CS247562B1 - New substituted 5,10-dihydro-11h-dibenzo (b,e)(1,4)-diazepin-11-ons and method of their production - 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

(54) Novel 5-substituted 5'-dihydro-11H-dibanzo [b, e] [1 ₍ 4) -diazepin-11-ones and process for their preparation

The novel 5-substituted 5,10-dihydro-1H-dibenso [b, e] [1,4] diazepin-11-ones of formula I wherein the substituents are as defined in the definition.

The invention also relates to a process for the preparation of these substances.

The present invention relates to novel 5-substituted 5,10-dihydro-11H-dibenzo [b, 6] Q, 4'-diazepin-11-ones and to a process for their preparation. These are compounds of formula I

(I) where

r ^! represents hydrogen or C ^hl Oru, R ² is hydrogen or methyl R ³ represents a hydrogen atom, methyl or 2-hydroxythyl, R ⁴ represents 2-hydroxyythyl, N-methylphosphinylmethyl or 2-acetylaminoethyl or 3 4 can be substituents R a. R together with the nitrogen atom to which they are attached form a piperazine moiety which is substituted on the imino group with a 2-phthalcarbonyl, acetyo or 3,4,5-trimethoxybenzoyl moiety, and AND represents a group of formula -C -C-, -C ^C -C- or -01 (O 0) or a direct chemical bond,

as well as the physiologically acceptable salts of these compounds with inorganic or organic acids.

The compounds of formula I have a pronounced anti-ulcer effect and inhibit gastric juice secretion.

There are known 5-substituted 11H-dibenzo [b, e] -1,44'-azepin-11-ones (DAS 20 22 790,

65 570, 19 36 670, 17 95 176, 19 31 487, EP 44 989 and DOS 3 028

028 001) as well as the 11-substituted 5,6,6-dihydro-11H-pyrido 2,3-b 1,4 benzodiazepin-6-ones (e.g. pirenzepine, described in GDR 135 490), these have an anti-ulcer and anti-secretory effect, with little side effects, such as pupil enlargement, or no side effects at therapeutic doses.

The process of the present invention provides the novel 5-substituted 5,10-trimethyl-11H-ribenzylbenzylbenzyl-11-ones of formula (I) and their physiologically acceptable salts with inorganic or organic acids, e.g. a substance with valuable pharmacological properties.

As will be apparent from the following experiments, these are substances which have, in particular, an anti-ulcer and anti-secretory effect.

The experiments were carried out, for example, with the following compounds:

B-chloro-S, Ю-^ ^Г---bis- (2-hydroxyethyl) aminomethyl] -1 H -dibenzo [1,4,4] diazepin-11-one (= compound A)

5,10hdihydso 5- [bis-h ^(t 2Rh dyet ythyl ^h) 1- noinoayety ¹ lΗ- benzoEb ^{ri e]} 1,4 £] ^ azepine-l-one (= compound B)

5.10-Dihydro-5- 2- [ ^{4- [} 2-furancarbonyl] -1-piperazinyl / acetyl-1H-dibenzo [b, e] [1,1] diazepin-11-one (= compound C)

8^-ch^lsteed^-5.10^-dihydro^-5^- 2- /⁴-^[2^-Furankarbon^yl] -l-^piperaz^andnyl^/acetyl^-1O^-meth^yl^-11H -dibenzorb, ej [1, ^ '- iazepine-¹ 1-on (= compound D)

¹ 0- fifth ^{dihydroquinazolin-methylamino} ro- ^{10 -5} l - bis- ^{(2-hydroxypropane y} eth ^y l) aminoacetate ^yl -NH-dibenzo ^[b, e] ^{[l, 4 J-d} phase forms of PIN ll-on (= compound E)

These compounds were investigated in a model of immobilization ulcers and ulcers caused by phenylbutazone, pupil enlargement efficacy and acute toxicity were also investigated, compared with standard compounds pirenzepine and atropine.

The effect on gastric ulceration induced by a stressful situation was investigated as described by D, A. Brodie, Gastroenterology, 38 (1960), 50 on 150-180 g female rats (VEB Schonwalde experimental menagerie).

Prior to the experiment, the rats were fasted for 48 hours with water administered ad libitum. The test substances were administered orally by swallowing probe immediately prior to the experiment. Immobilization was performed with gypsum for 18 hours.

The ^p r ^u b ^of hu ^p o ^{on the} usu and maintain ^and tub st ^Ala te ^pl OTA ² 0 ° C. After ^the usu ^p o and ^{the IR} Vol ata sacrificed with ether, the stomachs were removed, sectioned along a small curvature and mucosal defects were evaluated by size and number compared to control group animals. Probit regression analysis was used for statistical evaluation.

The inhibition of ulceration after phenylbutazone was investigated according to the method of Beattie et al., Arzneimittelforschung, 29 (1979), 1812. Female female rats weighing 150-180 g were used.

The rats were kept without food for 24 hours prior to the experiment, water was administered ad libitum. On average, ^Ube hu ^p b ^y la grazing animals ^of the ATA-making at that ^I lo ^{p 22} to ²³ ° C. ^K r ^y alone ^would Ia ^d va n ^{d y} always administered in 7.00 h in the morning injection of 150 mg / kg of phenylbutazone, rats were sacrificed 6 hours after the last injection by a blow to the neck. The prepared stomachs were incised along a small curvature and mucosal defects were evaluated by number and size. Test substances were administered orally, 1/2 hour before each phenylbutazone injection.

The effect of the test substances on pupil size was studied in female mice weighing 18-23 g as described by R. Pulewka, Exp. Pathol. Pharmakol. 167 (1932), 307th pupil width was determined 30, 60, 90, 120, 180 and 240 minutes after oral administration of the test substance and the result was expressed as a multiple of the original pupil width.

The dose at which the pupil widened three times compared to the observed baseline was determined as EDg.

Acute toxicity was determined in groups of 5 male males and 5 female females weighing 18 to 23 g each for a single dose of the test substance. Test substances were administered orally. . The LDj-q value was calculated by the Litchfield and Wilcoxon method.

The results of all the above experiments are summarized in the following table:

Table

Merge- Immune ulcer Phenylbutazo- RooZšřeaí Akktní to- Kvvočent nina bilizace new ulcer pupils xicita mydriasis - ED value. ED 50 ₀ (mg / kg) ED50 (mg / kg) ED3 (mg / kg) LD _5Q (mg / kg) EDj-θ for immobilization ulcer AND 6 5 30 2 000 5 (B) 1 1.6 4 2 000 4 ' C 14 20 May 67 2 000 5 D 26 36 250 1 600 10 E 27 Mar: 22nd 95 1 000 3.5 pireauepia : 11 18 30 1 460 3 atropine 0.6 0.8 0.8 850 1

The results show that the novel compounds produced by the process of the invention prevent gastric ulcers.

In experiments with both ulceration models, approximately the same effect was seen which was comparable to or better than that of pirenzepine.

For all compounds produced by the method of the invention, the ratio of the pupil enlargement effect expressed as ED? And the effect on gastric ulcer expressed as εϋ ^ θ is greater or substantially greater than that of atropine. This means that there is no widening of the pupil at the treatment doses.

Accordingly, the present invention provides a process for the preparation of 5-substituted 5,11-dihydro-11H-dibenzo [b, e2 [1,4 '] - diauepin-1-one of the above formula (I) as well as its physiologically acceptable salts with inorganic or organic acids, characterized in that they are:

a) reacting 5,10'-dihydro-5-halo-yayl-11H-dibeauo [b, e] [1,4] Tdiazupine-Ion of formula II

(II)

0 = C-A-X where

2

R, R and A are as defined above and

X represents a halogen atom, with an amine of formula III wherein

4

R and R are as defined above.

(III) ^R e and ^the CE will burst ^{at t} e ^{p s} m ^I lo it indoors and ^{also from} that ^of 150 ^pl ot ί °, preferably ^p s t l ^ep I ^of up to ¹²⁰ ° C in inert, ⁱ ^^ ^r M Organ m ^p extended Oust dl.e ^{of p} on ^P of the ADA for ^{beta. p} řítomnosti agents kt ^e Re acid scavenger such as tertiary amine such as triethylamine, pyridine, dimethylaniline, alkali metal carbonate, alkali metal bicarbonate, sodium acetate or an excess of compound of formula III.

When using an acid-binding agent, the compound of formula III can also be used in the form of the hydrochloride.

The inert organic solvent may be an alcohol such as ethanol, n-propanol, isopropadioxane or tetrahydrofuran, a ketone such as acetone, cyclohexanone, aromatic benzene or toluene, halogenated aliphatic or aromatic hydrocarbons, 1,2-dichloroethane or chlorobenzene; an ether such as a hydrocarbon such as chloroform of the formula III.

The starting material of formula (II) is generally known from the literature or can be obtained from literature, for example, according to the method of AM Monro et al., J. Med. Chem. , 2 ^{55 (19} 63) ^to rea ^d C ⁵ -C ^{10 and} dihydro- ^l H-dibenzo ^{f b,} e] [j. ^{4] di- azepin-ll-one} it ^generally the formula IV:

(IV) with a haloacyl halide of formula V: O, II X - C - A - X (V) wherein

- in formula IV

2

R 2 and R 2 are as defined above

in the formula (V) as defined above, and X 1 the same or different, are halogen atoms, preferably chlorine or bromine, optionally in the presence of a hydrogen halide-binding agent.

The reaction is preferably carried out in an inert organic solvent at a higher temperature.

The solvents used may include aromatic hydrocarbons such as benzene, toluene, xylene, cyclic ethers such as dioxane or tetrahydrofuran, but also esters such as ethyl ester of the ethanoic acid.

In the preparation of the compounds of formula II, tertiary organic amines such as triethylamine, Ν, Ν, užit, Ν, Ν, alkal, alkal, Ν, alkal, alkal, alkal, alkal, alkal, alkal, -dimethlanine pyridine.

for example an alkali metal carbonate or bicarbonate or

The resulting halogenated acylated products of formula (II) can be used as such without further purification.

method (VI)

It is also possible to proceed

(b) reacting a compound of formula VI in the reaction:

where

R ¹ and R 2 are as defined above, in an inert organic solvent such as an alcohol such as ethanol, n-propanol, isopropanol, a ketone such as acetone, a high boiling ether such as tetrahydrofuran, dioxane or an aromatic hydrocarbon such as benzene or toluene with an amine of formula III

(III) where

4

R and R are as defined above, with heating, for example to the boiling point of the reaction mixture, to give the corresponding compounds of formula (I) wherein R and R are as defined above and A is an ethylene group.

The starting materials of the formula VI are known in part and can be obtained in a manner known per se by reacting, for example, the abovementioned compounds of the formula IV,

Wherein R 1 and R 2 are as defined above, with an acrylic halide, or a compound of formula (II) wherein R ¹ , R ² and X are as defined above is heated, and A is an ethylene group in an inert organic solvent, e.g. tetrahydrofuran or dioxane or an aromatic hydrocarbon such as benzene or toluene in the presence of a tertiary organic amine such as triethylamine, pyridine or N, N-dimethyaniline, preferably up to the boiling point of the reaction mixture.

The elimination reaction to the 5-acryloyl compounds of formula VI also takes place as a side reaction in the first process, wherein compounds of formula II are used as starting materials, wherein A is an ethylene moiety and when reacted with a compound of formula IV with a haloacyl halide of formula V wherein A is an ethylene moiety using a tertiary base as the hydrogen halide binding agent.

Compounds of formula (VI), which are formed as a by-product in the preparation of the starting materials of formula (II) in which A is an ethylene residue, not only interfere with the next reaction, but are involved in the preparation of compounds of formula

The compounds of formula (I) obtained can be converted into physiologically acceptable salts by treatment with inorganic or organic acids.

Acids include, for example, hydrochloric, hydrobromic, sulfuric, phosphoric, tartaric, citric, fumaric, maleic, succinic or oxalic acids.

The invention will be explained by the following examples.

Example 1 ^8- c ^hl or ^{5,10-dihydro-5- [bis -?} -Hydroxy-ttyUaměoacetyjJ ^-llH-d i ^b enzo [b, ^ ^{[1, 4] di- p} aze in-11-one ^{6.4 g (^, 02} mole) e-Cher - ^ - ^{chloroacetyl-5, 1} 0- ro ^{dihydro-l H} - ^dib enzo ^{[b, e]} [l ^ JdjLazepě-l-one are boiled in 200 ml of chloroform to the boiling point and 8.4 g (0.08 mol) of diethanolamine are added dropwise.

the mixture was stirred at reflux for 2 hours, then evaporated in vacuo, and the residue was crystallized from acettonitoil with activated carbon. of theory, 3.4 g of the title compound are obtained

The reaction boiled with butyl acetate and allowed this way in a yield of 43.7% counting ^Jan 18 ^8-192 ° C with decomposition.

58.54% found 58.32%

C, 5.17% H,

C, 4.85% H,

N, 10.78; Cl 9.09;

N, 10.69; Cl, 9.18.

Hydrochloride:

^8-chloro-5 O i-dihydro ^-5 [biis ⁽⁰ - ^{s y} DDOO ethyllarninoacetyl] -1lH-a, d ^b, e] £ 1,4] dězepě-H-one are dissolved in 80 I ¹ ^ eo opanoě behind and the ^{STE aT} e ^pL were ^added and mL isoρr-panalového hydrochloric acid solution having a concentration of 13%. After cooling, the crystalline product is filtered off under suction c is allowed to překrystclnzovct from 140 ml of ethanol-concentration of 93%. In this manner, in ^{4.6 g} of the above ^^ ^p ro ^d u uo ^{kt 7 8} g mo! .u) t ^ck yield of 53.8% of theory total yield

225 to 226 ° C for extended ACLU ^kl.

calculated: 53.53% C, 4.97% H, found 53.79% C, 4.79% H,

9.86

N, 16.63; Cl, 16.34;

% Cl.

The starting 8-chloro-5-chloroacetyl-5,10-dihydro-dihydrofuran ^y llH-di enzoC ^{b b <]} [l-4jdiazepin llon can be obtained in the following manner:

^39, 2 g (0.16 mol), AD-dihydro-lH-dibenzoQtyej Finja-čizepin-l-one oxime was su ^ Enzi in 400 m ¹ · x ^ ene suspension looks at the ejov ^{e la l} Zn ^and at ^{100 DEG-add,} and ^{18.1 g} (0.16 mole) chlarccehelchlaoidu C, the resulting mixture was stirred for 3 Уadnoe at said reaction temperature.

Then there was added dropwise 9.04 g (0.08 mol) of chloroacetyl chloride, the mixture was further hour them, ^{and m p} r ⁱ te ^pl ot ^{e la of} marks ¹⁰⁰ 'Cr ^y ^ ° hundred ^{alkyl if} c ^p T ^to the genus ^p o shifting the ZC ^{hl dfitl} oestrus under suction and dried at room temperature. The crude product is recrystallized from 800 ml of acetonitrile in the presence of activated carbon (EPN).

In an analogous manner, the following compounds of formula (II) can be obtained by reaction of the corresponding compounds of formula (IV):

- when chloroacetyl chloride in xylene is used as solvent, it is possible to obtain:

Б-сЬ гасе ^ ^ З-Б / Ю- Ьус ^ ^ ^ о-МН- гЬепго Ь ^, ej ^[1,4] of ^{the pn dn} AZT ^-II he teptata ^alpha-238.5 DEG -240 DEG ^C o Cr ^ ta ^ a ^ a ^and uh ^dl ccehá ^h u,

- when using cloloacttdlcndl-toluene and toluene as solvent, it is possible to obtain:

247562 8

8-chloro-5-chloroacetyl-5,10-dihydro-10-methyl-11H-dibenzofb, e] [1,4] diazepin-11-one, m.p. 220-221.5 ° C,

using chloroacetyl chloride in toluene as the solvent, 5-chloroacetyl-5,10-dihydro-10-methyl-11H-dibenzo [b, e] [1,4] diazepin-11-one is obtained at a melting point of 178.5 up to 181 ° C after recrystallization from acetonitrile,

- using 3-chloropropionyl chloride and toluene as solvent, the following are obtained:

8-chloro-5- (3-chloropropion) -5,10-dihydro-11H-dibenzofb, [1,4] diazepin-11-one, m.p. 223-225 ° C;

- using 3-chloropropionyl chloride as solvent, it is possible to obtain:

8-chloro-5- (3-chloropropionyl) -5,10-dihydro-10-methyl-11H-dibenzo [b, e] [1,4.] Diazepin-11-one, m.p. 163.5-166 ° C,

- using 3-chloropropionyl chloride and toluene as solvent, it is possible to obtain:

5- (3-chloropropionyl) -5,10-dihydro-10-methyl-11H-dibenzo [b, e] [1,4] diazepin-11-one, m.p. 181.5-182.5 ° C,

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

using 2-chloropropionyl chloride in toluene as the solvent yields 5- (2-chloro) propionyl) -8-chloro-5,10-dihydro-11H-dibenzo [b, e] [1,4] diazepin-11-one mp 281-284 ° C (dec.).

In an analogous manner but at room temperature, the following compounds can be obtained:

- using an excess of phosgene in the ethyl ester of the ethanoic acid or in the dioxane / solvent, it is possible to obtain:

8-chloro-5-chlorocarbonyl-5,10-dihydro-11H-dibenzo [b, e] [1,4] diazepin-11-one, m.p. 259-262 ° C;

- in excess of phosgene in tetrahydrofuran as solvent, it is possible to obtain:

5-chlorocarbonyl-5,10-dihydro-11H-dibenzo [b, c ^; m.p. 251-254 ° C with decomposition after crystallization from acetone.

Example 2

8-chloro-5,10-dihydro-5- [2- [4- [2-tetramoyl] -1-piperidinyl] -1,11-dibenzo [b, e] [1,4] diazepine -ll-he

12,8 g (0,04 mol) 8-chloro-5-chloroacetyl-1,5,1-dihydro-1 H -denzoic | l>, e] 1,4] diazepin-11-one was stirred in 200 ml of toluene with 15.4 g (0.08 mol) of 1- 2-furancarbonyl piporazine for 6 hours at reflux temperature.

After cooling, 200 ml of water are added to the reaction mixture, and the mixture is stirred well for 1 p. The filter residue is washed with water, mixed with 100 ml of water, shaken with 100 ml of water and then evaporated in vacuo.

The residue is shaken twice with chloroform and in each case the chloroform is evaporated off under vacuum, then 20 ml of isopropanol are added, the mixture is heated on a steam bath for 10 min, the crystalline product is seperated after suction filtration and crystallized from 200 ml of isopropanol with activated charcoal. (CFO)

In this way in a yield of 67.8% of the theoretical yield 12.6 g of product, melting th ^tup 190-193 ° C.

Analysis for ^C 24 ^H 21 ^N 4 ^O 4 ^C 1 calculated 62.00% C, 4.55% H, 12.05% N, 7.63% Cl; Found: C, 62.48; H, 4.74; N, 11.42; Cl, 7.68.

Hydrochloride:

^{22 g (0.047} mol.) Of 8-C ^H lor-5,10- ^dihydro ro- ^{5- {2} - / ^{4 [2} - ^f urankar ^b on ^y lj-lp ^and piperazine ^{and N-yl} / acet ^yl) -llH -di ^b enzo [b, e] ^{[1, 4]} diazepin-n-one is extended ^even in the provision ^{of p 35} 0 m u ^{l If} sopropano for ^L and ^run by heating and, after cooling, carefully add 200 ml of acid solution isopropanového hydrochloric acid at a concentration of 19%.

After standing for one hour, the solution is evaporated to dryness in vacuo, isopropanol is added, the solution is again evaporated and the residue is crystallized from 100 ml of n-propanol with activated carbon (CFO). The product is then recrystallized from 50% ethanol. In this way the ^{yields against 61.8%} for ^T ck eore ^{those LeVeLs} it ^{é í} ZIS ^ka stv ^{15.2 g} of the producer ^to te ^p lot ^of the ² T ^and 9 ° and ^{from 215} ° C with decomposition.

Analysis for hydrate: ^C 24 ^H 24 ^N 4 ° 5 ² 1 ^C calculated 55.50% C, 4.66% H, 10.79% N, 13.65% Cl; Found: C, 54.99; H, 4.93; N, 11.37; Cl, 13.70.

EXAMPLE ⁸ 3-c ^hl or- ^5, 10-d ⁱ h ^yd ro-5 / ^£ (N rnor ^{f ly} about l ^to r ^b on lmethy1 ^yl) amino acetyl / -lΙΗ dibenzo Q> e] fl ^4] diazepin-l-one.

^{6.4 g} / 0^,°² mol.u) 8-chloro-5-chloroacet^yl-^5,10-^dih^ydro^-11H-^dit> enzo [b ^] £ 1^{, 4 d}iaze^pin^-ll The mixture was stirred in 100 ml of dichloroethane with 14.4 g (0.08 mol) of glycylmorpholide and 10.0 g (1.00 mol) of triethylamine for 3 hours at reflux. During the reaction, some disubstituted by-product is formed.

The reaction mixture is shaken three times with 50 ml of water each, then shaken twice more with 10 ml of 1: 1 hydrochloric acid each, and then the two acid solutions are combined and basified with ammonia solution.

The alkaline solution is washed three times with 50 ml of chloroform each, the chloroform phases are combined, shaken with 10 ml of water, then dried over sodium sulphate and evaporated to dryness in vacuo.

Hydrochloride: ·

10.2 g of the above residue are dissolved in 100 ml of anhydrous acetone, and hydrogen chloride gas is introduced under stirring at room temperature until acidic, followed by stirring for half an hour, and the resulting crystalline product is collected by suction filtration, washed with a small amount of anhydrous acetone and, after drying, crystallized from 96% ethanol with activated carbon (CFO). In this way, in a yield of 32.1%

247562 10 Analysis for hydrate: ^C 21 ^H 24 ^N 4 ° 5 ^C1 2 calculated: 52.18% C, H, 4.79; N, 11.59; Cl, 14.66; 3.73% found 51.76 «C, 4.94% H, 11.47 »N, 14.68% Cl, 3.1 ·»

Example 4

8-chloro-5,10-dihydro-5 - {[4- (3,4,5-trimethoxybenzoyl) -1-piperazinyl] acetyl} -1H-dibenzo [b, e] Q1,4diazepin-11-one

6.4 g (0.02 mol) of 8-chloro-5-chloroacetyl-5,10-dihydro-HH-dibenzo [b, e] [1,4] diazepin-1-one are stirred in 50 ml of toluene with 8, 37 g 0.025 mol) of N- _(3-r 4,5 trimethoxybennooy) iperazine and 2.53 g (0.0725 mol) triehyyaaminu 2 hours at reflux.

The reaction mixture is then evaporated to dryness, 80 ml of chloroform are added, the reaction mixture is heated until all the solid product is dissolved, the chloroform phase is shaken twice with 50 ml of water each time to give a clear solution which is extracted twice with 20 ml of hydrochloric acid each. diluted 2: 1. The acidic phases are combined, shaken with 20 ml of chloroform, basified with 1: 1 dilute ammonia and then extracted three times with 50 ml of chloroform each.

The chloroform phase is shaken with 20 ml of water, dried over sodium sulphate and evaporated to dryness. The residue is boiled with 20 ml of acetoniiril and after cooling, the crystals are collected by suction filtration. After drying, the crystals were dissolved in 50 ml of isopropanol, the solution was warmed, and isopropanolic hydrochloric acid solution was added warmly until acidic reaction to dissolve all the product. The solution is boiled with activated carbon (CFO), boiled, filtered and dried to dryness.

The residue is boiled again with propane and, after cooling, the hydrochloride is collected by suction filtration. In this way, a total of 41.7% of theory is obtained

5.24 g of the title compound, m.p. 236 ° C per decomposition Analysis for hydrate: ^C 28 ^H 33 ^N 4 ° 7 ^jCl C, 55.42; H, 5.29; 8,91% N, 11.45 % Cl H2O: (1.5 mol) 4.4% Found: C 55.07, H 5.33, 8.21% N, 11.20 % Cl,

H2O: (1.5 mol) 4.5%

Example 5

5,10-β-ω-5- [-2- (Sdroxyethylamino) acetyl] -1H-α (E) or (e) [1,4] diazepin-11-one

5.73 g (0.02 mol) of 5-chloroacetyl-5,10-dihydro-11H-dibbonzo [b, e] [1,4] diazepin-11-one and

100 ml of chloroform are heated to boiling, 8.44 g (0.08 mol) of diethanolamium and a small amount of chloroform are added dropwise over 1 hour, and the mixture is stirred at boiling temperature for 3 hours. After cooling, the chloroform phase is shaken with 20 ml of a solution of sodium hydrogen carbonate in water (2 g of hydrogen carbonate per 50 ml of water) and the solution is then shaken twice more with 10 ml each and once with 5 ml of 1: 2 hydrochloric acid.

. The acidic phases are combined and poured into 50 ml of ammonia diluted 1: 1. The alkaline solutions are extracted three times with 50 ml of chloroform, the chloroform phase is concentrated, dried over sodium sulphate and evaporated to dryness. The residue is treated with 10 ml of isopropanol, heated to give a solution which is seeded and the resulting crystals are collected by suction filtration. The product is then crystallized from 35 ml of silica gel.

1.8 g of the title compound of melting point 144 DEG C. with decomposition are obtained in a yield of 25.3% of theory.

found: C, 64.65; H, 5.96; N, 11.82. % C, 6.12% H, 11.82% N

Hydrochloride:

5H-dibenzo [b, e] [1,4] riazepit-10-ol is dissolved in 210 ml of iscpocpatol by heating. After stirring 7 ml of 19% isopropanolic hydrochloric acid and then 35 ml of ether, the reaction mixture was allowed to stand for 12 hours and then the crystalline product was collected by filtration and dried in a desiccator.

g (0.015 mol)

The crude product is recrystallized from 60 ml of meehaan with CFO. Yield 2.99 g (39.5% of theory), m.p. 211 DEG-214 DEG C. (dec.).

Analysis calculated for: ^C 19 ^H 22 ^N 3 ° 4 ^Cl

58.24% C, 5.66%

58.23% C, 5.73%

H, 10.72% N, 9.05% c1; H, 11.01; N, 9.15% Cl

⁵ 10iyihydro-5- ^ 2- / 4- ^ 2 - fukanko-sulfonyl] - ^piperazine-j iaacejyl ^- -l Wddibenzc ^, ^ [1/4] diazepío-00-oo

5.8 g (0.02 mol) of 5-chlooahethyl-5,10-dlhyroo-01H-dibetlzo [b, e] [1,1 '] riazepio-10-oos, 100 ml of chloroform and 7.2 g of (0, 04 mol) of 1- 2-furancarbonyl piperazine is heated to reflux for 7 hours with stirring. After completion of the reaction, the cooled reaction mixture was shaken twice with 30 ml of water each, then twice with 10 ml and once with 5 ml of 1: 1 dilute acid.

The hydrochloric acid phases are combined, washed with 30 ml of chloroform and then poured into 100 ml of 1: 1 dilution to precipitate the product which is mixed with 50 ml of chloroform.

The aqueous alkaline phase is shaken twice more with 50 ml of halo-cocom _{/ each,} and then the chloroform phases are combined, dried over sodium sulphate and evaporated to dryness in vacuo. The residue is boiled with 20 ml of toluene, the crystals formed, after cooling, are collected by suction filtration and re-crystallized with 110 ml of 96% ethanol with activated carbon (CFO).

3.8 ^{g of the} title compound of m.p. 230 DEG-233 DEG C. are obtained in a yield of 44.2% of theory.

Analysis calculated for: C 24 H 22 N 4 O 4:% C, 66.97;% H, 5.15;% N, 13.02; Found: C, 6.54; H, 5.19; N, 12.33

Hydrochloride ^{g (0} 023 mole) of 5, ¹ 0-dihydropyrimidine droc5- ^{L -} 2- / 4 ^{4 [2-n} ffuoa kabonyl] ^l lp ^p ppeaainnl / ^-acetyl} - ^l .lH- ^dibenzo | [b, e] [1,4] diazepin-11-one is dissolved in 675 ml of isopoopanol, the solution is boiled for 15 minutes with activated carbon (CFO), evaporated to dryness and 10 ml of isopropaacylic hydrochloric acid are added while still hot, approximately 19% . After cooling, the hydrochloride crystallizes with one mole of water.

Analysis for hydrate: C 24 H 25 N 4 O 5 Cl requires C 59.44, H 5.20, N 11.55, Cl 7.31,

H ₂ Os 3.7% Found 59.08% C, 5.38% H, 11.03% N, 7.17% Cl

HjO: 3,4%

Example 7

5.10 ^{of HY} ih dro-5- [bis- (2 ^h ydroxyy ^e hy ^{s) aminnocetyy]} -10 'methyl-llH "dibenzo ^{[b, e] [1,} Diaz ^{J p} in-11-one

6.02 g (0.02 mole) of 5-chloroacetyl-5,10-dihydro-100- (1,1-) - (1,4,6,4,4) -diczepine-11- The mixture was heated to reflux in 100 ml of 1,2-dihydrothiazide, and 8.44 g (0.08 mol) of diethanolamine was slowly added dropwise, and the reaction mixture was stirred at reflux for 4 hours. condenser at boiling point.

After cooling, the mixture is shaken with 30 ml of 10% sodium hydrogen carbonate solution, then twice with 10 ml each and once with 5 ml of 1: 1 hydrochloric acid, and the acidic phases are combined and washed with 30 ml of chloroform.

100 ml of 1: 1 ammonia solution were added to the acidic phases, the mixture was washed three times with 30 ml of chloroform each, the chloroform phases were combined, extracted with sodium sulfate and evaporated to dryness in vacuo.

The residue is dissolved in 30 ml of anhydrous acetone and hydrogen chloride gas is passed through the solution until it is acidic. An oily product precipitates and starts to crystallize after boiling. The hydride-chloride is recrystallized from 40 ml of ethanol with a concentration of 96% activated carbon (CFO) and then dried at a temperature of 100 ° C and a pressure of 1 mmHg. Yield: 4.0 g (49.3% of theory); M.p. 196 DEG-199 DEG C. (dec.).

Annlýza for: C 20 ^H 24 ^N 3 ° ^C 4 1 calculated 59.19% C, 5.96% H, 10.35% N, 8.74 »Cl;

Found: C, 59.33; H, 5.97; N, 10.42; Cl, 8.70.

Example 8 '

8 ', 11', 5'-Ethyl-5-fluoro- (2-hydroxy-ethyl) -ciaacetyl-10-methyl-1H-diean-o-b, e] [0,4] dicoepin-11-a.

^6.7 g (0.02 moo) 8-cClo - ^5-Cl-c-AcOEt δ, 10far hyУir ^{i -} l ⁰ -methh ^j - l ^{H-dibenzo a -} b e ^e | 11.1H-epin-11-one and 100 ml of chloroform are heated to boiling with stirring, and then 8.44 g (0.08 mol) of diethanolamine in 5 ml of chloroform are added dropwise.

The reaction mixture is refluxed for 7 hours and then cooled, washed twice with 50 ml of water each time, and the chloroform phase is extracted twice with 10 ml of 1 x 1 ml of hydrochloric acid each time. the acidic phases are combined, extracted with 50 ml of chloroform, mixed with 100 ml of a 1: 1 dilute ammonia solution and washed three times with 50 ml of chloroform each time, whereupon the precipitated product goes into solution again.

The chloroform phases are combined, washed with 50 ml of water, dried over sodium sulphate and dried to dryness in vacuo.

The residue was dissolved under heating in 30 ml of ^well-pr opcnolu solution is again cooled and then a solution of HCl gas until acidic. An oily product precipitates and crystallizes after boiling. This product was collected by suction filtration and dried at room temperature. Yield: 6.2 g (70.4% of theory); m.p. 127 DEG-150 DEG C. (dec.).

Analysis for ^C 20 ^H 23 ^N 3 ° ^C, 4 ^ 2 calculated 54.56% C, 5.27% H, 9.54% N, 16.10% Cl;

found: C, 54.43; H, 6.01; N, 9.03. 15.48% Cl.

Example 9

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

12.3 g (0.04 mol) 8-chloro-5-chlorocarbonyl-5,10-dihydro-11H-dibenzo [b, e] [1,4] diazepin-1-one (m.p. 257-260 ° C) ) and 4.0 g (0.04 mol) of triethylamine are heated in 200 ml of chloroform with stirring at reflux, and then 5.3 g (0.05 mol) are added dropwise over 1/2 hour. diethanolamine.

The reaction mixture is stirred for a further half hour at reflux, then cooled, the chloroform solution is washed with 100 ml of water, dried briefly with sodium sulphate and evaporated in vacuo to dryness. The residue obtained is recrystallized from 20 ml of isopropanol.

Yield: 9.7 g (66.9% of theory); m.p. 190 DEG-195 DEG C. (dec.).

H, 4.83; N, 11.18; Cl, 9.44.

found: C 58.90, H 4.91, N 11.37, Cl 9.45.

Example 10

8-chloro-5,10-dihydro-5- [3- [bis- (2-hydroxyethyl) amino] propionyl] -1H-dibenzo [b, e] [1,4] diazepin-11-one

40.2 g (0.12 mol) of 8-chloro-5-chloropropionyl-5,10-dihydro-1H-dibenzo [b, e] [1,4] diazepin-11-one and 27.4 g (0, The diethanolamine (26 mol) was stirred at reflux temperature in 300 ml of chloroform for 6 hours. After cooling, the precipitated diethanolamine hydrochloride is separated off, the chloroform phase is evaporated to dryness in vacuo and the residue is partitioned between 300 ml of chloroform and 200 ml of 1: 2 hydrochloric acid and the acid phase is separated.

After pouring the acid phase over 300 ml of chloroform, the pH is adjusted to 10 with 1: 1 ammonia solution, the mixture is shaken, the chloroform phase is separated and briefly dried over sodium sulfate. After some time, the resulting product precipitates. The crude yield was 58% of the theoretical amount, i.e. 28.1 g. Melting point 164-168 ° C.

The product was recrystallized from 750 ml of activated carbonitrile (CFO).

The resulting product is still contaminated with an acrylic compound. The yield is 39.4% of the theoretical amount, i.e. 19.1 q, of the product having a melting point of 165-171 ° C.

Hydrochloride:

g (0.035 mol) 8-chloro-5, n-dihydroxy-5- [3- (4-bis- (2-hydroxyethyl) amino] propionyl) -1H247562

Dibenzo [b, e] 1,4-diazepin-11-one is dissolved in boiling isopropanol (200 ml) and, after cooling, 150 ml of isopropanolic hydrochloric acid solution are added to the acidic reaction. The solution is dried to dryness in vacuo, 10 ml of isopropanol are added three times in succession and the product is again evaporated to dryness, 15 ml of isopropanol are added, the solution is boiled on a steam bath, the crystalline product is evaporated. after cooling, it is separated by suction filtration and dried at a temperature of min.

The hyodoodoride is recrystallized from 100 ml of 96% alcohol with activated carbon (CFO). Yield: 5.3 g (34.6% of theory); m.p. 176 DEG-186 DEG C. (dec.).

Analysis for ^C 20 ^H 23 ^N 3 ^O 4 Cl 2 requires C, 54.56; H, 5.27; N, 9.54; Cl, 16.10; Found: C, 54.58; H, 5.44; N, 10.22; Cl, 16.26.

Example 11

8-Chloro-5,10-dihdyro-5- {2- (4- [i-furan-4-yl] -1,4-cyano-1H-piperazinyl} -1H-piperazinyl [1,4] phenylamino-11-yn-1-ynyl-1,4-thiazol-1-yl

12.2 g (0.04 mole) of 5- (2-bromo-proproiono) -8-chloro-5,10-dityrine-1H-dibenzo [b] e [1,4] diazepin-11-one, 17.2 g (0.04 mol) of 1- [2-O-urecarbonyl] -piperidin-4-yl-chloride and 16 g (0.16 mol) of triethylamine are stirred in 200 ml of dioxane at reflux for 8 hours, then a further 4 are added. 4 g (0.01 mol) of 1- 2-furanylcarbonylpiperazinohydride and 1.0 g (0.01 mol) of triethylamine are stirred again at reflux for 8 hours.

The dioxane is then distilled off in vacuo, 200 ml of chloroform and 100 ml of water are added, the mixture is stirred, the phases are separated and the chloroform phase is shaken with 100 ml of 2: 1 hydrochloric acid and then 50 ml of 1N hydrochloric acid. : 2.

The acidic phases are combined, washed with chloroform, the pH is adjusted to 9 with stirring and cooling with concentrated ammonia solution, the chloroform phase is separated, dried over sodium sulphate and evaporated to dryness in vacuo.

The residue is heated on a steam bath with 10 ml of isopropanol, left to crystallize, the crystals are collected by suction filtration, treated with a small amount of isopropanol and dried at ambient temperature. The crude product is boiled with 40 ml of acetorntril and dried at room temperature.

In this way, 38.1% of the theoretical bridge was recovered. mp 238 DEG-244 DEG C. with decomposition.

Analysis for ^C 25H23 ^N 2 4 ° ^{C 1} 'calculated 62.70% C, 4.84% H, 10.87% N, 7.40% Cl; Found: C 62.10, H 5.15, N 11.45, Cl 7.40.

HyУěoohtorid:

22.7 g (0.047 mol) of 8-methyl-5,10-dityone-5 {2- (4-methyl-2-furancarboxylic acid) piperazinyl] -piperidin-11H-dibenzo [f] Q] -diazepine-11 The suspension was suspended in 200 ml of isopropanol, 200 ml of isopoopanol- containing a 19% strength hydrochloric acid solution was added, and the mixture was heated in a water bath for half an hour.

The solution is again evaporated to dryness in vacuo, the oily residue is treated with 20 ml of isopropanol, evaporated to dryness in vacuo, 20 ml of absolute ethanol are added and the solution is again evaporated to dryness in vacuo. The residue is crystallized with 175 ml of isoponpunol of 60% conenenration with activated carbon (CFO) and then evaporated again to dryness.

A total of 6.2 g of the product with a melting point of 212 DEG C. with decomposition is obtained in a yield of 25% of theory.

Hemihydrate Analysis: ^C 25 ^H 25 ^N 4 ° 5 4 2 ^C1 Calculated 57.26% C, 4.81% H, 10.68% N, 13.52% C, 3.40% H ₂ O (0, 5 mol); found 57.23% C, 5.02% H, 10.73% N, 12.38% C, 2.50% H ₂ 0 (0.5 mol).

If, after recrystallization, the mother liquor is mixed with 500 ml of isopropanol, the hydrochloride crystallizes again, the crystals are collected by suction filtration and dried as above.

Yield: 12.1% of theory, i.e. 3.0 g of product, m.p. 224 DEG-231 DEG C. with decomposition.

Hemihydrate Analysis: ^C 25 ^H 25 ^N 4 ° 5 4 2 ^C1 Calculated 57.26% C, 4.81% H, 10.68% N, 13.52% Cl; Found: C, 57.51; H, 4.74; N, 10.49; Cl, 13.41.

Example 12

8-chloro-5,10-dihydro-5 - {[4- [1,2-furancarbonyl] piperazin-1-yl] acetyl] -10-methyl-11H-dibenzo [b, e] [b] diazepine-11 -he

6 # 7 g (0.02 mol) 8-chloro-5-chloroacetyl-5,10-dihydro-10-methyl-11H-dibenzo [b, e] [1,4] diazepin-11-one, 8.8 g ( 0.04 mol) of 1- [2-furancarbonyl] piperazine hydrochloride and 6.0 g (0.06 mol) of triethylamine were stirred in 70 ml of chloroform under reflux for 7 hours.

100 ml of water are added to the cooled reaction solution, the mixture is stirred well, the phases are separated and the chloroform phase is extracted with 100 ml of 100: 1 hydrochloric acid. To the acidic phase, 100 ml of chloroform and 140 ml of a 1: 1 dilute ammonia solution are added, the mixture is stirred well, the separated chloroform phase is dried over sodium sulphate and evaporated to dryness in vacuo.

The residue is boiled with 10 ml of isopropanol, the solid product is collected by suction filtration, dried at room temperature and crystallized from activated carbon absolute alcohol (CFO).

Yield: 5.4 g (56.01% of theory); M.p. 189 DEG-194 DEG C. (dec.).

Analysis for: ^C 25 ^H 23 ^N 4 ° 4 ^C1 Calculated 62.70% C, 4.84% H, 11.70% N, 7.40% Cl; found C 62.33, H 4.89, N 11.43, Cl 7.61.

Hydrochloride:

8-chloro-5,10-dihydro-5- [4- [2-furancarbonyl] -1-piperazinyl / acetyl] 14.4 g (0.03 mol)

-10-methyl-11H-dibenzo [b, f] [1,4] Diazepin-11-one is suspended in 80 ml of isopropanol and 100 ml of 19% isopropanolic hydrochloric acid is added.

The mixture was then gently warmed to completely dissolve the base. The solution is evaporated to dryness in vacuo, the residue is boiled with alcohol to crystallize an oily solid. The residue is redissolved in isopropanol and the hydrochloride is precipitated by addition of 500 ml of ether.

The crystalline fraction is collected by suction, dried with sodium hydroxide in a desiccator under water vacuum and then dried for 8 hours with phosphorus pentoxide at a pressure of 166 Pa. A total of 11.4 g of the product with a melting point of 100 ° C / 160-169 ° C with decomposition is obtained in a yield of 72.3% of theory.

Annlýza hydrate for: C25H25 ^N @ ₄ ° 4 CLJ calculated 57.26% C, 4.81% H, 10.68% N, 13.73% Cl, 1.72% H ₂ O (0.5 m ^ o );

found 57.43% C, 5.04% H, 10.48% N, 13.53% Cl, 2.40% H ₂ O.

In a similar manner as in Examples 1 to 12, the substances listed in the following table can also be obtained:

Table

Example R ¹ R ² R ³ R ⁴ A Melting point Yield%

13 cl H -CH 3 -I 2 OH -CH 2 ' M.p. 161-162.5 ° C (butyl acetate) H 2 O 2 S: dr 4 ° C 1 H 2 O: 24-4.5 to 246 ° C (dec.) 59.7 14 cl H -H-1 ₂ H ₄ OH -CH ₂ - Mp 134-139 ° C (with decomposition) (isopropanol) HyLdroClooid: 252.5 to 255 ° C (with decomposition) 49.6 15 Dec CL H ^-CH-1H ₂ ^- 120 ° C (dec.) 54.2 -СН ^ СО-М ^ __ / 0 (ethyl ester of ethanoic acid) 204 ° C (dec.) 16 CL H ^-CH 2 ^- 0 HyУdУžClorid: 222 ° C (dec.) 36 (absolute ethanol) 17 CL H H-CH ₂ CH ₂ NH-C-CH ₂ -CH _{2 -} HyУdУžClorid: 58.9 0 223 DEG-226 DEG C. (dec.) (Isopropanol) 18 CL H -l ₂ H ₄ OH -l ₂ H ₄ OH -CH (CH ₃ ) - Mp 167-170 ° C (isopropanol) 7.4 19 Dec H H -C 1 -C 2 CO-N 2 O-CH 2 172.5-177 ° C (isopropanol) 57.6 HySdУžClorid: 190 ° C (dec.) 20 May H -CH (161 ° L) 166-170 ° C (isopropanol) HHSdroClyrid: 65.2 O Oř

160 ° C (dec.)

Example 21.

^5, 10-dihydro-5- [bis- (2-hydroxyethyl) aminoacetylJ-llH-dibenzo [b, e [1,4] diazepin-11-on.HCl g (0.16 mol) of 5-chloracetyl55,10- dihydro-11H5dibeozo [b, e] [1,4] diazepin-11-aou, 200 ml of dimethyl Oormamide and 33.76 g (0.32 mol) of diethanolamine were stirred at room temperature for 8 hours and then allowed to stand at room temperature for 12 hours. hodio stand. Thereafter, 1 g of activated carbon (CFO) was added to the reaction mixture, and the mixture was stirred at room temperature for 1 hour. the coal is filtered off with suction and the solution is evaporated to dryness in vacuo.

The liquid residue is treated with 200 ml of chloroform, the mixture is shaken with 20 ml of water and evaporated. Acetone (200 ml) was added and then freshly prepared acetic acid solution or 15 ml of concentrated hydrochloric acid was added until acidic.

At first vzoikoe oily hmooa, but it slowly crystallizes. In this way, 54 g of crude product are obtained in a yield of 86.1% of theory. The crude product was collected by suction filtration, washed with acetone, then dissolved in 12-13 times microfloor moleool, heated for 5 hours with 5 g of CFO, then filtered under suction, evaporated to 1/3 volume and 200 ml of acetone are added.

The crystalline product was further dissolved in methanol in a 15-amp, 4-ampere, heated with 2.5 g of carbon activated carbon (CFO), filtered off with suction, evaporated to 1/3 volume and the crystalline product was filtered off with suction.

The product is then cooked with a five-blade cutter of acetone. 43.5 g of product are obtained in a yield of 69.4% of theory.

Example 22

a) 5-acdlayl585Chlaol-5,10-rihyrr a5 11H5ribtcza (b, e] [1M] riazepic-11-ac

17.1 g (0.051 mol) of 8-chloro-555-chloroprapiacyl-5,10-dihydra-11H5-dibenzo [b, €] [1,4] riazthio-10-one and 6 g (0.06 mal) of trtetdyaric are stirred in 750 ml of absalute ethanol 6, 5 hours with heating to reflux.

Then the clear solution is evaporated to dryness in vacuo, - the residue is triturated with 100 ml of water, - filtered with suction, washed again with - 100 ml of water and dried at 80 ° C. The crude product was recrystallized from 150 ml of tthacal. Yield: 9 g (59.1% of theory). mp, mp 204-207 ° C.

Analysis for C-6H-N2Cl:

Calcd for C 64.33%, H 3.71%, N 9.38%, Cl. 11.87%, found: C 64.10%, H 3.70%, N 9.34%, CL 12.30%.

b) 8-chloro-5,10-dihydroc-5-3- [bit 5 (2-hydroxyethyl) arincЗ prapionyl] -1H-dibenzo [b, t] Q, 4-riazepine-11-ac

5.3 g (0.02 mol) of 5-acrylayl-8-chloro-5,10-dihydro-11H-dibeozo [b, e] [1,4] riazepic-11-one was dissolved at room temperature while stirring in 25 ml of ε-farms were added, 4 drops of concentrated acetic acid and then 2.32 g (0.22 mol) of diethanalarics in 10 ml of dimeric acid were added.

The mixture is stirred for 8 hours at room temperature and then evaporated in vacuo. 25 ml of chloroform are added to the oily residue, the mixture is boiled, left to stand for 3 hours and the solid product is filtered off with suction. This product was recrystallized from 95 mL of 10% charcoal acetone.

247562 18

The yield is 3.5 g, i.e. about 43.3% of the theoretical amount, the melting point is 150 to 150 DEG C .;

159 [deg.] C.

Analysis for C ₂₀ ^H 22 ^N 3 ^Cl! calculated: C 59.48%, H 5.49%, N 10.40%,

Cl 8.78%, found:

C 59.06%, H 5.80%, N 10.40%, Cl 8.90%.

Claims (12)

SUBJECT OF THE INVENTION New 5-substituted 5,10-dihydro-11H-dibenzo [b, e] f, 4'-diazepin-11-ones of the general formula I wherein: R is hydrogen or chlorine, R is hydrogen or methyl, R ³ is hydrogen, methyl or 2-hydroxyethyl, R is 2-hydroxyethyl, N-morpholylcarbonylmethyl or 2-acetylaminoethyl; R 4 and R 4 together with the nitrogen atom to which they are attached may form a piperazine radical which is substituted on the imino group with a 2-furancarbonyl, acetyl or 3,4,5-trimethoxybenzoyl radical and A represents a group of formula -CH ₂ -, -CH ₂ - or-CH ₂ -CH (CH _3> or a direct bond, and salts thereof. 2. A process for preparing the novel 5-substituted 5,10-dihydro-llH-dibenzo b, e] diazepin-Г1,41 111 2 3 4 ^"in The compounds of formula (I), wherein R, R, R, R and A are as defined above, as well as their physiologically acceptable salts of these compounds with inorganic or organic acids, characterized in that they are reacted with 10-dihydro-5-haloacyl-11H-dibenzo [b, e] [1,4] diazepin-1-one of formula II (II) wherein (III) wherein 1 2. R, R and A are as defined above and represents a halogen atom with an amine of formula III wherein 3 4 ^R and ^{R s} owner after which the resulting salt. svrc ^h at defined, the product optionally converted to its pharmaceutically-acceptable 3. A process for the preparation of the compounds of general formula -CH ₂ -CH ₂ -, and other substituents having the meaning given in the reaction of a compound of the general formula VI, wherein A is as defined above, wherein: 1 2 R and R have an amine of general formula followed by the resulting acid salt. O = C-CH = CH 2 as defined above, formula III as defined above, product 4. The method according to the point of solvent. (VI) optionally converting it into a pharmaceutically acceptable one 2 and 3, characterized in that the reaction is carried out in an inert organic 2 and 4, characterized in that the reaction of a compound of the formula II with a compound of formula III or its hydrochloride is carried out at room temperature ^from that ^{of pl} ot ¹⁵⁰ ° C ,. Preferably when ^p te ture ^50-12 0C. 5. The method of item 6. A process according to claim 2, wherein an alcohol such as ethanol, n-propanol, isopropanol, an ether such as dioxane or tetrahydrofuran, a ketone is used as the inert organic solvent in the reaction of the compounds of formulas II and III or their hydrochlorides. such as acetone or cyclohexanone, an aromatic hydrocarbon such as benzene or toluene or halogenated aliphatic or aromatic hydrocarbons such as chloroform, 1,2-dichloroethane or chlorobenzene. 7. A process for the excess of the amine of (2) and (4) to (6) of Formula III. characterized in that it is used as a solvent 8. Method according to formulas II and points 2 and 4 to 7, III is carried out characterized in that the presence of the compound is a reaction between the acid binding compounds. 2. A compound according to any one of Claims 2 and 4 to 8, characterized in that it binds as a compound The method of the acid uses an alkali metal carbonate or alkali metal bicarbonate. 10. A process according to claims 2 and 4 to 8, wherein the acid binding compound is a tertiary amine such as triethylamine, pyridine or Ν, Ν-dimethylamine. 11. A process according to any one of Claims 3 and 4, wherein an alcohol, such as ethanol, n-propanol, or isopropanol, a ketone such as acetone or cyclohexanone, is used as an indifferent organic solvent in the reaction of VI with III. ethers such as dioxane or tetrahydrofuran or aromatic hydrocarbons such as benzene or toluene. 12. The process of claims 3, 4 and 11, wherein the reaction between the compounds of formula VI and the amines of formula III is carried out at a higher temperature, preferably up to the boiling point of the reaction mixture.