NO169230B - ANALOGUE PROCEDURE FOR THE PREPARATION OF THERAPEUTIC ACTIVE AMINOALKANOYL-DIBENZO (D, G) (1,3,6) DIOXAZOCINES - Google Patents

Description

The present invention relates to the production of new aminoalkanoyl-dibenzo[d,g][1,3,6]dioxazocines.

The new compounds exhibit valuable pharmaceutical properties such as local anesthetic activity, sedative-sedative activity and/or antidepressant activity, are anti-Parkinsonian agents and furthermore exhibit anti-arrhythmic and anti-anginal activity.

12-Aminoalkyl-12H-dibenzo[d,g][1,3,6]dioxazocines with local anesthetic and antiparkinsonian activity are described in U.S. Pat. patent document 4 208 410.

From US patent documents 4,299,350 and 4,208,410, the compound 2-chloro-12-(3-dimethylamino-2-methylpropyl)-12H-dibenzo[d,g][1,3,6]dioxazocine is described in example 6. This compound is readily available under its international name traboxopin.

Comparing the activity indicated in Table III of the present specification, the ED50 value for traboxopin is 25.0 mg/kg and the therapeutic index for the compound is 10.8. If you compare the activity of the compounds according to examples 1 and 4, the activity of traboxopin is much lower. With respect to antagonism of tetrabenazine dose (see Table IV), traboxopin does not exhibit any inhibitory activity in this test as toxic interaction occurs.

This test is characteristic of the antidepressant activity. With respect to the nicotine lethality inhibitory activity (see Table V), the ED50 value for traboxopin is 11.2 mg/kg while its therapeutic index is 25. Comparing the values for the compound according to examples 3 and 5, it is clear that traboxopin has lower activity .

With regard to the tremor-inhibiting activity (see Table VI), the ED50 value of a traboxopin is 11 mg/kg, while its therapeutic index is 25. Comparing the values of the compounds of Examples 1, 3 and 13, it is clear that traboxopin is less active.

With regard to the antiarrhythmic activity, traboxopin exhibits no such effect at all, while all the compounds produced according to the invention listed in Table VII have an excellent activity.

With regard to antianginal activity, traboxopin has no detectable activity. In contrast, the compound according to examples 15 and 21 are advantageous antianginal agents.

As a conclusion, it can thus be established that replacing the aminoalkyl group of the known compounds with an aminoalkanoyl group results in a lower local anesthetic activity but at the same time new activities occur, namely antidepressant, antiarrhythmic and antianginal activity. The spectrum of activities could thus not be predicted based on familiarity with the known publications.

It was found that the pharmaceutical activity of the known compounds can be favorably modified by substituting the ring nitrogen with an aminoalkanoyl group instead of an aminoalkyl group.

The invention thus relates to an analogous process for the production of new, therapeutically active aminoalkanoyl-dibenzo[d,g][1,3,6]dioxazocines of the formula

in which

X denotes hydrogen or chlorine,

A denotes a valence bond or straight-chain or branched alkylene with 1-4 carbon atoms,

R-j_ and R2 independently denote hydrogen, alkyl with 1-4 carbon atoms or cyclohexyl, or

R 1 and R 2 , together with the nitrogen to which they are attached, form a methylpiperazinyl or pyrrolidinyl group, and pharmaceutically acceptable acid addition salts

hence.

The compounds of formula (I) can form pharmaceutical

acceptable acid addition salts. Suitable inorganic or organic acids for salt formation are, for example, hydrogen chloride, hydrogen bromide, sulfuric acid, acetic acid, fumaric acid, lactic acid, maleic acid, methanesulfonic acid, ethanesulfonic acid, citric acid, etc.

The compounds of formula (I) may comprise one or more chiral carbon atoms, depending on the meaning of A. In such cases, optically active isomers may exist. The invention relates to the optically active antipodes and any mixture thereof.

Particularly preferred compounds of formula (I) are the following: 12H-12-[(4-methylpiperazinyl)-acetyl]-dibenzo[d,g]-[1,3,6]dioxazocine,

12H-2-chloro-12-[(4-methylpiperazinyl)-acetyl]-dibenzo-[d,g][1,3,6]dioxazocine,

(±)-12H-2-chloro-12-[(4-methylpiperidinyl)-acetyl]-dibenzo[d,g][1,3,6]dioxazocine,

12H-12-diethylcarbamoyl-2-chloro-dibenzo[d,g][1,3,6]dioxazocine,

12H-2-chloro-12-[3-(diethylamino)propionyl]-dibenzo-[d,g][1,3,6]dioxazocine, and pharmaceutically acceptable acid addition salts thereof. The analogy method according to the invention is characterized in that

a) a dibenzo[d,g][1,3,6]dioxazocine of formula

wherein X is as defined above, is acylated with a compound,

of formula

in which A is as defined above, Hal and Hal' independently denote a halogen, and that the obtained alkanoyl-dibenzo-[d,g][1,3,6]dioxazocine of formula in which X, A and Hal' are as defined above , is reacted with an amine of formula

wherein R]_ and R 2 are as defined above; or

b) a dibenzo[d,g][1,3,6]dioxazocine of formula (II) is acylated with a compound of formula

wherein A, R 1 and R 2 are as defined above, and Hal denotes halogen;

and, if desired, that a compound of formula (I) is converted into an acid addition salt with a pharmaceutically acceptable inorganic or organic acid, or that the compound of formula (I) is released from an acid addition salt with a base in a known manner.

In the compounds of formula (III), (IV), (V) and (VI), halogen is preferably chlorine or bromine.

The dibenzo[d,g][1,3,6]dioxazocines of formula (II), which are used as starting compounds for the preparation of the compounds according to the invention, are prepared as described in U.S. Pat. patent document 4 208 410.

The compounds of formula (III), (V), (VI) and (VIII) are known reagents which are commercially available or can be prepared by known methods.

In method a) according to the invention, the compounds of formula (II) are acylated in an apolar or dipolar aprotic solvent, preferably benzene, toluene, xylene or dimethylformamide, in the presence or absence of an acid-binding agent. The acetylating agent of formula (III) is used in an equivalent amount or in excess in relation to the amount of dibenzo[d,g][1,3,6]dioxazocine of formula (II).

It is preferred to acylate the compound of formula (II) in toluene, generally at a temperature of 60-110°C with the compound of formula (III) used in an excess of 200-300%.

Omega-halo-alkanoyl-dibenzo[d,g][l,3,6]dioxazocine of formula (IV) formed by the acylation reaction is reacted in a polar, apolar or dipolar solvent with the amine of formula (VIII). Benzene, toluene, xylene, isopropanol or dimethylformamide are preferably used as solvent. The amine of formula (VIII) can be used in an equimolar amount or in excess. Excess of the amine of formula (VIII) can bind the hydrogen halide which is formed by the reaction. However, other common acid binding agents can also be used for this purpose.

The acid binding agent used in both the acylation and the amination can be a suitable inorganic base, e.g. sodium carbonate, potassium carbonate etc, or a suitable organic base such as a tertiary amine, e.g. triethylamine, N,N-diisopropyl-N-ethylamine, pyridine.

It is preferred to react the compound of formula (IV) in benzene with an excess of the amine of formula (VIII).

Method a) according to the invention can be carried out by starting from a metal salt of the compound of formula (II). In this case, the compound of formula (II) is reacted with, for example, sodium hydride or sodium amide in a polar aprotic solvent, preferably dimethylformamide, forming the corresponding sodium salt thereof, which is generally acylated at 0-40°C. With this acylation, of course no acid-binding agent is necessary.

In method b) according to the invention, the compound of formula (II) is acylated with the compound of formula (V) in a similar way, generally at 0-140°C.

It is preferred to prepare the alkali metal salt of the compound of formula (II) first, and then react this with an excess of the compound of formula (V) at a temperature of from 0-50°C.

In method c) according to the invention, the reaction between the compounds of formula (II) and (VI) is carried out in an apolar organic solvent, such as benzene, toluene or xylene, generally at 50-140°C. The obtained compound of formula (VII) is reacted with the amine of formula (VIII) at atmospheric pressure or under higher pressure. For the reaction, the solvent is an apolar organic solvent or an excess of the amine of formula (VIII).

In compounds of formula (I), comprising one or more chiral carbon atoms, the enantiomers can be separated by resolution of the racemic compound. To effect this, the racemic compound, comprising a basic nitrogen, is reacted with an optically active carboxylic acid to form pairs of diastereomeric salts which separate, and the enantiomers are released. As an optically active organic acid, any carboxylic acid used for solutions can be used, such as optically active tartaric acid, dibenzoyltartaric acid, lactic acid, atrolactic acid, mandelic acid, etc., and optically active sulphonic acids such as 10-camphor sulphonic acid.

The enantiomers of the new aminoalkanoyl-dibenzo[d,g]-[l,3,6]dioxazocines, comprising a chiral carbon atom, can also be prepared by acylation of the compound of formula (II) with an optically active agent of formula (III), (V) or

(WE).

The compounds of formula (I) exhibit valuable pharmacological activities as shown by the subsequent screening tests.

Acute toxicity in white mice

Acute toxicity of the compounds was tested on white mice of both sexes from strain CFLP in groups consisting of 10 animals weighing 18-22 g. The test compounds were administered orally in a volume of 20 ml/kg. After the administration, the mice were observed for 7 days while kept in plastic cages over a litter made of shavings at room temperature. The animals could consume tap water and standard mouse chow ad lib. The LD5Ø values were determined according to Litchfield and Wilcoxon [J. Pharma-col. Exp. Ther., .96, 99 (1949)]. The results obtained are shown in table I.

Local anesthetic activity

The tests were carried out in accordance with Truant d'Amato [Acta Chir. Scand., 116, 351 (1958)]. 0.2 ml of a 0.25 or 0.50% solution of the test compound was injected around the sciatic nerve into the center of the thigh. Absence of motor control of the calf muscles was considered a criterion for anesthesia. The test animals were mice. The duration of the effect was recorded, and from the dose versus effect curve the concentration at which the activity was 50% (EC50) was determined. In the test, lidocaine [2-diethylamino-2',6'-acetoxy-xylidide] was used for the sake of comparison. The results obtained are shown in table II.

Table II shows that most tested compounds are effective in a lower concentration than lidocaine. The duration of the effect of all the compounds according to the invention is much longer than the effect of lidocaine at both concentrations.

Sleep induced with hexobarbital in mice

Groups consisting of 6 mice were each treated orally with the test compound. After one hour, hexobarbital [5-(1-cyclohexenyl)-1,5-dimethylbarbituric acid was injected intravenously at a dose of 40 mg/kg. The control group was only treated with hexobarbital to induce sleep. The duration of sleep was recorded. If the duration of sleep of an animal exceeded that of the mean value of the control group by a factor of 2.5, this was considered a positive reaction. From the data referring to animals showing a positive reaction, the ED50 value was calculated. From the LD50 and ED50 values, the therapeutic index was determined for each test compound. In the test, meprobamate [2-methyl-2-propylpropanediol-1,3-dicarbamate] and chlordiazepoxide [7-chloro-2-methylamino-5-phenyl-3H-1,4-benzodiazepine-4-oxide] were used for the sake of comparison . The results obtained are listed in table III.

From the data given in Table III it appears that the therapeutic index of the most effective new compound (ie the compound prepared in Example 4) is an order of magnitude higher than that of chlordiazepoxide. At the same time, the compounds according to the invention are more effective than meprobamate used as a reference.

Antagonism of tetrabenazine ptosis in mice

The tests were carried out according to the method according to Hoffmeister et al., which was adapted to mice [Arzneim.-Forschung, 19, 846-858 (1969)]. Groups consisting of 10 mice each were treated orally with different doses of the test compounds. The control group was treated only with the corresponding vehicle. After 30 min. tetrabenazine[3-isobutyl-9,10-dimethoxy-1,2,3,4,6,7-hexahydrobenzo[a]quinolizin-2-one] was administered intraperitoneally at a dose of 50 mg/kg. The number of animals with a closed eyelid cleft was determined in each group after 30, 60, 90 and 120 min. Then the mean value of ptosis was calculated in each group, and the deviation from this of the control group (ie the inhibition) was expressed as a percentage. From the data obtained, the ED5Q value and the therapeutic index were determined for each new test compound, as well as for amitriptyline [5-(3-di-methyl-aminopropylidine)-10,11-dihydro-5H-dibenzo[a,d] -cycloheptene hydrochloride] used for the sake of comparison. The results obtained are shown in table IV.

The therapeutic index of the compounds according to the invention is generally higher than that of amitriptyline used for comparison.

Inhibition of nicotine lethality in mice

The tests were performed on white mice using the method according to Stone [Arch. Int. Pharmacodyn., 177, 419

(1958)]. The animals were treated with the test compounds orally, after which nicotine was injected intravenously at a dose of 1.4 mg/kg after one hour. The spasms as well as the lethality observed within one hour were recorded, the ED5Q value and the therapeutic index were calculated for each new test compound and for trihexyphenidyl alpha-cyclohexyl-alpha-phenyl-piperidine-propanol hydrochloride] used for comparison. The test results are given in Table V.

Inhibition of tremors induced by tremorin in mice

The tests were carried out in accordance with Everett [Science, 124, 79

(1956)]. Tremor was induced with tremorin[1,1'-(2-butyn-ylene)-dipyrrolidine] administered intraperitoneally at a dose of 20 mg/kg. The test compounds were given orally to the animals one hour before the administration of tremorin, and the developed tremor was determined 45 min. after administration of tremorin. The results are shown in Table VI.

Since inhibition of nicotine lethality and of tremor is characteristic of antiparkinsonian activity of a compound, it can be concluded from Tables V and VI that the antiparkinsonian activity of the compounds exceeds that of the known compound used for comparison, considering either the absolute dose or the therapeutic index.

Antiarrhythmic activity in rats

The antiarrhythmic activity of the new compounds was investigated by the effect on arrhythmia induced by aconitine in rats weighing 160-200 g, according to a modified method of Marmo et al. [Arzneim.-Forsch., 20, 12 (1970)]. The animals were anesthetized by administering 1.2 g/kg ethyl urethane intraperitoneally. Aconitine was given in a dose of

75 ug/kg intravenously. The test compounds were administered orally for 30 min. before treatment with aconitine. The observed inhibition is shown in Table VII in percentage. In the test, lidocaine and quinidine were used for comparison.

From table VII it appears that the antiarrhythmic activity of the compounds according to the invention exceeded the activity of known compounds used for comparison.

Antianginal activity in rats

The antianginal activity of the compounds was determined on anesthetized (for this purpose chloralose urethane was used) male rats weighing 180-200 g according to Nischultz [Arzneim.-Forsch., 5_, 680 (1955)]. An experimental coronary insufficiency was developed by the administration of glanduitrin - an extract from the posterior pituitary - in an intravenous dose of 4 IU/kg. The height of the T wave in the ECG was measured before and after the administration of glanduitrin in both the control and the treated groups, and the inhibition provided by the test compounds was calculated. In the test, prenylamine [3,3-diphenylpropyl-1-methylphenethylamine lactate] was used for comparison.

From the pharmacological test results stated above, it can be concluded that the new compounds of formula (I), or the pharmaceutically acceptable acid addition salts thereof, can be used as the active substance in pharmaceutical preparations. The pharmaceutical preparation according to the invention comprises a therapeutically active amount of a compound of formula (I) or a pharmaceutically acceptable acid addition salt thereof and one or more common additives.

The pharmaceutical preparation according to the invention, which has a particularly local anaesthetic, sedative-sedative effect or antiparkinson activity, is prepared by mixing a compound of formula (I) or a pharmaceutically acceptable acid addition salt thereof with one or more pharmaceutically acceptable additives, for example carriers , after which the resulting mixture is converted into a pharmaceutical preparation in a manner known per se. For additives and methods, reference is made to Remington's Pharmaceutical Sciences, 16th ed., Mack Publishing Company, Easton, USA, 1980.

In general, the pharmaceutical preparations according to the invention are suitable for peroral or parenteral administration or for local treatment, and can be solid or liquid.

The solid pharmaceutical preparations can be powders, capsules, tablets, dragees, etc. and can include binders such as gelatin, sorbitol, polyvinylpyrrolidone, etc.; fillers such as lactose, glucose, starch, calcium phosphate etc; excipients for tableting, such as magnesium stearate, talc, polyethylene glycol, silica etc; humectants such as sodium lauryl sulphate etc as an additive.

The additives of the liquid pharmaceutical preparations used for oral treatment are preferably suspending agents such as sorbitol, sugar solution, gelatin, carboxymethylcellulose etc.; emulsifiers such as sorbitan monooleate etc; solvents such as oils, oil esters, glycerol, propylene glycol, ethanol etc.; preservatives such as methyl-p-hydroxybenzoate etc

Pharmaceutical preparations suitable for parenteral administration generally consist of sterile solutions.

The pharmaceutical preparation according to the invention generally contains 0.1-95.0% active ingredient. A typical dose for adult patients is 0.1-20 mg of the compound of formula (I), or a pharmaceutically acceptable acid addition salt thereof daily. The relevant dose is determined depending on many factors, such as the condition of the person to be treated, treatment method etc.

The invention is further illustrated by means of the following examples.

Example 1

12H- 12-[( 4- methylpiperazinyl)-acetyl]-dibenzo[ d, q][ 1, 3, 6]-dioxazocindimaleate A) A mixture of 30.0 g (0.141 mol) 12H-12-dibenzo[d, g]-[1,3,6]dioxazocine (m.p.: 189-191°C), 150 cm<3> of anhydrous toluene and 19.5 g (0.173 mol) of chloroacetyl chloride were heated to the boiling point and refluxed in 2 hours. Then an additional 19.5 g (0.173 mol) of chloroacetyl chloride was added to the reaction mixture which was refluxed for an additional 4 hours. The mixture was cooled to 25°C and poured into crushed ice with stirring. After stirring for one hour, the solid material was filtered off, washed with water and recrystallized from isopropanol.

35.6 g (87.3%) of 12H-12-(2-chloroacetyl)-dibenzo[d,g]-[1,3,6]dioxazocine was obtained. Melting point: 151-153°C.

Analysis for C15H12C1N03 (289.7):

calculated: C 62.19%, H 4.18%, Cl 12.24%, N 4.83%, found: C 62.57%, H 4.12%, Cl 12.23%, N 4.77 %. B) A mixture of 12.0 g (0.041 mol) 12H-12-(2-chloroacetyl)-dibenzo[d,g] [1,3,6]dioxazocine, 130 cm<3> of anhydrous benzene and 27, 6 g (0.276 mol) of 4-methylpiperazine was refluxed for 6 hours and then cooled to 25°C, and the precipitated salt was filtered. The organic filtrate was washed with water, dried over anhydrous magnesium sulfate, the solvent was distilled off, and the residue was recrystallized from isopropanol. The product was recrystallized from isopropanol.

9.7 g (66.4%) of 12H-12-[(4-methylpiperazinyl)-acetyl]-dibenzo[d,g][1,3,6]dioxazocine was obtained. Sm.p.: 160-

162°C.

Analysis for C20<H>23<N>3<O>3 (353,425):

calculated: C 67.97%, H 6.56%, N 11.89%,

found: C 68.14%, H 7.02%, N 11.78%. C) To a stirred solution of 8.4 g (0.024 mol) 12H-12-[(4-methylpiperazinyl)-acetyl]-dibenzo[d,g][1,3,6]dioxazocine in 100 cm<3> isopropanol a solution of 5.6 g (0.048 mol) maleic acid in 30 cm<3> of isopropanol was added at 20°C. The reaction mixture was stirred for 2 hours and was then cooled to 0°C, was stirred for an additional hour, the product was filtered, washed with isopropanol and recrystallized from methanol.

10.5 g (74.7%) of the title compound was obtained. Melting point: 179-183°C.

Analysis for C28H3iN3O1:L (585,572):

calculated: C 57.43%, H 5.34%, N 7.18%,

found: C 57.38%, H 5.31%, N 7.06%.

Example 2

12H- 12-[( N- cyclohexyl- N- methylamino)- acetyl]- dibenzo[ d, g ] -

[ 1, 3, 6 ] dioxazocine maleate

A) A mixture of 13.0 g (0.045 mol) 12H-12-chloroacetyl-dibenzo[d,g][1,3,6]dioxazocine, 150 cm<3> of anhydrous benzene and 32.2 (0.28 mol ) N-cyclohexyl-N-methylamine was heated under reflux for 8 h. The product was isolated as described in Example 1, section B), and was recrystallized from isopropanol to give 13.9 g (84.2%) of 12H-12-[(N-cyclohexyl-N-methylamino)-acetyl]-dibenzo [d,g]-[1,3,6]dioxazocine. Melting point: 103-105°C.

Analysis for C22<H>26<N>2°3 (366,463):

calculated: C 72.11%, H 7.15%, N 7.64%,

found: C 72.17%, H 7.18%, N 7.60%.

B) 12.8 g (0.035 mol) of 12H-12-[(N-cyclohexyl-N-methyl-amino)-acetyl]-dibenzo[d,g][1,3,6]dioxazocine was reacted with 4,2 g (0.036 mol) maleic acid as described in Example 1, section C). After recrystallization from isopropanol, 14.9 g (88.2%) of the title compound was obtained. Sm.p.: 148-

150°C.

Analysis for C26<H>30<N>2O7 (482.536):

calculated: C 64.72%, H 6.27%, N 5.81%,

found:' C 64.58%, H 6.34%, N 5.67

Example 3

12H- 12-[ 2-( isopropylamino)-acetyl]- 2- chloro- dibenzo[ d, g3-[ 1, 3, 6] dioxazocine hydrochloride A) A mixture of 24.8 g (0.10 mol) 12H -2-chloro-dibenzo-[d,g][1,3,6]dioxazocine (m.p.: 182-184°C), 300 cm<3> anhydrous toluene and 23.0 g (0.20 mol ) 2-chloroacetyl chloride was heated under reflux for 4 hours. The mixture was cooled to 25°C, the solvent was removed under reduced pressure, and the residue was triturated with benzene to induce crystallization. The product was recrystallized from isopropanol to give 23.1 g (71.3%) of 12H-12-chloroacetyl-2-chloro-dibenzo[d,g][1,3,6]dioxazocine. Melting point: 149-151°C.

Analysis for C15<H>11C12N03 (324.2):

calculated: C 55.57%, H 3.42%, Cl 21.87%, N 4.32%, found: C 55.48%, H 3.63%, Cl 21.95%, N 4.28 %. B) A mixture of 15.0 g (0.046 mol) of the chloroacetyl derivative prepared in Example 3, section A), 180 cm<3> of anhydrous benzene and 17.7 g (0.30 mol) of isopropylamine was heated under reflux in 4 hours. The organic solvent was removed under reduced pressure, the residue was mixed with 100 cm<3> of diethyl ether and 80 cm<3> of water for 30 min. The organic phase was separated, dried over anhydrous magnesium sulfate, cooled to 0°C and treated with diethyl ether saturated with hydrogen chloride with stirring until a pH value of 4 was reached. The crystals were filtered, suspended in diethyl ether and filtered again. The procedure was repeated twice and the product was recrystallized from ethanol to give 13.0 g (74.0%) of the title compound as white crystals. Melting point: 235-240°C.

Analysis for C18<H>2oCl2N2O3 (383,282):

calculated: C 56.41%, H 5.26%, Cl 18.50%, N 7.31%,

Cl' 9.25%, found: C 56.15%, H 5.60%, Cl 17.96%, N 7.16%,

Cl" 9.08%.

Example 4

12H- 12-[( 4- methylpiperazinyl)-acetyl]- 2- chloro- dibenzo[d, g]-[ 1, 3, 6] dioxazocindimaleate A) A mixture of 49.0 g (0.129 mol) 12H-12- chloroacetyl-2-chloro-dibenzo[d,g][1,3,6]dioxazocine, 80.0 g (0.80 mol) 4-methylpiperazine and 410 cm<3> of anhydrous benzene were heated under reflux for 4 hours. The organic solvent and excess 4-methylpiperazine were removed under reduced pressure. To the residue was added 150 cm<3> of benzene and 10 cm<3> of water, the mixture was stirred for 30 min., the organic phase was separated and washed with water three times using 80 cm<3> of water each time. 45.0 g (0.30 mol) of tartaric acid in 150 cm<3> of water was added to the organic solution, the mixture was stirred for one hour, and the phases were separated. To this aqueous phase was added 150 cm<3> of water, the mixture was stirred and treated with 25% aqueous ammonia until a pH value of 9-10 was reached. Stirring was continued for one hour, after which the organic phase was separated, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue was treated with benzene to induce crystallization, the crystals were filtered, suspended in benzene and filtered again. The product was recrystallized from isopropanol to give 38.0 g (76.0%) of 12H-12-[(4-methylpiperazino)-acetyl]-2-chloro-dibenzo[d,g]-[1,3,6] dioxazocine. Melting point: 124-127°C.

Analysis for C2o<H>22<c>1N3°3 (387.870):

calculated: C 61.93%, H 5.72%, Cl 9.14%, N 10.83%, found: C 62.18%, H 5.93%, Cl 9.18%, N 10.61 %. B) 34.1 g (0.088 mol) of 12H-12-[(4-methylpiperazinyl)-acetyl]-2-chloro-dibenzo[d,g][1,3,6]dioxazocine was reacted with 20.4 g (0.176 mol) of maleic acid as described in Example 1, section C), forming the acid addition salt. After recrystallization from methanol, 44.2 g (81%) of the title compound was obtained. Melting point: 188-190°C.

Analysis for C28H30CIN3O3.;]. (620,014):

calculated: C 54.24%, H 4.88%, Cl 5.72%, N 6.78%, found: C 54.18%, H 5.12%, Cl 5.70%, N 6.62 %. Example 5 12H-12-[(N-cyclohexyl-N-methylamino)-acetyl3-2-chloro-dibenzo-[d,g][1,3,6]dioxazocine maleate A) A mixture of 35.0 g (0.108 mol ) 12H-12-chloroacetyl-2-chloro-dibenzo[d,g][1,3,63dioxazocine, 350 cm<3> anhydrous benzene and 2 x 76.9 g (2 x 0.678 mol) N-cyclohexyl-N- methylamine was heated under reflux for a total of 12 hours. The product was isolated as described in example 4, section A). The crude product was crystallized and then recrystallized from petroleum ether to give 32.1 g (79.8%) of 12H-12-[(N-cyclohexyl-N-methylamino)-acetyl3-2-chloro-dibenzo[d,g ][1,3,63dioxazocine. Melting point: 93-95°C.

Analysis for C22H25CIN2O3 (400.909):

calculated: C 65.91%, H 6.29%, Cl 8.84%, N 6.99%, found: C 65.60%, H 7.00%, Cl 8.89%, N 6.61 %. B) 30.0 g (0.075 mol) of 12H-12-[(N-cyclohexyl-N-methyl-amino)-acetyl]-2-chloro-dibenzo[d,g][1,3,6]dioxazocine was reacted with 8.7 g (0.075 mol) of maleic acid as described in Example 1, section C). The product was recrystallized from methanol to give 34.8 g (89.7%) of the title compound. Melting point: 191-193°C.

Analysis for C26<H>29<C>1N2O7 (516.980):

calculated: C 60.41%, H 5.65%, Cl 6.86%, N 5.42%, found: C 61.23%, H 5.92%, Cl 6.79%, N 5.30 %. Example 6 12H-12-(diethylaminoacetyl)-2-chloro-dibenzo[dtq][1,3,6]-dioxazocine hydrochloride A) A mixture of 32.4 g (0.10 mol) 12H-12- chloroacetyl-2-chloro-dibenzo[d,g][1,3,6]dioxazocine, 2 x 36.5 g (2 x 0.50 mol) diethylamine and 250 cm<3> of anhydrous benzene were heated under reflux for a total 6 hours. The product was isolated as described in Example 4, section A). The yellow-brown viscous liquid obtained as the crude product was crystallized and then recrystallized from n-hexane. 28.5 g (78.9%) of 12H-12-(diethylaminoacetyl)-2-chloro-dibenzo-[d,g][1,3,6]dioxazocine was obtained. Melting point: 75-80°C.

Analysis for C19H21C1N203 (360.844):

calculated: C 63.24%, H 5.87%, Cl 9.83%, N 7.76%, found: C 63.96%, H 5.32%, Cl 9.85%, N 7.50 %. B) 19.0 g (0.053 mol) of dioxazocine prepared in Example 6, section A), was treated with isopropanol containing 20% hydrogen chloride to form the corresponding acid addition salt. After crystallization from isopropanol, 17.5 g (82.9%) of the title compound was obtained. Melting point: 198-201°C.

Analysis for C19<H>22C12N203 (397.302): calculated: C 57.44%, H 5.58%, Cl 17.85%, N 7.05%,

Cl" 8.92%,

found: C 57.56%, H 5.84%, Cl 17.50%, N 7.06%,

Cl" 8.88%.

Example 7

( ±)- 12H- 12-[( 2- methylpiperidinyl)- acetyl]- 2- chloro- dibenzo-[ d, g][ l, 3, 6] dioxazocine hydrochloride A) A mixture of 32.4 g (0 .10 mol) 12H-12-chloroacetyl-2-chloro-dibenzo[d,g][1,3,6]dioxazocine, 39.7 g (0.40 mol) 2-methylpiperidine and 250 cm<3> anhydrous benzene was heated under reflux for 4 hours. The reaction product was isolated as described in example 4, section A). The crude product was crystallized and then recrystallized from isopropanol to give 30.8 g (79.6%) of (±)-12H-12-[(2-methylpiperidinyl)-acetyl]-2-chloro-dibenzo[d, g]-[1,3,6]dioxazocine. Melting point: 90-92°C.

Analysis for C21<H>23C1N2O3 (386.882):

calculated: C 65.20%, H 5.99%, Cl 9.16%, N 7.24%, found: C 65.01%, H 6.33%, Cl 9.15%, N 7.08 %.

B) 9.6 g (0.0248 mol) of the base prepared in Section A) was treated with diethyl ether saturated with hydrogen chloride as described in Example 3, Section B) to give 10.3 g

(98.1%) of the title compound. Melting point: 146-154°C (decomposition).

Analysis for C21<H>24CI2N2O3 (423,342):

calculated: C 59.58%, H 5.71%, Cl 16.75%, N 6.62%,

Cl" 8.38%,

found: C 58.45%, H 6.11%, Cl 16.92%, N 6.65%,

Cl" 8.47%.

Example 8

12H- 12- pyrrolidinylacetyl- 2- chloro- dibenzo[d, g][ 1, 3, 6] dioxa-zocine maleate A) A mixture of 22.0 g (0.068 mol) 12H-12-chloroacetyl-2-chloro-dibenzo [d,g][1,3,6]dioxazocine, 24.2 g pyrrolidine and 250 cm<3> benzene were heated under reflux for 3 hours. The reaction product was isolated as described in example 4, section A). The crude product was crystallized and then recrystallized from petroleum ether to give 19.8 g (81.1%) of 12H-12-pyrrolidinylacetyl]-2-chloro-dibenzo[d,g][1,3,6]dioxazocine. Melting point: 80-83°C.

Analysis for C19H19C1N2C>3 (358.827):

calculated: C 63.60%, H 5.34%, Cl 9.88%, N 7.81%, found: C 63.11%, H 4.82%, Cl 9.80%, N 7.71 %. B) 14.0 g (0.039 mol) of 12H-12-pyrrolidinylacetyl]-2-chloro-dibenzo[d,g][1,3,6]dioxazocine was reacted with 4.6 g (0.04 mol) of maleic acid which described in example 1, section C). The acid addition salt formed was recrystallized from ethanol to give 15.8 g (85.5%) of the title compound. Melting point: 187-192°C.

Analysis for C23<H>23<C>IN2O7 (474,899):

calculated: C 58.17%, H 4.88%, Cl 7.47%, N 5.90%, found: C 58.48%, H 4.50%, Cl 7.47%, N 5.93 %.

Example 9

12H- 12- diethylcarbamoyl- 2- chloro- dibenzo[ d, g][ l, 3, 6] dioxazocine

A 50% dispersion of 4.8 g (0.10 mol) sodium hydride in mineral oil was added to 100 cm<3> dimethylformamide at 25°C with stirring. 24.8 g (0.10 mol) of 12H-2-chloro-dibenzo-[d,g][1,3,6]dioxazocine was then added to the mixture at a constant temperature of 25°C. The reaction mixture was heated to 40°C and was stirred for one hour at this temperature and was then cooled to 20°C. 20.3 g (0.15 mol) of N,N-diethylcarbamoyl chloride was added to the mixture, after which the reaction mixture was stirred for 16 hours at 40°C. 120 cm<3> of water was added to the mixture, cooled to 0°C. The viscous oil formed was separated, dissolved in 150 cm<3 >benzene, washed three times with water using 80 cm<3> of water each time. The organic solution was dried over anhydrous magnesium sulfate, the solvent was removed under reduced pressure, the residue was treated with petroleum ether to induce crystallization. The crude product was recrystallized from isopropanol. 22.9 g (66.0%) of the title compound was thus obtained. Melting point: 93-95°C.

Analysis for C18<H>19C1N2O3 (346.823):

calculated: C 62.34%, H 5.52%, Cl 10.22%, N 8.08%, found: C 62.83%, H 5.45%, Cl 10.48%, N 8.00 %. Example 10 12H-12-[3-(4-methylpiperazinyl)-propionyl]-2-chloro-dibenzo-[d,g][l,3,6]dioxazocindimaleate A) A mixture of 24.8 g (0.10 mol) 12H-2-chloro-dibenzo-[d,g][1,3,6]dioxazocine, 150 cm<3> of anhydrous benzene and 25.4 g (0.20 mol) of 3-chloropropionyl chloride were heated under backflow cooling for 5 hours. The solvent was removed under reduced pressure, the residue was dissolved in 150 cm<3> benzene, and the resulting solution was poured into crushed ice. The mixture was stirred for one hour, the organic phase was separated, washed with 4 x 100 cm<3> of 5% aqueous sodium bicarbonate solution and then with 100 cm<3> of water. The organic solution was dried over anhydrous magnesium sulfate, the solvent was removed under reduced pressure, and the residue was crystallized with isopropanol. The crude product was recrystallized from isopropanol to give 26.7 g (79.0%) of 12H-12-(3-chloropropionyl)-2-chloro-dibenzo[d,g][1,3,6]dioxazocine. Sm.p.: 76-81°C.

Analysis for C16<H>13C12N03 (338,193):

calculated: C 56.82%, H 3.87%, Cl 20.97%, N 4.14%, found: C 56.41%, H 3.30%, Cl 21.35%, N 4.04 %. B) A mixture of 33.8 g (0.10 mol) 12H-12-(3-chloro-propionyl)-2-chloro-dibenzo[d,g][1,3,6]dioxazocine, 60.0 g (0.60 mol) of 4-methylpiperazine and 250 cm<3> of anhydrous benzene were heated under reflux for 5 hours. The reaction product was isolated as described in example 4, section A). 30.0 g of impure 12H-12-[3-(4-methylpiperazino)-propionyl]-2-chloro-dibenzo[d,g][1,3,6]dioxazocine was obtained as a brown, viscous liquid. C) 30.0 g of the impure base prepared in Section B), was reacted with 18.6 g (0.16 mol) of maleic acid as described in Example 1, Section C), forming the corresponding salt which was recrystallized from methanol. 24.6 g (67.0%) of the title compound was obtained. Melting point: 185-187°C.

Analysis for 02911320^30^ (634.041): calcd: C 54.94%, H 5.09%, Cl 5.59%, N 6.63%, found: C 54.74%, H 5.46%, Cl 5.56%, N 6.52%. Example 11 12H-12-[3-(diethylamino)-propionyl]-2-chloro-dibenzo[d,g]-[1,3,6]dioxazocine hydrochloride A) A mixture of 33.8 g (0.10 mol) 12H-12-(3-chloro-propionyl)-2-chloro-dibenzo[d,g][1,3,6]dioxazocine, 2 x 29.2 g (2 x 0.40 mol) diethylamine and 250 cm<3> of anhydrous benzene were heated under reflux for 6 hours. The reaction was carried out, and the reaction product was isolated as described in Example 4, section A). The crude product was crystallized and then recrystallized from n-hexane to give 30.9 g (82.5%) of 12H-12-[3-(diethylamino)-propionyl]-2-chloro-dibenzo[d,g] [1,3,6]dioxazocine. Melting point: 68-72°C.

Analysis for C20<H>23CIN2O3 (374.870):

calculated: C 64.08%, H 6.18%, Cl 9.46%, N 7.47%, found: C 63.52%, H 6.61%, Cl 9.59%, N 7.25 %. B) 18.7 g (0.05 mol) of 12H-12-[3-(diethylamino)-propionyl]-2-chloro-dibenzo[d,g][1,3,6]dioxazocine was dissolved in 70 cm< 3>isopropanol. To the stirred solution cooled to 0°C, isopropanol, comprising 20% gaseous hydrogen chloride in dissolved form, was added until a pH value of 3 was reached. The mixture was stirred for one hour, the crystals were filtered and recrystallized from isopropanol. 17.9 g (81.0%) of the title compound was obtained. Melting point: 176-182°C.

Analysis for C20<H>24CI2N2O3 (441.329):

calculated: C 58.40%, H 5.88%, Cl 17.24%, N 6.81%,

Cl" 8.62%;

found: C 58.12%, H 6.07%, Cl 17.12%, N 6.68%,

Cl" 8.66%.

Example 12

12H- 12-[ 3-( isopropylamino)- propionyl]- 2- chloro- dibenzo[ d, g]-[ 1, 3, 6] dioxazocine hydrochloride

A mixture of 30.0 g (0.089 mol) 12H-12-(3-chloropropionyl)-2-chloro-dibenzo[d,g][1,3,6]dioxazocine, 2 x 21.0 g (2 x 0.356 mol) of isopropylamine and 250 cm<3> of anhydrous benzene were heated under reflux for 6 hours. The reaction was carried out and the reaction product isolated as described in Example 4, section A), yielding 28.5 g of 12H-12-[3-(isopropylamino)-propionyl]-2-chloro-dibenzo[d,g][1, 3,6]dioxazocine as a viscous liquid.

The dioxazocine base was converted to the hydrochloride as described in Example 3, section B). After recrystallization from ethanol, 25.8 g (73.0%) of the title compound was obtained. Melting point: 240-243°C.

Analysis for C-^r^C^^C^ (397,301):

calculated: C 57.44%, H 5.58%, Cl 17.86%, N 7.05%,

Cl" 8.93%;

found:' C 57.66%, H 5.45%, Cl 17.86%, N 6.98%,

Cl" 8.92%.

Example 13

12H- 12-( 3- pyrrolidinyl- propionyl)- 2- chloro- dibenzo[d, g]-[ 1, 3, 6] dioxazocine maleate A) A mixture of 25.0 g (0.074 mol) 12H-12-(3 -chloropropionyl)-2-chloro-dibenzo[d,g][1,3,6]dioxazocine, 21.3 g (0.30 mol) pyrrolidine and 250 cm<3> of anhydrous benzene were heated under reflux for 3 hours. The reaction product was isolated as described in Example 4, section A), the crude product was crystallized from petroleum ether and recrystallized from the same solvent to give 21.8 g (79.0%) of 12H-12-(3-pyrrolidinyl-propionyl) '-2-chloro-dibenzo-[d,g][1,3,6]dioxazocine. Melting point: 115-118°C.

Analysis for C2oH2iClN2O3 (372.854):

calculated: C 64.43%, H 5.68%, Cl 9.51%, N 7.51%, found: C 64.00%, H 5.12%, Cl 9.61%, N 7.40 %. B) 20.0 g (0.054 mol) of the base prepared in section A), was reacted with 6.4 g (0.055 mol) of maleic acid as described in Example 1, section C), forming the corresponding salt which was recrystallized from ethanol. 22.7 g (85.9%) of the title compound was obtained. Melting point: 161-164°C.

Analysis for C24<H>25C1N2O7 (488,926):

calculated: C 58.96%, H 5.15%, Cl 7.25%, N 5.73%, found: C 59.52%, H 5.28%, Cl 7.35%, N 5.79 %.

Example 14

( t )- 12H- 12-[ 2-( 4- methylpiperazinyl)- propionyl]- 2- chloro-dibenzo [d, g][ l, 3, 6] dioxazocine maleate

A) A mixture of 123.9 g (0.50 mol) 12H-2-chloro-dibenzo-[d,g][1,3,6]dioxazocine, 750 cm<3> anhydrous toluene and 127.0 g ( 1.00 mol) of 2-chloropropionyl chloride was heated under reflux for 3 hours. The reaction product was isolated as described in example 3, section A). After recrystallization from isopropanol, 131.1 g (77.5%) of (+)-12H-12-(2-chloropropionyl)-2-chloro-dibenzo[d,g][1,3,6]dioxazocine

obtained. Melting point: 152-155°C.

Analysis for C16<H>13C12N03 (388,201):

calculated: C 56.82%, H 3.87%, Cl 20.97%, N 4.14%, found: C 56.32%, H 3.99%, Cl 21.20%, N 4.10 %. B) A mixture of 20.0 g (0.059 mol) chloropropionyldioxazocine, prepared in section A), 2 x 25.1 g (2 x 0.25 mol) 4-methylpiperazine and 200 cm<3> of anhydrous benzene was heated under reflux for 11 hours. The reaction was carried out and the reaction product isolated as described in example 4, section A). The crude product was treated with petroleum ether to induce crystallization, and the crystals were recrystallized from isopropanol. 18.8 g (79.2%) of (±)-12H-12-[2-(4-methylpiperazinyl)-propionyl]-2-chloro-dibenzo[d,gl-Cl,3,6]dioxazocine was obtained. Melting point: 133-136°C.

Analysis for C21<H>24<C>IN3O3 (401,896):

calculated: C 62.76%, H 6.02%, Cl 8.82%, N 10.46%, found: C 61.98%, H 6.60%, Cl 8.93%, N 10.20 %. C) 13.0 g (0.032 mol) of the dioxazocine base prepared in section B) was reacted with 7.6 g (0.066 mol) of maleic acid as described in Example 1, section C), forming the acid addition salt. After recrystallization from ethanol, 17.1 g (84.2%) of the title compound was obtained. Melting point: 177-182°C.

Analysis for C29H32CIN3OH (634,041):

calculated: C 54.94%, H 5.09%, Cl 5.59%, N 6.63%, found: C 55.27%, H 4.89%, Cl 5.63%, N 6.61 %. Example 15 (±)-12H-12-(2-pyrrolidinylpropionyl)-2-chloro-dibenzo[d,g]-[1,3,6]dioxazocine hydrochloride A) A mixture of 28.0 g (0.083 mol) (+)-12H-12-(2-chloro-propionyl)-2-chloro-dibenzo[d,g][1,3,6]dioxazocine, 21.3 g (0.30 mol) pyrrolidine and 250 cm< 3> anhydrous benzene was heated under reflux for 10 hours. The reaction product was isolated as described in example 4, section A). The crude product was treated with petroleum ether to induce crystallization, and the crystals were recrystallized from the same solvent. 24.9 g (80.3%) of (±)-12H-12-(2-pyrrolidinylpropionyl)-2-chloro-dibenzo[d,g][1,3,6]dioxazocine were obtained. Melting point: 98-102°C.

Analysis for C2oH2iClN2O3 (372.854):

calculated: C 64.43%, H 5.68%, Cl 9.51%, N 7.51%, found: C 63.89%, H 6.03%, Cl 9.60%, N 7.43 %. B) 16.0 g (0.043 mol) of the dioxazocine base prepared in Section A) was converted to the hydrochloride as described in Example 3, Section B). After recrystallization from isopropanol, 14.2 g (80.7%) of the title compound was obtained. Melting point: 223-225°C.

Analysis for C2o<H>22cl2N2°3 (409,315):

calculated: C 58.69%, H 5.42%, Cl 17.32%, N 6.84%,

Cl" 8.66%,

found: C 59.03%, H 5.88%, Cl 16.93%, N 6.91%,

Cl" 8.47%.

Example 16

( ±)- 12H- 12-( 2- isopropylaminopropionyl)- 2- chloro- dibenzo[ d, g]-[ 1, 3, 6] dioxazocine hydrochloride A) A mixture of 23.7 g (0.070 mol) (± )-12H-12-(2-chloro-propionyl)-2-chloro-dibenzo[d,g][1,3,6]dioxazocine, 17.7 g (0.21 mol) isopropylamine and 250 cm<3> anhydrous benzene was heated under reflux for 6 h. The reaction product was isolated as described in example 4, section A). The crude product was treated with petroleum ether to induce crystallization, and the crystals were recrystallized from the same solvent. 18.2 g (72.1%) of (±)-12H-12-(2-isopropylaminopropionyl)-2-chloro-dibenzo[d,g][1,3,6]dioxazocine were obtained. Melting point: 102-105°C.

Analysis for C19H2iClN2O3 (360.843):

calculated: C 63.24%, H 5.87%, Cl 9.83%, N 7.76%, found: C 62.85%, H 6.13%, Cl 9.98%, N 7.61 %. B) 10.0 g (0.0277 mol) of the dioxazocine base prepared in Section A) was converted to the hydrochloride as described in Example 3, Section B). After recrystallization from isopropanol, 9.6 g (87.3%) of the title compound was obtained. Melting point: 224-227°C.

Analysis for C19H22C12N2O3 (397.304): calculated: C 57.44%, H 5.58%, Cl 17.85%, N 7.05%,

Cl" 8.92%,

found: C 57.44%, H 5.70%, Cl 17.63%, N 6.94%,

Cl" 8.90%

Example 17

( ±)- 12H- 12-[ 2- methyl- 3-( 4- methylpiperazinyl)- propionyl]- 2-chloro- dibenzo[ d, g][ l, 3, 6] dioxazocindimaleate A) A mixture of 26.1 g (0.11 mol) 12H-2-chloro-dibenzo-[d,g][1,3,6]dioxazocine, 300 cm<3> anhydrous toluene and 39.0 g (0.21 mol) 3-bromo -2-methylpropionyl chloride was heated under reflux for 8 hours and then cooled to 25°C, and poured into 300 g of crushed ice with stirring. The mixture was stirred for 2 hours, the organic phase was separated, washed with 3 x 100 cm<3> of 5% aqueous sodium bicarbonate and 100 cm<3> of water, and was dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, the residue was treated with isopropanol to induce crystallization, and the crystals were recrystallized from the same solvent. 33.2 g (76.1%) of (±)-12H-12-(3-bromo-2-methyl-propionyl)-2-chloro-dibenzo[d,g][1,3,6]dioxazocine were obtained . Melting point: 115-119°C.

Analysis for C17<H>15<B>rClN03 (396.688):

calculated: C 51.47%, H 3.81%, Br 20.15%, Cl 8.94%,

N 3.53%,

found: C 51.35%, H 3.98%, Br 20.20%, Cl 8.90%,

N 3.52%. B) A mixture of 28.6 g (0.072 mol) bromomethylpropionyl-dioxazocine, prepared in section A), 2 x 30.0 g (2 x 0.295 mol) 4-methylpiperazine and 250 cm<3> of anhydrous benzene was heated under reflux for 7 hours. The reaction was carried out and the reaction product isolated as described in example 4, section A). The crude product was treated with petroleum ether to induce crystallization, and the crystals were recrystallized from n-hexane to give 25.3 g (84.6%) of (+)-12H-12-[2-methyl-3-(4 -methylpiperazinyl ) -propionyl] -2-chloro-dibenzo [d,g] [1,3,6]dioxazocine. Melting point: 128-131°C.

Analysis for C22<H>26<c>1N3°3 (415,921):

calculated: C 63.53%, H 6.30%, Cl 8.52%, N 10.10%, found: C 62.80%, H 6.75%, Cl 8.63%, N 9.87 %. C) 9.0 g (0.022 mol) of the dioxazocine base prepared in Section B) was reacted with 5.2 g (0.045 mol) maleic acid as described in Example 1, Section C), forming the acid addition salt. After recrystallization from acetonitrile, 11.8 g (82.5%) of the title compound was obtained. Melting point: 152-157°C.

Analysis for 03(^3401^0!! (648.068): calcd: C 55.60%, H 5.29%, Cl 5.47%, N 6.48%, found: C 55.78%, H 5 .52%, Cl 5.42%, N 6.42%.

Claims (6)

1. Analogy process for the preparation of new, therapeutically active aminoalkanoyl-dibenzo[d,g][1,3,6]dioxazocines of formula in which X denotes hydrogen or chlorine, A denotes a valence bond or straight chain or for the branched alkylene with 1-4 carbon atoms, R;L and R2 independently denote hydrogen, alkyl with 1-4 carbon- atoms or cyclohexyl, or R1 and R2 form together with the nitrogen, to which they are bound, a methylpiperazinyl or pyrrolidinyl group, and pharmaceutically acceptable acid addition salts thereof, characterized in that a) a dibenzo[d,g][1,3,6]dioxazocine of formula wherein X is as defined above, is acylated with a compound of formula wherein A is as defined above, Hal and Hal' independently denote a halogen, and that the obtained alkanoyl-dibenzo-[d,g][1,3,6]dioxazocine of formula in which X, A and Hal' are as defined above, is reacted with an amine of formula wherein and R 2 are as above defined; or b) a dibenzo[d,g][1,3,6]dioxazocine of formula (II) is acylated with a compound of formula wherein A, R 1 and R 2 are as defined above, and Hal denotes halogen; and, if desired, that a compound of formula (I) is converted into an acid addition salt with a pharmaceutically acceptable inorganic or organic acid, or that the compound of formula (I) is released from an acid addition salt with a base in a known manner. 2. Process according to claim 1 for the production of 12H-12-[(4-methylpiperazinyl)-acetyl]-dibenzo[d,g][1,3,6]dioxazocine and pharmaceutically acceptable acid addition salts thereof, characterized in that corresponding starting materials are used. 3-. Process according to claim 1 for the production of 12H-2-chloro-12-[(4-methylpiperazinyl)-acetyl]-dibenzo[d,g][1,3,6]-dioxazocine and pharmaceutically acceptable acid addition salts thereof, characterized in that corresponding starting materials are used. 4. Method according to claim 1 for the production of (±)-12H-2-chloro-12-[(2-methylpiperidinyl)-acetyl]-dibenzo[d,g]-[1,3,6]dioxazocine and pharmaceutically acceptable acid addition salts hence, characterized in that corresponding starting materials are used. 5. Method according to claim 1 for the production of 12H-12-diethylcarbamoyl-2-chloro-dibenzo[d,g][1,3,6]dioxazocine and pharmaceutically acceptable acid addition salts thereof, characterized in that corresponding starting materials are used. 6. Process according to claim 1 for the production of 12H-2-chloro-12-[3-(diethylamino)propionyl]-dibenzo[d,g][1,3,6]-dioxazocine, and pharmaceutically acceptable acid addition salts thereof, characterized in that corresponding starting materials are used.