DE2410982B2 - Medicines with sedative and tranquilizer effects - Google Patents

Description

Compounds in which the dibenzobicyclo [3.2, l] octadiene nucleus in the 8-position is bonded to an amino group via a carbonyl or alkylene group, are known In DE-OS 19 53 314 are various Derivatives of S-hydroxydibenzobicyclopAlJoctadiene and three derivatives of the dibenzobicyclo-pAlJoctadieiikernes indicated, including 8-carboxamidodibenzobicyclo [3.2, l] octadiene and 8-aminomethyldibenzobicydossAlJ-octadiene. The compounds can also be referred to as 5,10-methane-5H-dibenzo [a ^] cycloheptene derivatives. These compounds are described as diuretics. In DE-OS 22 16 884 antidepressants are and anticonvulsants disclosed in which an amino radical (-NRi Rj) in the 8-position to a dibenzobicyclic> - [3.2, l} octadiene nucleus The compound 8-N-methylpiperazinyl-N'-carbonyldibenzobicyclo [3.2.1] octadiene is bound in Example 15 mentioned as an intermediate product for the production of the substances claimed there that this compound itself Has pharmacological effectiveness, however, there is no indication of it.

Nowhere in the prior art is the meaning of the geometric isomerism of that in the 8-position substituted dibenzobicycIopAlJoctadieneverbindungen It has been shown that the anti isomer is a much better therapeutic one Ratio possesses as the corresponding syn isomer and the compounds with the anti configuration are therefore preferred

The invention relates to the use of 8-anti-N-

Methylpiperazinyl-N'-carbonyldibenzobicvclo- [3.2, l] octadiene the formula

H ₃ C-

N-C

and its pharmaceutically acceptable salts in sedation or tranquilization.
The compounds used according to the invention are prepared in the form of the free base by reacting N-methylpiperazine with an acyl halide, preferably the chloride, of 8-anti-carboxydibenzobicyclo [3.2.1] octadiene,} _n solution in one

inert solvents such as dichloromethane, chloroform, Benzene, Hsxan or the like. The reaction goes to completion quickly in less than 1 hour at 20-30 ° C. The product can easily be isolated by removing the solvent and is purified by recirculation ο install or clean other common procedures

The required intermediate, 8-anti-carboxydibenzobicyclo [3 ^, l] octadiene, are made from the known compound 8-anti-Cblordibenzocydo [3.2, l] octadiene (J. Am. Chem. Soc, 87, 2877 [1965J.

The chlorine compound is converted into the magnesium Grignard reagent by a Grignard reaction and then reacted with carbon dioxide to obtain the corresponding 8-anti-carboxylic acid.
The carboxylic acid is converted into the corresponding acyl halide by reaction with an inorganic acid halide.It has been shown that thionyl chloride reacts rapidly with S-anti-carboxydibenzobicyclo [3.2, l] octadiene when the reactants are mixed and briefly heated to reflux temperature (up to to an hour). The acid chloride can be recovered by evaporation of excess thionyl chloride and used as described above without further purification.

The resulting free base can easily be converted into a

Acid addition salts are converted by treatment with an appropriate equimolar amount an acid. This is usually done by Treatment of the free base in isopropyl alcohol with the acid, the resulting salt precipitating, if necessary the precipitation can be facilitated by adding a non-solvent. Suitable according to the invention pharmaceutically acceptable acid addition salts can be organic or inorganic salts and include the Hydrochloric !, hydrobromide, maleate, sulfate, phosphate, acetate, lactate, tartrate, citrate, organic sulfonates such as methanesulfonates etc.

It has been shown that the agents according to the invention in standard pharmacological examinations to demonstrate the calming or tranquilizing effects Effectiveness in mammals are active. They act on the mortality caused by close coexistence after the administration of amphetamine opposed. The experiment is described by Lasagna, L. and McCann, W. P, Science 125: 1241 (1957); Burn, J. H. and

so Hobbs.R ^ Arch.intPharmacodynlJ ^ 290 (1958) et al.

In this experiment, male mice (17 to 27 g), with 10 mice in each cage, administered the test compound, and the mice are again placed in a cage for 30 minutes before giving them IO mg / kg of d.l-amphetamine sulfate intraperitoneally injected. Immediately after the administration of amphetamine, the group of 10 Place mice in a rectangular glass jar approximately 15.2 by 12.7 by 25.4 cm. One only with the carrier

ω treated group (comparison) is similarly transferred to another vessel. The close coexistence of the animals over an area of approximately 194 cm ² leads to death after the administration of the amphetamine dose, which is not lethal in mice in individual cages. After 5 hours of close coexistence, mortality of more than 70%, usually 90 to 100%, occurs in the comparison mice. The control mice are pretreated with the vehicle and then with amphetamine

been charged. Effective compounds protect against the occurrence of group mortality, with the Mortality in 5 h with effective doses is often reduced to 0.

The effect and toxicity of the compound of the present invention were similar to those of the known one Tranquilizers compared to chlordiazepoxide (Librium). The following values were obtained with intraperitoneal Administration:

Chlordiazepoxide

according to the invention

link

(anti shape)

LD ₅₀
ED _S0
TI

175 mg / kg
58.9 mg / kg
~ 3

282 mg / kg

8.7 mg / kg
-28

That is, the therapeutic index is for that compound according to the invention about 9 times as high as for the known compound.

The tranquilizing effect on mammals can also be demonstrated by the compounds' ability to inhibit spontaneous locomotor activity. In this experiment, a single mouse (16 to 24 g) is weighed and given the compound to be tested in appropriate doses at a geometrical distance. Immediately after administration, each treated group, consisting of 15 mice, is placed in the counting chamber of Woodward activity cages given. The cumulative activity counts caused by the interruption of infrared rays by the mice in the counting chamber are recorded at 15, 30, 45, 60 and 90 minutes after the mice are placed in the counting chamber. The ratio of the mean of three cages per treatment to the mean of three mice treated only with the vehicle is determined and a value of less than 1 indicates a depressant effect. Further tests which were used and which showed the tranquilizing effect of the compound according to the invention include the Sidman avoidance test in rats and the antagonistic effect on caffeine-induced movement stimulation in mice.

The compounds of the invention can be administered intraperitoneally or administered orally. When given intraperitoneally, they become in Solution in a pharmaceutically acceptable solvent in doses of about 1 to 30 mg / kg Body weight of the test animal administered. It is preferred to use doses of 2 to 20 mg / kg of the anti-isomer given as the doses in this range have been shown to be well effective in animal studies. Such Doses give good therapeutic ratios as the intraperitoneal LD »is about 282 mg / kg for the Hydrochloride was determined.

When the hydrochloride is administered orally, doses of 10 to 50 mg / kg are used to achieve a transquilizing effect. Since the oral LD _{50 is} greater than 800 mg / kg, the anti-isomer has therapeutic ratios of 40 and more.

If a test animal or a person is treated with the compound of the invention, must the dose according to the patient's response and age, weight, general health and the like can be varied. A regulation of the respective dose is within the scope of the usual knowledge of the specialist,

The compounds used in the present invention and their salts are used in any of the usual Dosage forms for drugs administered The salts are easily soluble in water and solutions in the known pharmaceutical carriers or pills or capsules can be prepared as desired and can be applied. Both the connection seldom as ίο also their salts are solids and can be easily mixed with Diluents and excipients can be combined to make various pharmaceutical dosage forms Kind of manufacture.

It has been shown that the compound and its salts generally contain some water of crystallization.

The following examples show the most favorable manufacturing process.

example 1

a) 29.5 g (0.126 mol) of 8-ami-chlorodibenzobicycIo [3.2.1] octadiene were added to a suspension of 3.15 g (0.13 mol) of magnesium turnings in 20 ml of tetrahydrofuran, the solution being refluxed was held. Five drops of 1,2-dibromomethane were added. The mixture was held at reflux temperature for approximately 16 hours. The mixture was then cooled with a dry ice-acetone bath to -25 ⁰ C and carbon dioxide quickly passed through the addition of carbon dioxide was continued 1.5 and

then the mixture was warmed to room temperature. The mixture then carefully turned to an aqueous one Solution, which was saturated with ammonium chloride, given. The aqueous layer was separated and with Extracted dichloromethane and then put together twice with diethyl ether and the organic layers. The combined organic layers became a non-volatile under reduced pressure The residue was evaporated. Diethyl ether was added and the ether solution twice with an identical one Volume of 5% aqueous sodium hydroxide solution washed. The aqueous solution was then acidified and washed with dichloromethane and the dichloromethane extracts combined and dried over magnesium sulfate. This solution was filtered and the filtrate was evaporated under reduced pressure to give 8-carboxydibenzobicyclo [3.2.1] octadiene This solid product was fractionally crystallized from benzene to give a white solid obtained melting point 175 to 180 ° C. The nuclear magnetic resonance spectrum this isomer indicated that it was essentially the pure (greater than 95%) anti-isomer.

Analysis:

% c

for C ₁₇ Hi ₄ O ₂ 81.5

found 81.8

The mother liquors from the recrystallization of the anti isomer were evaporated to give a Was obtained residue, which was fractionally crystallized from benzene or ethanol. You got that in essentially pure syn-d, l-isomer, m.p. 218-222 ° C.

The purity was confirmed by the nuclear magnetic resonance spectrum.

It should be noted that the amount of syn-isomer obtained can be substantially decreased,

if one keeps the temperature of the solution, is added at the carbon dioxide to -55 ⁰ C, to the aqueous solution of ammonium chloride was added.

b) A solution of 50 ml of thionyl chloride and 7.8 g (0.032 mol) of anti-8-carboxydibenzobicyclo [3 Äl] octadiene was heated to reflux temperature and kept at this temperature for 1 hour. The excess thionyl chloride was unier reduced pressure evaporated was added benzene (about 50 ml) and the mixture evaporated again under reduced pressure to dryness The solid product was anti-8-Carboxydibenzobicyclo [3Al] octadienchlorid, m.p. 102 to 104 ⁰ C.

c) The anti-8-carhoxydibenzobicyclooctadiene chloride (0.032 mol) was dissolved in dichloromethane and 10 g (0.10 mol) of N-methylpiperazine were added with stirring. After 30 min the mixture was successively washed with equal volumes of water, saturated sodium bicarbonate solution and saturated sodium chloride solution. The organic layer was then over dried anhydrous sodium sulfate and filtered

Analysis:

The filtrate was evaporated in vacuo to give an oil which solidified on waxing with hexane. The solid product was triturated with hexane and filtered Man mp 172 (not corrected) received the solid free base e-anti-fN-methylpiperazino-N'-carbonylJ-dibenzobicyclo [3,2, l] octadiene. To 174 ⁰ C.

The structure was determined by the infrared spectrum confirmed

d) To a suspension of 84 g (0.039 mol)

ίο e-anti-fN-methylpiperazine-N'-carbonyl-dibenzobicyclo [3.2, l] octadiene base 7 ml of 7 η-hydrogen chloride in isopropanol were added to 100 ml of isopropanol, whereby the hydrochloride was formed. The solution was then treated with diisopropyl ether, the salt precipitated, which was filtered off. The solid was made from a mixture of isopropyl alcohol and diisopropyl ether recrystallized A tan-colored solid of 8-anti- (N-methylpiperazine-N'-carbonyl) dibenzobicycio [3.2, l] octadiene hydrochloride, M.p. 265

up to 267 ° C

% C

%H

% N

for C ₂₂ H ₂₄ N ₂ O found

HCl · '/ 2 H ₂ O 69.4
69.9

6.8
6.9

7.4
7.4

Claims (1)

Claim: Use of 8-anti-N-methylpiperazinyl-N'-carbonyldibenzobicyclo [3.2, l] octadiene the formula H ₃ CN or its acid addition salts in sedation or tranquilization.