CH675877A5 - - Google Patents

Description

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CH 675 877 A5

description

The invention further relates to new aminoalkanoyl-dibenzo [d, g] [1, 3.6] dioxazocine derivatives, a process for their preparation and medicaments containing these compounds, in particular those with local anesthetic, tranquilo-sedative and / or antidepressive, antiparkinsonian antiarrhythmic and antianginal effects.

Some 12-aminoalkkyI-12H-dibenzo [d, g] [1,3,6] dioxazocin derivatives which have a local anesthetic and anti-tiparkinsonian action are described in U.S. Patent 4,208,410.

It has been found that the pharmacological action of the known compounds is changed favorably if the nitrogen atom of the dioxazocin ring is substituted by an aminoalkanoyl group instead of the aminoalkyl group.

The invention thus relates to aminoalkanoyl-dibenzo [d, g] [1,3,6] derivatives of the general formula

X represents hydrogen or a halogen atom,

A represents a chemical bond or a straight-chain or branched alkylene group with 1 to 10 carbon atoms,

R 1 and R 2 independently represent hydrogen, an alkyl group with 1 to 4 carbon atoms or a cycloalkyi group with 3 to 6 carbon atoms, or

R 1 and R 2 with the nitrogen atom to which they are attached, and optionally with one or more further nitrogen, oxygen and / or sulfur atoms, a 5- to 6-membered heterocyclic group which is optionally substituted by an alkyl group having 1 to 4 carbon atoms form,

as well as their pharmaceutically acceptable acid addition salts.

The halogen atom that can represent X is a fluorine, chlorine, bromine or iodine atom.

The straight-chain or branched alkylene group having 1 to 10 carbon atoms, which can stand for A, is for example a methylene, ethylene, isopropylene, n-propylene, n-butylene, isobutylene, pentylene, hexylene, heptylene , Octylene, nonylene or decylene group. It is preferred that the alkylene group which A may represent is one having 1 to 3 carbon atoms.

The alkyl groups for which R 1 and R 2 can stand independently are methyl, ethyl, isopropyl, n-propyl, n-butyl, isobutyl, sec-butyl or tert-butyl groups. It is preferred that the alkyl groups which R 1 and / or R 2 can stand for are methyl, ethyl, isopropyl or n-propyl groups.

The cycloalkyl groups which can independently represent R 1 and R 2 are cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl groups. It is preferred that the cycloalkyl groups; R 1 and / or R 2 can be cyclopropyl or cyclohexyl groups.

The 5- to 6-membered heterocyclic group which can represent R 1 and R 2 together with the nitrogen atom to which they are attached and optionally with a further hetero atom is advantageously a piperazinyl, piperidinyl, pyrrolidinyl or morpholinyl group. The heterocyclic group can be substituted by a lower alkyl group, preferably a methyl group.

When A represents a chemical bond, the group of the general formula is where

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CH 675 877 A5

directly bound to the nitrogen atom of the heterocyclic ring.

The compounds of general formula I can form acid addition salts. The acid addition salts of the compounds according to the invention are expediently those with therapeutically acceptable acids. They can be those with inorganic acids, especially hydrochloric acid, hydrogen bromide or sulfuric acid, or organic acid, especially acetic acid, fumaric acid, lactic acid, maleic acid, methanesulfonic acid, ethanesulfonic acid, or citric acid, etc.

The compounds of general formula I can contain one or more chiral carbon atoms. In these cases, the optical isomers of the compounds according to the invention exist. The invention relates to the optically active antipodes and any mixtures thereof.

A preferred group of the compounds according to the invention consists of the compounds of the general formula I in which X represents a hydrogen atom or a chlorine atom,

A represents a chemical bond or an alkylene group with 1 to 3 carbon atoms,

Ri and R2 independently represent hydrogen, an alkyl group with 1 to 3 carbon atoms or a cyclo-

propyl group or a cyclohexyl group, or

R 1 and R 2 form a 4-methylpiperazinyl, 2-methylpiperidinyl, pyrrolidinyl or a morpholinyl group with the nitrogen atom to which they are attached and optionally with a further nitrogen or oxygen atom,

as well as their pharmaceutically acceptable acid addition salts.

Very particularly preferred compounds according to the invention are the following: 12H-12 - [/ 4-methylpiperazinyl / -acetyl] -dibenzo [d, g] - [1,3,6] dioxazocin, 2-chloro-12H-12 - [/ 4 -methylpiperazinyl / -acetyl] -dibenzo [d, g] [1,3,6] dioxazocin, l ± l-2-chloro-12H-12 - [/ 4-methylpiperazinyl / -acetyl] -dibenzo [d, g] [1,3,6] dioxazocin, 2-chloro-12H-12- / diethyl-carbamoyl / -dibenzo [d, g] [1,3,6] -dioxazocin, 2-chloro-12H-12- [3- / diethylamino / -propionyl] -dibenzo- [d, g] [1,3,6] dioxazocin,

as well as the pharmaceutically acceptable acid addition salts thereof.

The invention also relates to a process for the preparation of the compounds according to the invention, which is characterized in that a dibenzo [d, g] [1,3,6] dioxazocin of the general formula in which A has the above meaning, shark and shark 'independently each represent a halogen atom, acylated, and the alkanoyl-dibenzo [d, g] [1,3,6] dioxazocin of the general formula wherein X has the above meaning, with a compound of the general formula

Hat — C — A - Hal '

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CH 675 877 A5

l »v).

wherein X, A and Hai 'are as above, with an amine of the general formula

HN

*1

* 2

tvitr).

where Ri and R2 have the meaning given above. This method is referred to below as variant a). Furthermore, the compounds of the formula I can be prepared by the process below, variant b), by adding a dibenzo [d, g] [1,3,6] dioxazocin of the general formula II to a compound of the general formula

Shark — C - A — N

J

Ri

* 2

(V),

wherein A, Ri and R2 have the above meaning, and Hai represents a halogen atom, acylated; or according to variant c): a dibenzo [d, g] [1,3,6] dioxazocin of the general formula II with a compound of the general formula

Has — C— A'-CH = CH2

II

0

(VI).

wherein shark represents a halogen atom, A 'represents a chemical bond or a straight-chain or branched alkylene group having 1 to 8 carbon atoms, acylated, and the compound of the general formula obtained

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CH 675 877 A5

A'-CHsCHÎ (VII),

wherein X and A 'have the above meaning, with an amine of the general formula VIII.

If desired, the diazocine derivatives obtained by these processes are converted into acid addition salts or the diazocine derivatives are released from the acid addition salts obtained.

In general formulas III, IV, V and VI, the halogen atom is preferably a chlorine or bromine atom.

The dibenzo [d, g] [1,3,6] dioxazocins of the general formula II used as the starting compound are prepared in the manner described in US Pat.

The compounds of the general formulas III, V, VI and VIII are known reagents which are commercially available or can be prepared in a known manner.

In process a) according to the invention, the compound of the general formula II is acylated in apolar or dipolar aprotic solvents, preferably in benzene, toluene, xylene or dimethylform amide, in the presence of an acid binder. The acylating agent! of the general formula III is used in an equivalent amount or in an excess with respect to the amount of diben-zo [d, g] [1,3,6] dioxazocin of the general formula II.

The compound of the general formula II is advantageously acylated in toluene at 60 to 110 ° C. with the compound of the general formula III, which is used in a 200 to 300% excess.

The haloalkanoyl-dibenzo [d, g] [1,3,6] dioxazocin of the general formula IV formed by the acylation reaction is reacted with the amine of the general formula VIII in a polar, apolar or dipolar solvent. The preferred solvents for this reaction are the following: benzene, toluene, xylene, isopropanol or dimethylformamide. The amine of the general formula VIII is used in an equivalent amount or in excess.

The hydrogen halide formed in the reaction can be bound by the excess of the amine of the general formula VIII, but other conventional acid-binding agents can also be used for this purpose.

The acid binder used in acylation and amination can be a suitable inorganic base such as sodium carbonate, potassium carbonate, etc., or a suitable organic base such as a tertiary amine, for example triethylamine, N, N-diisopropyl-N-ethylamine, pyridine, etc.

The compound of the general formula IV is preferably reacted in benzene with an excess of the amine of the general formula VIII.

In process a) according to the invention, it is also possible to start from a metal salt of the compound of the general formula II. In this case, the compound of general formula II is first reacted in a dipolar aprotic solvent, for example dimethylformamide, with, for example, sodium hydride or sodium amide, and the corresponding sodium salt obtained is then generally acylated at a temperature of 0 to 40 ° C. Of course, no further acid binder needs to be used in this case.

In process b) according to the invention, the compound of the general formula II is acylated in a similar manner with the compound of the general formula V, generally at a temperature of 0 to 140 ° C. Advantageously, an alkali metal salt of the compound of general formula II is first prepared and the salt obtained is then reacted with an excess of the compound of general formula V at 0 to 50 ° C.

In process c) according to the invention, the reaction of the compound of the general formula II with the compound of the general formula VI in a non-polar organic solvent such as benzene, toluene or xylene is generally carried out at 50 to 140 ° C. The compound of general formula VII obtained is reacted with the amine of general formula VIII under atmospheric pressure or under higher pressure. An apolar organic solvent or an excess of the amine of the general formula VIII is used as solvent.

If the compound of general formula I contains one or more chiral carbon atoms, the enantiomers can be separated by cleaving the racemic compound. For that

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the racemic compound of the general formula II, which contains a basic nitrogen atom, is reacted with an optically active organic acid, the diastereomeric salt pairs formed are separated, and the enantiomers are released. Any optically active sulfonic acids, such as 10-camphorsulfonic acid, such as tartaric acid, dibenzoyltartaric acid, lactic acid, atrolactonic acid, mandelic acid, etc., can be used as optically active organic acid.

The enantiomers of the new compounds according to the invention which contain one or more chiral carbon atoms can also be prepared directly from the corresponding compound of the general formula II by acylation with an optically active compound of the general formula III, V or VI.

The compounds according to the invention have valuable pharmacological effects, in particular local anesthetic, tranquilo-sedative, and / or antidepressive, antiparkinsonian, further antiarrhythmic and antianginal effects.

Acute toxicity in mice

The acute toxicity of the compounds according to the invention was determined on white mice of the CFLP strain. The experimental groups used consisted of 10 mice of both sexes, and the weight of the animals was 18 to 22 g. The animals were treated orally with the compounds in a volume of 20 ml / kg. After administration, the mice kept in plastic boxes over wood chip litter at room temperature were observed for 7 days while consuming tap water and usual mouse food as desired. The LD 50 values were determined according to Litchfield and Wilcoxon [J. Pharmacol. exp. Ther., 96, 99/1949 /]. The LD 50 values obtained are summarized in Table I below.

Table I

Connection Peroral LD 50 value in mg / kg

(Example)

1 2000

2,700

3,280

4 2000

5 2000

6 250

7 1000

8 450

9,900

10,900

11 2000

12 260

13,300

14 160

15 250

16 250

17,650

18 250

19 370

20 220

21 300

The local anesthetic effect

The experiments were carried out according to Truant d'Amato [Acta Chir. Scand., 116. 351/1958 /]. 0.5 ml of a 0.25 or 0.50% solution of the compound to be tested was injected around the hip nerve into the center of the femur of mice. Motor control error of paw muscles

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was considered the criterion of anesthesia. The duration of the effect achieved was recorded and the concentration at which the activity was 50%, that is to say the EC 50 value, was determined. Lidocaine [2-diethylamino-2 ', 6'-acetoxy-xylidide] with the same direction of action was used as the reference substance. The results obtained are shown in Table II below.

Table II

connection

ECso value

Duration of action with a conc

(Example)

in %

tration of 0.25% in minutes

0.50%

4th

0.21

55.8

97.7

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0.25

51.1

98.8

12

0.15

54.1

107.3

13

0.14

122.1

217.3

14

0.19

83.2

160.0

15

0.16

52.4

113.8

16

0.25

80.0

114.6

18th

0.10

85.7

146.4

19th

0.22

43.7

73.8

20th

0.11

53.5

67.8

21st

0.08

93.1

93.1

Lidocaine

0.17

23.9

40.1

It can be seen from Table II that most of the compounds according to the invention are effective in a concentration lower than the EC 50 of lidocaine. The duration of action of all tested compounds according to the invention is much longer at both concentrations than the duration of action of lidocaine.

Sleep in mice caused by hexobarbital

The groups of animals, each consisting of 6 mice, were treated orally with the compounds to be tested. After one hour, hexobarbital [5- (1-cyclohexenyl) -1,5-dimethylbarbituric acid] was injected intravenously in a dose of 40 mg / kg. The control group was treated with hexobarbital only. The duration of sleep was recorded in each animal. It was considered a positive countermeasure if the duration of sleep from an animal was 2.5 times longer than the average duration of sleep from the control group. The ED 50 value was calculated from the information relating to the mice which had a positive counteraction. Meprobamate [2-methyl-2-propyl-propanediol-1,3-dicarbamate] and chlorodiazepoxide [7-chloro-2-methylamino-5-phenyl-3H-1,4-benzodiazepine-4-oxide] with the same direction of action were used as reference substances used. The results obtained are summarized in the following Table III, in which both the ED 50 values and the therapeutic indices are given.

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Table III

Connection (example)

Peroral EDso value in mg / kg

Therapeutic index

LDso value

EDso value

1

21.0

95.2

3rd

25.0

31.2

4th

8.5

235.0

6

15.0

16.7

12

30.0

8.7

15

9.8

25.5

19th

15.0

24.7

Meprobamate (LD 50 = 1100 mg / kg)

260

4.2

Chlordiazepoxide (LD50 = 620 mg / kg)

10.0

62.0

It can be seen from Table III that the therapeutic index of the most effective compound according to the invention (i.e. the compound prepared according to Example 4) is an order of magnitude higher than the therapeutic index of chlordiazepoxide. At the same time, the compounds according to the invention are superior to the comparison substance meprobamate.

The antagonism of tetrabenazinptoses in mice

The tests were carried out according to the method of Hoffmeister and co-workers [Pharmaceutical Research, 19. 846-858 (1969)], which was adapted to mice. The groups of animals, each consisting of 10 mice, were treated orally with various doses of the compounds to be tested. The control group mice were given only the appropriate vehicle. After 30 minutes, tetrabenazin [3-isobutyl-9,10-dimethoxy-1,2,3,4,6,7-hexahydrobenzo [a] quinolizin-2-one] was administered intraperitoneally to the animals in a dose of 50 mg / kg . The number of animals with closed eye cleft was determined after 30, 60, 90 and 120 minutes in each animal group. Then the average of Ptose in each group was calculated and the deviation from the average of the control group (i.e. the inhibition) was expressed as a percentage. From the information obtained, the ED 50 value for each tested compound according to the invention and the comparison substance amitriptyline [3- (3-dimethylamino-propylidene) -10,11 -dihydro-5H-dibenzo [a, d] cycloheptene hydrochloride] of the same direction of action was determined . The results obtained are summarized in Table IV below, in which both the ED50 values and the therapeutic indices are given.

Table IV

Connection (example)

EDso value in mg / kg

Therapeutic index

LDso value

EDso value

2nd

13.0

53.9

11

23.0

86.9

20th

13.5

13.6

Amitriptyline

12.0

18.7

Inhibition of nicotine lethality in mice

The tests were carried out on white mice using the method of Stone [Arch. Int. Pharmacodyn., 177, 419 (1958)]. The animals were treated orally with the compounds to be tested. After one hour, nicotine was injected intravenously at a dose of 1.4 mg / kg. The convulsions observed in one hour and the possible lethality were recorded and the ED 50 value was calculated for each compound tested according to the invention and the comparison substance trihexyphenidyl [alpha-cyclo-hexyl-alpha-phenyl-piperidine-propanol-hydrochloride]. The results obtained are summarized in Table V below, in which both the ED 50 values and the therapeutic indices are given.

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Table V

Connection (example)

EDso value in mg / kg

Therapeutic index

LDso value

EDso value

1

72

27.8

3rd

7

111.0

4th

35

57.0

5

13

154.0

6

5

50.0

7

15

66.7

8th

15

30.0

9

17th

52.9

10th

21st

42.9

Trihexyphenidyl

20th

18.25

Inhibition of tremor-induced tremor in mice

The experiments were carried out according to the Everett method [Science, 124, 79 (1956)]. The tremor was caused by the intraperitoneal administration of 20 mg / kg tremorin. The compounds to be tested were entered into the animals one hour before treatment with tremorin and the developed tremor was evaluated 45 minutes after the entry of tremorin. Trihexyphenidyl was used as the reference substance. The results obtained are summarized in Table VI below, in which both the ED 50 values and the therapeutic indices are given.

Table VI

Connection (example)

EDso value in mg / kg

Therapeutic index

LDso value

EDso value

1

16.0

125.0

3rd

15.0

52.0

4th

42.0

47.6

7

37.5

26.7

13

4.0

75.0

14

8.1

19.8

Trihexyphenidyl

15.0

24.3

In view of the fact that the antiparkinsonian activity of a compound is characterized by the inhibition of nicotine lethality and the tremor caused by tremorin, the superiority of the antiparkinsonian activity of the compounds according to the invention over the comparison substances can be followed on the basis of the results from Tables V and VI .

Antiarrhythmic activity in rats

The antiarrhythmic activity of the compounds according to the invention and of the comparison substances lidocaine and quinidine was tested by influencing the arrhythmia triggered with akonitin in rats according to the modified method by Marmo and co-workers [Arzneimittel.-Forschung, 20, 12 (1970)]. The rats of 160 to 200 g body weight were anesthetized by intraperitoneal injection of 1.2 g / kg ethyl urethane. After that, Akonitin was injected intravenously in a dose of 75 jig / kg. The compounds to be tested were introduced orally 30 minutes before the treatment with Akonitin. The percent inhibitions observed are summarized in Table VII below.

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Table VII

Connection (example)

Can in mg / kg

% Inhibition

3rd

4th

45.5

15

4th

54.2

21st

4th

62.9

Lidocaine

4th

23.4

Quinidine

4th

27.3

It can be seen from Table VII that the compounds according to the invention are superior to the comparison substances with regard to the antiarrhythmic activity.

Antianainous activity in rats

The antianginal activity of the compounds according to the invention was investigated in anesthetized male rats of 180 to 220 g body weight according to Nischultz [Arzneimittel.-Forschung, 5, 680 (1955)]. Experimental coronary insufficiency was caused by the intravenous administration of 4 lU / kg glanduitin - the posterior pituitary extract. The height of the wave T in the ECG was determined before and after the glanduitrin input in the control group and the treated animal groups, and the inhibition promoted by the tested compounds was calculated as a percentage. Prenylamine [3,3-diphenyl-propyl-1-methyl-phenethylamine-lactate] was used as the reference substance. The results obtained are summarized in Table VIII below.

Table VIII

connection

Can in mg / kg

% Inhibition

(Example)

15

2nd

55.4

21st

3rd

83.6

Prenylamine

2nd

41.3

The compounds according to the invention can thus advantageously be used in therapy as active ingredients, in particular with local anesthetic, tranquilo-sedative and / or antidepressant, antiparkinsonian, further antiarrhythmic and antianginal effects.

The compounds can be in the form of drugs. The pharmaceuticals according to the invention contain a therapeutically effective amount of a compound of general formula I or an acid addition salt thereof, optionally together with one or more inert liquid or solid carriers.

The pharmaceuticals according to the invention can have been prepared by methods known per se from the pharmaceutical industry. See e.g. Remington's Pharmaceutical Sciences, 16th Edition, Mack Publishing Company, Easton, USA, 1980.

The medicaments according to the invention can advantageously be in the form of formulations to be administered orally, for example tablets, capsules, dragees, solutions or suspensions, or formulations to be administered parenterally, for example sterile solutions or suspensions.

The solid drugs to be administered orally can be used as carriers, for example, various conventional binders such as gelatin, sorbitol, polyvinylpyrrolidone, etc .; Fillers such as milk sugar, glucose, starch, calcium phosphate, etc .; Auxiliaries such as magnesium stearate, talc, polyethylene glycols, silicon dioxide, etc .; and / or crosslinking agents such as sodium lauryl sulfate, etc.

The liquid drugs can be various suspending agents such as sorbitol, sugar solution, gelatin, carboxymethyl cellulose, etc .; Emulsifiers such as sorbitan monooleate, etc .; Solvents such as oils, oily esters, glycerin, propylene glycol, ethanol, etc .; and / or preservatives such as methyl p-hydroxybenzoate, etc., contain.

In general, the medicament according to the invention contains 0.1 to 95% of active ingredient. The typical daily dose for adults is 0.1 to 20 mg of the compound of general formula I or an acid addition salt thereof.

The invention is illustrated by the following examples.

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example 1

12H-12-K4-MethvlpÌDerazinvfl-acetvll-dibenzord.airi .3.61dioxazocin-dimaleinate

A) A mixture of 30.0 g (0.141 mol) of 12H-12-dibenzo [d, g] [1,3,6] dioxazocin with a melting point of 189 to 191 ° C., 150 cm 3 of anhydrous toluene and 19.5 g (0.173 mol) chloroacetyl chloride is heated under reflux for 2 hours. A further 19.5 g (0.173 mol) of chloroacetyl chloride are added to the reaction mixture, and the mixture is heated under reflux for a further 4 hours. The reaction mixture is cooled to 25 ° C. and poured onto crushed pieces of ice with stirring. The mixture is stirred for one hour, the solid product is filtered, washed with water and recrystallized from isopropanol.

This gives 35.6 g of 12H-12- (2-chloroacetyl) dibenzo [d, g] [1,3,6] dioxazocin with a melting point of 151 to 153 ° C. The yield is 87.3% of theory.

Analysis for C15H12CINO3 (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) of 12H-12- (2-chloroacetyl) dibenzo [d, g] [1,3,6] dioxazocin, 130 cm3 of anhydrous benzene and 27.6 g (0.276 mol ) 4-Methylpiperazine is heated under reflux for 6 hours, then cooled to 25 ° C, and the salt which has separated out is filtered. The organic filtrate is washed with water, dried over anhydrous magnesium sulfate and evaporated. The residue is crystallized from isopropanol and the product is also recrystallized from isopropanol.

9.7 g of 12H-12 - [(4-methylpiperazinyl) acetyl] dibenzo [d, g] [1,3,6] dioxazocin with a melting point of 160 to 162 ° C. are obtained. The yield is 66.4% of theory.

Analysis for C20H23N3O3 (353.425):

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

found: C 68.14%, H 7.02%, N 11.78%.

C) 8.4 g (0.024 mol) of 12H-12 - [(4-methylpiperazinyl) acetyl] dibenzo [d, g] [1,3,6] dioxazocin are dissolved in 100 cm3 of isopropanol and the stirred solution is a solution of 5.6 g (0.048 mol) of maleic acid in 30 cm3 of isopropanol was added at 20 ° C. The reaction mixture is stirred for 2 hours, then cooled to 0 ° C and stirred for an additional hour. The precipitated product is filtered, washed with isopropanol and recrystallized from methanol.

This gives 10.5 g (74.7%) of the title compound with a melting point of 179 to 183 ° C. The yield is 74.7% of theory.

Analysis for C28H31N3O11 (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-iïN-cvclohexvl-N-methvlamino) -acetvll-dibenzofd.aïï1,3.61dioxazocin-maleate

A) A mixture of 13.0 g (0.045 mol) of 12H-12-chloroacetyl-dibenzo [d, g] [1,3,6] dioxazocin, 150 cm3 of anhydrous benzene and 32.2 g (0.28 mol ) N-Cyclohexyl-N-methylamine is heated under reflux for 8 hours. The product is separated off by the method described in Example 1 B) and recrystallized from isopropanol.

13.9 g of 12H-12 - [(N-cyclohexyl-N-methylamino) acetyl] dibenzo [d, g] [1,3,6] dioxazocin with a melting point of 103 to 105 ° C. are obtained. The yield is 84.2% of theory.

Analysis for C22H26N2O3 (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) 12H-12 - [(N-cyclohexyl-N-methylamino) acetyl] dibenzo [d, g] [1,3,6] dioxazocin are mixed with 4.2 g (0.036 mol ) Maleic acid in the manner described in Example 1 C) implemented, and the crude product is recrystallized from isopropanol. This gives 14.9 g of the title compound with a melting point of 148 to 150 ° C. The yield is 88.2% of theory.

Analysis for C26H30N2O7 (482.536):

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

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

Example 3

2-Chloro-12H-12-r2-fisopropvlaminoVacetvll-dibenzord.aïï1.3.61dioxazocin-hydrochloride

A) A mixture of 24.8 g (0.10 mol) of 2-chloro-12H-dibenzo [d, g] [1,3,6] dioxazocin with a melting point of 182 to 184 ° C, 300 cm3 of anhydrous toluene and 23.0 g (0.20 mol) of 2-chloroacetyl chloride

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CH 675 877 A5

Heated under reflux for 4 hours, then cooled to 25 ° C. The solvent is removed under reduced pressure and the residue is treated with benzene to promote crystallization. The product is recrystallized from isopropanol.

This gives 23.1 g of 2-chloro-12H-12- (chloroacetyl) dibenzo [d, g] [1,3,6] dioxazocin with a melting point of 149 to 151 ° C. The yield is 71.3% of theory.

Analysis for C15H11GI2NO3 (324.2):

calculated: C 55.57%, H 3.42%, Cl 21, 7%, 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 2-chloro-12H-12- (chloroacetyl) dibenzo [d, g] [1,3,6] dioxazocin, 180 cm3 of anhydrous benzene and 17.7 g ( 0.30 mol) of isopropylamine is heated under reflux for 4 hours. The organic solvent is removed under reduced pressure, 100 cm 3 of diethyl ether and 80 cm 3 of water are added to the residue, and the mixture is stirred for 30 minutes. The organic phase is separated off, dried over anhydrous magnesium sulfate, cooled to 0 ° C. and treated with diethyl ether, which has been saturated with hydrogen chloride, with stirring until the pH has reached 4. The crystal mass is filtered, suspended in diethyl ether and filtered again. The process is repeated two more times and finally the product is recrystallized from ethanol.

13.0 g of the title compound are obtained in the form of white crystals with a melting point of 235 to 240 ° C. The yield is 74.0% of theory.

Analysis for C18H20CI2N2O3 (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%, C1 "9.08%.

Example 4

2-chloro-12H-12-IY4-methvlpiperazinvn-acetvn-dibenzord.aïï1.3.61dioxazocin-dimaleinate

A) A mixture of 49.0 g (0.129 mol) of 2-chloro-12H-12- (chloroacetyl) dibenzo [d, g] [1,3,6] dioxazocin, 80.0 g (0.80 mol) 4-Methylpiperazine and 410 cm3 of anhydrous benzene are heated under reflux for 4 hours. The organic solvent and excess 4-methylpiperazine are removed under reduced pressure, 150 cm 3 of benzene and 100 cm 3 of water are added to the residue, and the mixture is stirred for 30 minutes. The organic phase is separated off and washed three times with 80 cm 3 of water each. A solution of 45.0 g (0.30 mol) of tartaric acid in 150 cm 3 of water is added to the organic solution, the mixture is stirred for one hour and the phases are separated. 150 cm 3 of benzene are added to the aqueous phase, the mixture is stirred and treated with 25% aqueous ammonium hydroxide solution until a pH of 9 to 10 is reached. The mixture is stirred for an additional hour, then the organic phase is separated, dried over anhydrous magnesium sulfate and the solvent is removed under reduced pressure. The residue is stirred with benzene to promote crystallization, the crystal mass is filtered, suspended in benzene and filtered again. The crude product is recrystallized from isopropanol.

This gives 38.0 g of 2-chloro-12H-12 - [(4-methylpiperazinyl) acetyl] dibenzo [d, g] [1,3,6] dioxazocin with a melting point of 124 to 127 ° C. The yield is 76.0% of theory.

Analysis for C20H22CIN3O3 (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 2-chloro-12H-12 - [(4-methylpiperazinyl) acetyl] dibenzo [d, g] [1,3,6] dioxazocin are mixed with 20.4 g (0.176 Mol) maleic acid in the manner described in Example 1 C) implemented. The salt is recrystallized from methanol. This gives 44.2 g of the title compound with a melting point of 188 to 190 ° C. The yield is 81% of theory.

Analysis for C28H30CIN3O11 (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

2-chloro-12H-12-r (N-cvclohexvl-N-methvlaminoVacetvl1-dibenzord.qïï1.3.61dioxazocin-maleate

A) A mixture of 35.0 g (0.108 mol) of 2-chloro-12H-12- (chloroacetyl) dibenzo [d, g] [1,3,6] dioxazocin, 350 cm3 of anhydrous benzene and 2 x 76 , 9 g (2 x 0.678 mol) of N-cyclohexyl-N-methylamine is heated under reflux for a total of 12 hours. The product is separated in the manner described in Example 4 A), crystallized from extraction gasoline and recrystallized from the same solvent.

32.1 g (79.8%) of 2-chloro-12H-12 - [(N-cyclohexyl-N-methylamino) -acetylj-dibenzo [d, g] [1,3,6] -dioxazocin with a melting point obtained from 93 to 95 ° C. The yield is 79.8% of theory.

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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 2-chloro-12H-12 - [(N-cyclohexyl-N-methylamino) -acetyl] -dibenzo [d, g] [1,3,6] di-oxazocin are added with 8.7 g (0.075 mol) of maleic acid in the manner described in Example 1 C) implemented. The crude product is recrystallized from methanol. This gives 34.8 g of the title compound with a melting point of 191 to 193 ° C. The yield is 89.7% of theory.

Analysis for C26H29CIN2O7 (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

2-chloro-12H-12- (diâthvlamino-acetvn-dibenzo-fd.aïï1.3.61dioxazocin-hydrochloride

A) A mixture of 32.4 g (0.10 mol) of 2-chloro-12H-12- (chloroacetyl) dibenzo [d, g] [1,3,6] dioxazocin, 2 x 36.5 g (2nd x 0.50 mol) of diethylamine and 250 cm3 of anhydrous benzene is heated under reflux for a total of 6 hours. The product is secreted in the manner described in Example 4 A). The yellow-brown, viscous liquid obtained is crystallized from n-hexane and the crystal mass is recrystallized from the same solvent.

This gives 28.5 g of 2-chloro-12H-12- (diethylaminoacetyl) dibenzo [d, g] [1,3,6] dioxazocin with a melting point of 75 to 80 ° C. The yield is 78.9% of theory.

Analysis for C19H21CIN2O3 (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 2-chloro-12H-12- (diethylaminoacetyl) dibenzo [d, g] [1,3,6] dioxazocin are treated with isopropanol containing 20% hydrogen chloride. The acid addition salt formed is recrystallized from isopropanol. This gives 17.5 g of the title compound with a melting point of 198 to 201 ° C. The yield is 82.9% of theory.

Analysis for C19H22CI2N2O3 (397,302):

calculated: C 57.44%, H 5.58%, Cl 17.85%, N 7.05%, CI "8.92%;

found: C 57.56%, H 5.84%, Cl 17.50%, N 7.06%, Ci "8.88%.

Example 7

(± V2-chloro-12H-12-iï2-methvlpiperidinvlVacetvH-dibenzord.aïï1.3.61dioxazocin-hydrochloride

A) A mixture of 32.4 g (0.10 mol) of 2-chloro-12H-12- (chloroacetyl) dibenzo [d, g] [1,3,6] dioxazocin, 39.7 g (0.40 Mol) 2-methylpiperidine and 250 cm3 of anhydrous benzene is heated under reflux for 4 hours. The reaction product is separated in the manner described in Example 4 A), crystallized from isopropanol and recrystallized from the same solvent. Thus 30.8 g (±) -2-chloro-12H-12 - [(2-methylpiperidinyl) acetyl] dibenzo [d, g] [1,3,6] dioxazocin with a melting point of 90 to 92 ° C received. The yield is 79.6% of theory.

Analysis for C21H23CIN2O3 (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 (±) -2-chloro-12H-12 - [(2-methylpiperidinyl) acetyl] dibenzo [d, gj [1,3,6] dioxazocin are added with diethyl ether , which was saturated with hydrogen chloride, treated in the manner described in Example 3 B). This gives 10.3 g of the title compound with a melting point of 146 to 154 ° C (with decomposition). The yield is 98.1% of theory.

Analysis for C21H24CI2N2O3 (423,342):

calculated: C 59.58%, H 5.71%, Cl 16.75%, N 6.62%, CI "8.38%;

found: C 58.45%, H 6.11%, Cl 16.92%, N 6.65%, CI "8.47%.

Example 8

2-chloro-12H-12- (pvrrolidinvl-acetvfl-dibenzo-rd.aïï1.3.6ldioxazocin-maleate

A) A mixture of 22.0 g (0.068 mol) of 2-chloro-12H-12- (chloroacetyl) dibenzo [d, g] [1,3,6] dioxazocin, 24.2 g pyrrolidine and 250 cm3 of anhydrous benzene is heated under reflux for 3 hours. The reaction product is separated in the manner described in Example 4 A), crystallized from extraction gasoline and recrystallized from the same solvent.

19.8 g of 2-chloro-12H-12- (pyrrolidinyl-acetyl) -dibenzo [d, g] [1,3,6] dioxazocin with a melting point of 80 to 83 ° C. are obtained. The yield is 81.1% of theory.

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Analysis for CJ9H19CIN2O3 (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 2-chloro-12H-12- (pyrrolidinyl-acetyl) -dibenzo [d, g] [1,3,6] dioxazocin are mixed with 4.6 g (0.04 mol) Maleic acid implemented in the manner described in Example 1 C). The acid addition salt formed is recrystallized from ethanol. 15.8 g of the title compound with a melting point of 187 to 192 ° C are thus obtained. The yield is 85.5% of theory.

Analysis for C23H23CIN2O7 (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

2-chloro-12H-12- (morpholinvl-acetvn-dibenzo-rd.aïï1.3.61dioxazocin-maleate

A) A mixture of 25.0 g (0.077 mol) of 2-chloro-12H-12- (chloroacetyl) dibenzo [d, g] [1,3,6] dioxazocin, 30.4 g (0.35 mol) -Morpholine and 250 cm3 of anhydrous benzene are heated under reflux for 3 hours. The reaction mixture is separated in the manner described in Example 4 A), then crystallized from hexane and recrystallized from isopropanol.

This gives 24.9 g of 2-chloro-12H-12- (morpholinyl-acetyl) -dibenzo [d, g] [1,3,6] dioxazocin with a melting point of 123 to 125 ° C. The yield is 86.2% of theory.

Analysis for C19H19CIN2O4 (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%.

B) 20.0 g (0.053 mol) of 2-chloro-12H-12- (morpholinyl-acetyl) -dibenzo [d, g] [1,3,6] dioxazocin are mixed with 6.2 g (0.053 mol) of maleic acid in treated in the manner described in Example 1 C). The malate salt formed is recrystallized from ethanol. This gives 20.2 g of the title compound with a melting point of 197 to 199 ° C. The yield is 77.7% of theory.

Analysis for C23H23CIN2O8 (490.898):

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

2-Chloro-12H-12-r2- (cvclopropvlamino ^ -acetvll-dibenzofd.aïï1.3.61dioxazocin-maleate

A) A mixture of 25.0 g (0.077 mol) of 2-chloro-12H-12- (chloroacetyl) dibenzo [d, g] [1,3,6] dioxazocin, 2 x 8.6 g (2 x 0 , 15 mol) of cyclopropylamine and 200 cm3 of anhydrous benzene are heated under reflux for 11 hours. The reaction product is separated in the manner described in Example 4 A), then crystallized from petroleum ether and recrystallized from the same solvent.

Thus 18.3 g of 2-chloro-12H-12- [2- (cyclopropylamino, -acetyl] -dibenzo [d, g] [1,3,6] dioxazocin with a melting point of 80 to 85 ° C. are obtained Yield is 69.1% of theory.

Analysis for C18H17CIN2O3 (344,800):

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 2-chloro-12H-12- [2- (cyclopropylamino) acetyl] dibenzo [d, g] [1,3,6] dioxazocin are mixed with 3.9 g (0.034 mol ) Maleic acid treated in the manner described in Example 1 C). The maleate salt formed is recrystallized from ethanol. This gives 11.9 g of the title compound with a melting point of 176 to 181 ° C. The yield is 78.3% of theory.

Analysis for C22H21CIN2O7 (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

2-chloro-12H-12-fdiâthvl-carbamovh-dibenzo-rd.aïï1.3.61dioxazocin

A 50% dispersion of 4.8 g (0.10 mol) of sodium hydride in mineral oil is added to 100 cm3 of dimethylformamide at 25 ° C. with stirring. 24.8 g (0.10 mol) of 2-chloro-12H-diben-zo [d, g] [1,3,6] dioxazocin are added to the mixture at a constant temperature of 25 ° C. The reaction mixture is heated to 40 ° C, stirred at this temperature for one hour, then cooled to 20 ° C. 20.3 g (0.15 mol) of N, N-diethyl-carbamoyl chloride are added to the reaction mixture and the mixture is stirred at 40 ° C. for 16 hours. 120 cm3 of water are added to the mixture cooled to 0 ° C. The viscous oil formed is separated and dissolved in 150 cm3 of benzene. The organic solution is with each

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Washed 80 cm3 water three times, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue is treated with extraction gasoline to promote crystallization.

The crude product is recrystallized from isopropanol. This gives 22.9 g of the title compound with a melting point of 93 to 95 ° C. The yield is 66.0% of theory.

Analysis for C18H19CIN2O3 (346,823):

calculated: C 62.34%, H 5.52%, Ci 10.22%, N 8.08%;

found: C 62.83%, H 5.45%, Ci 10.48%, N 8.00%

Example 12

2-Chloro-12H-12-r3-f4-methylene piperazinv0-propionvll-dibenzo [d.aïï1.3.61dioxazocin-dimaleinate

A) A mixture of 24.8 g (0.10 mol) of 2-chloro-12H-dibenzo [d, g] [1,3,6] dioxazocin, 150 cm3 of anhydrous benzene and 25.4 g (0.20 mol ) 3-Chloropropionyl chloride is heated under reflux for 5 hours. The solvent is removed under reduced pressure, the residue is dissolved in 150 cm 3 of benzene, and the solution obtained is poured onto crushed ice. The mixture is stirred for one hour, the organic phase is separated off, each time with 100 cm 3 of 5% aqueous sodium bicarbonate solution four times, then washed with 100 cm 3 water once, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue is crystallized from isopropanol and recrystallized from the same solvent.

This gives 26.7 g of 2-chloro-12H-12- (3-chloropropionyl) dibenzo [d, g] [1,3,6] dioxazocin with a melting point of 76 to 81 ° C. The yield is 79.0% of theory.

Analysis for C16H13CI2NO3 (338,193):

calculated: C 56.82%, H 3.87%, Cl 20.97%, N 4.14%;

found: C 56.41%, H 3.30%, Ci 21.35%, N 4.04%.

B) A mixture of 33.8 g (0.10 mol) of 2-chloro-12H-12- (3-chloropropionyl) dibenzo [d, g] [1,3,6] di-oxazocin, 60.0 g (0.60 mol) of 4-methylpiperazine and 250 cm 3 of anhydrous benzene is heated under reflux for 5 hours. The reaction product is secreted in the manner described in Example 4 A). So 30.0 g of crude 2-chloro-12H-12- [3- (4-methylpiperazinyl) propionyl] dibenzo [d, g] [1,3,6] di-oxazocin in the form of a brown, viscous Get liquid.

C) 30.0 g of crude 2-chloro-12H-12- [3- (4-methylpiperazinyl) propionyl] dibenzo [d, g] [1,3,6] dioxazocin is mixed with 18.6 g (0, 16 mol) of maleic acid in the manner described in Example 1 C) implemented. The acid addition salt formed is recrystallized from methanoi. This gives 24.6 g of the title compound with a melting point of 185 to 187 ° C. The yield is 67.0% of theory.

Analysis for C29H32CIN3O11 (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 13

2-Chloro-12H-12-r3-fdiâthvlaminoi-propionvn-dibenzord.aïï1.3.61dioxazocin-hydrochloride

A) A mixture of 2-chloro-12H-12- (3-chloropropionyl) dibenzo [d, g] [1,3,6] dioxazocin, 2 x 29.2 g (2 x 0.40 mol) Diethylamine and 250 cm3 of anhydrous benzene are heated under reflux for a total of 6 hours. The reaction product is prepared and secreted in the manner described in Example 4 A). The crude product is crystallized from n-hexane and recrystallized from the same solvent.

This gives 30.9 g of 2-chloro-12H-12- [3- (diethylamino) propionyl] dibenzo [d, g] [1,3,6] dioxazocin with a melting point of 68 to 72 ° C. The yield is 82.5% of theory.

Analysis for C20H23CIN2O3 (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 2-chloro-12H-12- [3- (diethylamino) propionyl] dibenzo [d, g] [1,3,6] dioxazocin are dissolved in 70 cm3 of isopropanol . Isopropanol containing 20% hydrogen chloride is added dropwise to the stirred and cooled to 0 ° C. solution until a pH of 3 is reached. The mixture is stirred for one hour, the crystals are filtered and recrystallized from isopropanol.

This gives 17.9 g of the title compound with a melting point of 176 to 182 ° C. The yield is 81.0% of theory.

Analysis for C20H24CI2N2O3 (441,329):

calculated: C 58.40%, H 5.88%, Cl 17.24%, N 6.81%, CI "8.62%;

found: C 58.12%, H 6.07%, Cl 17.12%, N 6.68%, CI "8.66%.

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Example 14

2-Chloro-12H-12-r3-flsopropvlaminoi-propionvll-dibenzord.aïï1.3.61dioxazocin-hydrochloride

A mixture of 30.0 g (0.089 mol) of 2-chloro-12H-12- (3-chloropropionyl) dibenzo [d, g] [1,3,6] dioxazo-cin, 2 x 21.0 9 (2 x 0.356 mol) of isopropylamine and 250 cm3 of anhydrous benzene is heated under reflux for a total of 6 hours. The reaction product is prepared and separated in the manner described in Example 4 A). This gives 28.5 g of 2-chloro-12H-12- [3- (isopropylamino) propionyl] -diben-zo [d, g] [1,3,6] dioxazocin in the form of a viscous liquid.

The base obtained is converted into the hydrochloride in the manner described in Example 3 B). After recrystallization from ethanol, 25.8 g of the title compound with a melting point of 240 to 243 ° C. are obtained. The yield is 73.0% of theory.

Analysis for G19H22CI2N2O3 (397,301):

calculated: C 57.44%, H 5.58%, Cl 17.86%, N 7.05%, CI-8.93%;

found: C 57.66%, H 5.45%, Cl 17.86%, N 6.98%, Cl "8.92%.

Example 15

2-chloro-12H-12- (3-pvrrolidinvl-propionvl) -dibenzo-rd. In .3.61dioxazocin-maleate

A) A mixture of 25.0 g (0.074 mol) of 2-chloro-12H-12- (3-chloropropionyl) dibenzo [d, g] [1,3,6] dioxa-zocin, 21.3 g (0.30 mol) pyrrolidine and 250 cm3 of anhydrous benzene is heated under reflux for 3 hours. The reaction product is separated in the manner described in Example 4 A), crystallized from extraction gasoline and recrystallized from the same solvent.

This gives 21.8 g of 2-chloro-12H-12- (3-pyrrolidinyI-propionyl) dibenzo [d, g] [1,3,6] dioxazocin with a melting point of 115 to 118 ° C. The yield is 79.0% of theory.

Analysis for C20H21CIN2O3 (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 2-chloro-12H-12- (3-pyrrolidinyl-propionyl) dibenzo [d, g] [1,3,6] dioxazocin are mixed with 6.4 g (0.055 mol) Maleic acid implemented in the manner described in Example 1 C). The acid addition salt formed is recrystallized from ethanol. This gives 22.7 g of the title compound with a melting point of 161 to 164 ° C. The yield is 85.9% of theory.

Analysis for C24H25CIN2O7 (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 16

2-Chloro-12H-12-r3- (cvclopropvl-aminoVpropionvl1-dibenzord.aïï1.3.61dioxazocin-hydrochloride

A mixture of 25.0 g (0.074 mol) of 2-chloro-12H-12- (3-chloropropionyl) dibenzo [d, g] [1,3,6] di-oxazocin, 2 x 8.7 g (2 x 0.16 mol) of cyclopropylamine and 250 cm3 of anhydrous benzene are heated under reflux for a total of 15 hours. The reaction product is prepared and secreted in the manner described in Example 4 A). This gives 21.7 g of 2-chloro-12H-12- [3- (cyclopropylamino) propionyl] dibenzo [d, g] [1,3,6] dioxazocin in the form of a viscous liquid.

The base obtained is converted into the hydrochloride in the manner described in Example 3 B). After recrystallization from ethanol, 18.7 g of the title compound with a melting point of 196 to 204 ° C. are obtained. The yield is 64.0% of theory.

Analysis for C19H20CI2N2O3 (395,288):

calculated: C 57.73%, H 5.10%, Cl 17.94%, N 7.09%, Ch8.97%;

found: C 58.34%, H 5.38%, Cl 18.18%, N 7.10%, Ch8.89%.

Example 17

2-chloro-12H-12-f3-morpholinvl-propionvh-dibenzo-fd.aïï1.3.617dioxazocin-hydrochloride

A) A mixture of 25.0 g (0.074 mol) of 2-chloro-12H-12- (3-chloropropionyi) dibenzo [d, g] [1,3,6] dioxa-zocin, 30.4 g (0.35 mol) of morpholine and 250 cm3 of anhydrous benzene is heated under reflux for 5 hours. The reaction product is separated in the manner described in Example 4 A) and crystallized from n-hexane. The crude product is recrystallized from isopropanol.

This gives 23.9 g of 2-chloro-12H-12- (3-morpholinyl-propionyl) -dibenzo [d, g] [1,3,6] dioxazocin with a melting point of 122 to 125 ° C. The yield is 83.0% of theory.

Analysis for C20H21CIN2O4 (388.854):

calculated: C 61.78%, H 5.44%, CI 9.12%, N 7.20%;

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found: C 60.98%, H 5.93%, Cl 9.21%, N 7.03%.

B) 15.0 g (0.0386 mol) of 2-chloro-12H-12- (3-morpholinyl-propionyl) -dibenzo [d, g] [1,3,6] dioxazocin is used in the example 3 B) described described in the corresponding hydrochloride. After recrystallization from ethanol, 13.5 g of the title compound with a melting point of 225 to 229 ° C. are obtained. The yield is 82.3% of theory.

Analysis for C20H22CI2N2O4 (425,315):

calculated: C 56.48%, H 5.21%, Cl 16.67%, N 6.59%, Ch8.34%;

found: C 56.92%, H 5.35%, Cl 16.77%, N 6.55%, Ch8.36%.

Example 18

/^)-2-Chlor-12H-12-r2-f4-methvlpiperazinvl)-propionvn-dibenzord.a1f1.3.6ldioxazocin-dimaleinat

A) A mixture of 123.9 g (0.50 mol) of 2-chloro-12H-dibenzo [d, g] [1,3,6] dioxazocin, 750 cm3 of anhydrous toluene and 127.0 g (1.00 mol ) 2-Chloropropionyl chloride is heated under reflux for 3 hours. The reaction product is separated in the manner described in Example 3A) and recrystallized from isopropanol.

This gives 131.1 g of (+) - 2-chloro-12H-12- (2-chloropropionyl) dibenzo [d, g] [1,3,6] dioxazocin with a melting point of 152 to 155 ° C. The yield is 77.5% of theory.

Analysis for C16H13CI2NO3 (338.201):

calculated: C 56.82%, H 3.87%, Ci 20.97%, H 4.14%;

found: C 56.32%, H 3.99%, Cl 21.20%, H 4.10%.

B) A mixture of 20.0 g (0.059 mol) of (±) -2-chloro-12H-12- (2-chloropropionyl) dibenzo [d, g] [1,3,6] di-oxazocin, 2 x 25.1 g (2 x 0.25 mol) of 4-methylpiperazine and 200 cm3 of anhydrous benzene are heated under reflux for a total of 11 hours. The reaction mixture is prepared and secreted in the manner described in Example 4 A). The crude product is treated with extraction gasoline to obtain crystals, and the crystals are recrystallized from isopropanol. 18.8 g (±) -2-chloro-12H-12- [2- (4-methylpiperazinyl) propionyl] dibenzo [d, g] [1,3,6] dioxazocin with a melting point of 133 to Get 136 ° C. The yield is 79.2% of theory.

Analysis for C21H24CIN3O3 (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) (±) -2-chloro-12H-12- [2- (4-methylpiperazinyl) propionyl] dibenzo [d, g] [1,3,6] di Oxazocin are reacted with 7.6 g (0.066 mol) of maleic acid in the manner described in Example 1C). The corresponding acid addition salt formed is recrystallized from ethanol. This gives 17.1 g of the title compound with a melting point of 177 to 182 ° C. The yield is 84.2% of theory.

Analysis for C29H32CIN3O11 (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 19

(± ì-2-chloro-12H-12- (2-pvrrolidinvl-propionv0-dibenzord.aïï1.3.61dioxazocin-hydrochloride

A) A mixture of 28.0 g (0.083 mol) of (±) -2-chloro-12H-12- (2-chloropropionyl) -diben-zo [d, g] [1,3,6] dioxazocin, 21, 3 g (0.30 mol) of pyrrolidine and 250 cm 3 of anhydrous benzene are heated under reflux for 10 hours. The reaction product is secreted in the manner described in Example 4 A), then treated with extraction gasoline to promote crystallization. The crystals are recrystallized from the same solvent.

So 24.9 g (±) -2-chloro-12H-12- (2-pyrrolidinyl-propionyl) -dibenzo [d, g] [1-, 3.6] dioxazocin with a melting point of 98 to 102 ° C. receive. The yield is 80.3% of theory.

Analysis for C20H21CIN2O3 (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 (±) -2-chloro-12H-12- (2-pyrrolidinyl-propionyl) dibenzo [d, g] [1,3,6] dioxazocin are described in Example 3 B) described manner converted into the corresponding hydrochloride, which is recrystallized from isopropanol. This gives 14.2 g of the title compound with a melting point of 223 to 225 ° C. The yield is 80.7% of theory.

Analysis for C20H22CI2N2O3 (409.315):

calculated: C 58.69%, H 5.42%, Cl 17.32%, N 6.84%, Cl "8.66%;

found: C59.03%, H 5.88%, Cl 16.93%, N 6.91%, Cl "8.47%.

17th

5

10th

15

20th

25th

30th

35

40

45

50

55

60

65

CH 675 877 A5

Example 20

f + l-2-chloro-12H-12- (2-isopropvlamino-propionvn-dibenzord.aïï1.3.61dioxazocin-hydrochloride

A) A mixture of 23.7 g (0.070 mol) of (±) -2-chloro-12H-12- (2-chloropropionyl) dibenzo [d, g] [1,3,6] di-oxazocin, 17, 7 g (0.21 mol) of isopropylamine and 250 cm3 of anhydrous benzene are heated under reflux for 6 hours. The reaction product is separated in the manner described in Example 4 A). The crude product is treated with extraction gasoline, and the crystals which have separated out are recrystallized from the same solvent. 18.2 g of (+) - 2-chloro-12H-12- (2-isopropylamino-propionyl) dibenzo [d, g] [1,3,6] dioxazocin with a melting point of 102 to 105 ° C received. The yield is 72.1% of theory.

Analysis for G19H21CIN2O3 (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) (±) -2-chloro-12H-12- (2-isopropylamino-propionyl) -dibenzo [d, g] [1,3,6] dioxazocin are in the in Example 3 B) described in the corresponding hydrochloride, which is recrystallized from isopropanol. This gives 9.6 g of the title compound with a melting point of 224 to 227 ° C. The yield is 87.3% of theory.

Analysis for C19H22CI2N2O3 (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 21

tri-2-chloro-12H-12-r2-methvl-3- (4-methvlpiperazinvn-propionvn-dibenzord.aïï1.3.61dioxazocin-dima-linate

A) A mixture of 26.1 g (0.11 mol) of 2-chloro-12H-dibenzo [d, g] [1,3,6] dioxazocin, 300 cm3 of anhydrous toluene and 39.0 g (0.21 mol 3-Bromo-2-methyl-propionyl chloride is heated under reflux for 8 hours, then cooled to 25 ° C. and poured onto crushed ice with stirring. The mixture is stirred for 2 hours, the organic phase is separated off, washed with 100 cm 3 of 5% aqueous sodium bicarbonate solution three times and 100 cm 3 water once, and dried over anhydrous magnesium sulfate. The solvent is removed under reduced pressure, the residue is treated with isopropanol, and the crystals formed are recrystallized from the same solvent. So 33.2 g (±) -2-chloro-12H-12- (3-bromo-2-methylpropionyl) -dibenzo [d, g] [1,3,6] dioxazocin with a melting point of 115 to 119 ° C received. The yield is 76.1% of theory.

Analysis for Ci7Hi5BrCIN03 (396,688):

calculated: C 51.47%, H 3.81%, Br20.15%, CI 8.94%, N 3.53%;

found: C 51.35%, H 3.98%, Br 20.20%, CI 8.90%, N 3.52%.

B) A mixture of 28.6 g (0.072 mol) of (±) -2-chloro-12H-12- (3-bromo-2-methylpropionyl) -diben-zo [d, g] [1,3,6] dioxazocin, 2 x 30.0 g (2 x 0.295 mol) of 4-methylpiperazine and 250 cm3 of anhydrous benzene are heated under reflux for a total of 7 hours. The reaction product is prepared and secreted in the manner described in Example 4 A). The crude product is treated with extraction gasoline and the crystals formed are recrystallized from n-hexane.

Thus 25.3 g (±) -2-chloro-12H-12- [2-methyl-3- (4-methylpiperazinyl) propionyl] dibenzo [d, gj- [1,3,6] dioxazocin with a Melting point of 128 to 131 ° C obtained. The yield is 84.6% of theory.

Analysis for 22H26CIN3O3 (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) (±) -2-chloro-12- [2-methyl-3- (4-methylpiperazinyl) propionyl] dibenzo [d, g] [1,3,6] - dioxazocin are reacted with 5.2 g (0.045 mol) of maleic acid in the manner described in Example 1C). The acid addition salt formed is recrystallized from acetonitrile. 11.8 g of the title compound with a melting point of 152 ° to 157 ° C. are thus obtained. The yield is 82.5% of theory.

Analysis for C30H34CIN3O11 (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 (12)

Claims 1. Aminoalkanoyl-dibenzo [d, g] [1,3,6] dioxazocin derivatives of the general formula 18th 5 10th 15 20th 25th 30th 35 40 45 50 55 60 65 CH 675 877 A5 X R2 CD / wherein X represents hydrogen or a halogen atom, A represents a chemical bond or a straight-chain or branched alkylene group with 1 to 10 carbon atoms, R 1 and R 2 independently represent hydrogen, an alkyl group with 1 to 4 carbon atoms or a cycloalkyl group with 3 to 6 carbon atoms, or R 1 and R 2 with the nitrogen atom to which they are attached, and optionally with one or more further nitrogen, oxygen and / or sulfur atoms, a 5- to 6-membered heterocyclic group which is optionally substituted by an alkyl group having 1 to 4 carbon atoms form as well as their pharmaceutically acceptable acid addition salts. 2. Aminoalkanoyl-dibenzo [d, g] [1,3,6] dioxazocine derivatives according to claim 1, characterized in that the alkylene group which can represent A is one having 1 to 3 carbon atoms. 3. Aminoalkanoyl-dibenzo [d, g] [1,3,6] dioxazocine derivatives according to claim 1, characterized in that the alkyl group which can independently represent R 1 and R 2 is one having 1 to 3 carbon atoms. 4. Aminoalkanoyl-dibenzo [d, g] [1,3,6] dioxazocine derivatives according to claim 1, characterized in that the cycloalkyl group, which can represent R 1 and R 2 independently, is a cyclopropyl or cyclo-hexyl group. 5. Aminoalkanoyl-dibenzo [d, g] [1,3,6] dioxazocine derivatives according to Claim 1, characterized in that the heterocyclic group which is responsible for R 1 and R 2 with the nitrogen atom to which they are bonded and optionally with another Can be nitrogen atom or oxygen atom, is a 4-methylpiperazinyl group, a 2-methylpiperidinyl group, a pyrrolidinyl group or a morpholinyl group. 6. 12H-12 - [(4-methylpiperazinyl) acetyl] dibenzo [d, g] [1,3,6] dioxazocin and the pharmaceutically acceptable acid addition salts thereof as dioxazocin derivatives according to claim 1. 7. 12H-2-chloro-12 - [(4-methylpiperazinyl) acety!] - dibenzo [d, g] [1,3,6] dioxazocin and the pharmaceutically acceptable acid addition salts thereof as dioxazocin derivatives according to claim 1. 8. (±) -12H-2-chloro-12 - [(2-methylpiperidinyl) acetyl] dibenzo [d, g] [1,3,6] dioxazocin and the pharmaceutically acceptable acid addition salts thereof as dioxazocine derivatives according to claim 1. , 9. 12H-2-chloro-12-diethylcarbamoyl-dibenzo [d, g] [1,3,6] dioxazocin and the pharmaceutically acceptable acid addition salts thereof as dioxazocin derivatives according to claim 1. 10. 12H-2-chloro-12- [3- (diethylamino) propionyl] dibenzo [d, g] [1,3,6] dioxazocin and the pharmaceutically acceptable acid addition salts thereof as dioxazocin derivatives according to claim 1. 11. Process for the preparation of aminoalkanoyl-dibenzo [d, g] [1,3,6] dioxazocin derivatives of the general formula 19th 5 10th 15 20th 25th 30th 35 40 45 50 55 60 65 CH 675 877 A5 wherein X represents hydrogen or a halogen atom, A represents a chemical bond or a straight-chain or branched alkylene group with 1 to 10 carbon atoms, R 1 and R 2 independently represent hydrogen, an alkyl group with 1 to 4 carbon atoms or a cycloalkyl group with 3 to 6 carbon atoms, or R 1 and R 2 with the nitrogen atom to which they are attached and optionally with one or more further nitrogen, oxygen and / or sulfur atoms form a 5- to 6-membered heterocyclic group which is optionally substituted by an alkyl group having 1 to 4 carbon atoms , and the pharmaceutically acceptable acid addition salts thereof, characterized in that a dibenzo [d, g] [1,3,6] dioxazocin of the general formula in which A has the above meaning, shark and shark 'each independently represent a halogen atom, and the resulting alkanoyidibenzo [d, g] [1,3,6] dioxazocin of the general formula rh in which X has the above meaning, with a compound of the general formula Ha! —C — A — Hai1 II 0 20th 5 10th 15 20th 25th 30th 35 40 45 50 55 60 65 CH 675 877 A5 (IV), wherein X, A and Hai 'are as above, with an amine of the general formula HN (VIII), wherein R 1 and R 2 have the above meaning, and if desired, the dioxazocin derivative obtained is converted into acid addition salts, or the dioxazocin derivative is released from the acid addition salt obtained. 12. Medicament, characterized by a content of a compound according to one of claims 1 to 10 as an active ingredient. 21st