DD236731A1 - PROCESS FOR PREPARING NEW 5-POSITION SUBSTITUTED 5,10-DIHYDRO-11H-DIBENZO (B, E) (1,4) DIAZEPINE-11-ONEN - Google Patents

Abstract

Novel 5,10-dihydro-11H-dibenzo[b,e][1,4]diazepin-11-ones of the formula I and their physiologically tolerable salts with inorganic or organic acids, in which R<1> denotes hydrogen or chlorine, R<2> denotes hydrogen or methyl, R<3> denotes hydrogen, methyl or 2-hydroxyethyl, R<4> denotes 2-hydroxyethyl, N-morpholylcarbonylmethyl or 2-acetylaminoethyl or R<3> and R<4>, together with the N atom to which they are bonded, denote a piperazine radical which is substituted on the imino group by a (2-furanyl)carbonyl, an acetyl or a 3,4,5-trimethoxybenzoyl radical, and A denotes a group of the formula -CH2-, -CH2-CH2- or -CH(CH3)- or a direct bond, can be prepared, inter alia, by reacting a 5,10-dihydro-5-haloacyl-11H-dibenzo[b,e]- [1,4]diazepin-11-one of the formula II in which R<1>, R<2> and A have the abovementioned meaning and X denotes a halogen atom, with an amine of the formula III in which R<3> and R<4> have the abovementioned meaning, or a hydrochloride of an amine of the formula III. The compounds of the formula I have an excellent antiulcerative and secretion-inhibiting action.

Description

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Field of application of the invention

, The invention relates to a process for the preparation of new iri 5-substituted 5,10-dihydro-HH-dibenzo- [b, e] [1,4] diazepin-11-ones of the general formula I and their physiologically acceptable salts with inorganic or organic acids in which R ^{1 is} hydrogen or chlorine, R ^{2 is} hydrogen or methyl, R ^{3 is} hydrogen, methyl or 2-hydroxyethyl, R ^{4 is} 2-hydroxyethyl, N-morpholylcarbonylmethyl or 2-acetylaminoethyl or also R ³ and R ⁴ together with the N Atom to which they are attached, a piperazino radical which is substituted at the imino group by a 2-furan-carbonyl, an acetyl or 3,4,5-trimethoxybenzoyl radical, and A is a group of the formula -CH ₂ -; -CH ₂ -CH ₂ -or-CH (CH ₃ ) -a direct bond "may mean

 The compounds of the formula I have an excellent antiulceröse and sekretibnhibitory effect.

Characteristic of the known technical solutions

There are in the 5-position substituted 11H-dibenzo [b, e] [1,4] -diazepin-11-one (DE-AS 20 22790, 2065570, 1936670, 1795176, 1931487, EP 44989, DE-OS 3028001) and in the 11-position substituted 5,6-dihydro-11H-pyrido [2,3-b] - [1,4] benzodiazepin-6-ones (eg pirenzepine) (DD-PS 135490) known that a good antiulceröse and secretion inhibiting Have activity, with little or no side effects (eg, mydriatic effect) occur in the therapeutic dose range.

Object of the invention

The invention makes it possible to use new 5-substituted-5-dihydro-11H-dibenzo [b, e] [1,4] diazepine-11-ones of the formula I and their physiologically tolerated salts with inorganic or organic acids to produce with valuable pharmacological properties.

As can be seen from the comments below, they have a particular anti-ulcer and secretion-inhibiting effect.

For example, the effects of the compounds

8-chloro-5,10-dihydro-5- [bis (2-hydroxyethyl) aminoacetyl] -11H-dibenzo [b, e] [1,4] diazepin-11-one = A

5,10-dihydro-5- [bis (2-hydroxyethyl) aminoacetyl-11H-dibenzo [b, e] [1,4] diazepin-11-one. = B

5,10-Dihydro-5- (2- {4 - [(2-furanyl) carbonyl] -1-piperazinyl} -acetyl) -11H-dibenzo [b, e] [1,4] diazepine-11- on = C

8-chloro-5,10-dihydro-5- (2- {4 - [(2-furanyl) -carbonyl] -1-piperazinyl} -acetyl) -10-methyl-11H-dibenzo [b, e] [ 1,4] -diazepin-11-one = D

5,10-dihydro-10-methyl-5- [bis (2-hydroxyethyl) aminoacetyl] -11H-dibenzo [b, e] [1,4] diazepin-11-one = E on the immobilization sulk and models Phenylbutazonulkus checked, the mydriatic effect as well as the acute toxicity determined and compared with the standard compounds pirenzepine, and atropine.

The inhibitory effect on the formation of stress-induced gastric ulcers was determined by the method of DA Brodie, Gastroenterolody, 38 (1960), 50, on female rats weighing 150-180 grams from the VEB experimental animal production Schönwalde. The food limit before the start of the experiment was 48 hours, with water ad libitum. The test substances were administered orally, by gavage, immediately before the start of the test. The immobilization took place by means of plaster bandages over 18 hours. At room temperature, the room temperature was constant at 20 ^° C. At the end of the experiment, the animals were sacrificed by ether, the stomachs removed, sliced along the minor curvature, and the glandular mucosal defects assessed for number and length compared to the control group. The statistical calculation was based on probit regression analysis.

The inhibitory effect of the compounds on phenylbutazone-induced gastric ulcers was determined following the model of Beattie and coworkers, Arzneimittelforschung, 29, (1979), 1812. For the investigation, female rats of the in-house breed in the weight of 150-180 grams were used.

The food limit before the start of the test was 24 hours, with water ad libitum. During the experiment, the animals were kept in a climatic room at a temperature between 22 ⁰ C and 23 ° C. The rats were each kept at 7 o'clock in the morning for two consecutive days, c. Injection of 150 mg / kg phenylbutazone and killing took place six hours after the last injection by stroke of the neck. The prepared stomachs were cut open along the small curvature and the mucosal defects were assessed by number and length. The test substances were administered orally, half an hour before each phenylbutazone injection. The effect of the substances on the size of the pupil was measured on female mice weighing between 18 and 23 grams according to the experimental set-up of R. Pulewka, Exp. Pathol. Pharmacol. 167, (1932), 307 examined. 30, 30, 90, 120, 180 and 240 minutes after the administration of oral preparation, the pupil width was determined and the x-fold change to the starting value was calculated. An ED ₃ fold is the dose at which there is a threefold dilation of the pupil compared to baseline.

Acute toxicity was determined on 5 male and 5 female mice, respectively, weighing 18-23 grams per dose. The application of the test substances was carried out orally. The calculation of the LD ₅₀ was carried out according to Litchfield and Wilcoxon. The results of all investigations are summarized in the following table:

substance Real estate Phenylbuta Pupillo- acute toxicity quotient  - sationsulkus zonulkus   motor activity LD ₅₀ (mg / kg) MydriasisED ₃ times -ED ₅₀ (mg / kg) ED ₅₀ (mg / kg) (Mg / kg) Ulcus inhibition ED ₅₀ (Immobilisationsulkus) A: 6 5 30 2000 5 B 1 1.6 4 2000 4 C 14 20 67 2000 5 D 26 36 250 1600 10 e 27 22 95 1000 3.5 pirenzepine 11 18 30 1460 3 atropine 0.6 0.8 0.8 850 1

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The results show that the new compounds prevent the development of gastric ulcers of different origin. On both ulcer models, they show a uniform potency, which is comparable or better with the structurally similar compound pirzepine.

For all the compounds the ratio ED ₃ f _ach of the pupillary to ED ₅₀ Ulkushemmung greater or substantially greater than atropine. Thus, no mydriatic effects occur in the therapeutic dose range.

Explanation of the essence of the invention

The present invention is based on the object, in the 5-position substituted 5,11-dihydro-11H-dibenzo [b, e] - [1,4] diazepine-11-one of the general formula I and their physiologically acceptable salts with produce inorganic and organic acids and valuable pharmacological properties.

According to the present invention, the compounds of the general formula I can be prepared in various ways

getting produced. "

So you can either,.

a) a BJO-dihydro-S-haloacyl-HH-dibenzotb ^ lti ^ l-diazepine-H-on the general formula II wherein R ¹ , R ² and A have the abovementioned meaning and X represents a halogen atom, with a Amin of the general formula III, in which R ³ and R ^{4 have} the abovementioned meaning implement.

The reaction may be carried out at temperatures between room temperature and 150 ° C, preferably between 50 and 120 ⁰ C and in an inert organic solvent, optionally in the presence of an acid-binding agent such as a tertiary amine z. For example, triethylamine, pyridine, dimethylaniline, an alkali carbonate, alkali metal bicarbonate, sodium acetate or an excess of the compound of general formula III, are performed.

In the presence of an acid-binding agent, the compound of general formula III may also be used as the hydrochloride. be used.

As indifferent organic solvents, alcohols such as ethanol, n-propanol, isopropanol, ethers such as dioxane, tetrahydrofuran, ketones such as acetone, cyclohexanone, aromatic hydrocarbons such as benzene, toluene, halogenated aliphatic or aromatic hydrocarbons such as chloroform, 1,2-dichloroethane, chlorobenzene or an excess of the compound of general formula III to be reacted is used.

The starting compounds of the general formula II are known in the literature or can be prepared by reaction of a 5,10-dihydro-11H-dibenzo [b. B. Amman et al., J. Med. Chem. 6, 255 [1963] based on methods known from the literature , e] [1,4] diazepin-11-ones of the general formula IV in which R ¹ and R ^{2 have} the above meaning, with a haloacyl halide of the general formula V in which A has the abovementioned meaning, and X and X ' , which may be the same or different, are halogen atoms, such as chlorine or bromine, optionally in the presence of hydrogen halide-binding agents.

This reaction is preferably carried out in an inert organic solvent at elevated temperatures. As solvents, aromatic hydrocarbons such as benzene, toluene, xylene, cyclic ethers such as dioxane, tetrahydrofuran, but also esters such as ethyl ethanoate can be used.

In the preparation of the compounds of formula II, inorganic bases such as alkali metal carbonates or alkali metal bicarbonates may be used as the hydrogen halide or, if A is the methylene group or a direct bond, and tertiary organic amines such as triethylamine, Ν, Ν-dimethylaniline or pyridine. The resulting haloacyl products of general formula II can be used without further purification in the reaction according to the invention. ,

But you can also

b) a compound of the general formula VI, wherein R ¹ and R ² are as defined above, in an inert organic solvent, for example alcohols such as ethanol, n-propanol, isopropanol, ketones such as acetone, high-boiling ethers such as tetrahydrofuran, dioxane or aromatic Hydrocarbons such as benzene or toluene, with an amine of general formula III, wherein R ³ and R ^{4 have} the abovementioned meaning, with heating, preferably up to the boiling temperature of the reaction mixture, to the corresponding compounds of the general formula I implement, in which Radicals R ¹ to R ^{4 have} the abovementioned meaning and A is an ethylene group.

The compounds of the general formula VI used as starting compounds are known in some cases and can be prepared by methods known per se, for example by reacting a compound of the general formula IV, wherein R ¹ and R ^{2 have} the abovementioned meaning, with an acrylic acid halide or by a compound of the general formula II in which R ¹ , R ² and X have the abovementioned meaning and A is an ethylene group, in an inert organic solvent, for example higher-boiling ethers such as tetrahydrofuran and dioxane or aromatic hydrocarbons such as benzene or toluene, in the presence of tertiary organic amines such as triethylamine, pyridine or NN-Dimeihylanilin, preferably heated to the boiling point of the reaction mixture. The same elimination reaction to the 5-acryloyl compounds of general formula Vl also runs as a side reaction in the preparation of the compounds of general formula II used as starting materials in the first method (A = ethylene), if there are compounds of general formula IV with haloacyl halides of the general Formula V (A = ethylene) with the addition of tertiary bases as hydrogen halide-binding agents. The compounds of the general formula VI which are then contained as by-products in the starting compounds of the general formula II (A = ethylene) not only do not disturb the further reaction, but themselves participate in the preparation of the compounds of the general formula I (A = ethylene).

calculated found 58.54% 58.32% 5.17% 4.85% 10.78% 10.69% 9.09% 9.18%

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But you can also

c) a compound of general formula IV in which R ¹ and R ^{2 have} the abovementioned meaning, with a compound of general formula VII in which R ³ , R ⁴ and A have the abovementioned meaning and Y is a hydroxyl group or a halogen atom or when A is a direct bond, only a halogen atom, or their salts in an inert organic solvent, for example halogenated hydrocarbons such as chloroform or dichloromethane, optionally with heating, preferably at boiling heat, implement.

If the reaction is carried out with a compound of general formula VII, in which Y is a hydroxyl group, it is preferable to work in the presence of 1-methyl-2-halo-pyridinium iodide and triethylamine (1: 1). The resulting compounds of general formula I can be converted by known methods with inorganic or organic acids in their physiologically acceptable salts.

As acids, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, tartaric acid, citric acid, fumaric acid, maleic acid, succinic acid or oxalic acid can be used.

embodiments example 1

8-chloro-5,10-dihydro-5- [bis (2-hydroxyethyl) aminoacetyl-11H-dibenzo [b, e] [1,4] diazepin-11-one 6,4g (0,02 mol) S-chloro-S-chloroacetyl-OJO-dihydro-i 1H-dibenzo [b, e] [1,4] diazepin-11-one are heated to boiling point in 200 ml of chloroform and 8.4 g (0.08 mol) of diethanolamine are added dropwise ,

The reaction mixture is stirred for 2 hours under reflux, concentrated in vacuo, the residue is boiled with butyl acetate and crystallized from acetonitrile with the addition of CFO coal. The yield is 3.4 g (43.7% of theory), melting point:

188-192X (with decomposition).

Analysis for C ₁₉ H ₂ ON ₃ O ₄ Cl:

C:

H:

N:

Cl:

hydrochloride

7.8 g (0.02 mol) of 8-chloro-5,10-dihydro-5- [bis (2-hydroxyethyl) aminoacetyl] -11H-dibenzo [b, e] [1,4] diazepine 11-on are dissolved in 80 ml of isopropanol in the heat and added while still warm with 40 ml of about 13% strength isopropanolic hydrochloric acid. After cooling, the crystalline product is filtered off with suction and recrystallized from 140 ml of 93% ethanol. The yield is 4.6 g (53.8% of theory), melting point: 225-226 ° C (with decomposition). Analysis for C ₁₉ H ₂ IN ₃ O ₄ Cl ₂ :

calculated found

C: 53.53% 53.79%

H: 4.97% 4.79%

N: 9.86% 9.83%

Cl: 16.63% 16.34%

The starting S-chloro-S-chloroacetyl-SJO-dihydro-HH-dibenzoylidiazepine-H-on can be prepared as follows:

39.2 g (0.16 mol) of 8-chloro-5,10-dihydro-11H-dibenzo [b, e] - [1,4] diazepine-11 -one are suspended in 400 ml of xylene, on the oil bath heated to 100 ⁰ C bath temperature, mixed with 18.1 g (0.16 mol) of chloroacetyl chloride and stirred for 3 hours at the indicated bath temperature. Is then added dropwise again 9,04g (0.08 mol) of chloroacetyl chloride, stirred for one hour at 100 ⁰ C Badtemperatu r, drawn after cooling the crystals and dried at room temperature. The crude product is recrystallized from 800 ml of acetonitrile with addition of EPN-carbon. The yield is 34.1 g (66.3% of theory). Melting point: 245.5 ° C-247.5 ⁰ C (with decomposition).

In an analogous manner, the following compounds of general formula II were obtained by reacting the corresponding compounds of general formula IV:

With chloroacetyl chloride in xylene as solvent the 5-chloroacetyl-5,10-dihydro-11H-dibenzo [b, e] [1,4] diazepin-11-one, m. 238.5-140 ° C (from butyl acetate)

With chloroacetyl chloride in toluene as solvent, the S-chloro-S-chloroacetyl-OJO-dihydro-IO-methyl-HH-dibenzo [b, e] [1,4] diazepin-11-one, m.p. 220-221.5 ° C.,

With chloroacetyl chloride in toluene as solvent, the S-chloroacetyl-OJO-dihydro-IO-methyl-HH-dibenzotb ^ HI ^ Jdiazepinl'l-on, mp 178.5-181 ⁰ C (from acetonitrile),

With S-chloropropionyl chloride in toluene as solvent the S-chloro-is-i-chloropropionyl-SJO-dihydro-i 1 H-dibenzo- [b, e] [1,4] diazepin-11-one, F.223- 225 ° C,

With S-chloropropionyl chloride in toluene as solvent, the S-chloro-S-fS-chloropropionyl-O-SJO-dihydro-IO-methyl-HH-dibenzo [b, e] [1,4] diazepin-11-one, m.p. 163.5 -166 ° C,

With S-chloropropionyl chloride in toluene as solvent, the S-tS-chloropropionyl J-SJO-dihydro-IO-methyl-HH-dibenzo [b, e] [1,4] diazepin-11-one, m.p. 181.5-182.5 ⁰ C,

With 2-bromopropionyl chloride in toluene as solvent, the 5 - [(2-bromo) -propionyl] -8-chloro-5,10-dihydro-11H-dibenzo [b, e] [1,4] diazepin-11-one, F 268-269.5 ° C and

With 2-chloropropionyl chloride in toluene as solvent, the 5 - [(2-chloro) -propionyl] -8-chloro-5,10-dihydro-11H-dibenzo [b, e] [1,4] diazepin-11-one , F. 281-284 ⁰ C (with decomposition).

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In an analogous manner, but at room temperature, the following compounds were prepared:

With excess phosgene in ethyl or dioxane solvent S-chloro-S-chlorocarbonyl-BjiO-dihydro-11H-dibenzo [b, e] [1,4] diazepin-11-one, F. 259-262X,

With excess phosgene in tetrahydrofuran as solvent, the 5-chlorocarbonyl-5,10-dihydro-11H-dibenzo [b, e] - [1,4] diazepin-11-one, F.251-254 ° C (with decomposition) ( from acetone).

Example 2

8-chloro-5,10-dihydro-5- (2- {4 [(2-furanyl) carbonyl] -1-piperazinyl} acetyl) -11H-dibenzo [b, e] [1,4] diazepin 11-one, 12.8 g (0.04 mol) of S-chloro-B-chloroacetyl-e.iO-dihydro-HH-dibenzotbenzlH ^ ldiazepine-i 1-one are dissolved in 200 ml of toluene with 15.4 g (0.08 Mol) of 1 - [(2-furanyl) carbonyl] -piperazine was stirred at reflux for 6 hours. After cooling, 200 ml of water are added to the reaction mixture, it is stirred well and the mixture is filtered off with suction. The filter residue is washed with water, taken up in 100 ml of chloroform, shaken out with 100 ml of water and then concentrated in vacuo.

The residue is treated twice with chloroform and each time concentrated in vacuo, then 20 ml of isopropanol are added, heated for 10 minutes on the steam bath, the crystals are filtered off with suction after seeding and crystallized from 200 ml of isopropanol with the addition of CFO-Kohleum. The yield is 12.6 g (67.8% of theory), melting point: 190-193 ° C.

Analysis for C ₂₄ H ₂ IN ₄ O ₄ Cl:

calculated found

C: 62.00% 62.68%

H: 4.55% 4.74%

N: 12.05% 11.42%

Eq: 7.63% 7.68%

hydrochloride

22g (0.047 mol) of 8-chloro-5,10-dihydro-5- (2- {4 [(2-furanyl) -carbonyl] -1-piperazinyl} -acetyl) -11H-dibenzo [b, e] [ 1,4] diazepin-11-one are dissolved in 350 ml of isopropanol with gentle heating and, after careful cooling, 200 ml of about 19% strength isopropanolic hydrochloric acid are added. After standing for one hour, the solution is concentrated to dryness in vacuo, a little more isopropanol is added, the mixture is concentrated again and the slightly greasy residue is recrystallized from 100 ml of n-propanol with CFO-carbon. It is then recrystallized again from 50% ethanol. The yield is 15.2 g (61.8% of theory), melting point: 209-215 ⁰ C (with decomposition)

Analysis for the hydrate C ₂₄ H ₂₄ N ₄ O ₅ Cl ₂ :

C:

H:

N:

Cl: Example 3

S-chloro-SJO-dihydro-S-iKN-morpholylcarbonylmethoxy-aminol-acetyl-HH-dibenzotb ^ JII ^ diazepine-H-one 6.4g (0.02% MoDS-chloro-6-chloroacetyl-S ^ O-dihydro- IIH-dibenzotb.elH ^ Jdiazepin-ii-on are stirred in 100 ml of dichloroethane with 14.4 g (0.08 mol) of glycylmorpholide and 10.0 g (1.00 mol) of triethylamine at reflux for 3 hours disubstituted by-product formed.

The reaction mixture is shaken three times with 50 ml of water, then twice with 10 ml of 1: 1 dilute HCl and then the combined hydrochloric acid phases with 1: 1 dilute ammonia solution alkaline, the alkaline solution is made three times with 50 ml of chloroform, the combined chloroform phases Once extracted with 10 ml of water, then dried over Na ₂ SO ₄ and concentrated to dryness in vacuo

 hydrochloride

The above residue (10.2 g) is dissolved in 100 ml of dry acetone, passed under stirring at room temperature HCl gas until acidic reaction, can be stirred for another 2 hours, the crystals are filtered off with suction, washed with a little dry acetone and crystallized after Dry from 96% ethanol with CFO-charcoal. The yield is 3.1 g (32.1% of theory), melting point: 212 ^° C. (with decomposition) Analysis for the hydrate C ₂₁ H ₂₄ N ₄ O ₅ Cl ₂ :

, calculated found

C: 52.18% 51.76%

H: 4.79% 4.94%

N: 11.59% 11.47%

Cl: 14.66% 14.68%

H ₂ O: 3.73% 3.1%

Example 4

8-chloro-5,10-dihydro-5 - {[4- (3,4,5-trimethoxybenzoyl) -1-piperazinyl] acetyl} -11H-dibenzo [b, e] [1,4] diazepin-11 -on 6.4 g (0.02 mol) of S-chloro-6-chloroacetyl-SJO-dihydro-HH-dibenzotbenzyldiazepine-i 1-one are dissolved in 50 ml of toluene containing 8.37 g (0.025 mol) of N- (3, 4,5-trimethoxybenzoyl) piperazine and 2.53 g (0.025 mol) of triethylamine were stirred for 2 hours at reflux.

The reaction mixture is then concentrated to dryness, added to 80 ml of chloroform, heated until almost all solid product has gone into solution, shaking the chloroform phase twice with 50ml of water, whereby a clear solution is formed and then extracted twice with 20ml of 2: 1 dilute hydrochloric acid , The combined hydrochloric acid phases are shaken out with 20 ml of chloroform, made alkaline with 1: 1 dilute ammonia solution and extracted three times with 50 ml of chloroform.

The chloroform phase is extracted once with 20 ml of water, dried over Na ₂ SO ₄ and concentrated to dryness. The residue is boiled up with 20 ml of acetonitrile and, after cooling, the crystallizate is filtered off with suction.

After drying, it is added to 50 ml of isopropanol, heated and added in the heat of isopropanolic hydrochloric acid until acidic reaction, the entire product goes into solution. The solution is boiled with CFO-carbon, filtered and evaporated to dryness.

calculated found 55.50% 54.99% 4.66% 4.93% 10.79% 11.37% 13.65% 13.70%

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The residue is re-boiled with isopropanol and sucks after cooling, the hydrochloride. The yield is 5.24 g (41.7% of theory), melting point: 236 ° C (with decomposition).

Analysis for the hydrate C 29H ₃₃ N ₄ O ₇ , ₅ CI: found calculated 55.07% C: 55.42% 5.33% H: 5.29% 8.21% N: 8.91% 11.20% Cl: 11.45% 4.5% H ₂ O: (1,5MoI) 4.4%

Example 5

5,10-Dihydro-5- [bis- (2-hydroxyethyl) aminoacetyl] -11H-dibenzo [b, e] [1,4] diazepine-11-one 5.73g (0.02 mol) S- Chloroacetyl-S ^ O-dihydro-HH-dibenzo-Ib ^ Hi ^ ldiazepin-H-on and 100 ml of chloroform are heated to boiling, added dropwise within 1 hour 8.44g (0.08 mol) of diethanolamine in a little chloroform and 3 hours at Boiling temperature stirred. After cooling, the chloroform phase is shaken with 20 ml of NaHCO ₃ solution (2 g of NaHCO ₃ in 50 ml of water), twice with 10 ml and once with 5 ml of 1: 2 dilute hydrochloric acid. The combined hydrochloric acid phases are poured into 50 ml of 1: 1 dilute ammonia solution. The basic solution is then extracted three times with 50 ml of chloroform, the combined chloroform is dried over Na ₂ SO ₄ and concentrated to dryness. The residue is mixed with 10 ml of isopropanol, brought into solution with heating and after inoculation, the crystals are filtered off with suction. It is recrystallized from 35 ml of acetonitrile. The yield is 1.8 g (25.3% of theory), melting point: 144 ° C (with decomposition). Analysis for Ci _g H ₂ i N ₃ O ₄ :

calculated found

C: 64.21% 64.65%

H: 5.96% 6.12%

N: 11.82% 11.82%

hydrochloride

7g (0.015 mol) of 5,10-dihydro-5- [bis (2-hydroxyethyl) -amineacetyl] -11H-dibenzo [b, e] [1,4] diazepine-11-one are dissolved in 210 ml of isopropanol with heating , After cooling, 7 ml of isopropanolic hydrochloric acid (about 19% strength) and then 35 ml of ether are added with stirring, the reaction mixture is allowed to stand for 12 hours, the crystals are filtered off with suction and dried in a desiccator. The crude product is recrystallized from 60 ml of methanol with CFO-carbon. The yield is 2.99 g (39.5% of theory), melting point: 211 ° C-214 ° C (with decomposition). Analysis for C-IgH ₂₂ N ₃ O ₄ Cl:

calculated found

C: 58.24% 58.23%

H: 5.66% 5.73%

N: 10.72% 11.01%

Cl: 9.05% 9.15%

Example 6

5,10-Dihydro-5- (2- {4 - [(2-furanyl) -carbonyi] -1-piperazinyl} -acetyl) -11H-dibenzo [b, e] [1,4] diazepine-11- on 5.8 g (0.02 mol) of 5-chloroacetyl-5,10-dihydro-11H-dibenzo [b, e] [1,4] diazepine-11-one, 100 ml of chloroform and 7.2 g (0.04 mol) 1 - [(2-Furanyl) -carbonyl] -piperazine are refluxed for 7 hours with stirring. After the reaction, the cooled reaction solution is shaken twice with 30 ml of water, twice with 10 ml and once with 5 ml of 1: 1 dilute hydrochloric acid. The combined hydrochloric acid phases are shaken out once with 30 ml of chloroform and poured into 100 ml of 1: 1 dilute ammonia solution, whereby an oily product precipitates, which is taken up in 50 ml of chloroform after pouring off the aqueous-alkaline phase. The aqueous-alkaline phase is shaken out twice more with 50 ml of chloroform and the combined chloroform phases are dried after drying over Na ₂ SO _{4 in} a vacuum to dryness. The residue is boiled with 20 ml of toluene, the crystals are filtered off with suction after cooling and recrystallized from 110 ml of 96% ethanol with CFO-carbon. The yield is 3.8 g (44.2% of theory), melting point: 230 ° C-233 ° C. Analysis for C ₂₄ H ₂₂ N ₄ O _4:

calculated found

C: 66.97% 66.54%

H: 5.15% 5.19%

N: 13.02% 12.33%

hydrochloride

10g (0.023 moles) of 5,10-dihydro-5- (2- {4 - [(2-furanyl) -carbonyl] -1-piperazinyl} -acetyl) -11H-dibenzo [b, e] [1,4 ] diazepin-11-one are dissolved in 675 ml of isopropanol, boiled with CFO-carbon 15 minutr 1, sucked bare and added while hot with 10 ml of isopropanolic hydrochloric acid (about 19%). Upon cooling, the hydrochloride crystallizes with one mole of water. Analysis for the hydrate C ₂₄ H ₂₅ N ₄ O ₅ Cl:

found

59.08%

5.38%

11.03%

7.17%

3.4%

Example 7

5,10-Dihydro-5- [bis (2-hydroxyethyl) aminoacetyl] -10-methyl-11H-dibenzo [b, e] [1,4] diazepin-11-one 6,02g (0.02%) Moles) of S-chloroacetyl-O-O-dihydro-IO-methyl-N H-dibenzo [b, e] [1,4] diazepin-11-one are dissolved in 100 ml of 1,2-dichloroethane

calculated C: 59.44% H: 5.20% N: 11.55% Cl: 7.31% H ₂ O: 3.7%

-7- 557 66

heated to reflux, 8.44g (0.08 mol) of diethanolamine was slowly added dropwise and the reaction mixture stirred for 4 hours at reflux. After cooling, it is shaken once with 30 ml of 10% NaHCO ₃ solution, twice with 10 ml and once with 5 ml of 1: 1 dilute hydrochloric acid and the combined hydrochloric acid phases once with 30 ml of chloroform.

100 ml of 1: 1 dilute ammonia solution are added to the hydrochloric acid phases, extracted by shaking three times with 30 ml of chloroform, the chloroform phases are dried over Na ₂ SO ₄ and concentrated to dryness in vacuo.

The residue is dissolved in 30 ml of dry acetone and hydrogen chloride is passed in until acidic reaction. This results in a greasy product that crystallizes on boiling. The hydrochloride is recrystallized from 40 ml of 96% ethanol with CF 2 -coal and dried at 100 ° C and 1 torr. The yield is 4.0 g (49.3% of theory), melting point: 196-199 ⁰ C (with decomposition).

Analysis for C20H24N3O4CI:

calculated found

C: 59.19% 59.33%

H: 5.96% 5.97%

N: 10.35% 10.42

Cl: 8.74% 8.70%

Example 8

8-chloro-5,10-dihydro-5- [bis (2-hydroxyethyl) aminoacetyl] -10-methyl-11H-dibenzo [b, e] [1,4] diazepin-11-one 6,7g (0.02 mol) of S-chloro-O-chloroacetyl-S ^ O-dihydro-IO-methyl-IIH-dibenzo- [b, e] [1,4] diazepin-11-one and 100 ml of chloroform are added with stirring heated to boiling and 8.44g (0.08 mol) of diethanolamine in 5 ml of chloroform is slowly added dropwise. The mixture is stirred for 7 hours at reflux, the cooled reaction mixture is extracted twice with 50 ml of water, the chloroform extracted phase twice with 10 ml and once with 5 ml of 1: 1 dilute hydrochloric acid, the combined hydrochloric acid phases extracted with 50 ml of chloroform, mixed with 100 ml 1: 1 dilute ammonia solution and shaken three times with 50 ml of chloroform, the precipitated product goes into solution.

The combined chloroform phases are shaken out with 50 ml of water, dried over Na ₂ SO ₄ and evaporated to dryness in vacuo.

The residue is dissolved in 30 ml of isopropanol with heating, the solution is cooled again and hydrogen chloride is introduced until the acid reaction. It precipitates a greasy product that crystallizes on boiling. It is filtered off with suction and dried at room temperature. The yield is 6.2 g (70.4% of theory), melting point: 127-150 ⁰ C (with decomposition).

Analysis for C20H23N3O4CI2:

calculated found

C: 54.56% 54.43%

H: 5.27% 6.01%

N: 9.54% 9.03%

Cl: 16.10% 15.48%

Example 9

8-Chloro-5,10-dihydro-5- [bis (2-hydroxyethyl) -aminocarbonyl] -11H-dibenzo [b, e] [1,4] diazepin-11-one 12,3g (0,04 mol) S-chloro-O-chlorocarbonyl-OJO-dihydro-i 1 H-dibenzo [b, e] [1,4] diazepin-11-one (m.p .: 257-260 ° C) and 4.0 g (0.04 mol ) Triethylamine are heated in 200 ml of chloroform with stirring and reflux and added dropwise within half an hour 5.3 g (0.05 mol) of diethanolamine. The reaction mixture is stirred for half an hour at reflux, shaking after cooling, the chloroform solution with 100 ml of water, dried briefly over sodium sulfate and concentrated to dryness in vacuo. The remaining residue is recrystallized from 20 ml of isopropanol.

The yield was 9.7g (66.9% derTheorie), Melting point: 190-195 ⁰ C (with decomposition).

Analysis for Ci ₈ H ₁₈ N ₃ O ₄ Cl:

C H N Cl

calculated: 57.60% 4.83% 11.18% 9.44%

found: 58.89% 4.91% 11.37% 9.45%

Example 10

8-chloro-5,10-dihydro-5- {3- [bis (2-hydroxyethyl) amino] propionyl} -11H-dibenzo [b, e] [1,4] diazepin-11-one 40 , 2g (0.12 mol) of S-chloro-6-chloropropionyl-SJO-dihydro-H-dibenzo [b, e] [1,4] diazepin-11-one and 27.4g (0.26 mol) of diethanolamine stirred in 300 ml of chloroform for 6 hours at reflux. After cooling, the precipitated diethanolamine hydrochloride is separated off, the chloroform phase is concentrated to dryness in vacuo, the residue is partitioned between 300 ml of chloroform and 100 ml of 1: 2 dilute HCl and the hydrochloric acid phase is separated off. After the lower layers of the hydrochloric acid phase with 300 ml of chloroform, the pH 10 is adjusted with 1: 1 dilute ammonia solution, shaken well, the chloroform phase separated and dried briefly over Na ₂ SO ₄ . After some time, the final product falls (crude yield:

28.1 g = 58% of the theory, mp. 164-168 ⁰ C).

It is recrystallized from 750 ml of acetonitrile with CFO-carbon. The final product is still contaminated by acryloyl compound.

The yield was 19,1g (39,4% derTheorie), Melting point: 165-171 ⁰ C.

Hydrochloride:

14 g (0.035 mol) of 8-chloro-5,10-dihydro-5- {3- [bis (2-hydroxyethyl) amino] propionyl} -11H-dibenzo [b, e] [1,4] diazepine -11-one are dissolved in the boiling heat in 200 ml of isopropanol and after cooling with 150 ml of isopropanolic hydrochloric acid until acid reaction. The solution is concentrated to dryness in vacuo, 10 ml of isopropanol are added three times, the mixture is concentrated to dryness in vacuo, 15 ml of isopropanol are again added, the mixture is boiled on a steam bath, the crystallisate is filtered off with suction and dried at room temperature. The hydrochloride is recrystallized on 100 ml of 96% alcohol with CFO-carbon. The yield is 5.3 g (34.6% of theory), melting point: 176-186 ⁰ C (with decomposition).

Analysis for C ₂₀ H ₂₃ N ₃ O ₄ Cl ₂ :

C H N Cl

calculated: 54.56% 5.27% 9.54% 16.10%

found: 54.58% 5.44% 10.22% 16.26%

-5- 557

Example 11

8-chloro-5,10-dihydro-5- (2-} 4 - [(2-furanyl) carbonyl] -1-piperazinyl {-propionyl) -11H-dibenzo [b, e] [1,4] diazepin -11-one 12.2 g (0.04 mol) of 5- (2-bromo-propionyl) -8-chloro-5,10-dihydro-11H-dibenzo [b, e] [1,4] diazepine-11- of 17.2 g (0.04 mol) of 1 - [(2- * furanyl-1-carbonyl-1-piperazine hydrochloride and 16 g (0.16 mol) of triethylamine are stirred in 200 ml of dioxane for 8 hours under reflux, again 4.4 g (0.01 1) [(2-furanyl) -carbonyl] -piperazine hydrochloride and 1.0 g (0.01 mol) of triethylamine were added and the mixture was stirred under reflux for a further 8 hours, then the dioxane was distilled off in vacuo, 200 ml of chloroform and 100 ml of water, it is stirred well, the phases are separated and the chloroform phase is shaken once with 100 ml of 2: 1 dilute HCl and once with 50 ml of 1: 2 dilute HCl.

The combined hydrochloric acid phases are underlaid with chloroform, adjusted with stirring and cooling with concentrated ammonia solution to pH 9, the chloroform phase separated, dried over Na ₂ SO ₄ and concentrated to dryness in vacuo.

The residue is heated on the steam bath with about 10 ml of isopropanol, allowed to crystallize, filtered off with suction, washed with a little isopropanol and dried at room temperature. The crude product was boiled with 40 ml of acetonitrile and dried at room temperature. The yield is 7.3 g (38.1% of theory), melting point: 238-244 ° C (with decomposition).

Analysis for C ₂₅ H ₂₃ N ₄ O ₂ Cl:

C H N Cl

calculated: 62.70% 4.84% 10.87% 7.40%

found: 62.10% 5.15% 11.45% 7.40%

Hydrochloride:

22.7 g (0.047 mol) of 8-chloro-5,10-dihydro-5- (2-) 4 - [(2-furanyl) carbonyl] -1-piperazinyl {-propionyl) -11H-dibenzo [b, e] [1,4] diazepin-11-one are suspended in 200 ml of isopropanol, mixed with 200 ml of isopropanolic hydrochloric acid (about 19% strength) and heated for half an hour on a water bath. There remains a residue that is sucked off. The solution is concentrated to dryness in vacuo. The greasy residue is mixed with 20 ml of isopropanol, evaporated to dryness in vacuo and taken up again with 20 ml of absolute ethanol and again evaporated to dryness in vacuo. The residue is crystallized from 175 ml of 60% isopropanol with CFO-carbon and dried again as indicated above. The yield is 6.2 g (25% of theory), melting point: 212 ° C (with decomposition). Analysis for the Semihydrate C ₂₅ H ₂₅ N ₄ O ₄ , gCl ₂ :

CHN Cl 0.5MoIH ₂ O

calculated: 57.26% 4.81% 10.68% 13.52% 3.40%

found: 57.23% 5.02% 10.73% 12.38% 2.50%

If the mother liquor is recrystallized with 500 ml of isopropanol, hydrochloride is recrystallised, which is filtered off with suction and dried as above.

The yield of the replenishment is 3.0 g (12.1% of theory), melting point: 224-231 ⁰ C (with decomposition). Analysis for the Semihydrate C ₂ SH ₂₆ N ₄ O ₄₁₅ Cl ₂ :

C H N Cl

calculated: 57.26% 4.81% 10.68% 13.52%

found: 57,51% 4,74% 10,49% 13,41%

Example 12

8-chloro-5,10-dihydro-5 - (} 4 - [(2-furanyl) carbonyl] piperazine-1-yl {acetyl) -10-methyl-11H-dibenzo [b, e] [1 , 4] -diazepin-11-one 6.7 g (0.02 mol) of S-chloro-S-chloroacetyl-6JO-dihydro-10-methyl-IIH-dibenzoilb, ki ^ ldiazepin-ii-one, 8.8 g ( 0.04 mol) of 1 - [(2-furanyl) carbonyl] piperazine hydrochloride and 6.0 g (0.06 mol) of triethylamine are stirred in 70 ml of chloroform at reflux for 7 hours. 100 ml of water are added to the cooled reaction solution, the mixture is thoroughly stirred, the phases are separated and the chloroform phase is extracted with 100 ml of 2: 1 dilute hydrochloric acid. 100 ml of chloroform and 140 ml of 1: 1 dilute ammonia solution are added to the hydrochloric acid phase, stirred thoroughly, the separated chloroform phase dried over Na ₂ SO ₄ and concentrated to dryness in vacuo. The residue is boiled with 10 ml of isopropanol, filtered off with suction, dried at room temperature and; crystallized from absolute alcohol with CFO coal.

The yield is 5.4 g (56.01% of theory), melting point: 189-194 ⁰ C (with decomposition). Analysis for C ₂₅ H ₂₃ N ₄ O ₄ Cl:

C H N Cl

calculated: 62.70% 4.84% 11.70% 7.40%

found: 62.33% 4.89% 11.43% 7.61%

Hydrochloride:

14.4 g (0.03 mol) of 8-chloro-5,10-dihydro-5 - (} 4 - [(2-furanyl) -carbony!] - 1-piperazinyl {acetyl) -10-methyl-11H-dibenzo - [b, e] [1,4] diazepin-11-one are suspended in 80 ml of isopropanol and treated with 100 ml of isopropanolic hydrochloric acid (about 19%). The mixture is then heated gently, dissolving the entire free base. The solution is evaporated to dryness in vacuo and boiled up with alcohol> whereby a greasy solid mass crystallizes. The residue is redissolved in isopropanol and the hydrochloride is precipitated with 500 ml of ether. The crystals are filtered off with suction, dried in a desiccator over NaOH (water-jet vacuum) and dried at 2 torr over P ₂ O _{5 for} 8 hours. The yield is 11.4 g (72.3% of theory), melting point: 100X / 160-169 ⁰ C (with decomposition)

Analysis for the hydrate C ₂₅ H ₂₅ N ₄ O _4-5 Cl ₂ :

C 'HN Cl 0.5MoIH ₂ O

calculated: 57.26% 4.81% 10.68% 13.73% 1.72%

found: 57.43% 5.04% 10.48% 13.53% 2.40%

Analogously to Examples 1 to 12, the compounds listed in the following table were prepared.

Example R ¹ R ² R ³

melting point

Yield%

13 Cl H O - 147 ⁰ C (with decomposition) 65.6 (acetonitrile) 14 Cl H -C ₂ H ₄ OH -CH ₃ -CH ₂ - 161 to 162.5 ⁰ C (butyl acetate) 59; 7 hydrochloride: 244.5 to 246 ⁰ C (with decomposition) 15 Cl H -H-C ₂ H ₄ OH -CH ₂ - 134-139 ° C (with decomposition) 49.6 (isopropanol) hydrochloride: 252.5-255 ⁰ C (with decomposition)

Cl H

-CH ₃ -CH ₂ CO-

-CH ₂ - 120 ^° C (with decomposition)

(Ethanoic acid ethyl ester) hydrochloride: 204 ^° C. (with decomposition)

54.2

Cl

-CH CH ₀ CH ₀ -IT 0 - ^CH 2 2-2 2 x_y

Hydrochloride: 49.1

237.5 to 242 ⁰ C (with decomposition) (85% ethanol)

Cl

Cl

N-C-CH. I 0 "

Hydrochloride:

222 ⁰ C (decomposition)

(abs. ethanol)

36

19 Cl H H -CH ₂ CH, , BH-C-CH ₀ - ii ³ 0 -CH ₂ - Hydrochloride: 223-226 ⁰ C (with decomposition) (isopropanol) 58.9 20 Cl H -C ₂ H ₄ OH -C ₂ H ₄ OH -CH (CH ₃ ) - 167-17O ⁰ C (isopropanol) 7.4

r ~ \

-CH (CH ₃ ) - 132 ° C-137 ° C (acetonitrile) hydrochloride: 21O ⁰ C (with decomposition) (acetonitrile)

24.5

22 HH -CH ₃ -CH _n CO-

172.5-177 ° C

(Isopropanol)

Hydrochloride:

190 ^° C (with decomposition)

57.6

-CH ₃

IJ-C 0

-CH ₂ - (161 ° C) 166-17O ⁰ C

(Isopropanol) hydrochloride: 16O ⁰ C (with decomposition)

65.2

Example 13

5,10-Dihydro-5- [bis (2-hydroxyethyl) aminoacetyl] -11H-dibenzo [b, e] [1,4] -diazepin-11-one.HCl 46g (0.16 mol) of S- Chloroacetyl-SJO-dihydro-HH-dibenzoIb ^ IH ^ J-diazepine-ii-one, 200 ml of dimethylformamide and 33.76 g (0.32 mol) of diethanolamine are stirred for 8 hours at room temperature and allowed to stand for 12 hours at this temperature. Thereafter, the reaction mixture is mixed with 1 g of carbon black-carbon, stirred for 1 hour at room temperature, the charcoal is filtered off with suction and the solution is concentrated to dryness in vacuo. The liquid residue is mixed with 200 ml of chloroform, shaken out with 20 ml of water and concentrated again. 200 ml of acetone are then added and mixed with freshly prepared acetonic hydrochloric acid or concentrated hydrochloric acid (about 15 ml) until the acid reaction. It first deposits a greasy mass which slowly crystallizes (yield: 54g = 86.1% of theory). The crude product is filtered off with suction, washed with acetone, dissolved in the 12- to 13-fold amount of methanol, heated for half an hour with 5g CFO-carbon, clear sucked, concentrated to about ^1/3 and 200 ml of acetone. The crystals are dissolved again with 15 times the amount of methanol, heated again with 2.5 g of CFO-carbon, filtered off, concentrated to / 3 and sucks the crystals from. The product is still boiled with 5 times the amount of acetone. The yield is 43.5 g ^ 69.4% of theory. Melting point: 208 ^° C. (with decomposition).

Claims (13)

-1 - 557 66 Invention claim: A process for the preparation of novel 5-membered 5,10-dihydro-11H-dibenzo [be, e] [1,4] diazepine 11-independent general formula I and their physiologically acceptable salts with inorganic or organic acids, wherein R ^{1 is} hydrogen or chlorine, R ^{2 is} hydrogen or methyl, R ^{3 is} hydrogen, methyl or 2-hydroxyethyl, R ^{4 is} 2-hydroxyethyl, NM orpholylcarbonylmethyl or 2-acetylaminoethyl or R ³ and R ⁴ together with the N-atom to which they are attached, a piperazine radical which is substituted at the imino group by a (2-furanyl) carbonyl, an acetyl or a 3,4,5-Trimethoxybenzoylrest, and A is a group of the formula -CH ₂ -, -CH ₂ -CH ₂ - or -CH (CH ₃ ) - or a direct bond, characterized in that either a) a S.IO-dihydro-S-haloacyl-IIH-dibenzotb ^ HMl-diazepine-H-on the general formula II, wherein R ¹ , R ² , and A have the abovementioned meaning and X represents a halogen atom, with an amine of general formula III in which R ³ and R ^{4 have} the abovementioned meaning, or a hydrochloride of an amine of general formula III, or b) a compound of general formula VI, wherein R ¹ and R ^{2 have} the abovementioned meaning, with an amine of the general formula III, wherein R ³ and R ^{4 have} the abovementioned meaning, or c) a 5,10-dihydro-11H-dibenzo [b, e] [1,4] diazepin-11-one of general formula IV, wherein R ¹ and R ^{2 have} the abovementioned meaning, with a compound of general formula VII, in which R ³ , R ⁴ and A have the abovementioned meaning and Y represents the hydroxyl group or a halogen atom or, when A is a direct bond, only one halogen atom, or their salts. 2. The method according to item 1, characterized in that the reactions are carried out in an inert organic solvent. 3. The method according to points 1 a and 2, characterized in that the reaction of the compounds of general formula II with the compounds of general formula III or the hydrochlorides at temperatures between room temperature and 150 ⁰ C, preferably between 50 and 120 ⁰ C, is carried out. 4. The method according to points 1 a, 2 and 3, characterized in that as indifferent organic solvent in the reaction of the compounds of general formula II with the compounds of general formula III or their hydrochlorides, alcohols such as ethanol, n-propanol, isopropanol, Ethers such as dioxane or tetrahydrofuran, ketones such as acetone or cyclohexanone, aromatic hydrocarbons such as benzene or toluene or halogenated aliphatic or aromatic hydrocarbons such as chloroform, 1,2-dichloroethane or chlorobenzene. 5. The method according to points 1 a and 2 to 4, characterized in that an excess of the amine used of the general formula III is used as the solvent. 6. The method according to points 1 a and 2 to 5, characterized in that the reaction of the compounds of general formula II is carried out with the compounds of general formula III in the presence of an acid acceptor. 7. The method according to points 1 a and 2 to 6, characterized in that alkali metal carbonates or alkali metal bicarbonates are used as the acid acceptor. 8. The method according to points 1 a and 2 to 6, characterized in that are used as Saureacceptoren tertiary amines such as triethylamine, pyridine or Ν, Ν-dimethylaniline. 9. The method according to points 1 b and 2, characterized in that in the reaction of a compound of general formula VI with a compound of general formula III as indifferent organic solvent alcohols such as ethanol, n-propanol or isopropanol, ketones such as acetone or cyclohexanone , higher boiling ethers such as dioxane or tetrahydrofuran or aromatic hydrocarbons such as benzene or toluene are used. 10. The method according to points 1 b, 2 and 9, characterized in that the reaction of the compounds of general formula VI with the amines of general formula III with heating, preferably up to the boiling temperature of the reaction mixture, takes place. 11. The method according to points 1 c and 2, characterized in that are used as the inert organic solvent halogenated hydrocarbons such as chloroform or dichloromethane. 12. The method according to points 1 c, 2 and 11, characterized in that the reaction is carried out with heating to the boiling point. 13. The method according to the items 1 c, 2,11 and 12, characterized in that when yin of the general formula VII is a hydroxyl group, the reaction in the presence of 1-methyl-2-halopyridinium iodide and triethylamine is performed. For this 2 pages formulas