 68001c and corresponding US-A-40937
It has been reported in 34. This compound falls within the class of pyrrolidinyl and piperidinyl benzamides that are said to be effective as anxiolytics, anticonvulsants, antiemetics, and antiulcer agents. Like the compounds useful in this invention,
None of these compounds have ortho-alkoxy substitution on the benzamide.

It is widely accepted that substituted benzamides are a class of drugs known to be effective in psychiatry and gastroenterology (Sulpiride and Other Benzamides; International Workshop on Sulpiride and Other Benzamides). , Florence, Feb. 17
-18 (1978) Raven Press).

E P-A-0099789 and F R-A-
2529548 is a kind of N-(1-azabicyclo(2
, 2,2)-3-octyl)benzamide and its use as a gastrointestinal motility promoter.

U S-A -4593034 TOE P-A -015
8532ha 2-alkoxy N-(1-azabicycloC
2,2゜2 :) -3-Octyl)benzamide or thiobenzamide have been shown to treat emesis caused by the administration of platinum anticancer drugs (such as cisplatin).

B P -A -0201165 is a kind of N-(1-
A large class of compounds, including azabicyclo(2,2,2)-3-octyl)benzamide, are described and reported to be effective in the treatment of emesis, anxiety, and sensitive bowel syndrome (IBS).

N-(1-azabicyclo[:2,2.2]-3-
It has now been unexpectedly discovered that octylbenzamide exhibits anxiolytic effects in hyperemic animals. Compounds useful in the present invention are generally recognized to have anxiolytic activity, as well as being effective in the treatment of anxiety caused by withdrawal of ingested substances such as alcohol, narcotics (e.g., cocaine), and nicotine. It is believed that this is the case.

According to a first aspect of the invention, in the preparation of drugs with anxiolytic activity, compounds of the general formula I, which compounds are characterized in that X represents oxygen or sulfur, R1 represents lower alkyl, R2 is hydrogen, halo, 4,5-benzo, lower alkoxy,
represents amino, methylamino or dimethylamino, RA represents hydrogen or lower alkyl, and n is 1 or 2; or use of a pharmaceutically acceptable acid addition salt thereof is provided.

R2 represents a 3- or 5-8 substituent; R2 may alternatively or additionally represent 4-7mino, 4-methylamino or 4-dimethylamino.

X represents oxygen. Preferred R5 substituents are C1-4 argyl, such as methyl or ethyl.

The stereochemistry of the substituents on the quinuclidine ring is favorable l, < is t
rans, for example: The invention relates to the production of drugs with anxiolytic activity, in which 4-amino-N-(1-azabicyclo[:2,2゜2]-3
-octyl)-5-chloro-2-methoxybenzamide, N-(1-azabicyclo(2,'2,2''l-3-
octyl)-5-chloro-2-methoxy-4-methylaminobenzamide, N-(1-azabicyclo(2,2,2)-3-octyl)-2-methoxybenzamide, N-(1-azabicyclo[2, 2,2) -3-octyl)-2,4-dimethoxybenzamide, N-(1-azabicyclo(:2,2
．． 2)-3-octyl)-2-propoxybenzamide, 4-amino-N-(1-azabicyclo(: 2, 2
゜2]-3-octyl)-5-chloro-2-methoxybenzamide, N-(1-azabicyclo[:2,2.2]-3-octyl)-5-chloro-2-methoxy-4-methylamino Benzamide, N-(1-azabicyclo[2,2,2)-3-octyl)-3-methoxy-2-su7talenecarboximide, 4-amino-N-(1-aza-2-methyl-bicyclo(
2,2,2:]-]3-octyl-5-chloro-2-methoxybenzamide, or a pharmaceutically acceptable salt thereof.

4-amino-N-(1-azabicyclo(2,2゜2)-
The use of 3-octyl)-5-chloro-2-methoxybenzamide, whether as the free base or as a salt (eg, fumarate or hydrochloride), makes it a particularly preferred aspect of the invention.

To the extent permitted by law, the invention includes methods for the treatment or prevention of anxiety, and in particular anxiety caused by withdrawal of ingested substances such as alcohol, narcotics (e.g. cocaine) and nicotine, which comprising administering an anxiolytically effective amount of such a compound.

EP-A-0158532 reveals that some of the above compounds have gastric motility and anti-emetic effects at relatively high daily doses of 5)' to 300 Ya.

Unit doses of 0.05 to 1009 are suggested, with 59 to 50 my or 100 of active ingredient per unit dose being preferred. According to a second aspect of the invention there is provided a pharmaceutical composition comprising a compound of general formula I as defined above, or a pharmaceutically acceptable acid addition salt thereof, and a pharmaceutically acceptable carrier therefor. , the composition is adapted to release from 5 to no more than 5 of the compound of general formula I per day. According to a third aspect of the invention, there is provided a pharmaceutical composition in unit dosage form, the composition comprising an amount of at least 50 mcg or up to soo mcg of a compound of general formula I and a pharmaceutically acceptable carrier therefor. . The preferential features of the second and third aspects of the invention are those of the first aspect mutatis mutandis.

Compounds of general formula I in which Rs does not represent hydrogen are EP-A
-0158532 or PRA-252954
8 has not been revealed. According to a fourth aspect of the invention, a pharmaceutical composition consisting of a compound of general formula IA, in which X represents oxygen or sulfur, R1 represents lower alkyl, and R2 represents hydrogen, halo, 4,5- benzo, lower alkoxy,
amino, methylamino or dimethylamino, and n is 1 or 2, or a pharmaceutically acceptable acid addition salt thereof, and a pharmaceutically acceptable carrier therefor.

R2 represents a 5-halo substituent; alternatively or additionally R2 represents 4-amino, 4-methylamino or 4
-dimethylamino is preferred. A preferred substituent is C1-4 alkyl, such as methyl or ethyl. The stereochemistry of the substituents on the quinuclidine ring is tr
ans is better, for example: 4-amino-N-(1-aza-
2-methyl-bicyclo(2,2,2)-3-octyl)
-5-chloro-2-methoxybenzamide and pharmaceutically acceptable salts thereof (eg, hydrochloride and fumarate salts) are a preferred feature of this aspect of the invention.

In further definitions of the symbols in this formula and wherever they appear elsewhere in this specification and claims, the terms have the following meanings:

The term 'C,-C,alkyl' as used herein includes straight and side chain radicals of a total of 8 carbons, including methyl, ethyl, propyl, isopropyl, butyl, amyl, hexyl, heptyl and octyl radicals, etc. 'c, -
c, alkoxyl" refers to a preferred subclass of radicals having the formula -0-C1-C, alkyl. can be interpreted.

The term 1 halo I or 1 halogen" as it appears herein includes fluorine, chlorine, bromine and iodine unless otherwise stated. Chlorine and bromine are more preferred.

Part 1: Partly acceptable salts include acid addition salts, hydrates, alcohol compounds and salts of the compounds, which salts are physiologically compatible in warm-blooded animals. Acid addition salts are formed with either strong or weak acids. Representative strong acids are hydrochloric acid, sulfuric acid and phosphoric acid. Representative weak acids are fumaric acid, maleic acid, succinic acid, and 7J! j acid, citric acid,
These include tartaric acid and cyclohexamic acid.

The term '1 drug' can be understood to include '1 veterinary medicine', if the circumstances permit, and cognate terms should be interpreted accordingly. The conserved amino groups used in the synthesis These include acetylamino or benzoylamino radicals of the benzamide moiety, which are mentioned below in the method.

Anxiolytic activity was measured by the method of Co5tall '4, details of which can be found in the Pharmacology Examples later herein. Briefly, the method involves seeing whether the compound under test reduces macus' natural anxiety when exposed to bright light.

Preparation of Benzamide 2 Processing of Benzamide Compound A A suitably activated benzoic acid derivative is reacted with 3-aminoquinuclidine under various conditions to produce the corresponding benzamide. Two general methods, A and B1, are illustrated by the following reaction equations: R1, 几2. R' and n are defined in the general formula (2) and are the same as those in 6-, except that R2 is not an amino group.

(a) M VJ tx In L”< are chloroform and diethyl ether.

The methodology is demonstrated by Examples 5, 6.7 and 9.

R', B2. l'? ,! and n are the same as defined in Equation 1.

(a) A suitable solvent is tetrahydrofuran. Method B
is demonstrated by Examples 1.3 and 8.

Compounds in which R2 is 17-mino are also prepared from compounds prepared by Processman or B, and compounds in which R2 is nitro are prepared by catalytic reduction of nitro compounds.

Alternatively, compounds in which 2 is amino can be prepared using a starting benzoyl halide in which the amino group is protected using Method A.
Alternatively, it can be produced from a compound produced by method A or B in which R2 is nitro and the nitro group is linked to an amine group.

Compounds in which R2 is 7mino or methylamino are rather prepared by method B.

The free base from its acid addition salt of a compound of formula I is recovered by conventional techniques of partitioning between a dilute aqueous base and a continuous solvent, separating the solvent phase, drying, and evaporating at °C. .

Production of thiobenzamide The production of thiobenzamide of formula 1' is based on the benzamide compound of formula 1, phosphorus pentasulfide (P2S5) and potassium sulfide (K,
This can be carried out by mixing 3-aminoquinuclidine with a mixture of S) and reacting it, or by mixing 3-aminoquinuclidine with appropriately substituted benzaldehyde and sulfur and reacting it. The reaction sequence is illustrated by the following reaction scheme: In these methods, compounds where R2 is nitro are reduced to compounds where R2 is 7mino.

A preferred group of compounds encompassed by Formula 1 has the following formula: where the oil is amino (ie, -NH,) or methylamino. As can be seen from the foregoing description, these compounds (IC) are rather prepared by method B.

Therefore, N-(1-7zabisik4(2,2,2”)-3
-octyl)benzamide and thiobenzamide.

A further object is to provide N-(1-azabicyclo(2,2,2)-3-octyl)benzamide and thiobenzamide with anxiolytic action.

A further goal is to provide a means to control anxiety.

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

Example 1 In a closed system equipped with an oil bubbler, 30 m of tetravitrofuran was stirred and then 4-amino/-5-chloro-2-
Methobenzoic acid 2.029 (0,010 mol) 1
, 1'-carbonyldiimidazole, 1.62g! (0
,010 mol). When carbon dioxide evolution ceases, nitrogen is bubbled through the reaction mixture for 1 hour. A solution of 1.26 g (0,010 mol) of 3-7 minoquinuclidine in 10 r1t of tetrahydro7 run was added dropwise to the stirred reaction mixture and stirring at room temperature was continued for 3
It lasted for hours. TLC analysis (3% ice-broken ammonium hydroxide solution in methanol showed some product production. The mixture was heated at reflux for 18 hours and then concentrated to an oil.

TLC analysis showed the presence of the products imidazole and 3-aminoquinuclidine. The oil is methylene chloride (75
td) and washed twice with 50 g of aqueous sodium bicarbonate. The methylene chloride layer was dried over anhydrous magnesium sulfate and concentrated to yield a glass-like amorphous solid, the free base of the title compound, ZOg (67%).

In another reaction on a 0.020 molar scale, 5.189 (83.8%) of the product as free base was obtained.

The product was combined and dissolved in solution with methanol (20tnt) and fumaric acid (z7) in methanol (50d).
3). Anhydrous ether was added to precipitate the salt, which was collected by filtration and recrystallized from methanol-water (200:20) with isopropyl ether added at point of initial turbidity)-1. Recrystallized salt (
5,389) melted at 223-225°C.

Analysis''' + Calculated for tH24NS04C1: C,
53,59; H, 5,68; N, 9.89 actual measurement
C, 53,35; H, 5,72; N, 9.9
5 A 37% (conc.) solution of the free base of the title compound in isopropyl alcohol obtained by the procedure of Example 1.
Add equimolar amounts of hydrochloric acid. Separate the coarse salt by filtration,
Recrystallized from acetone-water to give the title compound, m,
p, 158-160°C was obtained.

Example 3 1.1'-carbonyldiimidazole, 1.237(0
,00756 mol) and 5-chloro-2-methoxy-4-
Methylaminobenzoic acid, 1.639 (0°00756
50+d of tetrahydro7ran was added to the mixture of mol). 1 Nitrogen was bubbled into the dark solution for 30 minutes to remove any carbon dioxide present. One part of 3-aminoquinuclidine, 0.95 g (0,00756 mol) was added to this solution,
The reaction mixture was stirred at ambient temperature for 16 hours. The reaction mixture was concentrated to an oil, which was shown to be a 1:1 mixture of product and free r4i base of imidazole.

The mixture was dissolved in 20ml of methanol and treated with a solution of 0.47ml of fumaric acid in 20ml of hot methanol. Upon cooling, 1.52 g of white solid formed.

Recrystallization from water-methanol produced 0 product as a white solid.
．． m-p, 237-238°C, analysis: 02°E(26N, 06(J) total 'gX:C
, 54,61; H, 5,96; N, 9.55 actual measurement C, 54,61; H, 5,98; N, 9.
51 Example 4 A solution K of the free base of the title compound in isopropyl alcohol obtained by the procedure of Example 3.

Add 1 equimole of 37% (+i?1) hydrochloric acid. The crude salt was separated by filtration and recrystallized from ethanol-water to give the title compound, m, p, 255-25
8℃.

Example 5 thing).

In a closed system with an oil bubbler, 2-methoxybenzoyl chloride in anhydrous ether of 50-2,769
(0,0016%) solution of 1.81 g (0,0
144 mol) of Icl1 over 0 min.
Added drop by drop. After the addition is complete, the mixture is
Stirred at room temperature for an hour. The solid hydrochloride salt was collected by filtration under nitrogen. The salt (3.83 g) was dissolved in sodium bicarbonate solution and extracted twice with 25 parts methylene chloride. The extract was dried over magnesium sulfate and concentrated to give 1.259 pure oil (33.3%). T.L.C.
Analysis (3% concentrated ammonium hydroxide in methanol) showed the free base to be pure. A solution of 1.17 g of the free base in methanol of 5- was treated with a solution of 0.5297 malic acid in methanol of 10-. Isopropyl ether was added to obtain a solution of about 100-100 ml in which the fumarate salt precipitated. The salts were collected under nitrogen and heated in a vacuum oven for 6
Dry overnight at 0°C.

NMR and elemental analysis showed the product to be a hemihydrate.

Analysis "l? H25N20!, Calculated for 5: C, 59
, 21; H, 6, 54; N, 7.27 actual measurement
C, 59,18; H, 6,30; N, 7.25 Example 6 3-aminoquinuclidine dihydrochloride, 6.957 (0,0
349 mol), 2,4-dimethoxybenzoyl chloride, 700 g (Q, 0349 mol), 36.99 g (0,349 mol) of anhydrous sodium carbonate, 175 g of water and 175 g of chloroform were quickly stirred. 2
Good mixing was obtained for 0 hours 2HI. The chloroform layer was then separated, washed with water, dried over anhydrous magnesium sulfate, and concentrated to a crude oil. The oil was triturated twice with 20 parts petroleum ether to remove some impurities. The oil was then dissolved in ether and filtered to remove small amounts of undissolved material. The di solution was treated with ether hydrogen chloride, the resulting salt was collected, and 2.70 g (
A white solid was obtained (23.7% yield). Salt is ethanol
Recrystallized from isopropyl ether. Recrystallization thereon from methanol-ethyl ether yielded a white solid, r? 1. p, 211-212°C. NM analysis was satisfactory.

Analysis Calculated for “I!H2MN20!”: C, 58
,80; H,7,09; N, &57 actual measurement C
, 58, 38; H, 7, 13;
l/)-2,4-dimethoxybenzamide, 2 in anhydrous ether 2007 in a closed system with an oil bubbler.
, 4-dimethoxybenzoyl chloride, 13.08 moles (0,0652 moles) in 200 moles of anhydrous ether, 3-aminoquinuclidine, 7.807 moles (0,0619 moles)
mol) dropwise over 30 minutes. blend? Stir overnight and filter the product solid salt #R under nitrogen. This material was dried in a vacuum oven at 40°C to yield 18.70 g (92%). Z94 (0,009 moles) of the salt eR salt in 20 methanol was treated with a solution of sodium methoxide prepared from 0.23 moles (0,010 moles) of sodium metal and 10 methanol. After a few minutes, the mixture was filtered, the filtrate was concentrated on a rotary evaporator, and the residue was triturated with 75 methylene chloride. After filtration to remove some insoluble solids, the filtrate was condensed to yield 2.53 g of the free base of the title compound (97% recovery from the hydrochloride salt). Free base dissolved in 100 t of acetone/
Concentrated sulfur (0,483 at) was dissolved drop by drop with stirring. The solid formed was collected under MIO and salt 2.
767 was obtained: this salt was crystallized from mepnol/l/-4 sopropyl ether and heated to 60°C in a vacuum oven for 2 hours.
h, then allowed to dry overnight at 78°C; m, p,
223-225°C.

Analysis: ・C,,)I2. N, 0. One word about S:
C, 49, 47; f(t G, 23; N, 7.
23 actual measurement C, 49, 41; H, 6, 30; f
'J, 7.25 Implementation 8 In a closed system equipped with an oil bubbler, 100d of tetrahydrofuran was converted into 2,4-dimethoxyamic acid, aromatic acid a 649
(0.020%/I/) and 1 g of 1'-carbonate were added to a mixture of 3.247 (0.020 mol) of diimidazole. No evolution of carbon dioxide was observed and after 3 hours of stirring, TLC (ethyl acetate) and mass spectrometry analysis showed that the starting materials reacted to form N-(2,4-dimethoxybenzoyl)imidazole and imidazole. It was shown that Tetrahydrofuran 3-7 in 10g
A solution of 2.522 (0.020 mol) of mi/quinuclidine was added to the mixture and the solution was heated to reflux humidity for 1 hour and then left at room temperature overnight. 2.32 liters (0.020 moles) of 7 ml in 50 d of methanol were added to the reaction mixture.

Tetrahydrofuran was added until the solution became slightly cloudy. The solution was chilled in cold Mf4. The solid that precipitated from the solution was collected by filtration and was found to be the 7-malate salt of 3-aminoquinuclidine. The filtrate was concentrated to a curvature and triturated with tetrahydrofuran. The solid precipitate formed therein is filtered through S and TL
C (3% ammonicum in methano-s) proved to be the desired product plus traces of imidazole and 3-aminoquinuclidine. Methanol-
Recrystallization from isopropyl ether gave a white crystalline solid of 5,419 (calculated as monofumarate,
67% yield).

NMR and elemental analysis showed that the salt contained less than one equivalent of 7 malic acid. The salt is boiled methanol (50
m) and an additional 0% solution in hot methanol.
．． It was treated with 77 g (0,0066 mol) of 7-maric acid. Isopropyl ether was added until the hot solution became cloudy. The solid obtained by cooling was collected, recrystallized with methanol-isopropyl ether color, and heated in a vacuum oven at 78°C for 1 hour.
Let dry overnight. NMR and elemental analysis show that the salt is 1.57
It was shown that malate, m, p, 192-19Z5℃.

Analysis” Calculation for 22H21BN20?: C, 56
,89; H, 6,08; N, 6.03 actual measurement
C, 56,81; H, 6,13; N, 6.04 Example 9 N-1-azabicyclo(:2,2.2-3-octyl-2-propoxybenzamide hydrochloride (:l1).

To a solution of 3.827 (0.0192 mol) of 3-aminoquinuclidine dihydrochloride in approximately 25 rnt of carbon dioxide-free water was added 8 g of barium hydroxide octahydrate.

The mixture was warmed for 5 minutes and then dried on a rotary evaporator to a powder. The powder was sequentially extracted with a 1:1 mixture of hot benzene and benzene-methylene chloride solution while avoiding contamination with atmospheric carbon dioxide. The combined extracts were dried over magnesium sulfate and the mixture was filtered.

Stir in the filtrate and add 50% methylene chloride.
-Chloboxybenzoyl chloride 3.49 (0,01
71 mol) was added dropwise. The mixture was warmed on a steam bath to evaporate approximately 75% of the methylene chloride.

Ligroin (60-110) was added and the mixture solidified. The solid was recrystallized from anhydrous ethyl alcohol; 3.
99 (6ZO%), m-p, 210-211°C.

Analysis Calculated for "17H25N202"': C, 6
2,86; H, 7,75; N, 8.62 actual measurement
C, 62,62; H, 7,59; N, a54 Example 10 = 1]).

3-methoxy- in methylene chloride 15 tItl
2-naphthoic acid chloride 1.697 (0,00768
A solution of 3-aminoquinuclidine 0°9 in methylene chloride 25- in a closed system equipped with an oil bubbler.
was added dropwise to a stirred solution of 0.7 ml (0.00768 mol). The reaction mixture was stirred at ambient temperature overnight and then concentrated to give an off-white glassy solid. Two recrystallizations from methanol-isopropyl ether gave the product 1.952 (7 & 4%) as an off-white solid which was dried under vacuum at ambient temperature, m.
p, 248-252°C.

Analysis: C,, H, Calculation for 3N20□C1: C,
65,79; I-I, 6.68; N,
8.08 real ff1Q C, 65, 40; I(
, 6,72; N, 8.01 Example 11 4-amino-N-(1-azabicyclo(2,2°2)-
One-half mole of fumaric salt (3-octyl)-5-chloro-2-methoxybenzamide was partitioned between dilute sodium hydroxide and benzene 400*d. The benzene solution was dried using sodium sulfate and 250 m7! Distilled to a volume of . Add to this a finely ground mixture of 9 parts of phosphorus pentasulfide and 9 parts of potassium sulfide. The mixture is refluxed for 4 hours, then 90% pentasulfide is added and reflux is continued for 2 hours. Discard the benzene. The solid was dissolved in a suitable solvent and reacted with 7 malic acid to give the title compound.

Example 12 =1].

Example 11 Following the general procedure of Example 1, but using 3-amino-2-methylquinuclidine instead of 3-aminoquinuclidine.
The title compound was prepared using 0.010 mol.

Example 13 To an isopropyl alcohol solution of the free base of the title compound obtained by the procedure of Example 10 is added an equimolar amount of 37% (concentrated) salt. '@L salt is separated by filtration,
Recrystallization from acetate, 7-water gave the title compound.

Pharmacology Example A Method: Male white BKW mouse 2, which has never been used in animal experiments.
5=30 liters were used for the total temperature experiment. 10 mice is 1
Animals were housed in cages at -uifTI and had access to food and water to the confessional. 79th is 12 hours light, 12
At 10 o'clock, I turned off the lights, following Saik A.
I turned on the lights at 22nd.

Anxiolytic Test The apparatus used to detect changes in anxiety consists of a box without a lid (81 x 36 x 27 αL height), one third of which is painted black, illuminated with dim red light (IX 60 W), and painted white. , I placed 10 on the top of the box at 17.
Distinguished from the rest of the box brightly illuminated with a 0W light source ≠:. Access to these spaces was made possible by a violet or square 7,5 x 7.5σ six on the floor level in the center of the partition. The Song Dynasty part had 9α square lines. The test was conducted between 1:00 PM and 6:00 PM in a quiet, darkened room with only red light on. The six animals were thus transferred from a dark storage room to a dark testing room in a dark container.

Animals injected with drug or vehicle were placed singly in the center of the white area and their behavior was observed by remote video recording for 5 minutes. Four behavioral parameters were observed every minute: the number of inkstone steps in the examination in the white and black areas, the number of line crossings in the white and black areas,
The number of movements of white and j or m and white parts and the time spent in white and black parts. The experimenter remained gradually unaware of the drug treatment, and the code was divided into seven; Controls were performed on each day of the study. Store results compare all treated animals to controls Dt+! Single-Factor Analyses tracked by 1net method
It was analyzed using the is of Vari-ance (single factor analysis of squared differences).

The compounds of Drug Examples 2 and 4 were administered intraperitoneally in sterile saline in an amount of 1 d/1009 body weight.

result The results are shown in one table.

Table 1 Drugs (~/kjL) Number of standing on hind legs White area Black area Control (10 digits)) 16 39
Actual example 2 0.0001 26”
32a// 0.001 44a2
2a/1 0.05 39a22a//
0.1 53a15a// 1
54a15” Example 13 1.25
81 17 control (10ml/kg)
46 67 Example 2 0.0001
52 38a// 0
．． 001 58a13a// 0.05
60a18a// 0.1 68a
18a// 1 73a15”ap<0
．． 05 bp from control <0.001 from control Pharmacology Example B Mice group (rl-5) received 8% in their drinking water for 14 days
The procedure of Pharmacology Example A was followed, except that the ethanol-treated mice were given ethanol; the ethanol-treated mice were then given ethanol. The results are shown in Table 2.

Table 2 Mouse control without ethanol treatment (10d/k)) 21 33
Example 2 0.1 68°
10c Ethanol-treated Mawas Ethanol-treated Hamaus control (10m//k)) 53 5
3 Example 2 0.1 76'
23° Ethanol-treated mice'p<0.05 From ethanol-interrupted mice Pharmacology Example C Mice group (n-5) received intraperitoneal administration of 1~/ky cocaine twice a day for 14 days The methods of the Pharmacology Example were followed with the exception that the cocaine-treated mice were then withdrawn from cocaine. The results are shown in Table 3.

Table 3 Mouse control without cocaine treatment (10 go/k1) 22 30
Example 2 0.1 50e12e Cocaine treated macus control (10111t/k)) 53
50 Example 2 0.1 71e15e
Cocaine-treated mice ep (0,05 from control 'p(0,05) from cocaine-discontinued mice.
/kiwo except that it is administered twice a day for 7 days.
The procedure for the Pharmacology Examples was followed; nicotine-treated mice were then withdrawn from nicotine. The results are illustrated in Figure 1, which illustrates the antagonism of nicotine withdrawal anxiety development by the compound of Example 2. In Figure 1, the columns and symbols have the following meanings: (5) One control (B) - Nicotine treated (but not withdrawn) mice (q - Nicotine withdrawn mice 0 - Compound of Example 2 1. p < o, oo10-(5) compared to nicotine-abandoned mice treated with 0~/ky twice a day*-(5)
compared to p (0,0010-reversal (C) p
(0,OOt The standard error of the mean value was less than 12-9%.

Pharmaceutical methods and compositions! btK, anxiety is calculated by formula 11 preferably N-(1
- azabicyclo(2,2,2)-3-octyl)benzamide and thiobenzamide, or non-toxic organic or inorganic acid addition salts thereof, in a variety of well-known drug forms for warm-blooded animals, including humans; Anxiety can be controlled by the method of the present invention by internal administration, preferably with a non-toxic drug carrier such as those described below in an anxiety-controlling amount. The active agent may be administered orally, subcutaneously, intravenously or intramuscularly, or parenterally, and if necessary, in repeated doses until a satisfactory response is obtained. The daily dose is approximately 1 m of active drug
Advantageously, it is about 50 Da from cg, and about 5.0 from about 5 mcg.

The composition is 5.5% per unit dose. Contains 50 da of active drug from Q mcg. The composition contains about 5 mcg to 50 η of drug.
From about 5 mcg to about 5.0 mcg per unit dose is advantageous. Compounds can thus be administered orally, parenterally, subcutaneously,
Therapeutic compositions may be formulated for intramuscular, intraperitoneal or intravenous administration. Thus, for example, oral administration can take the form of elixirs, capsules, tablets or tablets containing carriers conveniently employed in pharmaceutical technology. Typical solid carriers, including excipients for making tablets and degussels, include lactose, sucrose, potato and corn starch, Merck, gelatin, agar, pectin or gum arabic, stearic acid and silicic acid, magnesium stearate, and white china clay. and polyvinyl pyrrolidone.

For parenteral applications, the carrier or excipient consists of a sterile parenterally acceptable liquid; for example, water or liquid oil contained in liquid.

The pharmaceutical composition has about 1. Onlcg/mg to approx. 5
It is formulated to contain 0.01 n9/rnt, preferably 5 Q mcg/- or less. It is necessary that the active ingredient of Formula I be comprised in an effective amount.

In all of the above, it is necessary that the appropriate valid usage match the used usage ff1W. As with daily dosages, the exact dosages are of course determined in accordance with standard medical principles under the direction of a physician or veterinarian. The method is described in the foregoing specification. However, the invention sought to be protected herein should not be construed as being limited to the form of the lines published; rather, variations and changes may be made by those skilled in the art without departing from the spirit of the invention, and the invention is therefore not covered by the appended claims. It is understood that the scope of the invention shall be limited only by the scope of the invention.

[Brief explanation of the drawing]

The 11th prisoner is Mosquito 1; This is a graph showing the results of standing on the hind legs and line crossing of each group of mice in the physical experiment. Representative 3 Masao Kei and 1 other person 1st meeting

Claims (1)

[Claims] 1) Consists of a compound of the general formula I, ▲ has mathematical formulas, chemical formulas, tables, etc. ▼ (I) The compound is such that X represents oxygen or sulfur, and R^1 represents represents lower alkyl, R^2 represents hydrogen, halo, 4,5-benzo, lower alkoxy, amino, methylamino or dimethylamino,
R^3 represents hydrogen or lower alkyl, and n is 1 or 2, a pharmaceutical composition, or a pharmaceutically acceptable acid addition salt thereof, and releasing not more than 5 mg of a compound of general formula I per day. a pharmaceutically acceptable carrier therefor. 2) A pharmaceutical composition in unit dosage form, the composition having the formula
Consisting of 500mcg or more of the compound I, ▲There are mathematical formulas, chemical formulas, tables, etc.▼・・・・・・(I) The compound is: X represents oxygen or sulfur, R^1 represents lower alkyl, R^ 2 represents hydrogen, halo, 4,5-benzo, lower alkoxy, amino, methylamino or dimethylamino,
R^3 represents hydrogen or lower alkyl, and n is 1 or 2, a pharmaceutical composition, or a pharmaceutically acceptable acid addition salt thereof, and a pharmaceutically acceptable carrier therefor. 3) The pharmaceutical composition according to claim 1, which contains 50 mcg or more of the compound. 4) The pharmaceutical composition according to claim 1, 2 or 3, wherein R^2 in general formula I represents a 3- or 5-halo substituent. 5) The pharmaceutical composition according to any one of claims 1 to 4, wherein R^2 in general formula I represents a 4-amino, 4-methylamino or 4-dimethylamino substituent. 6) The pharmaceutical composition according to any one of claims 1 to 5, wherein in the general formula I, X represents oxygen. 7) A pharmaceutical composition according to any one of claims 1 to 7, wherein the compound is 4-amino-
N-(1-azabicyclo[2,2,2]-3-octyl)-5-chloro-2-methoxybenzamide, N-(1-azabicyclo[2,2,2]-3-octyl)-5-chlor -2-methoxy-4-methoxyaminobenzamide, N-(1-azabicyclo[2,2,2]-3-octyl)-2-methoxybenzamide, N-(1-azabicyclo[2,2,2]-3 -octyl)-2,4-dimethoxybenzamide, N-(1-azabicyclo[2,2,2]-3-octyl)-2-proboxybenzamide, 4-amino-N-(1-azabicyclo[2,2] ,2]-
3-octyl-5-chloro-2-methoxybenzamide, N-(1-azabicyclo[2,2,2]-3-octyl)-5-chloro-2-methoxy-4-methoxyaminobenzamide, N-(1 -azabicyclo[2,2,2]-3-octyl)-3-methoxy-2-naphthalenecarboxamide, 4-amino-N-(1-aza-2-methyl-bicyclo[
2,2,2]-3-octyl)-5-chloro-2-methoxybenzamide, or a pharmaceutically acceptable salt thereof. 8) A pharmaceutical composition consisting of a compound of the general formula I A, which has mathematical formulas, chemical formulas, tables, etc. (I A
) X represents oxygen or sulfur, R^1 represents lower alkyl, R^2 represents hydrogen, halo, 4,5-benzo, lower alkoxy, amino, methylamino or dimethylamino, R^3 represents lower A pharmaceutical composition, or a pharmaceutically acceptable acid addition salt thereof, representing alkyl, and n is 1 or 2, and a pharmaceutically acceptable carrier therefor. 9) 4-Amino-N-(1-aza-2-methyl-bicyclo[2,2,2]-3-octyl)-5-chloro-2-
A pharmaceutical composition comprising methoxybenzamide, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier therefor. 10) A method for the treatment or prevention of anxiety consisting of administering an effective amount as an anxiolytic of a compound of general formula I, which compound has the following formula: ▲Mathematical formula, chemical formula, table, etc.▼... I) X represents oxygen or sulfur, R^1 represents lower alkyl, R^2 represents hydrogen, halo, 4,5-benzo, lower alkoxy, amino, methylamino or dimethylamino, R^3 represents represents hydrogen or lower alkyl, and n is 1 or 2, or a pharmaceutically acceptable acid addition salt thereof. 11) The method according to claim 10, wherein R^2 in the general formula I represents a 3- or 5-halo substituent. 12) A process according to claim 10 or 11, wherein in general formula I, R^2 represents a 4-amino, 4-methylamino or 4-dimethylamino substituent. 13) The method according to claim 10, 11 or 12, wherein in the general formula I, X represents oxygen. 14) 4-amino-N-(1-azabicyclo[2,2,
2]-3-octyl)-5-chloro-2-methoxybenzamide, N-(1-azabicyclo[2,2,2]-3-octyl)-2-methoxybenzamide, N-(1-azabicyclo[2, 2,2]-3-octyl)-2,4-dimethoxybenzamide, N-(1-azabicyclo[2,2,2]-3-octyl)-2-proboxybenzamide, 4-amino-N-(1 -Azabicyclo[2,2,2]-
3-octyl)-5-chloro-2-methoxybenzamide, N-(1-azabicyclo[2,2,2]-3-octyl)-5-chloro-2-methoxy-4-methylaminobenzamide, N-( 1-Azabicyclo[2,2,2]-3-octyl)-3-methoxy-2-naphthalenecarboximide, 4-amino-N-(1-aza-2-methyl-bicyclo[
A method for the treatment or prevention of anxiety comprising administering an anxiolytically effective amount of 2,2,2]-3-octyl)-5-chloro-2-methoxybenzamide, or a pharmaceutically acceptable salt thereof. . 15) A pharmaceutical composition substantially as herein adapted to release 5 mg or less of a compound of general formula I per day. 16) A pharmaceutical composition substantially as described herein in unit dosage form, the composition comprising 500% of a compound of general formula I.
Consisting of mcg or more. 17) A pharmaceutical composition substantially as described herein, consisting of a compound of general formula IA. 18) A method of treating anxiety substantially as described herein.