HU198194B - Process for production of new derivatives of dioxazocin and medical compositions containing them - Google Patents

Description

The present invention relates to novel aminoalkanoyloxazocine derivatives and to pharmaceutical compositions containing them as active ingredients. The novel compounds have pharmacologically valuable effects such as local anesthetic, tranquillo-sedative and / or antidepressant, antiparkinone, as well as anliarhythmic and antianginal effects.

No. 174,126. U.S. Pat. No. 5,123,125 discloses 12-aminoalkyl-12H-dibenzene, g] [1,3,6] dioxazocine derivatives which are topical anesthetics and antiparkinsons.

It has been found that the pharmacological activity of the known compounds is favorably altered when the aminoalkyl group is substituted for the aminoalkyl group attached to the nitrogen atom of the dibenzo [d, g] [1,3,6] dioxazocine ring system. is in the molecule.

The present invention provides novel aminoalkanoyloxazocine derivatives of formula (I) and pharmaceutically acceptable acid addition salts thereof, wherein:

X is hydrogen or halogen,

A is a bond or a linear or branched alkylene group having 1 to 5 carbon atoms,

R ¹ and R ² each independently represent hydrogen, C 1-4 alkyl or C 3-6 cycloalkyl, or R ¹ and R ^{2 together with} the adjacent nitrogen atom and optionally another nitrogen or oxygen atom. It forms a 5- or 6-membered saturated heterocyclic group optionally substituted with C 1-4 alkyl.

Halogen means fluorine, chlorine, bromine and iodine, preferably chlorine and bromine.

In the case where A is a bond, the group -N (R 1) R ² is directly attached to the nitrogen of the ring system. When A 1 is C 1 -C 5 alkylene, it may be straight-chain or optionally branched, it may contain more than one branch.

When R ¹ and R ² together with the adjacent nitrogen atom form a heterocyclic group, the heterocyclic group is preferably piperidinyl, piperazinyl or morpholinyl, which may be optionally substituted. The substituent is a C 1 -C 4 alkyl group, preferably a methyl group.

The compounds of formula (I) may be formulated with pharmaceutically acceptable inorganic or organic acids such as hydrochloric acid, hydrogenboromide, sulfuric acid, acetic acid, fumaric acid, lactic acid, maleic acid and the like. The invention also relates to the preparation of acid addition salts thereof.

Depending on the meaning of A, some of the compounds of formula I may contain a chiral carbon atom, so that optical isomerism is possible with these compounds. The invention also relates to the preparation of each optically active antipode or mixture thereof.

The novel compounds of formula (ti) and their pharmaceutically acceptable acid addition salts are prepared by:

a) Acylating a dioxazocine of formula II wherein X is as defined above with a compound of formula II wherein A is as defined above, Hal and Hal 'are independently halogen, and the resulting alkanoyl of formula IV is obtained. -dioxazocin, wherein X, A and Hal 'are as defined above, with an amine of formula VIII wherein R ¹ and R ² are as defined above; or b) acylating a dioxazocine of formula (II) wherein X is as defined above with a compound of formula (V) wherein A, R ¹ and R ² are as defined above, i, Hal is halogen;

and optionally converting the resulting compound of formula (I) to a pharmaceutically acceptable inorganic or organic acid salt, or liberating the base of formula (I) from a resulting acid addition salt.

The starting dioxazocin (11) is disclosed in U.S. Pat. can be prepared in a manner known per se.

Reagents of the formulas (111), (V) and (VIII) are known compounds which are generally commercially available or may be prepared by organic chemistry techniques known to those skilled in the art.

In the process (a) of the present invention, the acylation of the compound of formula (II) is carried out in apolar or dipolar aprotic solvents, preferably benzene, toluene, xylene or dimethylformamide, in the presence or absence of an acid acceptor. The acylating agent (III) is used in an equivalent amount or excess relative to the dioxazocin (11).

Preferably, the dioxazocin of formula II is acylated in toluene, generally at a temperature between 60 ° C and 110 ° C, with a 2 to 3-fold excess of the acylating agent of formula III.

The omega-haloalkanoyl dioxazocin (IV) obtained by acylation is reacted with the amine (VIII) in a polar, apolar or dipolar aprotic solvent. Preferably, the solvent is benzene, toluene, xylene, isopropanol or dimethylformanoate. The amine of formula (VIII) may be obtained in equimolar amounts or in excess. The excess amine also serves to bind the hydrogen halide liberated in the reaction, but other conventional acid scavengers may be used for this purpose.

For both the acylation reaction and the amination of the compound of formula IV, the acid acceptor may be a suitable

Or an inorganic base such as tertiary amine such as triethylamine, N, N-diisopropyl-N-ethylamine, pyridine and the like.

Preferably, the compound of formula (V) is reacted in benzene with an excess of the amine of formula (VIII).

The process (a) of the present invention may also be carried out by preparing an alkali metal salt, preferably sodium salt, of the dioxazocin of formula II in a dipolar aprotic solvent, preferably dinethylformamide, for example sodium hydride or sodium amide, . In this case, of course, no additional acid or binder is required.

The reaction of the compounds of formula (11) and (V) in process (b) according to the invention can be carried out in a manner similar to that used in process (a) for acylation. The reaction is usually carried out at 0-140 ° C.

The process (b) of the present invention is preferably carried out by treating the compound (II) with an alkali metal salt as described above and reacting the latter with an excess of the compound (V) at a temperature of 0 to 50 ° C.

In the case of compounds of formula I containing a chiral carbon atom, the enantiomers can be separated by resolution of the racemic compound. To do this, the racemic compound containing the basic nitrogen atom is converted into diastereomeric salt pairs with optically active carboxylic acid, the salt pairs are separated and the individual enantiomers are liberated. As the optically active carboxylic acid, compounds commonly used for resolution can be used, such as optically active tartaric acid, dibenzoyl tartaric acid, lactic acid, canophor-10-sulfonic acid and the like.

Certain enantiomers of the compounds of formula (I) containing the chiral carbon atom may also be prepared by acylation of the dioxazocin of formula (II) with an optically active compound during the synthesis.

The compounds of Formula I have valuable biological activity. These are illustrated by the following pharmacological studies.

Acute toxicity in mice

White mice (18-22 g) of both sexes from CFLP strain cultures were tested per animal. Materials were administered orally at a volume of 20 ml / kg. After treatment 7 days follow-up was performed. The animals are housed in a plastic mouse box on my wood chips in a room temperature room. They could consume tap water, a standard mouse diet ad libitum. Toxicity data were determined by the Litchfield-Wilcoxon method (J. Pharmacol.

exp. Thar., 96, 99 (1949). The results are shown in Table I.

Table I

Compound LD50 mg / kg oral (number of example)

4 2000 5 2000 12 260 6 250 21 300 13 300 14 160 7 1000 3 280 18 250 8 450 19 370 20 220 9 900 15 250 10 900 Youth 250 17 650 11 2000 1 2000 2 700

Investigation of Local Anesthesia The tests were performed according to the method of Truanl d'Amato (Acta Chir. Scand., 116, 351 (1958)). 1 cm long needle Inject 0.2 ml of test substance around Nervus ischiadicus at the center of the femui. Lack of motor control of the leg muscles was considered a criterion for anesthesia. The duration of action was recorded and the 50% effective concentration (ECm%) was calculated from the dose response curve. Lidocaine was used as a comparator. The results obtained are shown in Table II. Table.

II. spreadsheet

Compound EC50 Duration in minutes (number of examples)% 0.25% 0.5%

4 0:21 55.8 97.7 12 0:15 54.1 107.3 21 0:08 93.1 93.1 13 0:14 122.1 217.3 14 0:19 83.2 160.0 18 0:10 85.7 146.4 8 0:25 51.1 98.8 19 0:22 43.7 73.8 20 0:11 53.5 67.8 15 0:16 52.4 113.8 16 0:25 80.0 114.6 lidocaine 0:17 23.9 40.1

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Most of the compounds are effective at lower concentrations than lidocaine, and all are significantly superior to lidocaine in terms of duration of action at both concentrations.

Hexobarbital sleep test in mice

Groups of 6-6 mice were studied. 1 hour after oral administration, 40 mg / kg iv. addition of hexobarbital induced sleep on both control and compound-treated groups.

The control group consisted of sleep-time

Sleep animals greater than 2.5 fold were considered to be positive responders, and ED50 values were calculated from the transformed data. The results obtained a

III. Table.

III. spreadsheet

Compound (example number) ED Therapeutic index, LD50 / ED50 3 25 31.2 4 8.5 235.0 12 30.0 8.7 6 15.0 16.7 19 15.0 24.7 15 9.8 25.5 1 21.0 95.2 meprobamate 260.0 4.2 (LD50 = 1100 mg / kg) chlordiazepoxide 10.0 62.0 (LD50 = 62O mg / kg) The most effective nyabb derivative therapy

index is superior to chlordiazepoxide, but all compounds are more effective than meprobamate, both in absolute dose and therapeutic index.

Tetrabenazine ptosis antagonism in mice

Our experiments were carried out using the method adapted to the mouse by Hoffmeister et al., Arzneim.-Forschung, 19, 846-858 (1969). Groups of 10 to 10 mice were dosed with oral doses of the compounds, and the control group with the appropriate vehicle was also given orally. After 30 minutes, tetrabenazine 50 mg / kg was administered i.p., and after 30-60-90-120 minutes, closed-blind animals were counted per group.

Mean ptosis was calculated per group based on all measurements and expressed as percentage of control animals (inhibition).

Based on the data, an EDw value was calculated. The results obtained are shown in Table IV. is shown in Table.

Compound (example number) ARC. spreadsheet ED50 mg / kg Therapeutic index LD50 / ED50 11 23.0 86.9 2 13.0 53.9 20 13.5 13.6 amitriptyline 12.0 18.7

The compounds have the same or significantly more favorable therapeutic index than the reference amitriptyline in this test.

Nicotine-induced anticonvulsant and lethal inhibition in mice

Our studies were performed on white mice by the method of Stone (Arch. Int. Pharmacodyn., 177, 419 (1958)). One hour after oral administration, 1.4 mg / kg of nicotine was injected iv. and recorded seizures and lethality within 1 hour in the treated and control animals. The results obtained are shown in Table V.

Table V.

Compound ED 50 mg / kg Therapeutic index, (Example number) LD 50 / ED 50

4 35 57.0 5 13 154.0 6 5 50.0 7 15 66.7 3 7 111.0 8 15 30.0 9 17 52.9 10 21 42.9 1 72 27.8 trihexyphenidyl 20 18:25

Study of antitremorine activity in mice

Our experiments were performed in Everett's method on white mice (Science, 124, 79 (1956)). Oral doses of the compound were administered at 20 mg / kg ip. was administered 1 hour prior to a dose of 10 to 10 animals per dose. The resulting tremor was assessed 45 minutes after tremorin treatment (Spontaneous tremor: 2, Provoked tremor: 1, Tremor absence: 0 points).

The calculated ED50 and therapeutic index values are shown in Table VI. Table.

VI. spreadsheet

Compound (example number ED50 mg / kg) Therapeutic index LD50 / ED50 4 42 47.6 13 4 75.0 14 8.1 19.8 7 37.5 26.7

Compound ED50 mg / kg Therapeutic index LDm / EDm (example number) 3 15.0 52.0 1 16.0 125.0 5 trihexyphenidyl 15.0 24.3

Each compound outperforms the reference antiparkinsone (trihexyphenidyl, huta-1) in the latter two representative tests.

Examination of antiarrhythmic effect

Antiarrhythmic activity was investigated by affecting aconitrine-induced arrhythmia according to the method of Marmo et al. Rats weighing 160-200 g (Arzneim.Forsch., 20, 12 (1970)). The animals were elilurethane 1.2 g / kg ip. aconitine at a dose of 75 pg, iv. We added. 20

ECG lesions are standard II. was followed for 5 minutes after aconitine administration. Test substances are administered iv. 2 minutes and 30 minutes prior to aconitine administration. The percent inhibition values are shown in Table VII. is shown in Table.

VII. spreadsheet

Compound Dose Inhibition% (Example Number) mg / kg

4

4

4

Glider 4

Quinidine 4

54.2

45.5 35

62.9

23.4

27.3

The compounds outperform the two reference substances 40.

Examination of antianginal effects in rats

Our experiments were performed on male rats weighing 180-220. The animals were anesthetized with choralose urethane. Electrocardiograms were obtained using standard electrodes using strain electrodes. led off. The anti-angina effect was assayed by the method of Nischultz (Arzneim.Forsch., 5, 680 (1955)). Experimental crown failure 50 glanduitrin 4NE / kg iv. dose. The magnitude of the T-wave was measured before and after administration of glanduitrin in the control and treated groups. The results obtained are shown in Table VIII. Tablespoon table to 55 glazes.

VIII. spreadsheet

Compound Dose Inhibition% 60 (Example Number) mg / kg

2 55.4

3 83.6

Prenilamin 2 41.3 65

Based on the results of the above pharmacological tests, the compounds of the formula I can be used as active ingredients in pharmaceutical preparations. The pharmaceutical compositions are prepared by admixing a compound of formula (I) or a pharmaceutically acceptable acid addition salt thereof with a pharmaceutically acceptable carrier (s), and preparing the mixture in a manner known per se.

In general, pharmaceutical compositions are prepared for oral or parenteral administration or for topical administration.

Solid dosage forms such as tablets, capsules, dragees, etc., can be administered orally. excipients such as gelatine, sorbitol, polyvinylpyrrolidone; fillers such as lactose, sugar, starch, calcium phosphate; tabletting aids such as inagnesium stearate, talc, polyethylene glycol, silica, wetting agent such as sodium lauryl sulfate and the like. contain.

In liquid dosage forms for oral administration such as solutions and suspensions, excipients are conveniently suspending agents such as sorbitol, sugar solution, gelatin, carboxymethylcellulose, emulsifying agents such as sorbitan monoleate; solvents such as oils, oily esters, glycerol, propylene glycol, ethyl alcohol; preservatives such as methyl p-hydroxybenzoic acid, etc.

Formulations for parenteral administration will generally comprise sterile solutions.

If desired, the pharmaceutical compositions may also contain flavoring and coloring agents.

The daily dose of the compounds of the formula I is generally between 0.1 mg / kg and 10 g / kg. The actual value required will be determined by the physician, depending on the disease being treated, the individual being treated, and the mode of treatment.

The following examples further illustrate the process without limiting the invention to the examples.

Example I, 211-12 ((4-diethylpiperazino) acetyl] dibenzole, g] (1,3,6J-dioxazocine-dimaleinate)

A.) 30.0 g (0.141 mol) of 12 H -dibenzo [d, g] II, 3.6 J dioxazocine (m.p. 189-191 ° C), 150 cm ^{3 of} anhydrous toluene and 19.5 g (0.173 mol) of chlorine. The acetyl chloride mixture was heated to reflux and refluxed for 2 hours. Another 19.5 g (0.173 mol) of chloroacetyl chloride was added and refluxed for an additional 4 hours. The reaction mixture was cooled to 25 ° C and poured onto crushed ice with stirring. After stirring for 1 hour, the product is filtered off and washed with water. After recrystallization from isopropyl alcohol, 35.6 g (87.3%) of 12H-12- (2-chloroacetyl) di-59

HU 198194 Ε

benzo [d, g] yl, 3,6] dioxazocine we get which 151-3 ° C. Analysis for C15H12CINO3 (Ms: 289.7) amount- formula: C H cl N Calculated: 62.19% 4.18% 12.24% 4.83% Found: 62.57% 4.12% 12.23% 4.77%

Β) A mixture of 12.0 g (0.041 mol) of the product obtained in A) above, 130 cm ^{3 of} anhydrous benzene and 27.6 g (0.276 mol) of 4-methylpiperazine is heated under reflux for 6 hours. . The mixture was cooled to 25 ° C and the precipitated salt was filtered. The benzene filtrate was washed with water and dried over anhydrous magnesium sulfate.

After removal of the solvent, the product is crystallized with isopropyl alcohol and recrystallized from isopropyl alcohol. There was obtained 9.7 g (66.4%) of 12H-12-1- (4-methylpiperazin-1-yl) acetyl] dibenzo [d, gK1, 3.6] dioxazocine, m.p. 160-162 ° C. .

Analysis calculated for C 20 H 23 N 3 O 3 (MS: 353,425):

C H N

Calculated: 67.97% 6.56% 11.89%

Found: 68.14% 7.02% 11.78%

C.) 8.4 g (0.024 mol) of 12H-12- To a solution of (4-methylpiperazin-1-yl) acetyl] dibenzene, g] 11, 3.61 dioxazocin in 100 cm ^{3 of} isopropyl alcohol at 20 ° C with stirring, 5.6 g (0.048 mol) of maleic acid. A solution of ³ cm of isopropanol is added. After stirring for 2 hours, the mixture was cooled to 0 ° C, filtered after stirring for 1 hour, and washed with isopropyl alcohol. Recrystallization from methanol gave 10.5 g (74.7%) of product, m.p. 179-183 ° C.

Analysis calculated for C28H31N30n (MS: 585,572):

C Η N

Calculated: 57.43% 5.34% 7.18%

Found: 57.38% 5.31% 7.06%

Example 2

12H-12 - [(N-cyclohexyl-N-methylamino) acetyl] dibenzo [d, g] yl, 3,6] dioxazocin-maleate

A.) 13.0 g (0.045 mol) of 12H-12- (chloroacetyl) dibenzo (d, g) (1,3,6) dioxazocine, 150 cin ^{3 of} anhydrous benzene and 32.2 g (0.28 g). mole) of N-cyclohexyl-N-diethylamine was refluxed for 8 hours. The reaction mixture was worked up as described in Example 1B. After recrystallization from isopropyl alcohol, 13.9 g (84.2%) of 12H12 - [(N-cyclohexyl-N-diethylamino) -acetyl] dibenzo [d, g] [1,3,6] dioxazocine base m.p. 103-105 ° C.

Analysis calculated for C 22 H 26 N 2 O 3 (MS: 366.463):

C Η N

Calculated: 72.11% 7.15% 7.64%

Found: 72.17% 7.18% 7.60%

Β. 12.8 g (0.035 mole) of the base prepared above and 4.2 g (0.036 mole) of maleic acid were formed as described in Example 1C. Recrystallization from isopropyl alcohol gave 14.9 g (88.2%) of product, m.p. 148-150 ° C.

Analysis calculated for C26 H30 N2 O7 (MS: 482,536):

C Η N

Calculated: 64.72% 6.27% 5.81%

Found: 64.58% 6.34% 5.67%

Example 3

1211-12-1 (Isopropylamino) -acetyl] -2-chloro-dibenzo [d, g Jl 1.3.6 J dioxazocine hydrochloride

A.) 24.8 g (0.10 mol) of 12H-2-chloro-dibenzo [d, glll, 3.6] dioxazocin (m.p. 182-184 ° C),

A mixture of 300 cm ^{3 of} anhydrous toluene and 23.0 g (0.20 mol) of chloroacetyl chloride was refluxed for 4 hours. After cooling to 25 ° C, the solvent was removed in vacuo and the residue was crystallized by trituration with gasoline. After recrystallization from isopropyl alcohol

23.1 g (71.3%) of 12H-2-chloro-12- (chloroacetyl) di30

benzo [d, g) [1,3,6] dioxazocine, m.p. 149-151 ° C. Analysis for C15H11Cl2NO3 (Ms .: 324.2) amount- formula based on: C H cl up Calculated: 55.57% 3.42% 21.87% 4.32% Found: 55.48% 3.63% 21.95% 4.28%

B.) 15.0 g (0.046 mol) prepared according to A above. apparatus equipped with chloro-acetyl derivative 180 ^cm3 of anhydrous benzene and isopropyl Aini (17.7 g, 0.30 mol) were refluxed for 4 hours, then the solvent was removed. The residue was stirred with 100 cm ^{3 of} diethyl ether and 80 cm ^{3 of} water for 30 minutes. The ether layer was separated and dried over anhydrous magnesium sulfate. The solution was cooled to 0 ° C and diethyl ether saturated with dry hydrochloric acid gas was added to p = 1 = 4 with stirring. The precipitated crystals are filtered off and washed three times with slurry in diethyl ether. Recrystallization from ethanol gave 13.0 g (74.0%) of a white product, m.p. 235-240 ° C.

Analysis a C18H20CI2N2O3 (Ms .: 383,282) fall- by nail formula: C H cl N Cl Theory: 56.41% 5.26% 18.50% 7.31 9.25% Found: 56.15% 5.60% 17.96% 7.16% 9.08% Example 4

H-2-Chloro-12 - [(4-methylpiperazino) -acyl] -dihenzo (d, gJL1, 3 _t 6J-dioxazocin-dimaleinate)

A.) 49.0 g (0.129 mol) of 12H-2-chloro-12-chloroacetyl dibenzo [d, g] [1,3,6] dioxazocine,

A mixture of 80.0 g (0.80 mol) of 4-methylpiperazine and 410 cm ^{3 of} anhydrous benzene was refluxed.

-611 for 4 hours with refrigerator. boil. The solvent and excess 4-methylpiperazine were then removed in vacuo. To the residue were added 150 cm @ ^{3 of} benzene and 100 cm @ ^{3 of} water, the mixture was stirred for 30 minutes, separated and the benzene solution was washed three times with 80 cm @ ^{3 of} water. To the benzene phase was added an aqueous solution of 45.0 g (0.30 mol) of tartaric acid in 150 cm <^3> and the mixture was stirred for 1 hour. After separation, 150 cm ^{3 of} benzene are added to the aqueous phase and 25% aqueous ammonia solution is added with stirring to pH 9-10. After stirring for one hour, the benzene layer was separated, dried over anhydrous magnesium sulfate, and the solvent was removed. The residue was crystallized by stirring with petrol, filtered and washed with petrol. After recrystallization from isopropyl alcohol, 38.0 g (76.0%) of 12H-2-chloro-12 - [(4-methylpiperazino) acetyl) dibenzo [d, g] 11,3,6] dioxazocine mp 124-127 ° C.

Analysis based on C20H22CIN3O3 (Ms .: 387,870):

C H

Calculated: 61.93% 5.72%

Found; 62.18% 5.93%

Cl N

9.14% 10.83%

9.18% 10.61%

B.) 34.1 g (0.088 mol) of 12H-2-chloro-12-1 (4-Methyl-piperazino) -acetyl-J-dibenzene, g) From 11.3.6 J of dioxazocin and 20.4 g (0.176 mol) of maleic acid was prepared as described in Example 1C. Recrystallization from methanol gave 44.2 g (81.0%) of product, m.p.

188-190 ° C.

Analysis based on C2SH30CIN3O11 (Ms. nail formula:

C H

Calculated: 54.24% 4.88%

Found: 54.18% 5.12%

620,014) Fall N

5.72% 6.78%

5.70% 6.62%

Example 5

12H-2-chloro-12 - [(N-cyclohexyl-N-methylamino) acetyl] dibenzo [d, g] [l, 3,6Jdioxazocin maleate

A.) 12H-2-chloro-12-chloroacetyl dibenzene (35.0 g, 0.108 mol), gj [1,3,6] dioxazocin,

A mixture of 350 cm ^{3 of} anhydrous benzene and 2x76.9 g (2x0.678 moles) of N-cyclohexyl-N-methylaniline was heated at reflux for a total of 12 hours. The reaction and working-up of the reaction mixture were carried out as described in Example 4 / A. The crude product is crystallized and recrystallized from gasoline. 12.1 g (79.8%) of 1211-2-chloro-12-l- (N-cyclohexyl-N-methylamino) -acetyl) -N-dibenzo (d, g] [1,3,6] dioxazocine mp 93-95 ° C.

Analysis for C22H25CIN2O3 (Ms. by nail formula: : 400,909) fall- C 11 cl N calculated: 65.91% 6.29% 8.84% 6.99% Found: 65.60% 7.00% 8.89% 6.61%

B.) 30.0 g (0.075 mol) of the base prepared above and 8.7 g (0.075 mol) of maleic acid were salted as described in Example 1C. After recrystallization from methanol, the product is obtained

5 weight 34.8 g (89.7%), m.p. -193 ° C. 191- fall- N Analysis for C26H29CIN2O7 (Ms .: by nail formula: 516.980) cl C H 10 calculated: 60.41% 5.56% 6.68% 5.42% Found: 61.23% 5.92% 6.79% 5.30%

Example 6

12-l (diethylamino) -acetyl-12H-2-chloro-dibenzene, g] (1,3,6 Dioxazocine hydrochloride)

A.) 32.4 g (0.10 mol) of 12H-2-chloro-12- (chloroacetyl) di-benzene d, g] [1,3,6] dioxazocin, 2x36.5 g (2x0.50 mol) a mixture of diethylamine and 250 cm ^{3 of} anhydrous benzene was heated at reflux for a total of 6 hours. The reaction and working-up of the reaction mixture were carried out as described in Example 4 / A. The crude product is a yellow-brown viscous liquid which is crystallized and recrystallized from n-hexane.

28.5 g (78.9 g) of 12 - ((diethylamino) acellyl) -12H-2-chlorodibenzene, g] [1,3,6] dioxazocine, m.p. 75-80 ° C.

Analysis for C 13 H 21 ClN 2 O 3 (Ms. 360.844).

nail formula Based on: C H cl N calculated: 63.24% 5.87% 9.83% 7.76% Found: 63.96% 5.32% 9.85% 7.50%

B.) 19.0 g (0.053 mol) of the base obtained above are prepared with hydrochloric acid salt with isopropyl alcohol containing 20% hydrochloric acid dissolved in isopropyl alcohol. Weight of product after recrystallization from isopropyl alcohol

17.5 g (82.9%), m.p. 198-201 ° C.

Analysis a C1UH22CI2N2O3 (Ms .: 397,302) nail formula Based on: C H cl N Cl calculated: 57.44% 5.58% 17.85% 7.05% 8.92% Found: 57.56% 5.84% 17.50% 7.06% 8.88%

Example 7 (±) -12H-2-Chloro-12 - [(- 2-methylpiperidino) acetyl) dibenzole, gll 1,3,6 Dioxazocine Hydrochloride

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

A mixture of 39.7 g (0.40 mole) of 2-methylpiperidine and 250 cm ^{3 of} anhydrous benzene was heated at reflux for 4 hours. The reaction mixture was worked up as described in Example 4 / A. The crude product crystallizes. and recrystallization from isopropyl alcohol ⁶⁰ µm. 30.8 g (79.6%) of (±) -12H-2-chloro-12-1 (2-methylpiperidino) acetyl] dibenzole, glt1,6,6] dioxazocine, m.p. 90-92 ° C.

Analysis of the total riveting formula CZ1II23CIN2O3 (Ms .: 386,882):

-713

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c ii ci N Analysis was performed on CisphlisCIN2Oi (Ms .: 374.827) fall- Calculated: 65.20% 5.99% 9.16% 7.24% by nail formula: Found: 65.01% 6.33% 9.15% 7.08% fiction H cl N Calculated: 60.88% 5, 11% 9.46% 7.47% B.) 9.6 g (0.0248 mol) as follows comp- utes 5 Found: 59.70% 5, 70% 9.52% 7.21% gapped base as described in Example 3 / B way hydrochloric acid salt. Weight of the Beings 10.3 g B.) 20.0 g (0.053 mol) above manufactured ba- (98.1%), m.p. 146-154 (dec.) zisole and 6.2 g (0.053 mole) of maleic acid while). J / fi salt as described forming. ETA Analysis for <RTI ID = 0.0> Cl2H2filzNzOy </RTI> (M.S .: 423.342) Recrystallization from 10 ol after the product by nail formula: weight 20.2 g (77.7%), mp 197 DEG

calculated .: fiction 59.58% H 5.71% cl 16.75% N 6.62% Cl 8.38% -199 C. Analysis a CzjllziClNzOs (Ms .: 490.898) fall- Found: 58.45% 6.11% 16.92% 6.65% 8.4 7% nail formula Based on: 15 fiction H cl N Example 8 calculated .: 56.28% 4.72% 7.22% 5.71% Found: 56.7 1% 4.88% 7.23% 5.72%

12H-2-chloro-12- (red from idino-acetyl) -diberizo [d, g J [1,3,6] dioxazocin maleate

A.) 22.0 g (0.068 mol) of 12H-2-chloro-12-chloroacetyl dibenzene, g / l 1,3,6] dioxazocine,

24.2 g (0.34 moles) in pyrrolidine and 250 cm ^{3 of} anhydrous benzene in a refluxing apparatus for 3 hours. The reaction mixture is worked up as described in Example 4 / A. The crude product is crystallized and recrystallized from gasoline. 19.8 g (81.1%) of 12H-2-chloro-12- (pyrrolidine)

no-acetyl) dibenzo [d, gl (1.3,6] oxazocin) K- our boy, with a melting point of 80 -83 "C. Analysis for Gi9Hi9ClN2O3 (Ms .: 358.827) fall- by nail formula: fiction H fi) N Calculated: 63.60% 5.34% 9.88% 7.81% Found: 63.11% 4.82% 9.80% 7.71%

B.) 14.0 g (0.039 mole) of 12H-2-chloro-12-pyrrolidinoacetyl dibenzene, g] l 1,3,6] dioxazocine and 4.6 g 0.04 mole) of maleic acid in 1 / fi as described in Example II. Weight of product after recrystallization from ethanol

15.8 g (85.5%), m.p.

Analysis a CzjUdCINzOt (Ms .: 471.899) fall- nail formula Based on: fiction H cl N calculated: 58.17% 4.88% 7.47% 5.90% Found: 58.48% 4.50% 7.47% 5.93%

Example 9

12H-2-chloro-12- (morpholinoacetyl-1-dibenzof d, g) [1,3,6] dioxazocin

A.) 25.0 g (0.077 mol) of 12H-2-chloro-12- (chloroacetyl) dibenzo [d, g) [1,3,6] dioxazocine,

A mixture of 30.4 g (0.35 mol) of morpholine and 250 cm ^{3 of} anhydrous benzene was heated at reflux for 3 hours. The reaction mixture was worked up as described in Example 4 / A. The crude product was crystallized with hexane and recrystallized from isopropyl alcohol. 24.9 g (86.2%) of 12H-2-chloro-12 (niorfolinacetyl) dibenzo (d, gl (1.3, J) dioxazocine, m.p. 123-125 ° C.

IC. example

12-l (cyclopropylamino) -acetyl) -12H-2-chloro-dibenzenesol (J1, 1,3,6) dioxazocin maleate

A.) 25.0 g (0.077 mol) of 12H-2-chloro-12- (chloroacetyl) dibenzo [d, g] (1,3,6 Idioxazocine,

A mixture of 2x8.6 g (2x0.15 moles) of cyclopropylamine and 200 cm ^{3 of} anhydrous benzene was heated at reflux for 11 hours. The reaction and working-up of the reaction mixture were carried out as described in Example 1A. Crystallization and recrystallization of crude product from petrol. 18.3 g (69.1%) of 12 - [(cyclopropyl) amino) acetyl] -12H-2-chlorodibenzo [dd, g] -1,3,6] dioxazocine are obtained, m.p. 80-85 ° C. .

Analysis a C16H17CIN2O3 (Ms.: 344.800) fall- nail formula Based on: fiction H cl N calculated: 62.70% 4.97% 10.28% 8.12% Found.: 63.02% 4.60% 10.35% 8.01% B.) 11 , 4 g (0.033 moles) above manufactured ba-

and 3.9 g (0.034 mol) of maleic acid were prepared as described in Example 1 / C. After decolorization with ethanol, product

falcon 11.9 g (78.3%), m.p. 176 -181 "C. Analysis a C22H21CIN2O7 (Ms.: 460.872) fall- szegköplet. Based on: fiction H cl N Calculated: 57.34% 4.59% 7.69% 6.08% Found: 57.70% 5.00% 7.91% 6.15%

Example 11} 2- (diethylcarbamoyl) -12H-2-k] hour dibenzide, gJ [1,3,6-dioxazocin

A solution of 4.8 g (0.10 mol) of sodium hydride in 50% mineral oil was added to 100 cm ^{3 of} dimethylformamide at 25 ° C with stirring θθ. 24.8 g (0.10 mol) of 12H-2-chloro-dibenzo [d, gll] 1,3,61-dioxazocinL are then added while maintaining the temperature at 25 ° C. Raise the temperature to 40 ° C. and stir for an hour. Cool to 20 ° C and add 20.3 g (0.15 mol) of N, N-di-815

HU 198191 Β

Young ethylbromobamoyl chloride and stirred for 1 hour at 40 ° C. The reaction mixture was cooled to 0 ° C. and 120 cm ^{3 of} water are added with stirring. A viscous oil is obtained which is separated. Dissolve in 150 cm ^{3 of} benzene, wash with ³ x 80 cm ^{3 of} water, dry over anhydrous magnesium sulfate, remove the solvent in vacuo. The residue was crystallized from gasoline and recrystallized from isopropyl alcohol. The product weighed 22.9 g (66.0%), m.p. 93-95 ° C.

Analysis for CmllwClNzOa (Ms .: 345,823). Based on:

C 11

Calculated: 62.34% 5.52%

Found: 62.83% 5.45%

Cl N

10.22% 8.08% 10.48% 8.00%

Analysis a CzuIizaCINzOa (Ms .: 374.870) fall- Example 12 szegképlel. Based on: C H cl N 12H-2-chloro-12- [3- (4-methyl-piperazino) propionyl 20 Calculated: 64.08% 6.18% 9.46% 7.47% nil] dibenzole, gj [1,3,6] dioxazoci n-d Found: 63.52% 6.61% 9.59% 7.25% A.) 24.8 g (0.10 billion) of 12H-2-chlorodib zo [d, g] [1,3,6] dioxazycin, 150 cm ³ anhydrous B.) 18.7 g (0.050 mol), A according to point

toluene and 25.4 g (0.20 mol) of 3-chloropropionyl chloride were refluxed for 5 hours. The solvent is removed in vacuo, the residue is taken up in 150 cm @ ^{3 of} benzene and poured onto 400 g of crushed ice with stirring. After stirring for 1 hour, the benzene phase was separated, washed with 4 x 100 cm ^{3 of} 5% aqueous sodium bicarbonate solution and then with 100 cm ^{3 of} water. The organic layer was dried over anhydrous magnesium sulfate and the solvent removed. The residue was crystallized with isopropyl alcohol and then recrystallized. 26.7 g (79.0%) of 1211-2-chloro-12- (3-chloropropionyl) dibenzene d, g | (1,3,6) dioxazocirite, m.p. 76-81 ° C.

Analysis for C 18 H 11 Cl 2 NO 5 (MS .: 338.193)

nail formula Based on: C lithium cl N calculated: 56.82% 3.87% 20.97% 4.14% Found: 56.41% 3.30% 21.35% 4.04% B.) 33.8 g (0.10 mid) above produced. 5-

chloropropionyl derivative, a mixture of 60.0 g (0.60 mole) of 4-methylpiperazine and 250 cm @ ^{5 of} anhydrous benzene was heated to reflux for 5 hours. The reaction mixture was worked up as described in Example 4 / A. The crude product was 1211-2-chloro-12-13- (4-methylpiperazino) propionyl] dibenzol, g I [1,3,6] dioxazocin base, brown viscous liquid, 30.0 g.

C.) 30.0 g of the base prepared above and

18.6 g (0.16 mole) of maleic acid were the. A salt is formed as described in Example 1 / C. Weight of product after recrystallization from methanol

21.6 g (67.0%), m.p. 185-187 ° C. Analysis based on CzslbzClNjOu (Ms .: 634,041) aggregate formula:

C H

Calculated: 54.94% 5.09% Found: 54.74% 5.46%

Cl N

5.59% 6.6.3% 5.56% 6.52%

Example 13

12- [3- (diethyl-amino) -propionyl] -12H-2-chloro-dibenzene d, g, 111.3.6 Idioxazocin hydrochloride

A.) 33.8 g (0.10 mol) of 12H-2-chloro-12- (3-chloropropionyl) dibenzo (d, g -1,3,6] dioxazocine, 2x29.2 g (2x0, 40 moles) of diethylamine and 250 cm ^{3 of} anhydrous benzene are refluxed for a total of 6 hours.

r.djuk. The reaction and working up the reaction mixture. as described in Example 4 / A. The crude product is crystallized and recrystallized from η-hexane. 30.9 g (82.5%) of 12-13 - (- diethylamino) -ρι · ορίοηί1] -12Η15 -2-chlorodibenzoyl, g] [1,3,6] dioxazocine base, m.p. -72 ° C.

The resulting base is dissolved in 70 cm ^{3 of} isopropyl alcohol. The solution. It is cooled to 0 [deg.] C. and isopropanolic alcohol solution containing 20% dissolved HCl gas is added up to p1 = 3. After stirring for 1 hour, the crystals are filtered off. After recrystallization from isopropyl alcohol, 17.9 g (81.0%) of product are obtained, m.p. 176-182 ° C.

Analysis a Czllz + CkNzOs (Ms .: 441,329) Fall · szegképlel . based on c H cl N Cl- calculated .: 58.40% 5.88% 17.24% 6.81% 8.62% Found: 58.12% 6.07% 17.12% 6.68% 8.66%

Example I ⁴ θ 12H-12- [3- (isopiopi] amino) propionyl] -2-chloro-dihenzo (d, g 111.3,6 Idioxazocin hydrochloride

30.0 g (0.089 mol) of 12H-2-chloro-12- (3-chloropropionyl) dibenzo [d, g H1,6,6] dioxazocine,

2k21.0 g (2x0.356 mol) of isopropylamine and

Boil a mixture of 250 cm ^{3 of} anhydrous benzene in a refluxing apparatus for a total of 6 hours. The reaction and working up of the reaction mixture were carried out as described in Example 4 / A. 28.5 g of 12H-12-L3- (isopropylamino) -propionyl-2-chloro-dibenzoLd, g] [1,3,6] dioxazocine base. which is a viscous liquid.

From the base, the hydrochloride salt is prepared as described in Example 3 / B.

After recrystallization from ethanol a

product weight 25.8 g (73.0%), m.p. 240-243 ° C. Analysis a Ci9lIzzClzNzO3 (Ms .: 397,301) total nail formula Based on: C 11 cl N Cl- You count l: 57.44% 5.58% 17.86% 7.05% 8.93% Found: 57.66% 5.45% 17.86% 6.98% 8.92%

-917

HU 198194 Β

Example 15

12H-2-Chloro-12- (3-pyrrolidinopropionyl) dibenzo [<, g] (1,3,6 J doxa-2-cinnamic acid).

A.) 25.0 g (0.074 mol) of 12H-2-chloro-12- (3-chloropropionyl) dibenzole, g] 11,6,6 Dioxazocine,

A mixture of 21.3 g (0.30 mole) of pyrrolidine and 250 cm ^{3 of} anhydrous benzene was refluxed for 3 hours. 7H (9.0%) of 12H-2-chloro-12- (3-pyrrole-di-propionyl) dibenzo [d, g] [1,3,6] dioxazocine base, m.p. 118 DEG C. Analysis for C20H12ClN2O3 (MS: 372,854).

by nail formula: C H cl Calculated: 64.43% 5.68% 9.51% Found: 64.00% 5.12% 9.61% B.) 20.0 g (0.054 mol), The dot

N

7.51%

7.40% of the base and 6.4 g (0.055 mol) of nialeic acid were salted as described in Example 1C. After recrystallization from ethanol, the product weighed 22.7 g (85.9%), m.p. 161-164 ° C.

Analysis based on C24H25CIN2O7 (Ms .: 488,926):

C H

Calculated: 58.96% 5.15%

Found: 59.52% 5.28%

Cl N

7.25% 5.73%

7.35% 5.79%

Example 16

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

25.0 g (0.074 mol) of 12B-2-chloro-12- (3-chloropropionyl) dibenzo [d, g] [1,3, (>]) dioxazocine,

A mixture of 2x8.7 g (2x0.16 moles) of article propyl anrin and 250 cm ^{3 of} anhydrous benzene was heated at reflux for a total of 15 hours. The reaction and the reaction mixture were refluxed for 15 hours. The reaction and working-up of the reaction mixture were carried out as in Example 4A. 21.7 g of 12-13- (cyclopropylamino) propionyl] -12H-2-chlorodibenzo [d, g) [1,3,6] dioxazocine base are obtained which is a viscous liquid.

From the base, the hydrochloride salt is prepared as described in Example 3 / B. After recrystallization from ethanol, the product weighed 18.7 g (64.0%), m.p. 196-204 ° C.

Analysis a C19H20CI2N2O3 (Ms .: 395,288) nail formula Based on: C H cl N Cl- Theory: 57.73% 5.10% 17.94% 7.09% 8.97% Found: 58.34% 5.38% 18.18% 7.10% 8.89%

Example 17

12H-2-chloro-12- (3-morfolirio-propionyl) dibenzo [d, g] [l, 3,6] dioxazocin hydrochloride

A.) 25.0 g (0.074 mol) of 12H-2-chloro-12- (3-chloropropionyl) dibenzo [d, g] [1,3,6] d ioxazoci η,

A mixture of morpholine (30.4 g, 0.35 mol) and anhydrous benzene (250 cm ^{3) was} heated to reflux for 5 hours. The reaction mixture was worked up as in Example 4A. The crude product is crystallized with n-hexane and recrystallized from isopropyl alcohol. There was obtained 23.9 g (83.0%) of 12H-2-chloro-12- (3-morpholinopropionyl) dibenzole, g] 11.3.6] dioxazocine, m.p. 122-125 ° C.

(Ms .: 388,854)

Analysis based on C20H21CIN2O4:

C H

Calculated: 61.78% 5.44%

60.98% 5.93%

cl

9.12%

9.21% from base

N

7.20% 7.03% a 3 / B

Found:

B.) 15.0 g (0.0368 mol) of the hydrochloride salt were prepared as described in the example above. After recrystallization from ethanol, the product weighed 13.5 g (82.3%), mp 225-229 ° C.

Analysis a C20H22CI2N2O4 (Ms .: 425,315) nail formula Based on: C H cl N Cl calculated: 56.48% 5.21% 16.67% 6.59% 8.34% Found: 56.92% 5.35% 16.77% 6.55% 8.36%

Example 18 for ('.) - 12H-2-chloro-12- [2- (4-methylpiperazino) propionyl] dibenzo [d, g] [1,3,6] dioxazocine di30n.

A.) 123.9 g (0.50 mol) of 12H-2-chlorodibenzene, g] fl, 3.6] dioxazocine, 750 cm ^{3 of} anhydrous toluene and 127.0 g (1.00 mol) of 2-chloro The propionyl chloride mixture was heated to reflux for 3 hours. The reaction mixture was worked up as described in Example 3 / A. After recrystallization from isopropyl alcohol, 131.1 g (77.5%) of (i) -12H-2-chloro-12- (2-chloropropionyl) dibenzo [d, g] (1,3,6) di -

oxazocint we get, which has a melting point 152-155 ° C. Analysis a C1SH13Cl2NO3 (Ms .: 338.201) fall- nail formula Based on: C H Cl N calculated: 56.82% 3.87% 20.97% 4.14% Found: 56.32% 3.99% 21.20% 4.10%

B.) A mixture of 20.0 g (0.059 mol) of the above 2-chloropropionyl derivative, 2x25.1 g (2x0.25 mol) of 4-methylpiperazine and 200 cm ^{3 of} anhydrous benzene in a reflux condenser for a total of 11 hours. boil. The reaction and work-up of the mixture were carried out as described in Example 4 / A. The crude product was crystallized from gasoline and recrystallized from isopropyl alcohol. 18.8 g (79.2%) of (S) -1211-2-chloro-12- [2- (4-methylpiperazino (propionyl) dibenzo [d, g] [1,3,6] dioxazocine) -

base, we obtain a melting point 133- -136 ° C. Analysis a C21H24CIN3O3 (Ms,: 401.896) fall- nail formula. Based on: C H cl N Theory: 62.76% 6.02% 8.82% 10.46% Found.: 61.98% 6.60% 8.93% 10.20% 11

-1019

11U 198194 Β

B.) 10.0 g (0.0277 mole) of the base prepared in A are prepared as the hydrochloride salt in Example 3B. After recrystallization from isopropyl alcohol, product

c) 13.0 g (0.032 mol) of the base prepared in B. and 7.6 g (0.066 mol) of nialeic acid are salted as described in Example 1C. Recrystallization from ethanol gave 17.1 g (84.2%) of the title compound, m.p. 177-182 ° C.

Analysis for C29ll32ClN30ii (Ms .: 634.041) fall- by nail formula: C H cl N calculated: 54.94% 5.09% 5.59% 6.63% Found: 55.27% 4.89% 5.63% 6.61%

Example 19 (±) -12H-2-Chloro-12- (2-pyrrolidinopropionyl) dibenzo (d, g] [1,3,6] dioxazocine hydrochloride

A.) 28.0 g (0.083 mol) of <i) -12H-2-chloro-12- (2-chloropropionyl) di-benzene, d, g [1,3,6] dioxazocine, 21.3 g. 0.30 moles) of pyrrolidine tube 250 cm @ 2 of anhydrous benzene was heated to reflux for 10 hours. The reaction mixture was worked up as described in Example 4 / A. Crystallization and recrystallization of the products is carried out from gasoline.

24.9 g (80.3%) of (i, -12H-2-chloro-12- (2-chloropropionyl, dibenzo d, g) [1,3,6] dioxazoc base are obtained, m.p. 98-102 ° C.

Analysis for C 20 H 21 ClN 2 O 3 (Ms .: 372.854) fall- by nail formula: C H cl N Calculated: 64.43% 5.68% 9.51% 7.51% Found: 63.89% 6.03% 9.60% 7.43%

B.) The hydrochloride salt (16.0 g, 0.043 mol) was prepared as described in Example 3B. After recrystallization from isopropyl alcohol, the product weighed 14.2 g (80.7%), m.p. 223-225 ° C.

Analysis calculated for C20H22Cl2N2O3 (Ms .: 409.315):

Calculated: 58.69% 5.42% 17.32% 6.84% 8.66% Found: 59.03% 5.88% 16.93% 6.91% 8.47%

Example 20 (±) -12H-12- [2- (Isopropylamino) -propyl] -2-chloro-dibenzo [d, g] [1,3,6] dioxazocir hydrochloride

A.) 23.7 g (0.070 mol) of (1) -12H-2-chloro-12- (2-chloropropionyl) dibezole, g / l 1,3,6] dioxazocine, 17.7 g (0.21 g). mole) of isopropylamine and 250 cm ^{3 of} anhydrous benzene in a refluxing apparatus for 6 hours. The reaction mixture was worked up as described in Example 4 / A. The crude product is crystallized and recrystallized from gasoline. 18.2 g (72.1%) of (±) -12H-12- [2- (isopropylamino) propionyl] -2-chlorodi-

benzo [d, g] 11, 3,6] dioxazoc base is obtained, which has a melting point 102-105 ° C. Analysis by C19H21CIN2O · ((Ms .: 360.843) fall- by nail formula: C H cl N Calculated: 63.24% 5.87% 9.83% 7.76% Found: 62.85% 6.13% 9.98% 7.61%

weight 9.6 g (87.3%), mp 224- -227 ° C. Analysis a C19II22CI2N2O3 (Ms .: 397,304) nail formula Based on: C H cl N Cl calculated: 57.44% 5.58% 17.85% 7.05% 8.92% T.dált: 57.44% 5.70% 17.63% 6.94% 8.90%

Example 21 (- ') -! 2H-2-chloro-12- [2-methyl-3- (4-methylpiperazino) -propionyl] -dibenzo [d, g) 11,3,6] dioxazocin-d.

A.) 26.1 g (0.11 mole) of 12H-2-chloro-dibenzo [d, g] [3, 3] fi] dioxazocine, 300 cm ^{3 of} anhydrous toluene and 39.0 g (0.21 mole) of 3 The mixture of bromo-2-methylpropionyl chloride was heated at reflux for 8 hours. The mixture was cooled to 25 ° C and poured onto 300 g of crushed ice while stirring. After stirring for 2 hours, the organic phase was separated, washed with 3 x 100 cm ^{3 of} 5% sodium bicarbonate solution and then with 100 cm ^{3 of} water. After drying over anhydrous magnesium sulfate, the solvent was removed in vacuo, and the residue was crystallized from isopropyl alcohol and recrystallized from isopropyl alcohol. Yield: 33.2 g (76.1%) of (i) -12H-2-chloro-12- (3-bromo-2-methylpropionyl) dibenzole, m.p. 115-119 ° C.

Analysis a CnllisBrClNOa (Ms .: 396,688) nail formula Based on: C H Br cl N calculated: 51.4 7% 3.81% 20.15% 8.94% 3.53% Found: 51.35% 3.98% 20.20% 8.90% 3.52% B.) 28.6 g (0.072 mol) of A point by

A mixture of the resulting 3-bromo-2-methylpropionyl derivative, 2x30.0 g (2x0.295 mol) of 4-methylpiperazine and 250 cm ^{3 of} anhydrous benzene was heated at reflux for a total of 7 hours. The reaction and working-up of the reaction mixture were carried out as described in Example 4 / A. The crude product was crystallized from gasoline and then recrystallized from n-hexane.

25.3 g (84.6%) of (±) -12H-2-chloro-1,2- [2-methyl-3- (4-methylpiperazino) -propionyl) dibenzo [d, g] yl, 3, A 6-dioxazocin base is obtained, m.p. 128-131 ° C.

Analysis for C22H26CIN3O3 (Ms .: 415,921) Autumn—

by nail formula: C H cl N Calculated: 65.53% 6.30% 8.52% 10.10% Found: 62.80% 6.75% 8.63% 9.87% C.) .9.0 g (0.022 mol), Point B. by from a base and 5.2 g (0.045 mol) male acid from l / C Example salt as described

trainers. Recrystallization from acetonitrile-1121

HU 198194 Β

product weight 11.8 g ; (82.5%); readers 152-157 ° C. Analysis for C 30 H 34 ClN 3 O (Ms .: 648.068) fall- by nail formula: C Η cl N Calculated: 55.60% 5.29% 5.47% 6.48% Found: 55.78% 5.52% 5.42% 6.42%

S

Claims (2)

PATENT CLAIMS A process for the preparation of an aninoalkanoyloxydioxazocine derivative of formula I wherein X is hydrogen or halogen. A is a bond or a linear or branched alkylene group having 1 to 5 carbon atoms, R ¹ and R ² are each independently hydrogen, C 1-4 alkyl or C 3-6 cycloalkyl, or R ¹ and R ^{2 together with} the adjacent nitrogen atom and optionally another nitrogen or oxygen atom are 5- or 6-membered. forming a saturated heterocyclic group optionally substituted with a C 1 -C 4 alkyl group and pharmaceutically acceptable acid addition salts thereof with an inorganic or organic acid; a) Acylating a dioxazocine of formula II wherein X is as defined above with a compound of formula III wherein A is as defined above, Hal and Hal 'are halogen, and a resulting compound of formula IV is obtained. alkanoyldioxazocin, wherein X, A, and Hal 'are as defined above, with an amine of formula VIII, wherein R ¹ and R ² are as defined in the foregoing; obsession b) reacting a dioxazocine of formula II wherein X is as defined in the preamble, with a compound of formula V wherein A, R ¹ and R ² are as defined in the preamble, Hal is halogen; and optionally converting the resulting compound of formula (I) to a acid addition salt with a pharmaceutically acceptable inorganic or organic acid, or liberating the base of formula (1) from a resulting acid addition salt. A process for the preparation of a pharmaceutical composition, wherein a compound of formula (I) according to claim 1, wherein X, A, R ¹ and R ² is as defined in claim 1, or a pharmaceutically acceptable acid addition salt thereof. mixing with the excipient (s) customary for pharmaceutical formulation and shaping the mixture into a pharmaceutical formulation.