DD293582A5 - NEW 5- (OMEGA-AMINOACYL) -5,10-DIHYDRO-11H-DIBENZO / B, E // 1,4 / -DIAZEPINE-11-ONE, METHOD FOR THE PRODUCTION THEREOF, AND THEIR USE AS MEDICAMENTS - Google Patents

Abstract

The invention relates to a process for the preparation of new * * of formula I, wherein R1, R2, R3 and n have the meaning given in the description, have antiarrhythmic and anticholinergic properties and can, for example, by reaction of * the formula II with amines of Formula III. {* Antiarrhythmics; anticholinergics; * *}

Description

For this 1 page formulas

Field of application of the invention

The invention relates to processes for the preparation of novel 5- (ü> -Aminoacyl) -5,10-dihydro-11H-dibenzo / b, e // 1,4 / diazepine-i 1 onen of the general formula I, wherein R ¹ Hydrogen or chlorine, R ² and R ³ , which may be identical or different, and are hydrogen, straight-chain or branched alkyl having 1 to 3 C atoms or, together with the N atom to which they are bonded, a morpholino or N- Methylpiperazino radical and η can be a number from 3 to 6, and when R ^{2 is} hydrogen, then R ^{3 can} also be cyclohexyl, and their salts with physiologically compatible inorganic or organic acids. These compounds can be used as drugs, particularly for the treatment of arrhythmias and cholinergic disorders.

Characteristic of the known state of the art

There are already known 5,10-dihydro-11H-dibenzo / b, e // 1,4 / diazepine-11-one, which have an aminoacetyl or a Aminopropionylrest in the 5-position (DE-AS 1936670,2022790,2065570 DE-OS 1795176, 19931487, 3028001, 3204157, 3204185, BE-PS 753664, DD-PS 236731, EP-OS 44989). These compounds have an antiulcer and antisecretory effect. Other 5,10-dihydro-11H-dibenzo / b, e // 1,4 / diazepin-11-ones substituted at the 5-position with an aminoacetyl or aminopropionyl moiety have been reported by A. M. Monro and coworkers in J. Med. Formerly 6,255 without indication of pharmacological properties described.

Furthermore, in the 11-position substituted 5,11-dihydro-6H-pyrido / 2,3-b // 1,4 / benzodiazepine-6-ones with an influence on the Heart rate known (DE-OS 3409237,3523002). Most Class I antiarrhythmic drugs such as lidocaine, ethmocine or propafenone have the property in addition to

antiarrhythmic effect to lower the heart rate. They are therefore suitable for the treatment of tachyarrhythmias.

For arrhythmias with low impact (bradyarrhythmias), these agents may therefore only be used in conjunction with atropine Application to prevent further lowering of the heart rate. Agents that act both antiarrhythmic and anticholinergic and thus used for the treatment of bradyarrhythmias

are of limited use and have the disadvantage that they are either predominantly anticholinergic (atropine,

Ipratropium bromides) or predominantly antiarrhythmic (quinidine, disopyramide). There is therefore a need to find medicines that have the most balanced possible ratio of antiarrhythmic and

possess anticholinergic activity and thus for the treatment of bradyarrhythmias (arrhythmias in slow episode of

Heart) are suitable. Object of the invention By the invention it is possible to prepare novel 5 - ((ω-aminoacyl) -5,10-dihydro-11H-dibenzo / b, e // 1,4 / diazepin-11-ones of the general Formula I and their salts with physiologically acceptable inorganic or organic acids. The compounds of general formula I are highly effective cardiovascular drugs which are extremely strong

have antiarrhythmic activity and can therefore be used for the treatment of cardiac arrhythmias.

While most antiarrhythmic drugs such as lidocaine or quinidine lower the heart rhythm, the compounds of the

general formula I due to the simultaneous presence of anticholinergic property, the existing heart rhythm over a longer period of time at the same level.

The combination of antiarrhythmic and anticholinergic activity in the compounds of general formula I is for the Production of drugs of great benefit, used for the treatment of bradycardic arrhythmia

become. The compounds exceed in their potency in animal experiments preparations such as quinidine and lidocaine.

Explanation of the essence of the invention The present invention has the object, new 5 - (<u-aminoacyl) -5,10-dihydro-11H-dibenzo / b, e // 1,4 / diazepin-11-ones of

general formula I, wherein R ¹ , R ² , R ³ and η have the abovementioned meaning, as well as their salts with physiologically acceptable inorganic or organic acids with valuable pharmacological properties find and produce.

According to the present invention, this is achieved by either

a) a 5,10-dihydro-5- (haloacyl) -11H-dibenzo / b, e // 1,4 / diazepin-11-one of the general formula II, wherein R ¹ and η have the abovementioned meaning and X a halogen atom, with an amine of the general formula III in which R ² and R ^{3 have} the abovementioned meaning or with a salt of this amine or reacting

b) a 5,10-dihydro-11H-dibenzo / b, e // 1,4 / diazepin-11-one of the general formula IV in which R ^{1 has} the abovementioned meaning, with an aminoacyl halide of the general formula V, wherein R ² , R ³ and η have the abovementioned meaning and X 'represents a Habgenatom, preferably a chlorine or bromine atom, or reacts with a salt of this aminoacyl halide

and the compounds of the general formula I obtained, if desired, are converted into their acid addition salts with physiologically tolerable inorganic or organic acids or from salts of the compounds of the general formula (I) obtained

Formula I, if desired, releases the bases. A particular embodiment of the invention is that the preparation of the compounds of general formula I

is carried out in an inert organic solvent. Suitable inert organic solvents are, for example

Alcohols such as ethanol, n-propanol or isopropanol, ethers such as dioxane or tetrahydrofuran, aromatic hydrocarbons

such as benzene, toluene or xylon, halogenated aliphatic or aromatic hydrocarbons such as chloroform, 1,2-dichloroethane, carbon tetrachloride or chlorobenzene, or dipolar aprotic solvents such as dimethylformamide,

Acetonitrile or dimethyl sulfoxide. Another embodiment of the invention is that the solvent is an excess of the compound of formula III

is used.

In the preparation of the compounds of general formula I, the temperature can vary within wide limits. A

However, special embodiment of the invention consists in that the production at temperatures between

Room temperature and 15O ⁰ C is performed. According to the present invention, the preparation of the compounds of general formula I in the presence of a Acid acceptors are performed. Suitable acid acceptors are, for example, alkali metal carbonates, Aikalihydrogenkarbonate or tertiary organic amines such as triethylamine, pyridine or N, N-dimethylaniline. The compounds of general formula I can be obtained by physiological methods known per se

compatible inorganic or organic acids are converted into their acid addition salts.

As an example of such physiologically acceptable inorganic or organic acids may be mentioned: Hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, acetic acid, tartaric acid, Citric acid, funic acid, maleic acid, succinic acid or ascorbic acid. The compounds of general formula I and their salts with physiologically acceptable inorganic or organic Acids can be added to generally customary pharmaceutical preparations containing at least one compound of the

general formula I or its salt are processed.

Such pharmaceutical preparations can be used for the treatment of arrhythmias, in particular bradyarrhythmias,

be used.

Another possible use of such pharmaceutical preparations is the treatment of cholinergically induced Diseases. Particularly suitable as pharmaceutical preparations are tablets, dragees, capsules, solutions, ampoules or Suppositories containing at least one compound of general formula I or their salts with physiological

compatible inorganic or organic acids, optionally mixed with inert, pharmaceutically suitable

Carrier and / or auxiliaries. They can be widely used in pharmaceutical practice and conventional methods

getting produced.

The 5,10-dihydro-11H-dibenzo / b, e // 1,4 / diazepin-11-ones used as starting compounds for process b)

general formula IV are known.

The starting compounds of general formula II used in process a) can be analogously known from the literature Methods by reacting a 5,10-dihydro-11H-dibenzo / b, e // 1,4 / diazepin-11-one of the general formula IV, wherein R ^{1 is} the

has the abovementioned meaning, with a Halogenacylhalogenid of the general formula Vl, wherein X, X 'and η have the abovementioned meaning, optionally in the presence of hydrogen halide-binding agents such as alkali metal carbonates or

Alkalihydrogenkarbonate, produce. This reaction is preferably carried out in an inert organic solvent at elevated temperatures. When Solvents can be aromatic hydrocarbons such as benzene, toluene or xylene, halogenated aromatic Hydrocarbons such as chlorobenzene, but also esters such as ethyl acetate can be used. The novel 5- (ω-aminoacyl) -5,10-dihydro-11H-dibenzo / b, e // 1,4 / diazepin-11-one of the general formula I according to the invention

show in the animal experimental test a pronounced antiarrhythmic effect. In various pharmacological

Models for testing the antiarrhythmic activity, the compounds of the invention proved to be essential

more effective than lidocaine and quinidine.

Thus, the CaCI ₂ arrhythmia of the rat (methodology in Femmer, K., and co-workers, Pharmacie 40, p. 836 [1985]) compared to the Comparative drugs lidocaine and quinidine have been demonstrated to have a significantly stronger antifibrillatory effect (see Table 1). The compounds of the general formula I show a better compatibility with rats when administered intravenously than theirs Reference preparations. Due to the increased potency and better compatibility of the compounds of general formula I results

a substantial increase in the therapeutic width (see Table 1, Q = LD ₆₀ ZED ₆ O).

Since all antiarrhythmics used so far have a narrow therapeutic range, is by the inventive

new compounds in this regard, a clear advantage for the safe medical use in the treatment of arrhythmias to expect.

On model two-stage coronary ligation on the dog after Harris (methodology at Kaverina and coworkers, Pharmacy 40, p.845 [1385])

The compounds of general formula I show a strong and long-lasting effect (see Tables 2 and 3).

It is noteworthy that the new compounds unlike other antiarrhythmics such as lidocaine without anticholinergic

and quinidine (Mokier, CM., and CG.van Arman, J. Pharmacol, exp. Ther., 136, p. 114 (1962), [1]) having anticholinergic activity, which on this model resulted in a decrease in the total number of Cause cardiac contractions and the ectopic arrhythmia, the

Leave the total number of heart contractions unaffected while lowering the ectopia rate. Already in the 5th minute after the intravenous injection of the compounds of general formula I in a concentration of

0.005mMol / kg (about 2.0mg / kg), the ectopic arrhythmia is suppressed by 2 to 3 times the baseline, while the

Total number of heart contractions remains constant. The effect on the ectopic arrhythmia lasts for 30-60 minutes. Table 1 Antifibrillatory effect on the CaCI ₂ arrhythmia of the rat, the coronary ligation in the dog as well as orienting acute toxicity

in rats compared to standard preparations

connection CaClj arrhythmia ED ₆₀ (mg / kg) acute toxicity rat i.V., (mg / kg) Q Harris dog effect Rat, LD ₆₀ LD ₆₀ / ED _M eff. dose duration min (0.22 to 0.78) (81-90) mg / kg i.v. 60 example 1 0.41 (0.018 to 0.12) 85 (62-81) 207 1.76 30 Example 4 0,044 (0.25-0.76) 71 (32-45) 1614 1.93 60 Example 6 0.44 (.042 to 0.58) 38 (37-47) 86 2.07 120 Example 9 0.16 (1.5 to 6.6) 41 (17-21) 256 2.21 15 lidocaine 3.1 (2.0-3.7) 18 (47-49) 5.8 8.0 15 quinidine 2.7 48 18 10.0 ''

Table 2 Effect on the total number of cardiac contractions in dogs, 24 hours after two-stage coronary ligation (Harrism model)

connection Dose in mmol / kg (mg / kg) N Total number of heart contractions / min Base 5 '30' "60 ' 192 10.4 193 6.3 177 4.3 120 ' 180 ' 300 ' 360 ' example 1 0.005 (1.76) 4 χ 164 s 10.1 175 15 180 15,9 181 14.5 175 8.1 169 11.2 - - Example 4 0.005 (1.93) 4 χ 183 s 13 170 8.2 159 9.3 162 7.2 183 11.7 - - - Example 6 0.005 (2.07) 5 χ 167 s 8,6 179 9.5 164 7.1 168 12.7 162 6.6 - - - Example 9 0.005 (2.21) 3 χ 156 s 12.8 139 6.7 138 3.8 - 156 13.7 159 11.9 163 19.1 180 0.4 lidocaine 0.02 (5.4) 5 χ 146 s 7.3 - - - -

Table 3 Effect on ectopic contractions in percent of dogs, 24 hours after two-stage coronary ligation (Harrism Model) connection

Dose in

mmol / kg

(Mg / kg)

N Ectopic contractions in percent / min

Base 5 '30' 60 '

120 '

180 '

300 '

360 '

example 1 0.005 (1.76) 4 X S 99.75 30 18.1 47 16.6 54 15.7 68 3.4 80 5.5 - - Example 2 0.005 (1.93) 4 X S 88 5.3 26 16.9 24 6.5 75 7.2 90 2,3 - - - Example 6 0.005 (2.07) 5 X S 78 7.5 20 10,1 4 3.1 37 14.9 76 6.6 - - - Example 9 0.005 (2.21) 3 X S 90 2.0 21 5.7 38 15.0 42 23.2 42 14,1 73 9.7 79 4.9 89 2,3

lidocaine

Legend: to Table 1: ED ₅₀ Lv.

LD _M iv

θ ff. dose

χ 83 s 6.2

34 17.7

78 7.0

Dose in mg / kg indicating the fibrillatory effect of CaCl ₂ on rats after iv application of the test substance

suppressed by 50%. Calculation according to the probit regression analysis with confidence interval, ρ = 0.05

(Values in parentheses)

Lethal dose in mg / kg in 50% experimental animals of an orienting acute toxicity to Wistar rats

in-house breeding, i. v. Application in the tail vein, 3-4 dosages in each case.

Calculation according to the probit regression analysis with confidence interval, ρ = 0.05 (values in brackets)

= Quotient off

LD ₆₀ iv ED ₅₀ iv

• to determine the therapeutic width

effective dose in mg / kg and duration of action in minutes in dogs, 24 hours after two-stage coronary ligation

To tables 2 and 3:

χ = average

s = standard deviation ±

embodiments example 1

ö-te-dimethylamino-capronyll-ö ,! O-dihydro-11H-dibenzo [b, e] [1,4] diazepine-11 -one · HCl 7.75 g (0.02 mol) S-Fe-bromo-capronyl-S-DIO-dihydro-HH-dibenzoIb. eKi ^ ldiazepine H-on are added in 50ml dimethylformamide

Room temperature dissolved, cooled to 2 ⁰ C, 10ml of a solution of dimethylamine in dimethylformamide (72%, corresponds

0.16 mol of dimethylamine) was added and slowly in a closed vessel to room temperature and then half

Heated at 40 ⁰ C bath temperature. Thereafter, another 10ml of dimethylamine solution is added and it will be like

described above. The dimethylformamide is then distilled off in vacuo, the remaining oil is distributed between 30 ml of dilute ammonia solution and 50 ml of chloroform, the ammoniacal phase is poured twice more with 20 ml of chloroform each time, and the combined chloroform phases are washed three times with 20 ml of 1: 1 dilute hydrochloric acid.

The hydrochloric acid phases are made basic with about 10 mM concentrated ammonia solution, twice with 10 ml chloroform each time

shaken and the combined chloroform phases dried over sodium sulfate.

After separation of the sodium sulfate, the chloroform is distilled off, mixed with 40 ml of acetone and passed into the solution of HCl

up to pH 1. It is then concentrated, the residue is mixed with 30 ml of ethyl acetate and 20 ml of acetone, the sucks

Crystallized after 12 hours and recrystallized from isopropanol. The yield is 4.7 g (61% of theory), melting point: 183 ⁰ C. Analysis for C ₂₁ H ₂₆ N ₃ O ₂ Cl: calculated

C 65.02% 64.69%

H 6.76% 6.78%

N 10.83% 10.73%

Cl 9.14% 9.29%

The starting product used is 5- (6-bromo-capronyl) -5,10-dihydro-11H-dibenzo [b, e] [1,4] diazepine-11-one as follows

manufactured:

14.4 g (0.07 mol) of 5,10-dihydro-11H-dibenzo [b, e] [1,4] diazepin11-one are dissolved in 100 ml toluene, 18.8 g (0.088 mol)

Bromcapronsäurechlorid slowly added dropwise and the reaction mixture stirred for 5 hours at reflux. Then sets

To 2 g of activated charcoal, heated again for 15 minutes at reflux, filtered and allowed to crystallize. The crystals are filtered off with suction, washed with a little toluene and recrystallized from isopropanol after drying.

The yield is 17.8 g (65.6% of theory), melting point: 138-139 ⁰ C. Analysis for C ₁ SHIgBrN ₂ O ₂ : calculated

C 58.92% 59.08%

H 4.94% 4.94%

N 7.23% 7.24%

Example 2

5- (4-diethylamino-butyryl) -5,10-dihydro-11H-dibenzo [b, e] [1,4] diazepin-11-one 3,59g (0.01 mol) 5- (4-bromobutyryl) -5,10-dihydro-11H-dibenzo [b, e] [1,4] diazepine-11-one are dissolved in 25 ml of diethylamine and heated at reflux for 5 hours. The excess diethylamine is then distilled off, the residue is combined with 15 ml of water and 5 ml of aqueous ammonia solution and the reaction product is extracted with dichloroethane. The

Dichloroethane solution is shaken out three times with 1: 2 dilute hydrochloric acid, the hydrochloric acid phases with ammonia solution

made basic and extracted with dichloroethane. The dichloroethane is distilled off and the residue is crystallized from toluene

The yield is 2.95 g (84% of theory), melting point: 166-167 ⁰ C. Analysis for C ₂₁ H ₂ SN ₃ O ₂ : calculated

C 71.77% 71.56%

H 7,17% 7,31%

N 11.96% 11.96%

The starting 5- (4-bromobutyryl) -5,10-dihydro-11H-dibenzo (b, e] (1,4) diazepin-11-one is analogous to the starting product of 5,10-dihydro described in Example 1 -11 H -dibenzo [b, e] [1,4] diazepin-11-one and 4-bromobutyryl chloride were prepared Yield: 74.3% of theory, m.p .: 159-161 ⁰ C (toluene).

calculated found C 56.84% 56.98% H 4.21% 4.30% N 7.80% 7.72% br 22.24% 22.02%

Example 3 S-te-diethylamino-capronylJ-S.IO-dihydro-HH-dibenzolb.eHi ^ ldiazepin-H-on

7.75 g (0.02 moles) of o-bromo-caprono-O-O-dihydro-HH-dibenzoyl.eHi-ldiazepine-ii-one are refluxed in 50 ml of diethylamine for 5 hours. The reaction mixture is concentrated and the residue is mixed with 30 ml of water and 10 ml of concentrated

Ammonia solution. Then shake with benzene three times. The combined benzene phases are extracted three times

with 1: 2 dilute hydrochloric acid, the hydrochloric acid phases basic with concentrated ammonia solution and shakes out the separating oil three times with benzene. The benzene is distilled off and the oily residue (7 g) under heating in 30 ml

Toluen solved. After cooling, a precipitate falls out, which is filtered off and washed with toluene and ether. The yield is 5 g (65.9% of theory), melting point: 104-105 ° C. AnSIySBfUrC ₂ SH ₂ SN ₃ O ₂ : calculated found

C 72.79% 72.63%

H 7.70% 7.68%

N 11.07% 11.20%

For the preparation of the S-fe-diethylamino-capronyl-S.IO-dihydro-IIH-dibenzolb.elli ^ ldiazepine-H-on-hydrochloride, the o.g. Oily residue (7g) in 50m! Dissolved hot isopropanol and introduced into the cooled to room temperature solution of HCl gas to pH 1. The reaction solution is then concentrated to dryness in vacuo, another 50 ml of isopropanol are added, and the mixture is again concentrated by evaporation and recrystallized from 50 ml of acetonitrile with the addition of activated carbon.

The yield is 3.8 g (45% of theory, based on 5- (6-bromo-capronyl) -5,10-dihydro-11H-dibenzo [b, e] [1,4] diazepin-11-one), m.p .: 179-18S ⁰ C.

Analysis for C ₂₃ H ₃₀ N ₃ O ₂ Cl:

calculated found C 66.41% 66.23% H 7.27% 6.99% N 10.10% 10.18%. Cl 8.52% 8.43%

Example 4

e-chloro-S-N-diethylamino-butyrico-O, -i-dihydro-HH-dibenzoyl.eHi-ldiazepin-ii-one 3.94g (0.01 moles) of 5- (4-bromobutyryl) -8-chloro-5, 10-dihydro-11H-dibenzo [b, e] [1,4] diazepin-11-one are refluxed in 25 ml of diethylamine with stirring for 5 hours, the excess of diethylamine is distilled off and the residue is washed with 15 ml

Water and 5 ml of concentrated ammonia solution. The mixture is then extracted three times with chloroform, shaken

The combined chloroform phases are extracted three times with 1: 2 dilute hydrochloric acid, made basic with concentrated ammonia solution, and the precipitating oil extracted three times with chloroform. The chloroform is then distilled off and the residue is stirred with a little dry benzene, whereby the crude product crystallizes. It is recrystallized from toluene.

The yield is 2.8 cg (73.8% of theory), melting point: 163-164 ⁰ C. Analysis for C ₂₁ H ₂₄ N ₃ O ₂ Cl: calculated

C 65.36% 65.53%

H 6.27% 6.41%

Cl 9.19% 9.01%

The starting 5- (5-bromobutyryl) -8-chloro-5,10-dihydro-11H-dibenzo [b, e] [1,4] diazepine-11-one is analogous

the starting product of 8-chloro-5,10-dihydro-11H-dibenzo [b, e] [1,4] diazepin-11-one described in Example 1 and

Bromobutyryl chloride. Yield: 83.1% of theory, m.p .: 176-177 ° C. Analysis for C ₁₇ H ₁₄ N ₂ O ₂ BrCl: calculated

C 51.87% 51.77%

H 3.58% 3.65%

Example 5

8-Chloro-5- (4-diethylamino-valeryl) -5,10-dihydro-11H-dibenzolb, e] (1,4) diazepin-11-one 4.07g (0.01 mol) S-bromo-bromoveryde -e-chloro-SIO-dihydro-IIH-dibenzoil.H ^ ldiazepin-ii-one are refluxed in 25 ml of diethylamine for 5 hours, then the diethylamine excess is distilled off and 15 ml of water and 5 ml of concentrated ammonia solution are added to the residue the ammoniacal phase with benzene, the benzene phase is extracted twice with 1: 2 dilute hydrochloric acid, basified with concentrated ammonia solution and extracted with benzene, the benzene is distilled off and the residue is recrystallised from toluene to yield 3.25 g (81.3%) % of theory), melting point: 159-160 ° C. Analysis for C ₂₂ H ₂₆ N ₃ O ₂ Cl: calculated

C 66.07% 66.00%

H 6,55% 6,63%

Cl 8.86% 8.65%

The starting compound used is the S-IB-bromvaleryD-e-chloro-.alpha.-dihydro-11H-dibenzo [b, e] [1,4] diazepine-11 -one obtained analogously to the starting material from 8- Chloro-5,10-dihydro-11H-dibenzo (b, e] [1,4] diazepin-11-one and 5-bromovaleryl chloride

Yield: 87% of theory, melting point: Analysis for C ₁₈ H ₁₆ N ₂ O ₂ BrCl: calculated

53.26%

4.02%

7.14%

Example 6

e-Chloro-S-diethylamino-capronyl-D-D-dioic-dihydro-IIH-dibenzoilbHelozepine-H-on 4.21 g (0.01 mol) of 5- {6-bromo-capronyl) -8-chloro -5,10-dihydro-11-ol-dibenzo [b, e] [1,4] diazepine-11-one are refluxed in 25 ml of diethylamine for 5 hours. Then, the excess diethylamine is distilled off, 15 ml of water and 5 ml of concentrated ammonia solution are added and the mixture is extracted three times with benzene. The combined benzene phases are extracted by shaking three times with 1: 2 dilute hydrochloric acid, the combined hydrochloric acid phases are made basic with concentrated ammonia solution and the precipitating oil is extracted three times with benzene. The benzenic phase is washed with water and concentrated. The

Residue is recrystallized from a little toluene. The yield was 2.65g (64.1% of theory), Melting point: 136-138 ⁰ C. Analysis for C ₂₃ H ₂₈ N ₃ O ₂ Cl:

C 53.03% H 3.96% N 6.87%

calculated found C 66.74% 66.72% H 6.82% 7.02% N 10.15% 1008% Cl 8.55% 8.54%

The starting S-bromo-capronyl-D-chloro-S.IO-dihydro-IIH-dibenzoilbeldiazepine-H-one is used

prepared analogously to the starting product described in Example 1 from 8-chloro-5,10-dihydro-11H-dibenzo [b, el [1,4] diazepin-11-one and e-bromcapronyl chloride.

Yield: 76.6% of theory, m.p .: 170-171 ° C (toluene). Analysis for C ₁₆ H ₁₈ N ₂ O ₂ BrCl: calculated

C 54.11% 54.01%

H 4.30% 4.26%

Example 7

8-Chloro-5- (7-diethylamino-enanthoyl) -5 _> 10-dihydro-11H-dibenzo [b _> e] [1,4] diazepin-11-one 4,35g (0.05 mol) 5- (5) 7-Bromoenanthoyl) -8-chloro-5,10-dihydro-11H-dibenzo [b, e] (1,4] diazepin-11-one are refluxed in 25 ml of diethylamine for 5 hours and then distilled off the excess of diethylamine. The residue is mixed with 15 ml of water and 5 ml of concentrated ammonia solution, extracted three times with benzene, the combined benzene phases three times with 1: 2 dilute hydrochloric acid and the hydrochloric acid phases with concentrated ammonia solution basic, then extracted three times with Bonzen, the benzene distilled off, the residue dissolved in toluene with heating and until the

Crystallization left. The crystals are filtered off with suction and washed successively with toluene and ether. The yield is 2.8 g (66.6% of theory), melting point: 145-146 ⁰ C. Analysis for CmH ₃₀ N ₃ O ₂ Cl:

calculated found C 67.35% 67.30% H 7.06% 7.08% N 9.81% 9.77% Cl 8.22% 8.17%

The starting 5- (7-bromoanthoyl) -8-chloro-5,10-dihydro-11H-dibenzo [b, e] [1,4] diazepin-11-one is used

prepared analogously to the Ausganysprodukt described in Example 1 of 8-chloro-5,10-dihydro-11H-dibenzo [b, e] [1,4] diazepin-11-one and 7-Bromönanthoylchlorid.

Yield: 71.5% of theory, melting point: 159-161 ⁰ C (toluene). Analysis for C ₂ oH ₂ oN ₂ 0 ₂ BrCl: calculated

C 55.13% 55.02%

H 4.63% 4.68%

N 6,43% 6,40%

Example 8

e-Chloro-S-N-morpholino-capronyl-O, di-O-dihydro-IIH-dibenzoilb.elli-ldiazepine-H-on 5.6 g (0.015 mol) B-ie-bromo-capronyl-S-chloro-ö. iO-dihydro-i 1H-dibenzo [b, e) (1,4) diazepin-11-one and 5,23g (0,06 mol) morpholine are stirred in 50ml toluene for 5 hours at reflux. After cooling, the desired product is extracted with 1: 2 dilute hydrochloric acid from the Toluenian phase, basified with concentrated ammonia solution and shaken out with benzene. After washing the benzene phase with water, the benzene is distilled off. The oily residue is dissolved

Warm in 120ml toluene, allow to cool, aspirate the precipitate, wash successively with toluene and ether and leave

dry.

The yield is 3.7 g (59.6% of theory), melting point: 135-136 ⁰ C. Analysis for C ₂₃ H ₂₈ N ₃ O ₃ Cl:

calculated found C 64.55% 64.40% H 6.12% 6.11% N 9.82% 9.90% Cl 8.28% 8.23%

Example 9

8-Chloro-5- (7-N-morpholino-enanthoyl) -5,10-dihydro-11H-dibenzo [b, e] [1,4] diazepin-11-one 3.27g (0.0075 mol) 5 - (7-Bromoanthoyl) -8-chloro-5 _/ 10-dihydro-11H-dibenzo [b, el (1,4] diazepin-11-one and 2g (0.0225 mol)

Morpholine are stirred in 25 ml toluene for 5 hours at reflux. After cooling, the reaction solution is extracted with

1: 2 dilute hydrochloric acid, basified with concentrated ammonia solution, the desired product is extracted three times

Dichloroethane, the dichloroethane phase is washed with water and the dichloroethane is distilled off. The residue is made up of heptane Toluene (1: 1) recrystallized, the crystals were filtered off with suction, washed with ether and dried. The yield is 2 g (60.7% of theory), melting point: 102-103 ⁰ C. Analysis for C ₂₄ H ₂₈ N ₃ O ₃ Cl:

calculated found C 65.22% 65.31% H 6.39% 6.32% N 9.51% 9.40% Cl 8.02% 7.77%

Example 10

8-chloro-5,10-dihydro-6- [6- (4-methylpiperazin-1-yl) capronyl] -11 H -dibenzo [b, e] [1,4] diazepin-11-one 8, 44 g (0.02 mol) of 5- (6-bromo-capronyl) -8-chloro-5,10-dihydro-11H-di-benzo [b, e] [1,4] diazepine-11-one, 4.21 g ( 0.042 mol) of N-methylpiperazine and 50 ml of toluene are stirred at reflux for 2 hours. Then shake out the Toluenische solution with 20ml of water. The toluene phase is extracted twice with 10 ml of 1: 1 dilute hydrochloric acid, the combined hydrochloric acid phases are made basic with concentrated ammonia solution, shaken once with 30 ml and twice with 10 ml of chloroform and the chloroform phases are concentrated. 50 ml of isopropanol are added twice to the residue and concentrated again each time. Then add 10ml toluene, heat slightly and the crystals are filtered off with suction. The yield is 6 g (68% of theory), melting point: 142-147 ⁰ C.

Analysis for C ₂₄ H ₂₉ N ₄ O ₂ Cl:

calculated found C 65.37% 65.47% H 6.68% 6.67% N 12.71% 12.31% Cl 8.04% 7.98%

Example 11

5,10-Dihydro- [6- (4-methylpiperazin-1-yl) capronyl] -11 H -dibenzo [b, el [1,4] diazepin-11-one 5.8g (0.015 mol) S- The bromo-capronyl-BDIO-dihydro-HH-dibenzolb.elH1-ldiazepin-ii-one, 3.2 g (0.032 mol) N-methylpiperazine and 40 ml toluene are stirred at reflux for 4 hours. Then the reaction solution is concentrated in vacuo, mixed with 50 ml of chloroform, the chloroform phase zv ever with 20ml each of 1: 1 dilute hydrochloric acid, the combined hydrochloric acid phases with 20ml chloroform, basic with concentrated ammonia solution, shaken out and separates the

Chloroform phase from. The ammoniacal phase is shaken twice more with 20 ml of chloroform each, the combined Chloroform phases are dried over Na ₂ SO ₄ and concentrated. The oily residue is boiled with 20 ml of isopropanol,

concentrated and crystallized under heating with 20ml toluene.

The yield is 4.7 g (77% of theory), melting point: 129 ° C (decomposition). Analysis for C ₂₄ H ₃ oN ₄ 0 ₂ : calculated

C 70.91% 70.52%

H 7.44% 7.37%

N 13.78% 13.46%

Example 12

e-Chloro-ethyl-ethyl-capronyl-D-S-di-O-dihydro-HH-dibenzolb.leliazepin-ii-on-HCl 8.44g (0.02 mol) S-IB-bromo-capronyd-e-chloro-ö. iO-dihydro-IIH-dibenzolb.elli ^ Jdiazepine H-on are available in 50ml

Dimethylformamide dissolved, added at 2 ° C with 10ml ethylamine solution (0.17 mol, about 74% in dimethylformamide),

Heated for 0.5 hours in a closed vessel to 5O ⁰ C, added again at 2 ⁰ C with 5ml of the above ethylamine solution, again heated for 0.5 hours at 50 ⁰ C in a closed vessel, stirred with 10% activated charcoal in the heat and in vacuo to

Dry concentrated. The residue is mixed with 50 ml of chloroform, concentrated to dryness, taken up in 50 ml of isopropanol, if necessary under Add 20 to 40% water, and introduce HCI gas to pH 1. The acidic solution is concentrated to dryness in vacuo, combined again with isopropanol, again to dryness

concentrated, recrystallized from isopropanol with activated charcoal (mp. Mettler: 187-191 "C) and boiled again with 30 ml of acetonitrile.

The yield is 3.0 g (35.4% of theory), melting point: 190-195 ⁰ C (decomposition). Analysis for C ₂₁ H ₂₆ N ₃ O ₂ Cl ₂

calculated found C 59.72% 59.40% H 5.97% 5.94% N 9.95% 9.96% Cl: 16.79% 16.97%

Example 13 S-te-ethylamino-capronyD-S.IO-dihydro-HH-dibenzoIb.eKi ^ ldiazepin-H onHCI

7.8 g (0.02 mol) of S-ie-bromo-capronyl-D-SJO-dihydro-HH-dibenzotb.elti ^ ldiazepine-H-on are dissolved in 50 ml of dimethylformamide, at 2 ° C with 10 ml of ethylamine solution (0.17 mol, ca. 75% in dimethylformamide), heated for 0.5 hours at 50 ° C in a closed vessel, added again 10ml derobigen ethylamine solution at 2 ° C and left at 50 ⁰ C for 1 hour.

The reaction solution is then stirred cold with 10% (based on the product used) of activated carbon and in vacuo

concentrated to dryness. Dissolve the residue in 30 ml of chloroform, shake twice with 20 ml of 1: 1 dilute HCl, add 20 ml of chloroform to the combined hydrochloric acid phases and make basic with concentrated ammonia solution. The

Chloroform phase is separated after shaking, the ammoniacal phase twice more with 20 ml of chloroform

shaken and the combined chloroform phases are dried over Na ₂ SO ₄ , with some activated carbon is added.

After filtration, the chloroform phase is concentrated, the oily residue is mixed with 20 ml of isopropanol and 6 ml Water, introduces HCI gas to pH 1, concentrated in vacuo to dryness, again 50ml isopropanol üu, concentrated again Dry and boil with 25ml acetonitrile.

The yield is 5.1 g (65.4% of theory), melting point: 189.5-196.5 ° C (decomposition).

Analysis for C ₂₁ H ₂₆ N ₃ O ₂ Cl:

calculated found C 65.02% 65.23% H 6.76% 6.54% N 10.83% 10.89% Cl 9.14% 8.91%

Example 14 S-ie-diisopropylamino-capronyO-SFIO-dihydro-HH-dibenzoIb.eKi ^ ldiazepin-H-on

5.8 g (0.015 mol) of S-tö-bromo-capronyl-D-SJO-dihydro-HH-dibenzoyl.eHi-ldiazepine-H-on are refluxed with 20 ml of diisopropylamine for 21 hours. Then the reaction mixture is concentrated, the residue is taken up in 50 ml of chloroform, extracted twice with 1: 1 dilute ammonia solution and then twice with 20 ml and once with 10 ml of concentrated

HCI. The combined hydrochloric acid phases are shaken out with 20 ml of chloroform and concentrated with concentrated ammonia solution

and extracted three times with 30 ml of chloroform. The combined chloroform phases are shaken twice with 20 ml

Water and concentrated to dryness. The residue is dissolved in the middle in Toluan and crystallized after standing for a long time. The yield is 1.7 g (25.6% of theory), Melting point: 100-106 ⁰ C (decomposition). Analysis for C ₂₆ H ₃₂ N ₃ O ₂ : calculated

C 73.68% 73.66%

H 8,16% 7,93%

N 10.31% 10.40%

Example 15 S-ie-diethylamino-capronyO-S.IO-dihydro-HH-dibenzo-lb.eHi ^ ldiazepin-H-on

10g (0.029 mol) of B-te-ChlorcapronyD-B.IO-dihydro-HH-dibenzoIb.eKi ^ ldiazepin-H-one are dissolved in 100 ml of dimethylformamide, treated with 50ml (0.48 mole) of diethylamine and 33 hours at 65 ⁰ C bath temperature stirred. Then you narrow that

Reaction mixture to dryness. The residue is distributed by heating between 120 ml of toluene, 70 ml of water and 40 ml

Concentrated ammonia solution, the toluene is separated off, the aqueous phase shakes out twice with 50 ml toluene and extracted the combined toluene phases three times with 50ml of 1: 1 diluted hydrochloric acid.

The combined falzsauren phases are made strongly basic with concentrated ammonia solution, three times with 50ml toluene

shaken out and the combined toluene phases shaken twice with 50 ml of water.

The toluene phases are concentrated in vacuo, added again with 50 ml of toluene and concentrated again. The residue will be

Recrystallized twice from toluene with the addition of activated charcoal. In the crystallization of the compound 10ml of cyclohexane are added.

The yield is 3.1 g (27.2% of theory), melting point: 98-100 ° C. Analysis for C ₂₃ H ₂₉ N ₃ O ₂ : calculated

C 72.79% 72.62%

H 7.70% 7.62%

N 11.07% 11.08%

(CH ₂ ) _n - N

(CH ₂ ) _n - X II III

IV

X ¹ -

O Il C

ά η

, J-

- X VI

Claims (7)

A process for the preparation of novel 5- (ω-aminoacyl) -5,10-dihydro-11H-dibenzo / b, e1 / 4 / diazepin-11-ones of general formula I, wherein R ^{1 is} hydrogen or Chloro, R ² and R ³ , which may be identical or different and hydrogen, an alkyl radical having 1 to 3 carbon atoms or together with the N-atom to which they are attached, a morpholino or N-methylpiperazino radical and η a can mean number of 3 to 6 and when R ² is hydrogen, then R ³ may also be cyclohexyl, as well as their salts with physiologically tolerable inorganic or organic acids, characterized in that either a) a 5,10-dihydro-5- ()) haloacyl) -11H-dibenzo / b, e // 1,4 / diazepin-11-one of the general formula II, wherein R ¹ and η are as defined above and X is a halogen atom, with an amine of the general formula III, in which R ² and R ^{3 have} the abovementioned meaning or with a salt of this amine or that reacts b) a 5,10-dihydro-11H-dibenzo / b, e // 1,4 / diazepin-11-one of the general formula IV, wherein R ^{1 has} the abovementioned meaning, with an aminoacyl halide of the general formula V, wherein R ² , R ³ and η have the abovementioned meaning and X 'denotes a halogen atom, preferably a chlorine or bromine atom, or reacts with a salt of this aminoacyl halide and the compounds of the general formula I obtained, if desired, are converted into their acid addition salts with physiologically compatible inorganic or organic acids or, if desired, the bases are liberated from the salts of the compounds of the general formula I obtained. 2. The method according to claim 1, characterized in that the reactions are carried out in an inert organic solvent. 3. Process according to claims 1 and 2, characterized in that as indifferent organic solvent alcohols such as ethanol, n-propanol or isopropanol, ethers such as dioxane or tetrahydrofuran, aromatic hydrocarbons such as benzene, toluene or xylene, halogenated aliphatic or aromatic hydrocarbons such as chloroform , 1,2-dichloroethane, carbon tetrachloride or chlorobenzene or dipolar aprotic solvents such as dimethylformamide, acetonitrile or dimethylsulfoxide. 4. The method according to claim 1 a, characterized in that an excess of the compound of formula III is used as the solvent. 5. Process according to claims 1 to 4, characterized in that the reactions are carried out at temperatures between room temperature and 150 ⁰ C. 6. Process according to claims 1 to 5, characterized in that the reactions are carried out in the presence of an acid acceptor. 7. Process according to claims 1 to 6, characterized in that are used as acid acceptors alkali carbonates, alkali metal bicarbonates or tertiary organic amines.