CS270579B2 - Method of new aminoalkanoyl-dibenzo (d,g) (1,3,6) dioxazocines production - Google Patents

Description

The invention relates to a process for the preparation of novel aminoalkanoyl-dibenzo [d, g] [1,3,6] dioxazocines and their pharmaceutically acceptable acid addition salts.

The compounds produced by the process of the invention have valuable pharmaceutical properties, for example, locally anesthetic, sedative, sedative and / or antidepressant, antiparkinsonian, as well as antiarrhythmic and anti-angina.

12-Aminoalkyl-1266-dibenzo [d, g] [1,3,6] dioxazocines having local anesthetic and antiparkinsonian activity are described in U.S. Patent 6,208,404.

It has been found that the pharmaceutical activity of the known compounds can be favorably altered by attaching an aminoalkanoyl group instead of an aminoalkyl group to the ring nitrogen atom.

SUMMARY OF THE INVENTION The present invention provides a process for the preparation of novel compounds of formula I *

(I) in which

X is hydrogen or halogen,

A represents a valence bond or a straight or branched alkylene radical having 1 to 10 carbon atoms, each of R @ 1; and is independently of the other C 1 -C 4 alkyl or C 3 -C 6 cycloalkyl, or

R y and R 2 together with the nitrogen atom to which they are attached and optionally with at least one other nitrogen, oxygen and / or sulfur atom form a 5-membered or 6-membered heterocyclic ring, optionally substituted with C 1 -C 4 alkyl, as well as and pharmaceutically acceptable acid addition salts thereof.

In both the specification and the definition, halogen is fluorine, chlorine, bromine or iodine.

A straight or branched C1-C10 alkylene radical is, for example, a methylene, ethylene, isopropylene, n-propylene, n-butylene, isobutylene, pentylene, hexylene, heptylene, octylene, nonylene or decylene radical.

An example of a C 1 -C 4 alkyl group is, for example, a methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl radical.

The C 3 -C 6 cycloalkyl group may be cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

The 5-membered or 6-membered heterocyclic radical is preferably a piperazine, piperidine, pyrrolidine or morpholine moiety. The heterocyclic group may be substituted with a C 1 -C 4 alkyl group, preferably a methyl group.

When A is a valence bond, it is a group of formula

CS 270579 02

bonded directly to the nitrogen atom in the ring.

The compounds of formula I may form ¹ pharmaceutically acceptable acid addition salts. Suitable inorganic or organic acids are, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, acetic acid, fumaric acid, lactic acid, maleic acid, methanesulfonic acid, ethanesulfonic acid, citric acid and the like.

The compounds of formula I may contain at least one chiral carbon atom, depending on the meaning of the symbol A. In such cases, the compounds of formula I may exist in the form of optically active isomers. The invention also includes optically active antipodes and mixtures thereof.

Preferred compounds of the invention are those compounds of formula (I) wherein:

X is hydrogen or halogen,

A represents a valence bond or a C 1 -C 3 alkylene radical, and each R ₂ is independently hydrogen, C 1 -C 3 alkyl or C 3 -C 6 cycloalkyl, or

R | and R ₂ together with the nitrogen atom to which they are attached and optionally form an oxygen atom with 4-methylpiperazinyl, 2-methylpiperidinyl, pyrrolidinyl or morpholinyl, and their pharmaceutically acceptable acid addition salts.

Particularly preferred compounds of formula I are:

12H-12 [(4-methylpiperazinyl) -acetyl] -dibenzo [d, g] [1,3,6] -dioxazocine, 12H-2-chloro-12 - [(4-methylpiperazinyl) -acetyl] -dibenzo [ d, g] [1,3, a] dioxazine, (R) -12H-2-chloro-12 - [(2-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] -dibenzol [d, g] [1 , 3,6] dioxazocine, and pharmaceutically acceptable acid addition salts thereof.

The process according to the invention for the preparation of the compounds of the formula I is characterized in that the dibenzo [d, g] [1,3,6] dioxazocine of the formula II

(II) in which

X is as defined above, acylated with a compound of formula III hal-C-A hal-thi 0 in which

A is as defined above and (III),

CS 270579 ⁰² (IV), each of hal and hal * is independently of the other halogen, and to the formed alkanoyl-dibenzo [d, g] [Г, 3,6] dioxazocine of formula IV

in which

X, A and hal 'are as defined above, with an amine of formula VIII

(Vlil) in which

R | and R ₂ have the meaning indicated výěe, and the resulting áLoičenina of formula I is optionally converted in their acid addition salt with a pharmaceutically acceptable inorganic or organic acid, or is released from the acid addition salts by reaction with an acid e base.

For compounds of formulas III and IV, halogen is preferably chlorine or bromine.

The dibenzo [d, g] [1,3,6] dioxazines of general formula II, which is used as starting compounds for the preparation of the compounds of the invention, are prepared as described in U.S. Patent No. 4,208,410.

The compounds of formulas III and VIII are known. Commercially available reagents or can be prepared by known methods.

In the process of the invention, the compound of formula II is 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 acylating agent of formula III is used in an equivalent amount or in excess, based on the amount of the dibenzo [d, g] [1,3, б] dioxazoline of formula II.

Preferably, the compound of formula (II) is acylated in toluene, usually at 60 to 10 ° C, with a compound of formula (III) which is used in a two to three-fold excess.

The ω-halo-alkanoyldibenzo [d, g] [1,3, б] dioxazocine of formula IV formed by the acylation reaction is treated with an amine of formula VIII in a polar, apolar or dipolar solvent. Benzene, toluene, xylene, isopropanol or dimethylformamide are preferably used as solvents. The amine of formula VIII can be used in equimolar amounts or in excess. An excess of the amine of formula VIII can bind the hydrogen halide formed in the reaction. However, other conventional reagents can also be used to bind the resulting acid.

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

Preferably, the compound of formula IV is left in benzene with an excess of the amine of formula VIII.

In the process according to the invention, salts of the compound of formula II can be used as starting materials. with metals. In this case, the compound of formula (II) is reacted, for example, with sodium hydride or sodium amide in a dipolar aprotic solvent, suitably in dimethylformamide, to give the corresponding sodium salt of the compound, which is then acylated, usually at 0-40 ° C. Of course, no additional acid-binding agent is required for this acylac.

When the compounds of formula I contain at least one chiral carbon atom, the enantiomers may be separated by resolution of the racemic compound. To this end, the early NON-BREAKING HYPHEN (8209) ammonia can react very well due to the reaction of the active carbuxylic acid reactants, thereby forming a biae of dlastomeric salts which separate from each other and the enantiomers are liberated. As the optically active organic acid, virtually any carboxylic acid used for the resolution of racemic compounds can be used, such as optically active tartaric acid, dibenzoyltartaric acid, lactic acid, atromic acid, mandelic acid, etc., also optically active sulfonic acids such as 10-camphorsulfone etc.

Enantiomers of novel aminoalkanoyl-dibenzo [d, g] [1,3,6] dioxazocines containing a chiral carbon atom can also be prepared by acylating a compound of formula II with an optically active agent of formula III.

The compounds of the formula I have valuable pharmacological properties, as can be seen from the results of the following tests.

Acute toxicity in white mice. ,

The acute toxicity of the compounds of the invention was tested in white mice of both sexes of the CFLP strain in groups of 10 animals weighing 18 to 22 g each. applied orally in a volume of 20 ml.kg ¹ . After application, mice are observed for 7 days while kept at room temperature in plastic cages containing litter of shredding. Test animals have any amount of water and standard food for mice. LD ^ q values are determined by the method of Litchfield and Wilcoxon [J. Pharmacol. Exp. Ther., 96, 99 (1949)]. The results are shown in Table I.

'Table I

Compound (Example #) LD _5q po in mg.kg ¹ 1 2000 ₍ 2 700 3 280 4 • 2000 5 2000 6 250 7 1000 8 450 9 900 ’10 900 11 260 12 300 13 160 14 , 250 15 Dec 250 16 650 17 250 18 370 19 Dec 220 20 May 300

С8270579 D2

Topical effectiveness of _t anestetiokd roam spring zjlůlfiní local uneeleUuké účlnnutíli titi carried truunl d'Inula Anitiluviw · HODO [Acta Chir.Scand.j 1.16, ETR. 551 (1950)], 0.2 ml of a 0.25% or 0.50% solution of the test compound is injected into the test animals around the sciatica nerve into the middle of the femur. The criterion of anesthetic effectiveness is the lack of movement control of the leg muscles. The duration of action is recorded and the concentration at which the efficacy reaches 50% (EC ₅ q) is determined from a graph showing the dose-response effect. In this test, lidocaine [2-diethylamino-2 ', 6-acetoxy-xylidide] was used as reference compound. The results are shown in Table II.

Table II

Compound (Example #) in conSntration 4 Duration of action at concentration (min) 0.25% 0.50% 4 0.21 55.8 97.7 8 0.25 51.1 98.8 11 0.15 54,1 ' 107.3 12 0.14 122.1 217.3 15 Dec 0.19 93.2 160.0 14 0.16 52.4 113.8 15 Dec 0.25 00,0 114.6 17 0.10 85.7 146.4 18 ‘ 0.22 43.7 73.8 19 Dec 0.11 53.5 67.8 20 May 0.08 93.1 93.1 lidokaln 0.17 23.9 40.1

It can be seen from Table II that most of the compounds tested are effective at a lower concentration than lidocal. The effect of all compounds produced by the process of the invention lasts much longer than that of lidocaine at both concentrations.

Hexobarbital-induced sleep in mice.

Test compounds are administered orally to groups of 6 mice. After 1 hour, the mice are injected intravenously with 40 mg / kg of ¹ hexobarbital [5- (1-cyclohexenyl) -1,5-dimethylbarblturic acid]. The control group receives only hexobarbital to induce sleep. The duration of sleep is recorded. If the animal's sleep lasts 2.5 times as long as the average sleep duration of the control group, this is considered a positive response. The data relating to animals with a positive reaction, the calculated value ED _5Q. The therapeutic index for each of the test compounds is determined from the LD ₅₀ and ED _5q values. In these experiments, meprobamate [2-methyl-2-propylpropanediol-1,3-dicarbamate] and chlorodiazepoxide [7-chloro-2-methylamino-5-phenyl-3H-1,4-benzodiazepine-4-oxide] were used for comparison . The results are shown in Table III.

The data in Table III show that the therapeutic index of the most potent novel compound (i.e., the compound prepared in Example 4) is one order of magnitude higher than the therapeutic index of chlordiazepoxide.

. Table III Compound (Example #) ^ED 50 (mg.kg) Therapeutic index ^L0 50 ^{/ E0} 50 1 21.0 95.2 3 25.0 И.2 4 8.5 235.0 6 15.0 16.7 11 30.0 8.7 14 9.8 25.5 18 15.0 _: 24.7. meprobamate. (LD ₅₀ = 1100 mg.kg- ¹ ) 260.0. 4.2 chlordiazepoxid. (L0 ₅₀ = 620 mg.kg ¹ ) 10,0 ' 62.0

From the data in Table III, it is evident that the therapeutic index of the most potent novel compound (i.e., the compound prepared in Example 4) is one order of magnitude higher than the therapeutic index of chlordiazepoxide. At the same time, the compounds of the invention are more potent than the meprobamate used for comparison.

Tetrabenazine-induced ptosis antagonism in mice

These tests are carried out by the Hoffmeister and co-workers method, which has been adapted for use in mice [Arzneimittel-Forschung, 12, pp. 846-858 (1969)]. Groups of 10 mice each were dosed orally at different doses. The control group receives only the appropriate vehicle. After 30 minutes, tetrabenazine [3-isobutyl-9,10-dimethoxy-1,2,3,4,6,7-hexahydrobenzo [a] quinolizin-2-one] is administered intraperitoneally at a dose 50 mg.kg ¹ . After 30, 60, 90 and 120 minutes, the number of animals having dropped eyelids was counted in each group of animals. The mean ptosis value is then calculated for each group and the deviation from that value in the control group (i.e. inhibition) is expressed as a percentage. From the data thus obtained, the EDjq value and the therapeutic index for each new test compound as well as for amitryptiline [hydrochloride-5- (3-dimethylaminopropylidine) -10,11-dihydro-5H-dibenzo [a, d] cycloheptene] used for comparison are determined. The results are

Table IV. Table IV Compound ED₽ _n Therapeutic index (example #) in mg.kg ^L0 50 ^{/ E0} 50 2 13.0 53.9 19 Dec 13.5 13.6 amitryptilin 12.0 18.7

The therapeutic index of the compounds of the invention is generally higher than the therapeutic index of amitryptilin used for comparison.

Inhibition of nicotine-induced mortality in mice ·

These assays are performed on white mice using the method described by Stone [Arch. Int. Pharmacodyn., 177, 419 (1958)]. The test compounds were orally administered with the test compounds, and nicotine was injected intravenously at a dose of 1.4 mg / kg ¹ after 1 hour. Convulsions as well as death of animals occurring within 1 hour of application are recorded. For each new compound and trihexyphenidyl [hydrochloride of (cyclohexyl - <- piperidinepropanol phenyl] used for comparison with the calculated value ED _5Q and therapeutic index. The results are shown in Table V. *

CS 270579 02 7

Table V

Compound (Example 6.) ^ED S0, in mg.kg Therapeutic index ^LD 50 ^{/ ED} 50 1 72 27.8 3 7 111.0 4 35 57.0 5 13 154., 0 6 5 50.0 7 15 Dec 66.7 ‘ 8 15 Dec 30.0 9 17 52.9 10 21 42.9 trihexyfenidyl ^{20 May} 18.25

Inhibition of tremorin-induced tremor in mice

These assays are performed according to the method described by Everett [Science, 124, p. 79 (1956)]. Tremor is induced by tremorine [1,1- (2-butinylene) -dipyrrolidine] administered intraperitoneally

20 mg.kg) *. Test compounds are administered prior to administration of tremorine, and the tremor is evaluated and the results are shown in Table VI. Table orally for one hour 45 minutes after application of tremorine. You- VI Therapeutic index ^LD 50 ^{/ ED} 50 Compound (Example #) ^ED 50, in mg.kg 1 16 125.0 3 15.0 52.0 4 42.0 47.6 7 37.5 26.7 12 4.0 75.0 13 θ, Ι 19.8 trihexyfenidyl 15.0 24.3

Since nicotine-induced lethality inhibition and tremor inhibition are characteristic of the antiparkinsonian efficacy of the substance, it can be inferred from the data in Tables V and VI that the antiparkinsonian efficacy of the compounds of the invention exceeds the antiparkinsonian efficacy of known compounds used for comparison, both in absolute dose. , as far as the thoretic index is concerned.

Antiarrhythmic activity in rats

The antiarrhythmic activity of the novel compounds of this invention is determined by the effect of aconitin-induced arrhythmia in rats weighing 160-200 g according to the modified Marmo method and co-workers [Arzneimittelforschung, 20, 12 (1970)]. The test animals are anesthetized by intraperitoneal administration of 1.2 g per kg body weight of ethylurethane. Akonitin is administered intravenously at a dose of 75 µg.kg ¹ . Test compounds are administered orally 30 minutes before the administration of aconitine. The inhibition observed is shown in Table VII in percent. In this test, lidocaine and quinidine are used for comparison.

T a b u 1 k а VII

Compound (example δ.)

Dose i mg.kg ¹

Inhibition in percent lidocaine quinidine

45.5

54.2

62.9

23.4

27.3

It is apparent from the data in Table VII that the antiarrhythmic activity of the compounds of the invention exceeds the antiarrhythmic activity of the known compounds used for comparison.

Antianginal efficacy in rats. . -:: ·.

The antianginal activity of the compounds of the invention is iSe. found in anesthetized (chloralozourethane narcosis) male rats weighing 180-220g according to Nischultz (Arzneimittelforschung, £, 680 (1955)). Intravenous application of glanduitrin (extract from the posterior lobe of the pituitary brain) at a dose of 4 IU.kg ¹ induces experimental coronary insufficiency. Measure the wave height T in the ECG before and after glanduitrin administration in the treated and control groups and calculate the inhibition caused by the test compounds. Preylamine [3,3-diphenylpropyl-1-methylphenethylamine lactate] is used for comparison in these experiments. The results are shown in Table VIII.

Compound (Example #)

Table VIII Dose i mg.kg

Inhibition in percent prenylamine

55.4

83.6

41.3

From the results of the pharmacological tests described above, it can be seen that the novel compounds of formula I or their pharmaceutically acceptable acid addition salts can be used as active ingredients in pharmaceutical compositions. The pharmaceutical compositions comprise a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable acid addition salt of the compound and at least one conventional excipient.

The pharmaceutical composition according to the invention, which has particularly local anesthetic, sedative or antiparkinsonian activity, is prepared by mixing a compound of formula I or a pharmaceutically acceptable acid addition salt thereof with at least one pharmaceutically acceptable excipient, for example a carrier, and converting the resulting mixture in known manner. pharmaceutical composition. For such additives and method of converting a mixture to a pharmaceutical composition, see, for example, Remington, Pharmaceutical Sciences, 16th Edition, Mack Publishing Company, Easton, USA, 1980.

In general, the pharmaceutical compositions of the invention are suitable for oral or parenteral administration or for local use and may be solid or liquid.

The solid pharmaceutical compositions may be in powder form, or in the form of capsules, tablets, dragees, and the like, and may contain binders such as gelatin as an additive. sorbitol, polyvinylpyrrolidone etc., fillers such as lactose, glucose, starch, calcium phosphate etc., tabletting aids such as magnesium stearate, talc, polyethylene glycol, silica etc., wetting agents such as sodium lauryl sulfate, etc. Additives to liquid pharmaceutical compositions for oral use are preferably suspending agents such as sorbitol, sugar solution, gelatin, carboxymethylcellulose, etc.,

CS 270579 D2 emulsifiers such as sorbitan monooleate etc., solvents such as oils, oily esters of glycerol, propylene glycol, ethanol etc., preservatives such as p-hydroxybenzoic acid methyl ester etc. *

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

The pharmaceutical compositions of the invention usually contain from 0.1 to 95.0% of active ingredient. A typical daily dose for adult patients is 0.1 to 20 mg of a compound of Formula I or a pharmaceutically acceptable acid salt thereof. The actual dose will be determined according to a number of criteria, such as the condition and person of the patient, the mode of administration, etc..

The invention is illustrated by the following examples.

Example 1,

12H-12 - [(4-Methylpiperazinyl) acetyl] -dibenzo [d, g] [1,5,6] dioxazocine maleate

A) A mixture of 12.0 g (0.141 mol) of 12H-12-dibenzo [d, g] [1,3, b] dioxazocine, m.p. 189-191 ° C, 150 ml of anhydrous toluene and 19.5 g (0.173 mol) of chloroacetyl chloride was heated under reflux for 2 hours. An additional 19.5 g (9.173 mol) of chloroacetyl chloride was then added and the reaction mixture was then refluxed for an additional 4 hours. After cooling to 25 ° C, the reaction mixture is poured onto crushed ice with stirring, stirred for 1 hour and the solids are then filtered off, washed with water and recrystallized from isopropanol. '

This gives 35.6 g (yield 87.3%) of 12H-12- (2-chloroacetyl) -dibenzo [d, g] [1,3,6] dioxazocine, m.p. 151-153 ° C.

Analysis for ^C 15 ^H 12 ^C1NO 3 (289.7) Calculated: C 62,19¾. H 4,18¾. Cl 12,24¾. N 4.83¾ Found: C 62.57%, H 4,12¾. Cl 12,23¾. N 4.77¾ B) Mixture 12.0 g (0.041 mol) 12H-12- (2-chloroacetyl) -dibenzo [d, g] [1,3,6] dioxazocine, 130 ml

of anhydrous benzene and 27.6 g (0.276 mol) of 4-methylpiperazine were refluxed for 6 hours, cooled to 25 ° C and the precipitated salt was filtered off. The organic filtrate was washed with water, dried over anhydrous magnesium sulfate, the solvent was distilled off and the residue was crystallized from isopropanol. The resulting product is recrystallized from isopropanol.

There was thus obtained 9.7 g (66.4% yield) of 12H-12 - [(4-methylpiperazinyl) acetyl] -dibenzo [d, g] [1,3, b] dloxazocine, m.p. 160-162 ° C.

Analysis for ^C 20 ^H 23 ^N 3 ° 3 (353.425)

Calculated: C 67.97 ¾. H 6,56¾.

Found: C 68.14¾. H 7,02¾.

N 11.89¾

N 11,70¾

C)

To a solution of 8.4 g (0.024 mol) of 12H-12 - [(4-methylpiperazinyl) -acetyl] -dibenzo [d, g] - [1,3,6] dioxazocine in 100 ml of isopropanol was added at 20 ° C. the solution is added

5.6 o (0) 048 mol) malelic acid in 30 ml Isopropanol. The reaction mixture was stirred for an hour, then cooled to 0 ° C, stirred for an additional hour. The precipitated product is filtered off, washed with isopropanol and recrystallized from methanol.

This gave 10.5 g (74.7% yield) of the title compound, m.p. 179-183 ° C. .

Anal. ^Calcd for ^C 28 ^H 31 ^{N 4 O} 11 · ⁵⁰⁵ > ⁵⁷²

Calculated: C 57.43 ¾. H 5.34¾.

Found: C, 57.38 ¾. H 5.31¾.

N 7.18¾

N 7.06¾

Example 2

12H-12 - [(N-Cyclohexyl-N-methylamino) -asyl] -dibenzo [d, g] [1,3,6] dioxazocine maleate

A) A mixture of 13.0g (0.045 mol) of 12H-12-chloroacetyldibenzo [d, g] [1,3,6] dioxazocine, 150 ml of anhydrous benzene and 32.2 g (0.28 mol) of N-cyclohexyl-N- The methylamine was heated at reflux for 8 hours. The resulting product was isolated as described in Example 1, part

В) and recrystallized from isopropanol. This gave 13.9 g (yield 84.2%) of 12H-12 - [(N-cyclohexyl-N-methylamino) -acetyl] -dibenzo [d, g] [1,3,6] dioxazocine, m.p. Deň: 32 ° C. ’,.

Analysis for ^C 22 ^H 26 ^N 2 ° 3 (366.463)

C, 72.11; H 7,15¾.

Found: C 72.17¾. H 7.18¾.

N 7.64¾

N 7,60¾

B) 12.8g (0.035 mol) of 12H-12 - [(N-cyclohexyl-N-methylamino) -acetyl] -dibenzo [d, g] [1,3,6] dioxazocine was reacted with 4.2 g ( 0.036 mol) of maleic acid as described in Example 1, part C). After recrystallization from isopropanol, 14.9 g (m.p.

88.2%) in the title of the compound m.p. 148-150 ° C Analysis for C. 26 ^H 30 ^N 2 ° 7 (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, g] [1,3,6] dioxazocine hydrochloride

A) A mixture of 24.8 g (0.10 mol) of 12H-2-chloro-dibenzo [d, g] [1,3, b] dioxazocine, m.p. 182-184 ° C, 300 ml of anhydrous toluene and 23.0 g ( 0.20 mol) of 2-chloroacetyl chloride was refluxed 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 resulting product was recrystallized from isopropanol to give 23.1 g (yield 71.3%) of 12H-12-chloroacetyl-2-chloro-dibenzo [d, g] [1,3,6] dioxazocine, mp 149-151 Deň: 32 ° C.

Analysis for C ^ HH ^C ^NO (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, Part A), 180 ml of anhydrous benzene and 17.7 g (0.30 mol) of isopropylamine was heated under reflux for 4 hours. The organic solvent is then removed under reduced pressure and the residue is stirred for 30 minutes with 100 ml of diethyl ether and 80 ml of water. The organic phase is separated, dried over anhydrous magnesium sulphate, cooled to 0 ° C and treated with diethyl ether saturated with hydrogen chloride with stirring until pH 4 is reached. This process was repeated twice and the product was recrystallized from ethanol. This gives 13.0 g (74.0% yield) of the title product as white crystals, m.p. 235-240 ° C.

Analysis for C 12 H 22 Cl 2 N 2 O 3 (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] -dibenzo [d, g] [1,3,6] dioxazocine dimaleate

A) A mixture of 49.0 g (0.129 mol) of 12H-12-chloroacetyl-2-chlorodibenzo [d, g] [1,3,6] dioxazocine, 80.0 g (0.80 mol) of 4-methylpiperazine and 410 ml of anhydrous benzene was refluxed for 4 hours. The organic solvent and excess 4-methylpiperazine were then removed under reduced pressure. 150 ml of benzene and 10 ml of water are added to the residue and the mixture is stirred for 30 minutes, then the organic phase is separated and washed three times with 80 ml of water each. Then, a solution of 45.0 g (0.30 mol) of tartaric acid in 150 ml of water was added to the organic solution, the mixture was stirred for 1 hour, then the two phases were separated. 150 ml of benzene are added to the aqueous phase and the mixture is stirred. 25% aqueous ammonia was added until the pH was 9-10. The mixture was stirred for one hour, then the organic phase was separated, dried over anhydrous sulfur.

And the solvent is removed under reduced pressure. The residue was triturated with benzene to induce crystallization. The crystals formed are filtered off, stirred in benzene and filtered off again. The resulting product was recrystallized from isopropanol to give 38.0g (76.0% yield) of 12H-12 - [(4-methylpiperazino) acetyl] -2-chloro-dibenzo [d, g] - [1,3, 6] dioxazocine, m.p. 124-127 ° C.

Analysis for Ε20 ^Η 22 ^ ^Ν 3θ3 (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) Using the procedure described in Example 1, Part C), 34.1 g (0.088 mol) of 12H-12 '- [(4-methylpiperazinyl) acetyl] -2-chloro-dibenzo [d, g] [1,3, Dioxazocine was treated with 20.4 g (0.176 mol) of maleic acid to give the acid addition salt. Recrystallization from methanol gave 44.2 g (81% yield) of the title compound, m.p. 188-190 ° C. .

Analysis for ^C 28 ^H 30 ^N 3 ^C ^ ° II (620014)

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) -asyl] -2-chloro-dibenzo [d, g] [1,3,6] dioxazocine maleate

A) A mixture of 35.0g (0.108 mol) of 12H-12-chloroacetyl-2-chloro-dibenzo [d, g] [1,3, a] dioxazocine, 350 ml of anhydrous benzene and 2x 76.9g (2 x 0.678 mol) The N-cyclohexyl-N-methylamine was heated under reflux for a total of 12 hours. The resulting product was isolated as described in Example 4, Part A). The crude product is crystallized and then recrystallized from petroleum ether to give 32.1 g (79.8% yield) of 12H-12 - [(N-cyclohexyl-N-methylamino) acetyl] -2-chloro- dibenzo [d, g] [1,3,6] -dioxazocine, m.p. 93-95 ° C.

Analysis for ^C 22 ^H 25 ^ClN 2 ° 3 (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) 30.0g (0.075 mol) of 12H-12 - [(N-cyclohexyl-N-methylamino) -acetyl] -2-chloro-dibenzo. [d, g] [1,3, b] dioxazocine is reacted with 8.7 g (0.075 mol) of maleic acid according to the procedure described in Example 1, part C). The resulting product is recrystallized from methanol to give 34.8g ( mp 191-193 ° C.

Analysis for ^ 6 ^ 29 ^ 2 ¹ ½ (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- (dimethylaminoacetyl) -2-chloro-dibenzo [d, g] [1,3, б] dioxazocine hydrochloride

A) A mixture of 32.4 g (0.10 mol) of 12H-12-chloroacetyl-2-chloro-dibenzo [d, g] [1,3,6] dioxazocine, 2 x 36.5 g (2x0.50 mol) of diethylamine and 250 ml of anhydrous benzene was refluxed for a total of 6 hours. The resulting product was isolated as described in Example 4, Part A). The yellowish-brown viscous liquid obtained as a crude product was crystallized and then recrystallized from n-hexane. This gave 28.5g (78.9% yield) of 12H-12- (diethylaminoacetyl) -2-chloro-dibenzo [d, g] [1,3,6] dioxazocine, m.p.

Mp 75-80 ° C. Analysis for ^C 19 ^H 21 ^C1N 2 ° 3 (360,844) Calculated: C 63.24%, H 5,87¾. Cl 9,83¾. N 7.76% Found: C 63.96%, H 5,32¾. Cl 9,85 V N 7.50%

CS 270579 02

(19) 19.0 g (0.053 mol) of dioxazocins prepared in Example 6, part A), are treated with isopropanol containing 20% hydrogen chloride to give the corresponding acid addition salt. After crystallization from isopropanol, 17.5 g (yield 02.9%) of the title compound of melting point 190 DEG-201 DEG C. are obtained.

Analysis for ^c 19 ^H 22 ^Cl 2 ^N 2 ° 3 '097,302)

Calculated: C 57.44%, H 5.58%, Cl 17.85%, N 7.05%, СГ 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, gj [1,3,6] dioxazocines hydrochloride

A) A mixture of 32.4 g (0.10 mol) of 12H-12-chloroacetyl-2-chloro-dibenzo [d, g] [1,3,6] dioxazocine;

39.7 g (0.40 mol) of 2-methylpiperidine and 250 ml of anhydrous benzene were refluxed for 4 hours. The reaction product is isolated as described in Example 4, Part A). The crude product was crystallized and recrystallized from isopropanol to give 30.8g (79.6% yield) of (-) - 12H-12 - [(2-methylpiperidinyl) acetyl] -2-chloro-dibenzo [d]. g] [1,3,6] dioxazocines, m.p. 90-92 ° C ₄

Analysis for ^ 21 ^ 23 ^^^ 2 ^ 3 (306,802)

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% ¹

8) 9.6 g (0.0240 mol) of the base prepared in part A) is treated with saturated hydrogen chloride dlothylether as described in Example 3, part 8) to give 10.3 g (98.1% yield) in the header mp 146-154 ° C (dec.);

Analysis for ^^ 21 ^ 24 ^^ 2 ^ 2 ^^ 3 (423.342)

Calculated; C 59.58%, H 5.71%, Cl 16.75%, N 6.62%, Cl 8.30%

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] dioxazocines maleate

A) A mixture of 22.0g (0.068 mol) of 12H-12-chloroacetyl-2-chloro-dibenzo [d, g] [1,3,6] dioxazocines,

24.2 g of pyrrolidine and 250 ml of benzene were refluxed for 3 hours. The resulting reaction product is isolated as described in Example 4, Part A). The crude product was crystallized and recrystallized from petroleum ether to give 19.8 g (81.1% yield) of 12H-12-pyrrolidinylacetyl-2-chloro-dibenzo [d, g] [1,3,6] dioxazocines mp 80-83 ° C.

Analysis for Cj ^H HpClNzOj (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%

14.0 g (0.039 mol) of 12H-12-pyrrolidinylacetyl-2-chloro-dibenzo [d, g] [1,3,6] dioxazocines is reacted with 4.6 g (0.04 mol) of maleic acid, as described in Example 1, part C). The resulting acid addition salt was recrystallized from ethanol to yield

15.8 g (85.5% yield) of the title compound, m.p. 187-192 ° C. Analysis for C ₂ ^H 23 ^ClN 2 ° 7 ⁽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-Morpholinylacetyl-2-chloro-dibenzo [d, g] [1,3, б] dioxazole maleate

A) A mixture of 25.0g (0.077 mol) of 12H-12-chloroacetyl-2-chloro-dibenzo [d, g] [1,3, a] dioxazocine,

30.4 g (0.35 mol) of morpholino and 250 ml of anhydrous benzene are heated at reflux for 3 hours. The resulting reaction product is isolated as described in Example 4, Part A). The crude product was crystallized from hexane and recrystallized from isopropanol. 24.9 g (86.2% yield) of 12H-12-morpholinylacetyl-2-chloro-dibene from [d, g] [1,3,6] dioxazocine, m.p. 123-125 ° C.

CS 270579 D2

Analysis for C ₁₉ h ₁₉ cn ₂ o ₄ (374,827) Calculated: C 60.88%, H 5,11%, Cl 9.46%, N 7.47% Found: C 59,70%, H 5,70%, Cl 9.52%, .N 7.21%

В) 20.0g (0.053 mol) of 12H-12-morpholinylacetyl-2-chloro-dibenzo [d, g] [1,3,6] dioxazocine was treated with 6.2g (0.053 mol) of maleic acid as described in the example 1, part C) to give the corresponding malate, which is recrystallized from ethanol. 20.2 g (yield 77.7%) of the title compound of melting point 197 DEG-199 DEG C. are obtained. Analysis for C ₂₁ H ₂₁ ClN ₂ O ₀ (490.890)

Calculated: C 56.28%, H 4.72%, Cl 7.22%, N 5.71% ’

Found: C 56.71%, H 4.88%, Cl 7.23%, N 5.72%

Example 10 ‘

12H-12- [2- (cyclopropylamino) -acetyl] -4-chloro-dibenzo [d, g] [1,3,6] dioxazocine maleate A) A mixture of 25.0g (0.077 mol) of 12H-12-chloroacetyl-2 -chlorodibenzo [d, g] [1,3,6] dioxazocine,

2x8.6 g (2x0.15 mol) of cyclopropylamine and 200 ml of anhydrous benzene were refluxed for 11 hours. The resulting reaction product is isolated as described in Example 4, Part A). The crude product is crystallized and then recrystallized from petroleum ether to give 18.3g (69.1% yield) of 12H-12- [2- (cyclopropylamino). (1-acetyl) -2-chloro-dibenzo [d, g] [1,3,6] dioxazocine, m.p. 80-85 ° C.

Analysis for ^C ₁ 8 ^H 17 ^C1N 2 ° 3 (344800)

Calculated: C 62.70%, H 4.97%, Cl 10.28%, N 8.12% Found: C 63.02%, H 4.60%, Cl 10.35%, N 8.01%

B) 11.4 g (0.033 mol) of the base prepared in part A) is treated with 3.9 g (0.034 mol) of maleic acid as described in Example 1, part C) to give the corresponding maleate which is recrystallized from ethanol. This afforded 11.9 g (yield 78.3%) of title compound, mp 176-181 C. ⁹

Analysis for C ₂₂ H ₂₁ C1N ₂ O ₇ (460.872)

Calculated: C 57.34%, H 4.59%, Cl 7.69%, N 6.08% Found: C 57.70%, H 5.00%, Cl 7.91%, N 6.15%

Example 11 ¹ .

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

A) A mixture of 24.8 g (0.10 mol) of 12H-2-chloro-dibenzo [d, g] [1,3,6] dioxazocine, 150 ml of anhydrous benzene and 25.4 g (0.20 mol) of 3-chloropropionyl chloride was heated at reflux for 5 hours. The solvent was then removed under reduced pressure and the residue was dissolved in 150 ml of benzene. The resulting solution was poured onto crushed ice. The mixture is stirred for 1 hour, then the organic phase is separated, washed four times with 100 ml of 5% aqueous sodium bicarbonate solution each and then with 100 ml of water. The organic solution was dried over anhydrous magnesium sulfate, the solvent was removed under reduced pressure, and the residue was crystallized from isopropanol. The resulting crude product was recrystallized from isopropanol to give 26.7g (79.0% yield) of 12H-12- (3-chloropropionyl) -2-chloro-dibenzo [d, g] - [1,3,6] dioxazocine mp 76-81 ° C.

Analysis for ^c 16 ^H 13 ^Cl 2 ^NO 3 (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%

8) A mixture of 33.8g (0.10 mol) of 12H-12- (3-chloropropionyl) -2-chlorodibenzo [d, g] [1,3,6] dioxazocine, 60.0 g (0.60 mol) 4-Methylpiperazine and 250 ml of anhydrous benzene were refluxed for 5 hours. The resulting reaction product is then isolated as described in Example 4, Part A). 30.0 g of crude 12H-12- [3- (4-methylpiperazino) -propionyl] -2-chloro-dibenzo [d, g] [1,3,6] dioxazocine is obtained as a brown viscous liquid.

Cg 270579 02

С) 30.0 g of the crude base prepared in part B) was reacted with 18.6 g (0.16 mol) of maleic acid according to the procedure described in Example 1, part C) to give the corresponding salt which was recrystallized from methanol. This gives 24.6 g (yield 67.0%) of the title compound, m.p. 185-187 ° C.

Analysis for C? ^H ^ dNNO ^ (634.041)

Calculated: 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 12

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

A) A mixture of 33.8g (0.10 moles) of 12H-12- (3-chloropropionyl) -2-chloro-dibenzo [d, gj [1,3,6] dioxazolone, 2x29.2g (2x0.40 moles) of diethylamine and 25 ml of anhydrous benzene were refluxed for a total of 6 hours. The reaction was carried out and the resulting reaction product was isolated as described in Example 4, Part A). The crude product was crystallized and recrystallized from n-hexane to give 30.9g (yield 82.5%) of 12H-12- [3- (diethylamino) propionyl] -2-chloro-dibenzo [d, g] [1,3,6] dioxazocine, m.p. 68-72 ° C.

Analysis for ^C 20 ^H 23 ^C 2 ^N 2 ° 3 (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) 18.7g (0.05 mol) of 12H-12- [3- (diethylamino) -propionyl] -2-chloro-dibenzo [d, g] [1,3,6] di oxazocine is dissolved in 70 ml of isopropanol . To the resulting solution, cooled to 0 ° C, isopropanol containing 20% dissolved hydrogen chloride gas was added with stirring until pH 3 was reached. The mixture is then stirred for 1 hour, the crystals formed are filtered and recrystallized from the title compound o

Analysis for ^C 20 ^H 24 ^Cl 2 ^N 2 ° 3 Calculated: C 58.40%, H

Found: C 58.12%, H of isopropanol. Mp 176-182 ° C.

(441,329)

5.88%, Cl 17.24%, N

6.07%, Cl 17.12%, N

17.9 g (yield 81.0%)

6.81%, С 8.62%.

6.68%, Cl 8.66%

Example 13

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

A mixture of 30.0g (0.089 mol) of 12H-12-C3-chloropropionyl) -2-chlorodibenzo [d, g] [1,3, б] dioxazocine, 2x21.0g (2 x 0.356 mol) of isopropylamine and 250 ml of anhydrous of benzene was heated under reflux for a total of 6 hours. The reaction is carried out and the resulting reaction product is isolated as described in Example 4, Part A) to give 28.5 g of 12H-12- [3- (isopropylamino) -propionyl] -2-chloro-dibenzo [d, g] [1,3,6] dioxazocine as a viscous liquid. The resulting dioxazocin base is converted to the hydrochloride as described in Example 3,

part B), Po recrystallization ethanol se 25.8 g (yield 73.0%) v žáh of said compound at 0 melting 240 a6 243 ° C. ’ Analysis for ^ 19 ^ 22 ^^ 2 ^ 2/3 (397,201) Calculated: C 57.44%, H 5.5ВЧ, Cl 17.86%, N 7,05%, СГ 8.93% Found: C 57.66%, H 5,45¾. Cl N, 17.86% 6.98%, Cl ' 8.92% Example 14

12H-12- (3-pyrrolidinylpropionyl) -2-chloro-dibenzo [d, g] [1,3, б] dioxazocine maleate

A) A mixture of 25.0g (0.074 mol) of 12H-12- (3-chloropropionyl) -2-chloro-dibenzo [d, g] [1,3,6] dioxazocine, 21.3 g (0.30 mol) of pyrrolldine and 250 ml of anhydrous benzene were refluxed for 3 hours. The resulting reaction product was isolated as described in Example 4, Part A). The crude product was crystallized from petroleum ether and recrystallized from the same solvent to give 21.8g (79.0% yield) of 12H-12- (3-pyrrolidinyl-propionyl) -2-chloro-dibenzo [d, g] [1,3,6] dioxazocine, m.p. 115-118 ° C.

CS 270579 02

Analysis for ^C 20 ^H 21 ^ClN 2 ° 3 (372.854)

Calculated; C 64.43 4, H 5.6B4, Cl 9.514, N 7.514

Found; C 64.00 4, H 5.124, Cl 9.614, N 7.404

B) 20.0 g (0.054 mol) of the base prepared in part A) is treated with 6.4 g (0.055 mol) of maleic acid as described in Example 1, part C) to give the corresponding salt, which is recrystallized from ethanol. This gives 22.7g (yield 85.94) of the title.

temperature melting 161 to 164 ^J C. Analysis for ^C 24 ^H 25 ^ClN 2 ° 7 (488,926) Calculated: C 58.96 4, H 5,154, Cl 7.25 4, N, 5.734 Found: C 59.52 4, H 5.28 4, Cl 7.35 4, N, 5.94 Example 15

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

A mixture of 25.0g (0.074 mol) of 12H-12- (3-chloropropionyl) -2-chlorodibenzo [d, g] [1,3,6] dioxazocine, 2x8.7g (2x0.16 mol) of cyclopropylamine and 250 ml of anhydrous benzene was heated under reflux for a total of 15 hours. The reaction is carried out and the reaction product is isolated as described in Example 4, Part A) to give 21.7g12H-12- [3- (cyclopropylamino) -propionyl] -2-chloro-dibenzo [d, g] [1, 3,6] dioxazocine in the form of a wax-like liquid.

The resulting dioxazocin base is converted to the hydrochloride salt as described in Example 3, Part B). Recrystallization from ethanol gave 18.7 g (64.0% yield) of the title compound, m.p. 196-204 ° C.

Analysis for ^c 19 ^H 20 ^Cl 2 ^N 2 ° 3 (395.208)

H, 5.104; Cl, 17.94; N, 7.09; Cl, 8.974.

Found; C 58.34 4, H 5.38 4, Cl 18.184, N 7.104, Cl 8.8894

Example 16

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

A) A mixture of 25.0g (0.074 mol) of 12H-12- (3-chloropropionyl) -2-chlorodibenzo [d, g] [1,3,6] dioxazocine, 30.4g (0.35 mol) of morpholine and 250 ml of anhydrous benzene was refluxed for 5 hours. The resulting reaction product was isolated as described in Example 4, Part A) and crystallized from n-hexane. The crude product was recrystallized from isopropanol to give 23.9g (yield 83.04) of 12H-12- (3-morpholinylpropionyl) -2-chloro-dibenzo [d, g] [1,3,6] dioxazocine, m.p. Mp 122-125 ° C.

Analysis for ^C 20 ^H 21 ^ClN 2 ° 4 (388.854)

H, 5.44; Cl, 9.124; N, 7.204

Found: C 60.984, H 5.93 4, Cl 9.214, N 7.034

B) Following the procedure described in Example 3, Part B), 15.0g (0.0386 mol) of 12H-12- (3-morpholinylpropionyl) -2-chloro-dibenzo [d, g] [1,3, a] dioxazocine is converted in the corresponding hydrochloride salt. Recrystallization from ethanol gave 13.5 g (62.3% yield) of the title compound, m.p. 225-229 ° C.

Analysis for C ₂₀ H ₂₂ Cl ₂ N ₂ 0 ₄ (425.315)

H, 5.214; Cl, 16.67; N, 6.59; Cl, 8.34%.

Found: C, 56.92; H, 5.35; Cl, 16.77; N, 6.55; Cl, 8.36.

Example 17

(I) -12H-12- [2- (4-Methyl-piperazinyl) -propionyl] -2-chloro-dibenzo [d, gj [1,3,6] dioxazocine maleate

A) A mixture of 123.9 g (0.50 mol) of 12H-2-chlorodibenzoCd, g] [1,3,6] dioxazocine, 750 ml of anhydrous toluene and 127.0 g (1.00 mol) of 2-chloropropionyl chloride was heated. 3 hours under reflux. The resulting reaction product was isolated as described in Example 3, Part A). After recrystallization from isopropanol, 131.1 g (yield 77.54) are added.

O) (-) - 12H-12- (2-chloropropionyl) -2-chloro-dibenzo [d, g] [1,3,6] dioxazocine, m.p. 152-155 ° C.

Analysis for ^C ₁₆ H _{i; j} N0 ₃ C1 ₂ (330201)

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%

A mixture of 20.0 g (0.059 mol) of chlorpropionyl dioxazocine prepared in Part A), 2 x

25.1 g (2 x 0.25 mol) of 4-methylpiperazine and 200 ml of anhydrous benzene were heated at reflux for 11 hours (total heating time). The reaction is carried out and the reaction product is isolated as described in Example 4, Part A). The crude product was triturated with petroleum ether to induce crystallization and the crystals formed were recrystallized from isopropanol. There was thus obtained 18.8g (yield 79.2%) of (-) - 12H-12- [2- (4-methylpiperazinyl) propionyl] -2-chloro-dibenzo [d, g] [1,3,6] dioxazocine, m.p. 133-136 ° C.

Analysis for ^C 21 ^H 24 ^N 3 ^C-3 ° (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% To 13.0 g (0.032 mol) dioxazocin base prepared in part 0) is applied

(0.066 mol) of maleic acid was carried out as described in Example 1, part C). Recrystallization of the resulting acid addition salt 8 from ethanol is obtained

17.1g (yield 84.24) in the title compound mp 117-182 ° C Analysis for _C29 ^H 32 ^clN 3 ° n (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 18

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

A) A mixture of (-) - 12H-12- (2-chloropropionyl) -2-chloro-dibenzo [d, g] [1,3, b] dioxazocine, 28.0g (0.083 mol), 21.3g (0.30) mol) of pyrrolidine and 250 ml of anhydrous benzene were heated under reflux for 10 hours. The resulting reaction product is isolated as described in Example 4, Part A). The crude product was triturated with petroleum ether to induce crystallization and the crystals formed were recrystallized from the same solvent. This is obtained

24.9 g (yield 80.3%) of (-) - 12H-12- (2-pyrrolidinylpropionyl) -2-chloro-dibenzo [d, g] - [1,3,6] dioxazocine, m.p. 98-102 Deň: 32 ° C.

Analysis for C ^ HH ^ClNjOj (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

0) Following the procedure described in Example 3, Part B), 16.0 g (0.043 mol) of dioxazocin base prepared in Part A) was converted to the hydrochloride salt. Recrystallization from isopropanol gave 14.2 g (80.7% yield) of the title compound, m.p. 223-225 ° C.

Analysis for C ^ HH ^Cl ^Oj (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%, С 8.47%

Example 19

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

A) A mixture of 23.7 g (0.070 mol) (-) _T 12H-12- (2-chloropropionyl) -2-chloro-dibenzo [d, g] [1,3,6] di oxazocine 17.7 g (0. 21 mol) of isopropylamine and 250 ml of anhydrous benzene are refluxed for hours. The resulting reaction product is isolated as described in Example 4, Part A). The crude product is triturated with 8 gasoline to induce crystallization and the crystals formed are recrystallized from the same solvent. 18.2 g (yield

72.1%) (-) - 12H-12- (2-isopropylaminopropionyl) -2-chloro-dibenzo [d, g] [1,3,6] dioxazocine, m.p. 102-105 ° C.

Analysis for ^c 19 ^H 21 ^ClN 2 ° 3 (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) Following the procedure described in Example 3, Part B), 10.0 g (0.0277 mol) of dioxazocin base prepared in Part A above was converted to the hydrochloride salt. After covering

Purification from isopropanol gave 9.6 g (87.3% yield) of the title compound, m.p. 224-227 ° C. ’ Analysis for C? H? Cl? N? O? (397,304) Calculated: C 57.44%, H 5,584, Cl 17,854, N 7.05 4, Cl 8.92% Found: C, 57.44%, H 5,704, Cl 17,63 4, N 6,94 4, Cl. 8,90%

Example 20

(-) - 12H-12- [2-Methyl-3- (4-methylpiperazinyl) -propionyl] -2-chloro-dibenzo [d, g] [1,3,6] dioxazocine dimaleate '

A) A mixture of 26.1 g (0.11 mol) of 12H-2-chloro-dibenzo [d, g] [1,3,6] dioxazocine, 300 ml of anhydrous toluene and 39.0 g (0.21 mol) of 3- of bromo-2-methylpropionyl chloride was heated at reflux for 8 hours, then cooled to 25 ° C and poured into 300 g of crushed ice with stirring. After stirring for 2 hours, the organic phase was separated, washed first with 3 x 100 ml of 5% aqueous sodium bicarbonate solution, then with 100 ml of water and dried over anhydrous magnesium sulfate. The solvent was then removed under reduced pressure and the residue was triturated with isopropanol to crystallize. The crystals formed are recrystallized from the same solvent. 33.2 g (yield

76.1%) (-) - 12H-12- (3-bromo-2-methylpropionyl) -2-chlorodibenzo [d, g] [1,3,6] dioxazocine, m.p. 115-119 ° C.

Analysis for HH ^ BrClNO ^ (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 0.90%, N 3.52%

B) A mixture of 26.6 g (0.072 mol) of the bromomethylproplonyl-dioxazolone prepared in Part A above, 2x30.0g (2 x 0.295 mol) of 4-methylplperazine and 250 ml of anhydrous benzene was heated at reflux for 7 hours (total heating time). ). The reaction is carried out and the resulting reaction product is isolated as described in Example 4, Part A). The crude reaction product was triturated with petroleum ether to induce crystallization. Recrystallization of the resulting crystals from n-hexane gave 25.3g (84.6% yield) of (-) - 12H-12- [2-methyl-3- (4-methylpiperazinyl) propionyl] -2-chloro-dibenzo [d, g] [1,3,6] dioxazocine, m.p. 126-131 ° C;

Analysis for ^C ₂ ^H 26 ^ClN 3 ° 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 dioxazocin base prepared in Part B above were treated with 5.2 g (0.045 mol) of maleic acid as described in Example 1, Part C) to form the corresponding addition salt. with acid. After recrystallization from acetonitrile, it is obtained

11.8 g (82.5% yield) of the title compound, m.p. 152-157 ° C. Analysis for ^c 34 ^H 34 ^{C 1 N 6 O} (648,068)

Calculated; 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)

A process for the preparation of novel aminoalkanoyl-dibenzo [d, g] [1,3, e] dioxazocines of the general formula I wherein: X is hydrogen or halogen, A represents a valence bond or a straight-chained C 1 -C 10 alkylene radical, each of R 1 and R ₂ being independently of the other hydrogen, C 1 -C 4 alkyl or C 3 -C 6 cycloalkyl, or R 1 and R ₂ together with the nitrogen atom to which they are attached and optionally with at least one other nitrogen, oxygen and / or sulfur atom form a 5- or 6-membered heterocyclic ring optionally substituted with a C 1 -C 4 alkyl group and 1 pharmaceutically acceptable salts thereof acid addition salts, characterized in that the dibenzo [d, g] [1,3, б] dioxazocine of the general formula II (II) in which: X is as defined above, acylated with a compound of formula III hal-C-A-hal * II o (III) in which: A is as defined above and hal and hal * are independently [1,3, dioxazine of formula IV halogen, and the resulting alkanoyl-dibenzo [d, g] - in which X, A and hal * are as defined above, reacted with an amine of formula VIII (VIII) in which R | and R @ ₂ have the abovementioned meaning, and the resulting compound of formula I is optionally converted by reaction with a pharmaceutically acceptable inorganic or organic acid addition salt or liberated from the acid addition salt by reaction with a base. 2. A process according to claim 1, wherein 12H-12 [(4-methylpiperazines) -acetyl] -dibenzo [d, g] [1,3,6] is prepared using the corresponding compounds of formulas II, III and VIII. diaxazocine, which is optionally converted to its pharmaceutically acceptable acid addition salt. 3. The process according to claim 1, wherein 12H-2-chloro-12 - [(4-methylpiperazinyl) acetyl] dibenzo [d, g] - [12] is produced using the corresponding compounds of formulas II, III and VIII. 1,3,6] dioxazocine, which is optionally converted into its pharmaceutically acceptable acid addition salt. 4. A process according to claim 1, wherein (-) - 12H-2-chloro-12 - [(2-methylpiperidinyl) acetyl] -dibenzo [d] is prepared using the corresponding compounds of formulas II, III and VIII. g] [1,3,6] dioxazocine, which is optionally converted into its pharmaceutically acceptable acid addition salt. 5. A process according to claim 1, wherein 12H-12-diethylcarbamoyl-2-chloro-dibenzo [d, g] [1,3,6] dioxazocine is produced using the corresponding compounds of formulas II, III and VIII, which is optionally converted into its pharmaceutically acceptable addition salt and acid. 6. A process according to claim 1, wherein 12H-2-chloro-12- [3- (diethylamino) propionyl] -dibenzo [d, g] [1, 2] is prepared using the corresponding compounds of formulas II, III and VIII. 3, 6] dioxazocine, which is optionally converted into its pharmaceutically acceptable acid addition salt.