DE2410982C3 - Medicinal products with sedative and tranquilizer effects - Google Patents

Description

Compounds in which the dibenzobicyclo [3.2, l] octadiene nucleus is bonded to an amino group in the 8-position via a carbonyl or alkylene group, are known. In DE-OS 19 53 334 various derivatives of S-hydroxydibenzobicyclo [3.2, l] octadiene are and three derivatives of the dibenzobicyclo-f ^ .ljoctadiene core indicated, including 8-carboxamidodibenzobieyclo [3.2, l] octadiene and 8-aminomethyldibenzobicyclo [3.2, l] octadiene. The compounds can also be referred to as 5,10-methane-5H-dibenzo [a, d] cycloheptene derivatives. These compounds are described as diuretics. In DE-OS 22 16 884 antidepressants are and anticonvulsants are disclosed in which an amino radical (—NR1R2) in the 8-position is attached to a dibenzobicyclo- [3.2.1] octadiene nucleus is bound. In Example 15, the compound is 8-N-methylpiperazinyl-N'-carbonyldibenzobicyclo [3.2, l] octadiene mentioned as an intermediate product for the production of the substances claimed there. That this connection 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 dibenzobicyclofS ^ .ljoctadiene compounds mentioned. The anti isomer has been shown to be a much better therapeutic one Ratio possesses as the corresponding syn isomer and the compounds with anti configuration are therefore preferred.

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

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

H ₃ CN

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-carboxydibenzobicyclop ^ ljoctadiene, in solution in an> inert solvent such as dichloromethane, chloroform, benzene, hexane or similar. The reaction runs quickly to completion in less than 1 hour at 20 to 30 ^° C. The product can easily be isolated by removal of the solvent and is purified by recirculation or other conventional methods

The required intermediate, 8-anti-carboxydibenzobicydo [3.2, l] octadiene, are made from the known compound 8-anti-chlorodibenzocyclo [3.2, l] octadiene (J. Am. Chem. Soc, 87, 2877 [1965]).

ι j The chlorine compound is produced by a Grignard reaction converted into the magnesium Grignard reagent and then reacted with carbon dioxide to produce the to obtain the corresponding 8-anti-carboxylic acid.

The carboxylic acid is reacted with a

2 »inorganic acid halide into the corresponding Acyl halide converted. It has been shown that thionyl chloride reacts rapidly with 8-anti-carboxydibenzobicyclo [3.2, l] octadiene reacts when the reactants are mixed and heated briefly to reflux temperature (up to an hour). The acid chloride can be removed by evaporation of excess thionyl chloride obtained and used without further purification as described above.

The resulting free base can easily be converted into a

so acid addition salt can be converted by treatment with an appropriate equimolar amount an acid. This is usually done by treating the free base in isopropyl alcohol with the Acid, whereby the resulting salt precipitates. Given-

j5 if the precipitation can be done by adding a non-solvent be relieved. Suitable pharmaceutically acceptable acid addition salts according to the invention can be organic or inorganic salts and include the hydrochloride, hydrobromide, maleate,

4i) 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 for Evidence of calming or tranquilizing

4 ^r > effectiveness in mammals are active. They counteract the mortality caused by close coexistence after the administration of amphetamine. The experiment is described by Lasagna, L. and McCann, WP, Science 125: 1241 (1957); Burn, JH and

V) Hobbs, R., Arch.int.Pharmacodyn 113: 290 (1958) et al.

In this experiment, male mice (17 to 27 g), with 10 mice in each cage, are the ones test compound is administered and the mice are returned to a cage for 30 minutes,

ν- before they are injected intraperitoneally with 10 mg / kg d, l-amphetamine sulfate. Immediately after the amphetamine administration, the group of 10 mice are placed in a rectangular glass jar approximately 15.2 by 12.7 by 25.4 cm. One only with the carrier

w) treated group (comparison) is similarly transferred to another vessel. The close coexistence of the animals over an area of approximately 194 cm ² results in death after the administration of the amphetamine dose, which is non-lethal in mice in individual cages. To

After 5 hours of close cohabitation, the comparison mice have a mortality of more than 70%, usually 90 to 100%. The control mice are pretreated with the vehicle and then with amphetamine

been charged. Effective compounds protect against the occurrence of group mortality, whereby 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 ₅₀ 175 mg / kg 282 mg / kg ED ₅₀ 58.9 mg / kg 8.7 mg / kg TI -28

That is, the therapeutic index for the compound of the invention is about 9 times as high as for the known connection.

The tranquilizing effect on mammals can also be demonstrated by the ability of the compounds to inhibit spontaneous movement activity. In this attempt, a single mouse (16 to 24 g) are weighed and the compound to be investigated is weighed in suitable doses in a geometric Distance administered. Immediately after administration, each treated group becomes, from 15 mice, placed in the counting chamber of Woodward activity cages. The cumulative activity counts, which are caused by an interruption of infrared rays by the mice in the Counting chamber, 15,30,45,60 and 90 min after Bringing the mice into the counting chamber is noted. The ratio of the mean of three cages per Treatment for the mean of three mice treated with vehicle only is determined and one Value less than 1 means a dampening effect. Further attempts that were applied and which showed the tranquilizing effect of the compound of the invention include the Sidman avoidance or evasive attempt in rats and the antagonistic effect on that of caffeine induced movement stimulation in mice.

The compounds of the invention can be administered intraperitoneally or orally. If you If administered intraperitoneally, they will be in solution in a pharmaceutically acceptable solvent administered in doses of about 1 to 30 mg / kg body weight of the test animal. It is it is preferred to administer doses of 2 to 20 mg / kg of the anti isomer, since the doses in this range will be Animal testing has proven to be well effective. Such doses result in good therapeutic ratios as the intraperitoneal LD50 was determined to be approximately 282 mg / kg for the hydrochloride.

When the hydrochloride is administered orally, doses of 10 to 50 mg / kg are used to reduce a to achieve a transquilizing effect. Since the oral LD50 is greater than 800 mg / kg, the anti isomer possesses 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 normal 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 compound itself and its salts are solids and can easily be 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) To a suspension of 3.15 g (0.13 mol) of magnesium turnings in 20 ml of tetrahydrofuran were 29.5 g (0.126 mol) of 8-anti-chlorodibenzobicyclo [3.2.1] octadiene are added, the solution at reflux temperature was held. Five drops of 1,2-dibromomethane were added. The mixture became approximately 16 hours held at reflux temperature. The mixture was then brought to -25 ° C with a dry ice-acetone bath cooled and carbon dioxide bubbled through quickly. The addition of carbon dioxide was continued for 1.5 hours and then the mixture was warmed to room temperature. The mixture then carefully turned into 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, washed with dichloromethane and the dichloromethane extracts combined and over magnesium sulfate dried. This solution was filtered and the filtrate evaporated under reduced pressure, whereby 8-carboxydibenzobicyclo [3.2.1] octadiene was obtained. This solid product was fractionated from benzene crystallized, giving a white solid, 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

calculated for C | ₇ H _M 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 determined by the nuclear magnetic resonance spectrum confirmed

It should be noted that the amount of the syn isomer obtained can be reduced significantly,

if the temperature of the solution at which carbon dioxide is added is kept at -55 ° C until the aqueous ammonium chloride solution is added.

b) A solution of 50 ml of thionyl chloride and 7.8 g (0.032 mol) of anti-8-carboxydibenzotiicyclo [3.2.1] ocladiene was heated to reflux temperature and kept at this temperature for 1 hour. The excess thionyl chloride was evaporated under reduced pressure. Was added benzene (about 50 ml) and the mixture evaporated again under reduced pressure to dryness The solid product was anti-8-Carboxydibenzobicyclo [3,2, l] octadienchlorid, mp. 102 to 104 ⁰ C.

c) The anti-8-carboxydibenzobicyclooctadiene chloride (0.032 mol) was dissolved in dichloromethane and 10 g (G, 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 then wu.de over dried anhydrous sodium sulfate and filtered.

Analysis:

The filtrate was evaporated in vacuo to give an oil which upon washing with hexane solidified. The solid product was triturated with hexane and filtered. The solid free base was obtained S-anti ^ N-methylpiperazino-N'-carbonylJ-dibenzobicyclo [3,2,1] octadiene, Mp 172-174 ° C (uncorrected).

The structure was confirmed by the infrared spectrum.

d) To a suspension of 3.5 g (0.039 mol)

κι 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

i> precipitated, which was filtered off. The solid turned off recrystallized from a mixture of isopropyl alcohol and diisopropyl ether. A tan colored one was obtained Solid of 8-anti- (N-MethyIpiperazin-N'-carbonyl) dibenzobicyclo [3.2, l] -octadiene hydrochloride, M.p. 265

j »up to 267 ° C.

% C % Il

"■,. N

calculated door C ₂₃ H ₃₄ N ₃ O -HCI- V ₃ 11.0 69.4 found 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 of the formula H ₃ CN NC or its acid addition salts in sedation or tranquilization.