DE3800986A1 - Novel 4-substituted 4,9-dihydro-10H-thieno-[3,4b][1,5]benzo-diazepin-10-ones, process for their preparation and medicaments containing these compounds - Google Patents

Abstract

The present invention relates to novel condensed diazepinones of the formula <IMAGE> in which R<1> represents a hydrogen atom or an alkyl group, R<2> represents an alkyl group, or a hydrogen, fluorine, chlorine or bromine atom, R<3> represents a hydrogen atom or an alkyl group, R<4> represents a hydrogen atom or an alkyl group, R<5> represents an alkyl group which is optionally substituted by a phenyl group or a 5- to 7-membered cycloalkyl group which is optionally substituted by a hydroxyl group or R<4> and R<5>, together with the nitrogen atom lying in between, represent a 5- to 7-membered saturated monocyclic ring which is optionally substituted by a dialkylamino radical, a hydroxyl group or an alkyl radical, or the 1-piperazinyl radical which is 4-substituted by an alkyl, phenylalkyl or phenyl group, and n represents the numbers 1, 2 or 3, their isomers and their acid addition salts, in particular for the pharmaceutical administration of their physiologically tolerable acid addition salts with inorganic or organic acids. The novel compounds have useful properties in their use as vagal pacemakers for the treatment of bradycardias and bradyarrhythmias and are obtained by methods known per se.

Description

In EP-A-02 13 293 are basic substituted condensed Diazepinone described the valuable pharmacological Possess properties, in particular favorable effects on the heart rate. These may be due to their missing gastric acid secretion inhibiting, salivationshemmenden and mydriatic Influences as a vagal pacemaker for treatment of bradycardia and bradyarrhythmias in the human and also be used in veterinary medicine.

It has now been found that the new condensed diazepinones the formula

their enantiomers, their diastereomers and their acid addition salts, especially for the pharmaceutical application their physiologically acceptable acid addition salts with inorganic or organic acids, superior properties when used as a vaginal pacemaker Treatment of bradycardia and bradyarrhythmias.

The present invention thus provides the new condensed diazepinones of the above formula I, their enantiomers, their diastereomers, their acid addition salts, in particular their physiologically acceptable acid addition salts, their use as medicines, these compounds containing medicaments and process for their preparation.

In the above formula I mean

R¹ represents a hydrogen atom or an alkyl group having 1 to 4 carbon atoms,
R 2 is an alkyl group having 1 to 4 carbon atoms, a hydrogen, fluorine, chlorine or bromine atom,
R³ is a hydrogen atom or an alkyl group having 1 to 3 carbon atoms,
R⁴ represents a hydrogen atom or an alkyl group having 1 to 4 carbon atoms,
R⁵ represents an optionally substituted by a phenyl group alkyl group having 1 to 3 carbon atoms or an optionally substituted by a hydroxy group 5- to 7-membered cycloalkyl group or
R⁴ and R⁵ together with the intervening nitrogen atom, a 5- to 7-membered optionally substituted by a dialkylaminoalkyl, hydroxy or alkyl radical saturated monocyclic ring or 1-Piperazinylrest substituted in the 4-position by an alkyl, phenylalkyl or phenyl group wherein each of the above-mentioned alkyl moieties may contain from 1 to 3 carbon atoms,
and
n are the numbers 1, 2 or 3.

Under the above definition of the

fall, for example, the

1-Oxo-6- (hexahydro-1H-1-azepinyl) -4-hexynyl, 1-oxo-6- (1-piperidinyl) -4-hexynyl, 1-oxo-6- (1-pyrrolindinyl) - 4-hexynyl, 1-oxo-7 - [(cyclohexyl) methylamino] -5-heptinyl, 1-oxo-6 - [(benzyl) methylamino] -4-hexynyl, 1-oxo-7- ( 4-methyl-1-piperazinyl) -5-heptinyl, 1-oxo-6- (4-benzyl-1-piperazinyl) -4-hexynyl, 1-oxo-6- (4-hydroxy-hexahydro-1H- 1-azepinyl) -4-hexynyl, trans-1-oxo-7 - [(4-hydroxycyclohexyl) methylamino] -5-heptinyl, 1-oxo-6- [2 - [(diethylamino) methyl] -1 -piperidinyl] -4-hexynyl, 1-oxo-8 - [(4-hydroxy-hexahydro-1H-1-azepinyl) -6-octynyl, 1-oxo-2-methyl-6- (hexahydro-1H- 1-azepinyl) -4-hexynyl, 1-oxo-2-methyl-6- (1-piperidinyl) -4-hexynyl, 1-oxo-2-methyl-6- (1-pyrrolindinyl) -4-hexynyl , 1-Oxo-2-methyl-7 - [(cyclohexyl) methylamino] -5-heptinyl, 1-oxo-2-methyl-6 - [(benzyl) methylamino] -4-hexynyl, 1-oxo 2-methyl-7- (4-methyl-1-piperazinyl) -5-heptinyl, 1-oxo-2-methyl-6- (4-benzyl-1-piperazinyl) -4-hexynyl, 1-oxo 2-methyl-6- (4-hydroxy-hexahydro-1H-1-azepinyl) -4-hexynyl, trans-1-oxo-2-methyl-7 - [( 4-hydroxycyclohexyl (methylamino) -5-heptinyl, 1-oxo-2-methyl-6- [2 - [(diethylamino) methyl] -1-piperidinyl] -4-hexynyl, 1-oxo-1-methyl -8 - [(4-hydroxy-hexahydro-1H-1-azepinyl) -6-octynyl, 1-oxo-2-ethyl-6- (hexahydro-1H-1-azepinyl) -4-hexynyl-, 1- Oxo-2-ethyl-6- (1-piperidinyl) -4-hexynyl, 1-oxo-2-ethyl-6- (1-pyrrolidinyl) -4-hexynyl, 1-oxo-2-ethyl-7- [(cyclohexyl) methylamino] -5-heptinyl, 1-oxo-2-ethyl-6 - [(benzyl) methylamino] -4-hexynyl, 1-oxo-2-ethyl-7- (4-methyl-1 -piperazinyl) -5-heptinyl, 1-oxo-2-ethyl-6- (4-benzyl-1-piperazinyl) -4-hexynyl, 1-oxo-2-ethyl-6- (4-hydroxyhexyhydro 1H-1-azepinyl) -4-hexynyl, trans-1-oxo-2-ethyl-7 - [(4-hydroxycyclohexyl) methylamino] -5-heptinyl, 1-oxo-2-ethyl-6- [ 2 - [(diethylamino) methyl] -1-piperidinyl] -4-hexynyl, 1-oxo-2-ethyl-8 - [(4-hydroxy-hexahydro-1H-1-azepinyl) -6-octynyl, 1 -Oxo-2-propyl-6- (hexahydro-1H-1-azepinyl) -4-hexynyl, 1-oxo-2-propyl-6- (1-piperidinyl) -4-hexynyl, 1-oxo-2 -propyl-6- (1-pyrrolidinyl) -4-hexynyl, 1-oxo-2-propyl-7 - [(cyclohexyl) methylamino [-5-heptinyl, 1-oxo-2-propyl-6 - [(benzyl) methylamino] -4-hexynyl, 1-oxo-2-propyl-7- (4-methyl-1-piperazinyl) -5 -heptinyl, 1-oxo-2-propyl-6- (4-benzyl-1-piperazinyl) -4-hexynyl, 1-oxo-2-propyl-6- (4-hydroxy-hexahydro-1H-1 azepinyl) -4-hexynyl, trans-1-oxo-2-propyl-7- [(4-hydroxycyclohexyl) methylamino] -5-heptinyl, 1-oxo-2-propyl-6- [2 - [(diethylamino ) methyl] -1-piperidinyl] -4-hexynyl and 1-oxo-2-propyl-8 - [(4-hydroxy-hexahydro-1H-1-azepinyl) -6-octynyl-group.

For example, in addition to those mentioned in the examples Compounds still called the following compounds, the fall under the above-mentioned general formula I:

4,9-Dihydro-3-methyl-4- [1-oxo-6- (1-pyrrolidinyl) -4-hexynyl] -10H-thieno [3,4-b] [1,5] benzodiazepine-10-one .
4,9-dihydro-3-methyl-4- [1-oxo-7 - [(cyclohexyl) methylamino] -5-heptinyl] -10H-thieno [3,4-b] [1,5] benzodiazepine-10 on,
4,9-dihydro-3-methyl-4- [1-oxo-6 - [(benzyl) methylamino] -4-hexynyl] -10H-thieno [3,4-b] [1,5] benzodiazepine-10 on,
4,9-Dihydro-3-methyl-4- [1-oxo-7- (4-methyl-1-piperazinyl) -5-heptinyl] -10H-thieno [3,4-b] [1,5] benzodiazepine -10-one,
4,9-Dihydro-3-methyl-4- [1-oxo-6- (4-benzyl-1-piperazinyl) -4-hexynyl] -10H-thieno [3,4-b] [1,5] benzodiazepine -10-one,
4,9-Dihydro-3-methyl-4- [1-oxo-6- (4-hydroxy-hexahydro-1H-1-azepinyl) -4-hexynyl] -10H-thieno [3,4-b] [1 , 5] benzodiazepine-10-one,
trans-4,9-dihydro-3-methyl-4- [1-oxo-7- (4-hydroxycyclohexyl) methylamino] -5-heptinyl] -10H-thieno [3,4-b] [1,5] benzodiazepine-10-one,
4,9-Dihydro-3-methyl-4- [1-oxo-6- [2 - [(diethylamino) methyl] -1-piperidinyl] -4-hexynyl] -10H-thieno [3,4-b] [ 1,5] benzodiazepine-10-one, -
4,9-Dihydro-3-methyl-4- [1-oxo-8 - [(4-hydroxy-hexahydro-1H-1-azepinyl) -6-octynyl] -10H-thieno [3,4-b] [ 1,5] benzodiazepine-10-one,
4,9-Dihydro-4- [1-oxo-6- (hexahydro-1H-1-azepinyl) -4-hexynyl] -10H-thieno [3,4-b] [1,5] benzodiazepine-10-one and
4,9-dihydro-4- [1-oxo-6- (1-piperidinyl) -4-hexynyl] -10H-thieno [3,4-b] [1,5] benzodiazepine-10-one,
and their isomers and their acid addition salts.

Preferred compounds of the formula I are those in to those

R¹ is a hydrogen,
R² is a hydrogen atom or a methyl group,
R³ is a hydrogen atom or a methyl group,
R⁴ is a methyl group,
R⁵ is a cyclohexyl, hydroxycyclohexyl or benzyl group or
R⁴ and R⁵ together with the intervening nitrogen atom, a 1-pyrrolidinyl, 1-piperidinyl, hexahydro-1H-1-azepinyl, 4-methyl-1-piperazinyl or 4-benzyl-1-piperazinylgruppe, one in 3- or 1-piperidinyl or hexahydro-1H-1-azepinyl group substituted by a hydroxy group or a 1-piperidinyl group substituted by a [(dimethylamino) methyl] - or [(diethylamino) methyl] group and
n are the numbers 1, 2 or 3,
their isomers and their acid addition salts.

However, particularly preferred compounds are those of formula

in the
R² is a methyl group,
R³ is a hydrogen atom or a methyl group,
R⁴ and R⁵ together with the intervening nitrogen atom represent a 1-piperidinyl or (hexahydro-1H-1-azepinyl) group, their isomers and their acid addition salts.

According to the invention gives the new compounds according to the following Method:

• a) By reacting a compound of the formula in the
  R¹, R², R³ and n are as defined above, with an amine of the formula in the
  R⁴ and R⁵ are as defined above, or with their salts in the presence of formaldehyde or paraformaldehyde and, optionally, in the presence of catalytic amounts of salts, such as copper (I) chloride, iron (II) chloride.
• As salts of the amines of the formula III are preferably the Hydrohalides, z. B. their hydrochlorides, or their acetates used.
• The reaction is carried out in an organic solvent Temperatures up to the boiling point of the reaction mixture. When Solvents are cyclic ethers, such as dioxane and Alcohols such as ethyl alcohol. When using dioxane, it is recommended itself the addition of acetic acid. The reaction can by addition of salts, such as copper (I) chloride or iron (II) chloride, be accelerated. In general, first the Formaldehyde or paraformaldehyde with an amine of the formula III or their salts, for. B. their hydrochlorides or acetates, combined in the solvent and then the compound added to the general formula II. After heating at temperatures to reflux is filtered from the insoluble and the end product isolated in the usual way. in the the rest of the usual mannich reactions apply (see Weygand and Hilgetag, Organic-Chemical Experimenting Art, p. 990 u.f.).
• b) By reacting the dilithium salt of a compound of the formula in the
  R¹ and R² are as defined above, with an ester of the formula in the
  R³ to R⁵ and n are as defined above and
  R⁶ represents a halogen atom, an alkoxy radical having 1 to 10 carbon atoms, a phenylalkoxy radical having a total of 7 to 10 carbon atoms or the phenyloxy group.

The conversion of a compound of formula IV into the dilithium salt succeeds with lithium alkyls such as n-butyllithium, n-butyllithium in the presence of tetramethylethylenediamine, tert-butyllithium, lithium dialkylamides such as lithium diisopropylamide or lithium dicyclohexylamide or with lithium aryls, z. With phenyllithium. The conversion into the dilithium salt and the further conversion to the final product takes place in an inert organic solvent at temperatures between -60 ° C and + 20 ° C, but preferably at -10 ° C. When inert solvents are those used for reactions with Lithium reagents are common; especially advantageous is the use of tetrahydrofuran or other ethers, such as diethyl ether, of aliphatic hydrocarbons, such as Hexane or of mixtures thereof, if appropriate also in the presence of hexamethylphosphoric triamide as cosolvent. A short time after the completion of the addition of the metallating Reagent is given the stoichiometric amount or one slight excess of the ester of general formula V added and leaves the reaction mixture to complete the reaction slowly, z. Within 2 hours, to room temperature come. The formed compound of formula I becomes isolated from the reaction mixture by conventional methods and  the free compound is obtained, which then, if desired can be converted into their salts.

So obtained bases of the general formula I can afterwards into their acid addition salts or acid addition salts obtained in the free bases or other pharmacological acceptable acid addition salts are converted. When Acids have, for example, hydrochloric acid, hydrobromic acid, Sulfuric acid, methyl sulfuric acid, phosphoric acid, Tartaric acid, fumaric acid, citric acid, maleic acid, succinic acid, Gluconic acid, malic acid, p-toluenesulfonic acid, Methanesulfonic acid or sulfamic acid proved suitable.

Are obtained according to the above methods compounds of the general formula I in which R³ is an alkyl group with 1 to 3 carbon atoms and the other substituents have the meanings mentioned above, so can these compounds in diastereomeric forms, especially in their two diastereomeric Antipodenpaaren occur. links of the general formula I in which R³ is a hydrogen atom is and the other substituents as defined above are, are as racemates or enantiomeric (+) - and (-) - forms. The invention includes the individual isomers as well as their mixtures. The separation of the respective diastereomers succeeds due to the different physicochemical Properties, e.g. B. by fractional recrystallization from suitable solvents, by high pressure liquid chromatography, Column chromatography or gas chromatographic Method.

The cleavage possibly racemates of the compounds of the general Formula I can be carried out by known methods, for example, using an optically active acid,  such as (+) - or (-) - tartaric acid, or a derivative thereof, such as (+) - or (-) - diacetyltartaric acid, (+) - or (-) - monomethyl tartrate or (+) - camphorsulfonic acid.

After a conventional process for isomer separation is the Racemate of a compound of general formula I with a the above-mentioned optically active acids in equimolar Amount reacted in a solvent and the resulting crystalline optically active diastereomeric salts separated using their different solubility. This reaction can be in any kind of solvent be carried out as long as this is a sufficient difference in the solubility of the salts. Preferably be methanol, ethanol or mixtures thereof, for example in the volume ratio 50:50, used. thereupon each of the optically active salts is dissolved in water, with a base such as sodium carbonate or potassium carbonate, neutralized and thereby the corresponding free connection in the (+) or (-) - form.

In each case only one enantiomer or only one of the general Formula I falling diastereomeric antipode pair is also obtained by the above-described synthesis a) with a constitutionally defined starting compound of general formula II.

The preparation of the starting compounds of the general Formula II is carried out by reacting the dilithium salt of a corresponding 4,9-dihydro-10H-thieno [3,4-b] [1,5] benzodiazepine-10-ones with a corresponding Alkinsäurehalogenid. The Conversion into the dilithium salt is possible with lithium alkyls, in particular with n-butyllithium, n-butyllithium in the presence of tetramethylethylenediamine, tert-butyllithium, with lithium dialkylamides such as lithium diisopropylamide or lithium dicyclohexylamide, or with lithium aryls, e.g. B. with lithium phenyl. The transfer into the dilithium salt and the others  Reaction to the end product takes place in an organic solvent at temperatures between -60 ° C and + 20 ° C, preferably at -10 ° C. Serve as organic solvents those commonly used for reactions with lithium reagents are; particularly advantageous is the use of tetrahydrofuran or other ethers, such as diethyl ether, of aliphatic hydrocarbons, such as hexane, or mixtures thereof, if appropriate also in the presence of hexamethylphosphoric triamide as a cosolvent. A short time after completion the addition of the metallating reagent is given the stoichiometric amount or a slight excess of corresponding Alkinsäurehalogenids and leaves the reaction mixture to complete the reaction slowly, e.g. B. within 2 hours, come to room temperature. you isolated the compound of formula II formed according to customary Methods from the reaction mixture.

The preparation of a corresponding 4,9-dihydro-10H-thieno [3,4-b] [1,5] benzodiazepine-10-ons is described in US-A-39 53 430 described.

The basic substituted condensed diazepinones of have general formula I and their acid addition salts valuable properties; In particular, they own cheap Effects on heart rate and are lacking salivationshemmender and mydriatic influences as vagale Pacemaker for the treatment of bradycardia and bradyarrhythmias suitable in human and veterinary medicine; some of the compounds also show spasmolytic properties on peripheral organs, especially colon and Bladder.

A favorable relation between tachycarden effects on the one hand and in therapeutics with anticholinergic active component occurring undesirable effects on the pupil width and tear, salivary and gastric acid secretions on the other hand  is for the therapeutic use of the substances of particular importance. The following experiments show that the compounds of the invention in this regard have surprisingly favorable relations.

A binding studies on muscarinic receptors Determination of the IC₅₀ value in vitro

As an organ donor male Sprague-Dawley rats were with 180-220 g body weight. After removal of heart, submandibularis and cerebral cortex were all further steps in ice cold Hepes HCl buffer (pH 7.4, 100 mmolar NaCl, 10 mmolar MgCl₂) made. The whole heart was scissored crushed. All organs were finally in a Potter homogenized.

For the binding test, the organ homogenates in the following Diluted way:

Total heart | 1: 400 cerebral cortex 1: 3000 submandibular 1: 400

The incubation of the organ homogenates took place at a certain Concentration of the radioligand and a concentration series of the non-radioactive test substances in the Eppendorf centrifuge tube at 30 ° C. The incubation period was 45 minutes. The radioligand was 0.3 n molar 3 H-N- Methylscopolamine (3 H-NMS). The incubation was by adding ice-cold buffer followed by vacuum filtration completed. The filters were rinsed with cold buffer and determines their radioactivity. She represents the sum of specific and nonspecific binding of H-NMS. The proportion of non-specific binding was defined  as that radioactivity which, in the presence of 1 μmolar Quinuclidinylbenzilate was bound. It always became Fourfold determinations made. The IC₅₀ values of the unlabelled Test substances were determined graphically. you represent that concentration of the test substance which specifically binds 3 H-NMS to the muscarinic Receptors in different organs by 50% was inhibited. The results are shown in Table 1.

B. Investigation on functional selectivity of the antimuscarinic effect

Inhibit substances with antimuscarinic properties the effects of exogenously added agonists or of Acetylcholine released from cholinergic nerve endings becomes. The following is a description of methods reproduced for the detection of cardioselective antimuscarinica are suitable.

"In vivo" methods

The methods used had the goal of selectivity to confirm the antimuscarinic effect. Those substances, selected on the basis of "in vitro" studies were on their

• 1. M₂-selectivity in the rat
• 2. Salivary secretion-inhibiting effect on the rat  
• 3. Inhibition of acetylcholine action on bladder, bronchi and Heart rate of guinea pig

examined.

1. M₂-selectivity in the rat

The method used was developed by Hammer and Giachetti (Life Sciences 31, 2991-2998 (1982)). 5 minutes after intravenous injection of increasing doses of the substance became the right vagus electrically stimulated (frequency: 25 Hz; Pulse width: 2 ms; Stimulus duration: 30 s; Voltage: supramaximal). The bradycardia caused by vagal stimulation became certainly. Dose of substances containing vagal bradycardia (M₂) reduced by 50%, was determined graphically. Results see Table II.

2. Salivary secretion-inhibiting effect on the rat

According to Lavy and Mulder (Arch. Int. Pharmacodyn. 178, 437-445, (1969)) were anesthetized male with 1.2 g / kg urethane THOM rats increasing doses of the substance i.v. The Salivary secretion was caused by s.c. Administration of 2 mg / kg pilocarpine triggered. The saliva was sucked up with blotting paper, The area occupied by him every 5 minutes planimetric certainly. The dose of the substance affecting the saliva volume decreased by 50%, was determined graphically. Results see Table II.

3. Inhibition of acetylcholine action on bladder, bronchi and Heart rate of guinea pig

On anesthetized guinea pigs were 5 minutes after administration of test substance 10 μg / kg acetylcholine intravenously and simultaneously  injected intraarterially. This was the heart rate by extracorporeal discharge of the ECG, the exhalation resistance after Konzett-Rößler and the contraction of the uncovered Bladder registered directly. For the inhibition of acetylcholine action on the investigated organs were dose-response curves recorded and from this -log ED₅₀ values determined. Results see Table III.

For example, according to the above, the following became Connection investigated:

A = 4,9-dihydro-3-methyl-4- [1-oxo-6- (hexahydro-1H-1-azepinyl) -4-hexynyl] -10H-thieno [3,4-b] [1, 5] benzodiazepin-10-one

Table I

Receptor binding assays, in vitro

Results

The data in Table I above prove that the new compound of general formula I between muscarinic Differentiate receptors of different tissues. This follows from the lower IC₅₀ values on examination Preparations from the heart against those from the cerebral cortex and submandibularis.  

Table II

M₂ selectivity and salivary secretion inhibition in the rat

Results

Table III

Inhibition of acetylcholine activity on the bladder, bronchi and heart rate of the guinea pig

Results

From the pharmacological data of Table II above results in complete agreement with the receptor Binding studies (see Table I) - that the heart rate increased by the compounds mentioned already at dosages which does not limit the salivary secretion is observed.  

In addition, the pharmacological data of the above Table III on a surprisingly large discernment between the heart and smooth muscles of the bladder.

Furthermore, the compounds according to the invention are Well tolerated, so could even with the highest applied Doses in the pharmacological tests none toxic side effects are observed.

For pharmaceutical application, the compounds of the general formula I in a conventional manner in the customary pharmaceutical preparations, for. In solutions, Suppositories, tablets, drag'es, capsules or tea preparations incorporated. The daily dose is generally between 0.02 and 5 mg / kg, preferably 0.02 and 2.5 mg / kg, in particular 0.05 and 1.0 mg / kg of body weight, optionally in the form of several, preferably 1 to 3 individual doses, to achieve the desired results.  

The following examples are intended to explain the invention in more detail:

Preparation of the starting materials example A 4,9-Dihydro-3-methyl-4- [1-oxo-4-pentynyl] -10H-thieno [3,4-b] [1,5] benzodiazepin-10-one

To a solution of 46.0 g (0.2 mol) of 4,9-dihydro-3-methyl 10H-thieno [3,4-b] [1,5] benzodiazepine-10-one in 500 ml absolute Tetrahydrofuran are added with stirring at 0-10 ° C 278.6 ml (0.42 mol) of n-butyllithium solution in n-hexane (1.5 molar) dropwise. Stirring is continued at room temperature for one hour and 25.6 g (0.22 mol) of pentynoic acid chloride are added dropwise at this temperature, dissolved in 50 ml of absolute tetrahydrofuran, in the reaction solution. The approach will take another three hours further stirred at room temperature, then in 2000 ml a saturated saline solution and stirred with 2000 ml Diluted vinegar. The organic phase is separated off, extracted twice with 500 ml of saturated saline, dried over magnesium sulfate and concentrated in vacuo to dryness. The desired compound is obtained as dark brown viscous resin, without further purification for the preparation of Examples 1 and 2 is used. Crude yield: 60.1 g (97% of theory).

Production of final products Example 1 4,9-Dihydro-3-methyl-4- [1-oxo-6- (hexahydro-1H-1-azepinyl) - benzodiazepin-10-one 4-hexynyl] -10H-thieno [3,4-b] [1,5]

A mixture consisting of 31.0 g (0.1 mol) of 4,9-dihydro- 3-methyl-4- [1-oxo-4-pentynyl] -10H-thieno [3,4-b] [1,5] benzodiazepin-10 - one, 3.3 g (0.11 mol) of paraformaldehyde, 10.8 g (0.11 mol) hexamethyleneimine, 0.2 g of copper (I) chloride and 300 ml of dioxane, is refluxed for four hours. After the reaction has ended, the mixture is filtered through activated charcoal insoluble constituents and the filtrate concentrated in vacuo to dryness. The residue is chromatographed on silica gel (30-60 mesh) using dichloromethane / cyclohexane / methanol / ethyl acetate / conc. Ammonia (720/57/57/195 / 7,5) for elution chromotographically cleaned. After recrystallization from ethyl acetate This gives 3.1 g (7.3% of theory) of the desired Compound of melting point 188-189 ° C.

A small sample of the described compound used as base is present, is dissolved in acetone and by addition of ethereal Hydrogen chloride solution precipitated as the hydrochloride. you Obtains colorless crystals of melting point 229-230 ° C.

example 2 4,9-Dihydro-3-methyl-4- [1-oxo-6- (1-piperidinyl) -4-hexynyl] - 10H-thieno [3,4-b] benzodiazepin-10-one [1,5]

Prepared analogously to Example 1 from 4,9-dihydro-3-methyl-4- [1-oxo-4-pentynyl] -10H-thieno [3,4-b] [1,5] benzodiazepine-10-one, paraformaldehyde and Piperidine in a yield of 12% of theory.
Melting point: 189-190 ° C.

The following is the preparation of pharmaceutical applications described with some examples

example I Tablets containing 50 mg of 4,9-dihydro-3-methyl-4- [1-oxo-6- (hexahydro-1H-1-azepinyl) -4-hexynyl] -10H-thieno [3,4-b] [ 1,5] benzodiazepine-10-one

composition 1 tablet contains: active substance 50.0 mg lactose 148.0 mg potato starch 65.0 mg magnesium stearate  2.0 mg 265.0 mg

production method

Potato starch is used to produce a 10% slime by heating. The active substance, lactose and the remaining potato starch are mixed and granulated with the above mucus through a sieve of mesh size 1.5 mm. The granules are dried at 45 ° C, rubbed again through the above sieve, mixed with magnesium stearate and pressed into tablets.
Tablet weight: 220 mg
Stamp: 9 mm

example II Drag'es with 50 mg of 4,9-dihydro-3-methyl-4- [1-oxo-6- (hexahydro-1H-1-azepinyl) -4-hexynyl] - 10H-thieno [3,4-b ] [1,5] benzodiazepine-10-one

The Tabeletten prepared according to Example I are coated by a known method with a shell consisting essentially of sugar and talc. The finished Drag'es are polished using beeswax.
Drag'e weight: 300 mg

example III Ampoules containing 10 mg of 4,9-dihydro-3-methyl-4- [1-oxo-6- (hexahydro-1H-1-azepinyl) -4-hexynyl] - 10H-thieno [3,4-b] [ 1,5] benzodiazepine-10-one

composition 1 ampoule contains: active substance 10.0 mg sodium chloride 8.0 mg Dest. Water, ad 1 ml

production method

The active substance and sodium chloride are dissolved in dist. Dissolved water and then filled up to the given volume. The solution is sterile filtered and filled into 1 ml ampoules.
Sterilization: 20 minutes at 120 ° C.

example IV Suppositories containing 50 mg of 4,9-dihydro-3-methyl-4- [1-oxo-6- (Hexahydro-1H-1-azepinyl) -4-hexynyl] -10H-thieno [3,4-b] [1,5] benzodiazepine-10-one

composition 1 suppository contains: active substance 50.0 mg Suppository mass (eg Witepsol W 45 ^(R) ) 1695.0 mg 1745.0 mg

production method

The finely pulverized active substance is suspended in the molten suppository mass which has been cooled to 40.degree. Pour the mass at 37 ° C in slightly pre-cooled suppository forms.
Suppository weight 1.745 g

example V 4,9-dihydro-3-methyl-4- [1-oxo-6- (hexahydroxy) 1H-1-azepinyl) -4-hexynyl] -10H-thieno [3,4-b benzodiazepin-10-one] [1,5]

composition 100 ml dripping solution contains: p-hydroxybenzoate 0.035 g p-hydroxybenzoate 0.015 g anise 0.05 g methanol 0.06 g Pure ethanol 10.0 g active substance 5.0 g sodium 1.0 g glycerin 15.0 g Dest. Water, ad 100.0 ml

production method

The active substance and sodium cyclamate are in about 70 ml Dissolved water and glycerol added. Dissolve p-hydroxybenzoic acid ester, Aniseed oil as well as menthol in ethanol and adds these Solution with stirring the aqueous solution. Finally is made up to 100 ml with water and free of floating particles filtered.

Claims (14)

1. New condensed diazepinones of the formula R¹ represents a hydrogen atom or an alkyl group having 1 to 4 carbon atoms,
R 2 is an alkyl group having 1 to 4 carbon atoms, a hydrogen, fluorine, chlorine or bromine atom,
R³ is a hydrogen atom or an alkyl group having 1 to 3 carbon atoms,
R⁴ represents a hydrogen atom or an alkyl group having 1 to 4 carbon atoms,
R⁵ represents an optionally substituted by a phenyl group alkyl group having 1 to 3 carbon atoms or an optionally substituted by a hydroxy group 5- to 7-membered cycloalkyl group or
R⁴ and R⁵ together with the intervening nitrogen atom, a 5- to 7-membered optionally substituted by a dialkylaminoalkyl, hydroxy or alkyl radical saturated monocyclic ring or 1-Piperazinylrest substituted in the 4-position by an alkyl, phenylalkyl or phenyl group wherein each of the above-mentioned alkyl moieties may contain from 1 to 3 carbon atoms,
and
n are the numbers 1, 2 or 3, their isomers and their acid addition salts. 2. Novel condensed diazepinones of the formula I according to claim 1, in which R¹ is a hydrogen atom,
R² is a hydrogen atom or a methyl group,
R³ is a hydrogen atom or a methyl group,
R⁴ is a methyl group,
R⁵ is a cyclohexyl, hydroxycyclohexyl or benzyl group or
R⁴ and R⁵ together with the intervening nitrogen atom, a 1-pyrrolidinyl, 1-piperidinyl, hexahydro-1H-1-azepinyl, 4-methyl-1-piperazinyl or 4-benzyl-1-piperazinylgruppe, one in 3- or 1-piperidinyl or hexahydro-1H-1-azepinyl group substituted by a hydroxy group or a 1-piperidinyl group substituted by a [(dimethylamino) methyl] - or [(diethylamino) methyl] group and
n are the numbers 1, 2 or 3, their isomers and their acid addition salts. 3. New condensed diazepinones of the formula in the R² is a methyl group,
R³ is a hydrogen atom or a methyl group,
R⁴ and R⁵ together with the intervening nitrogen atom represent a 1-piperidinyl or (hexahydro-1H-1-azepinyl) group, their isomers and their acid addition salts. 4. 4,9-dihydro-3-methyl-4- [1-oxo-6- (hexahydro-1H-1-azepinyl) -4-hexynyl] -10H-thieno [3,4-b] [1, 5] benzodiazepin-10-one and its acid addition salts. 5. 4,9-Dihydro-3-methyl-4- [1-oxo-6- (1-piperidinyl) -4-hexynyl] -10H-thieno [3,4-b] [1,5] benzodiazepine -10-one and its Acid addition salts. 6. Physiologically acceptable salts of the compounds according to at least one of claims 1 to 5 with inorganic or organic acids.   7. A pharmaceutical composition containing a compound after at least one of claims 1 to 5 or a physiologically acceptable Acid addition salt according to claim 6, optionally together one or more inert carriers and / or Diluents. 8. Use of the compounds according to at least one of the claims 1 to 6 for the manufacture of a medicament known as vagal pacemaker for the treatment of bradycardia and Bradyarrhythmias is appropriate. 9. A process for the preparation of a medicament according to claim 7, characterized in that non-chemical Ways a connection according to at least one of claims 1 to 6 in one or more inert carriers and / or Diluent is incorporated. 10. A process for the preparation of the novel compounds according to at least one of claims 1 to 6, characterized in that

• a) a compound of the formula in the
  R¹, R², R³ and n are as defined in claims 1 to 5, with an amine of the formula in the
  R⁴ and R⁵ are as defined in claims 1 to 5, or reacted with their salts in the presence of formaldehyde or paraformaldehyde or
• b) the dilithium salt of a compound of the formula in the
  R¹ and R² are as defined in claims 1 to 5, with an ester of the formula in the
  R³ to R⁵ and n are as defined in claims 1 to 5 and
  R⁶ represents a halogen atom, an alkoxy group having 1 to 10 carbon atoms, a phenylalkoxy group having a total of 7 to 10 carbon atoms or the phenyloxy group, and
  if desired, then a compound of formula I thus obtained is separated into its isomers and / or
  a compound of the formula I thus obtained is converted into its acid addition salts, preferably into its physiologically tolerated acid addition salts.

11. The method according to claim 10, characterized in that the reaction is carried out in a solvent. 12. Method according to claims 10a and 11, characterized in that that the reaction in the presence of catalytic Amounts of salts, preferably of copper (I) chloride or Iron (II) chloride, is performed. 13. The method according to claims 10a, 11 and 12, characterized characterized in that the reaction at the boiling point the reaction mixture is carried out. 14. Method according to claims 10b and 11, characterized in that that the reaction at temperatures between -60 and 20 ° C, preferably at -10 ° C, is performed.