DD284015A5 - METHOD FOR PRODUCING CONDENSED DIAZEPINONES - Google Patents

Abstract

The invention relates to a process for the preparation of condensed diazepinones. According to the invention, novel condensed diazepinones of the general formula (I) are prepared in which X, Z, A1, A2, R 1, R 2 have the meaning given in the description and in the claims. The diazepinones of the general formula I prepared according to the invention are used for the preparation of medicaments for the treatment of bradycardia and bradyarrhythmias and of spasms on the colon, bladder and bronchi. Formula (I) {new condensed diazepinones; Drug; bradycardia; bradyarrhythmias; Spasms on the colon, bladder, bronchi; enhanced effect and absorption by oral administration}

Description

Process for the preparation of condensed oiazepinones Field of application of the invention

The invention relates to a process for the preparation of novel condensed oiazepinones and medicaments containing these compounds.

Characteristic do9 known prior art

EP-A- ₀ 039 519 and 0 057 428 and US-A 3 ₀ 660 ₀ 380j 3 _o 691ol59j 4,213,984 »4,213,935; 4 "210 _0648, 4,410,527 / 4 _β 424.225 / 4,424,222 and 4,424,226 are condensed Oiazepinone with ulcushemmenden and magensafteekretionshemmenden properties known

EP-A-0 156 191 (US Pat. No. 4,550,107) describes condensed diazepinones! that by introducing novel Aminoacylre8te compared to the compounds of the above publications completely different, valuable pharmacological properties can be induced.

Object of the invention

The aim of the invention is to provide novel diazepinones ¹ which have a stronger pharmacological activity and improved selectivity,

Explanation of the essence of the invention

The invention has for its object to find new diazepinones with the desired properties and processes for their preparation.

The new condensed diazepinones have the general formula I ^v

O = C-A ¹ -N- Α

,in the

J TbJ one of the divalent radicals

(S)

CH-

LJL

(T)

(V)

represents and

12 1 7 X, A, A, Z and R to R have the following meanings

have:

X is a = CH group, a = C-Cl group or a

Nitrogen atom;

A and A are straight-chain or branched saturated alkylene radicals having 1 to 4 carbon atoms;

- 3 - 28 4 O 1 S

Z is an oxygen atom or an alkylene chain having 1 to 3 carbon atoms;

R is a branched or unbranched alkyl radical having 1 to 7 carbon atoms, a cycloalkyl or (cycloalkyl) alkyl radical having a total of up to 8 carbon atoms or a hydrogen atom;

R 'represents a branched or unbranched alkyl group having 1 to 6 carbon atoms or a cycloalkyl group having up to 7 carbon atoms;

R 3 and R 1, which may be the same or different, represent a hydrogen, fluorine, chlorine or bromine atom or an alkyl group having 1 to 4 carbon atoms;

R is a hydrogen or chlorine atom or a methyl group;

R and R, which may be the same or different, denote water Loffatome or alkyl groups having 1 to 4 carbon atoms, but R may also additionally represent a halogen atom.

J CbJ can only be the bivalent radical (V) if X represents the = CH group or = C-Cl group.

The compounds of general formula I can also be in the form of their physiologically acceptable salts after reaction with inorganic or organic acids. Hydrochloric acid, hydrobromic acid, sulfuric acid, methylsulphuric acid, phosphoric acid, tartaric acid, fumaric acid, citric acid, maleic acid, succinic acid, gluconic acid, malic acid, p-toluenesulphonic acid, methanesulphonic acid or amidosulphonic acid have proven suitable as acids, for example.

" ⁴ " 2 θ 4 O 1 S

ßeeonuers preferred compounds are ι

5> -II-dihydro-II - /// ^/ 2- (1-ethyl-2-pipericyclinyl) ethyl / -methylamino / acetyl / -6H-pyrido / 2,3-b // l, 4 / benzodiazepine 6 ~ on

5 _t ll-dihydro-ll - /// 2 "(l-niethyl-hexahydro-lH-2-azepinyl) -ethyl / mθthylamino / acθtyl / 6H-pyrido / 2,3"'b l // _t 4 / bθnzodiazθpin-

9-chloro-5, ll-dihydro-ll ~ /// 2- (i-methyl ~ hexahydro-LH-2-c: epinyl.) Ethyl / m6thylamino / ao tyl / '- 6H-pyrido / 2,? 3-b // l, 4 / benzodiazepine-6-one and

5,1'-Dihydro-8-methyl-II - /// 2- (1-methyl-hexahydro-1H-2-azepinyl) ethyl / methylamino / acetyl / 6H-pyrido / 2,3-b // l , 4 / - benzodiazepine-6-one

and their pharmacologically acceptable salts with inorganic or organic acids ₀

Compared with the known in the literature compounds, condensed diazepinones according to the invention are distinguished, surprisingly, comparable or improved selectivity tei by einfi significantly enhanced effect and ilesorption after oral administration from ₀

According to the invention, the novel basic substituted condensed diazepinones of general formula I are obtained by the following processes!

- 4a -

2 θ 4 O I S

a) Basic substituted condensed diazepinones of general formula Ia

C - A * - N - A

(IA)

in the

12 1 2

X, Z, A, A, R and R are as defined above and or (T ¹ )

one of the bivalent radicals (S), (U), (V) CH,

, (T ¹ )

R "

represents, wherein R is a chlorine atom or a methyl group,

is obtained by reacting haloacyl compounds of general formula II

(II)

O = C - A - shark

in which A, X and J (B *) have the abovementioned meanings and Hai is a chlorine, bromine or iodator, with amines of the general formula III

R ¹ - NH - A ²

N I R '

, (III)

pip

wherein A, Z, R and R have the meanings given above.

The amination is carried out in an inert solvent at temperatures between -1O ⁰ C and the boiling point of the solvent, preferably either with at least 2 moles of secondary amine of general formula III or with 1 to 2 moles of a secondary amine of general formula III and an auxiliary base. Examples of suitable solvents are chlorinated hydrocarbons, such as methylene chloride, chloroform or dichloroethane; open-chain or cyclic ethers, such as diethyl ether, tetrahydrofuran or dioxane; aromatic hydrocarbons, such as benzene, toluene, xylene, chlorobenzene or pyridine; Alcohols, such as ethanol or isopropanol; Ketones, such as acetone; Acetonitrile, dimethylformamide or 1,3-dimethyl-2-imidazolidinone in question. Suitable auxiliary bases are, for example, tertiary organic bases, such as triethylamine, N-methylpiperidine, diethylaniline, pyridine and 4- (dimethylamino) pyridine or inorganic bases, such as alkali metal or alkaline earth metal carbonates or bicarbonates, hydroxides or oxides. Optionally, the reaction can be accelerated by the addition of alkali metal iodides. The reaction times are depending on the amount and type of amine used of the general formula III between 15 minutes and 80 hours.

b.) The same basic substituted condensed diazepinones of general formula Ia are also obtained by acylation of diazepinones of general formula IV

(IV)

2.8 4 O 1 5

wherein X and jC ^B J ^{d; i} - ^e have the meanings given above, with carboxylic acid derivatives of the general formula V

N - C - A - N - A-

wherein Z, A ^x , A, R ^x and R * have the meanings given above and Nu represents a nucleofugic group or leaving group.

The reaction of the compounds of the general formula IV with the acid derivatives of the general formula V is carried out in a manner known per se. The leaving group Nu is a group which, together with the carbonyl group to which it is attached, forms a reactive carboxylic acid derivative. Suitable reactive carboxylic acid derivatives are, for example, acid halides, esters, anhydrides or mixed anhydrides, such as are formed from salts of the corresponding acids (Nu = OH) and acid chlorides, such as phosphorus oxychloride, diphosphoric acid tetrachloride or chloroformates, or in the reaction of compounds of general formula V (Nu = OH) with N-alkyl-2-halopyridinium salts resulting N-alkyl-2-acyloxypyridiniumsalze called.

The reaction is preferably carried out with the mixed anhydrides of strong mineral acids, in particular dichlorophosphoric acid. The reaction is optionally carried out in the presence of an acid-binding agent (proton acceptor). Examples of suitable proton acceptors are alkali metal carbonates or bicarbonates,

such as sodium carbonate or potassium bicarbonate; tertiary organic amines, such as pyridine, triethylamine, ethyldiisopropylamine, 4- (dimethylamino) pyridine, or called sodium hydride. The reaction is carried out at temperatures between -25 ⁰ C and 13O ⁰ C in an inert solvent. Suitable inert solvents are, for example, chlorinated aliphatic hydrocarbons, such as methylene chloride, 1,2-dichloroethane; open-chain or cyclic ethers, such as diethyl ether, tetrahydrofuran or 1,4-dioxane; aromatic hydrocarbons, such as benzene, toluene, xylene, o-dichlorobenzene; polar aprotic solvents such as acetonitrile, dimethylformamide or hexamethylphosphoric triamide; or mixtures thereof. Depending on the amount and type of acylating agent of the general formula V used, the reaction times are between 15 minutes and 80 hours. It is not necessary to prepare the compounds of general formula V in pure form, but they can rather be generated in situ in the reaction mixture in a known method.

c) The new pyrrolo-condensed diazepinones of the general formula Ib falling under the general formula I

O = C-A-N-A

(Ib)

12 12

X, Z, A, A, R and R have the meanings mentioned above.

R ⁵ "represents a hydrogen atom can be prepared by hydrogenolysis from those compounds of general formula Ib in which R represents a chlorine atom.

The hydrogenolysis is carried out in the presence of catalysts of metals from the VIII. Subgroup of the Periodic Table of the Elements, for example of palladium on animal charcoal, palladium on barium sulfate, Raney nickel or Raney cobalt, and at hydrogen pressures of 1 to 300 bar and temperatures of 0 ⁰ C to 13O ⁰ C in the presence of solvents, for example alcohols, such as methanol, ethanol; Ethern such as dioxane, tetrahydrofuran, carboxylic acids, such as acetic acid or tertiary amines, for example triethylamine performed. If you work in the absence of additional hydrogen chloride acceptors, such as sodium carbonate, potassium bicarbonate, triethylamine or sodium acetate, the result directly hydrochlorides of the compounds sought, which can be isolated after removal of the catalyst by evaporation of the reaction solution. If the hydrogen is replaced by formic acid in the preceding hydrogenolysis reaction, the reaction is in principle possible even with pressureless working. In this variant, in particular the reaction with formic acid in the presence of dimethylformamide as solvent and of palladium on carbon as catalyst at temperatures between 70 and 110 ⁰ C, and the reduction with triethylammonium in the presence of excess triethylamine and of palladium on animal charcoal or of palladium acetate and Triarylphosphinen, such as triphenylphosphine, tris (o-tolyl) phosphine, tris (2,5-diisopropylphenyl) phosphine, at temperatures between 40 and 110 ⁰ C, proven.

Bases of the general formula I thus obtained can then be converted into their acid addition salts or acid addition salts obtained into the free bases or other pharmacologically acceptable acid addition salts.

The basic substituted condensed diazepinones of the general formula I according to the invention contain, in particular if J QbJ represents the bivalent radical (U), up to two independent chiral elements. In addition to the asymmetric carbon atom in the side chain is to be regarded as a further chiral element of the acylated tricycle itself, which may be present in two mirror-image forms. It depends on the nature of the tricycle that the energy barrier for inversion at this center is so high that the individual isomers are stable at room temperature and become isolable. It has been found that in compounds of the general formula I, wherein X is a nitrogen atom and the positions adjacent to the diazepinone ring are unsubstituted, the required activation energy is so greatly reduced that diastereomers can no longer be detected at room temperature, let alone prepared by preparative isolation ,

The aminoacylated condensed diazepinones of the general formula I according to the invention thus contain up to three chiral elements, one of which may not be configurationally stable at room temperature. Such compounds may therefore exist in several diastereomeric and / or in each case as enantiomeric (+) and (-) forms. The invention includes the individual isomers as well as their mixtures. The separation of the respective diastereomers is possible due to the different physicochemical properties, e.g. by fractional recrystallization from suitable solvents, by high pressure liquid chromatography, column chromatography or gas chromatographic methods.

The cleavage of possibly racemates of the compounds of the general formula I can be carried out by known processes, for example using an optically active acid,

such as (+) - or (-) - tartaric acid, or a derivative thereof, such as (+) - or (-) - diacetyltartaric, (+) - or (-) - monomethyl tartrate or (+) - camphorsulfonic acid.

According to a conventional isomer separation method, the racemic compound of the general formula I is reacted with one of the above-mentioned optically active acids in an equimolar amount in a solvent, and the obtained crystalline diastereomeric salts are separated by utilizing their various solubilities. This reaction can be carried out in any kind of solvent as long as it has a sufficient difference in the solubility of the salts. Preferably, methanol, ethanol or mixtures thereof, for example in the volume ratio 50:50, are used. Then, each of the diastereomeric salts is dissolved in water, neutralized with a base such as sodium carbonate or potassium carbonate, thereby obtaining the corresponding free compound in the (+) or (-) form.

In each case only one enantiomer or a mixture of two optically active Untei. The general formula I falling diastereomeric compounds is also obtained by carrying out the syntheses described above with only one enantiomer ^, the general formula III or V.

The haloacyl compounds of general formula II are prepared by known methods (see U.S. Patent No. 4,550,107).

Zwischsnvsrbindungen the general formula III can be easily synthesized by the skilled person methods, for. B. by reduction of corresponding heterocyclic carboxylic acid alkylamides. The corresponding heterocyclic carboxylic acids are either commercially available or can be prepared according to literature specifications. So can unsubstituted

- 12 -

28 4 O 15

Heterocycloalkanes are converted by conversion into their 1,2-dehydro derivatives (or their trimers) and reaction with malonic esters to the corresponding a-Heterocycloalkylessigsäureestern (H. Fukawa, Y. Terao, K. Achiwa and M. Sekiya, Chem. Pharm. Bull , 31, ⁹⁴ (1983)]. Compounds with longer alkylene chains can be prepared from these by reduction with lithium aluminum hydride, reaction of the resulting alcohols with potassium cyanide [A. Mizuno, Y. Hamada, T. Shiori, Synthesis 1980 , 1007] and hydrolysis of the resulting nitriles getting produced.

The carboxylic acids or carboxylic acid esters formed in this way can, after alkylation of the nitrogen, be converted into the corresponding carboxylic acid amides by methods known to the person skilled in the art.

Compounds of the general formula III in which R 1 represents an alkyl radical are also obtained by reacting corresponding primary amines to give the carboxamides and reducing them with lithium aluminum hydride or diborane.

The starting compounds of the general formula V, in which Nu is an alkoxy group, are obtained by reacting diamines of the general formula III with halocarboxylic acid esters, if appropriate using additional auxiliary bases, e.g. Triethylamine, or catalysts, for example, Triton B. By saponification of the resulting esters, e.g. with baryta, one obtains the carboxylic acids covered by the general formula, which can serve for the preparation of derivatives with other nucleofugic groups.

Another object of the invention are pharmaceutical compositions containing one or more condensed diazepinones of general formula I or their physiologically acceptable salts.

For this purpose, the compounds of general formula I can be prepared in a manner known per se in the usual pharmaceutical preparation forms, e.g. into solutions, suppositories, tablets, dragees, capsules or tea preparations. 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 body weight, optionally in the form of several, preferably 1 to 3 Single doses to achieve the desired results.

The basic substituted condensed diazepinones of general formula I and their acid addition salts have valuable properties; in particular, they have favorable effects on the heart rate and are suitable in view of lack of gastric acid secretion-inhibiting, salivationshemmender and mydriatic influences as vaginal pacemaker for the treatment of bradycardia and bradyarrhythmias in human and also veterinary medicine; some of the compounds also show spasmolytic properties on peripheral organs, especially the colon, bladder and bronchi.

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

A. Binding Studies on Muscarinic Receptors: Determination of IC 50 In Vitro

As an organ donor served male Sprague-Dawley rats with 180-220 g body weight. After removal of Herz, Submandibu

- 14 -

28401

laris and cerebral cortex were all further steps in ice-cold Hepes-HCl buffer (pH 7.4, 100 molar NaCl, 10 molar MgCl ₂ ) made. The whole heart was crushed with scissors. All organs were finally homogenized in a Potter.

For the binding assay, the organ homogenates were diluted as follows:

Total heart 1: 400

Cerebral cortex 1: 3000

Submandibularis 1: 400

The incubation of the organ homogenates was carried out at a certain concentration of the radioligand and a concentration series of the nonradioactive test substances in the Eppendorf centrifuge tube at 30 ^° C. The incubation period was 45 minutes. The radioligand used was 0.3 η molar HN-methylscopolamine (H-NMS). The incubation was terminated by adding ice-cold buffer with subsequent vacuum filtration. The filters were rinsed with cold buffer and their radioactivity determined. It represents the sum of specific and unspecific binding of H-NMS. The proportion of nonspecific binding was defined as the radioactivity bound in the presence of 1 μ molar quinuclidinyl benzilate. There were always fourfold determinations. The IC ₅₀ values of the unlabelled test substances were determined graphically. They represent that concentration of the test substance at which the specific binding of H-NMS to the muscarinic receptors in the various organs was inhibited by 50%. The results are shown in Table 1.

- 15 -

B. Investigation of radio-selective selectivity of antimuscarinic activity

Substances with antimuscarinic properties inhibit the effects of exogenously added agonists or acetylcholine released from cholinergic nerve endings. The following is a description of methods suitable for detecting cardioselective antimuscarinica.

" In vivo" methods

The methods used were to confirm the selectivity of the antimuscarinic effect. Those substances that were selected on the basis of "in vitro" studies were tested for their

1. M ₁ -ZM ₂ selectivity in the rat and

2. Salivary secretion-inhibiting effect in the rat

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

examined.

1. M ₁ / M ₂ selectivity in the rat

The method used was described by Hammer and Giachetti (Life Sciences 31, 2991-2998 (1982)). Five minutes after intravenous injection of increasing doses of the substance either the right vagus was electrically stimulated (frequency: 25 Hz, pulse width: ms, stimulation time: 30 s, voltage: supran.aximal) or 0.3 mg / kg McN-A-343 in Male THOM rats injected intravenously. The symptoms due to vagal stimulation

- 16 -

fene bradycardia and the increase in blood pressure caused by McN-A-343 were determined. The dose of the subsumes, which reduced either the vagal bradycardia (M ₂ ) or the blood pressure increase (M ₁ ) by 50%, was determined graphically. Results see Table II.

2. Salivary anticonvulsant activity in the rat

According to Lavy and Mulder (Arch. Int Pharmacodyn., 178, 437-445, (1969)), male THOM rats anesthetized with 1.2 g / kg urethane received increasing doses of i.V. substance. Salivary secretion was induced by s.c. Administration of 2 mg / kg pilocarpine. The saliva was sucked up with blotting paper, the area occupied by it determined planimetrically every 5 minutes. The dose of substance that reduced salivary volume by 50% was graphically determined. Results see Table II.

3. Inhibition of acetylcholine activity on the bladder, bronchi and heart rate of the guinea pig / sincho ns

On anesthetized guinea pigs, 10 μg / kg of acetylcholine were injected intravenously and simultaneously intraarterially. 5 minutes after administration of the test substance. The heart rate was recorded directly by ECG extracorporeal discharge, Konzett-Rößler exhalation resistance and the contraction of the exposed bladder. Dose-response curves were recorded for the inhibition of the acetylchinin effect on the investigated qeins and from this, the EDcq values were determined. For results, see Table III.

For example, according to the above, the following compounds were investigated:

- 17 -

A = 5, 11-dihydro-II - [[[2- (1-methyl-2-piperidinyl) ethyl] methylamino] acetyl] -6H-pyrido [2,3-b] [1,4] benzodiazepine-6 -one

B = 5, 11-dihydro-II - [[[2- (1-methyl-hexahyuro-1H-2-azepinyl) ethyl-methylamino] -acetyl] -6H-pyrido [2,3-b] [1,4] benzcd. iazepin6-on

C = 9-chloro-5,1'-dihydro-II - [[[2- (1-methyl-hexahydro-1H-2-azepinyl) ethyl] methylamino] acetyl] -6H-pyrido [2,3-b] - [1,4] benzodiazepin-6-one hydrochloride

D - 5,11-dihydro-8-methyl-II - [[[2- (1-methyl-hexahydro-1H-2-azepinyl) ethyl] methylamino] acetyl] -6H-pyrido [2,3-b] - [1,4] benzodiazepin-6-one

and as comparison substances

E = 11 - ([2 - [(diethylamino) methyl] -1-piperidinyl] acetyl] -5,11-dihydro-6H-pyrido [2,3-b] [1,4] benzodiazepin-6-one (see U.S. Patent No. 4,550,107)

F = 5, 11-dihydro-ll - [(4-methyl-1-piperazinyl) acetyl] -6H-pyrido [2,3-b] [1,4] benzodiazepin-6-one (pirenzepine, see US Pat No. 3 660 380)

G = atropine

- 18 -

Table I ;

Receptor binding assays, in vitro: results ;

substance Receptor Binding Assays IC ₅₀ CnMl " ¹ ] Cortex Heart 9 submandibular A 40 5 80 B 40 3 50 C 20 4 40 D 30 80 140 e 1200 1500 5000 F LOO 4 200 G 2 4

The data in Table I above prove that the new compounds of the general formula I differ between muscarinic receptors of different tissue. This follows from the considerably lower _IC50 ~ values when tested on preparations from the heart compared with those from the cerebral cortex and submandibular gland.

Table II:

M ^ - / M2 ~ selectivity and salivary secretion inhibition in the rat:

Results:

substance -log E heart D ₅₀ [Mkg " ¹ ] blood pressure salivation A 7.48 6.34 5.91 B 7.41 6.46 5.47 C 7.5 5.52 D 7.67 6.21 e 6, 42 5.63 5.00 F 5.60 6.94 6.22 G 7.94 7.34 7.60

Table III:

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

Results :

substance -log E heart The [Molkg] bronchi bladder A 7.75 7.34 6.92 B 7.60 7.19 6.57 C 7.26 6.72 6,6'3 D 7.28 6.87 6.46 e 5.84 5.58 4.73 F 5.85 6.57 5.36 G 7.70 7.96 7.03

From the pharmacological data of the above Tables II and III it follows - in complete accordance with the receptor-binding studies - that the heart rate is increased by the compounds mentioned already at doses in which no limitation of the secretion of saliva is observed.

- 21 -

284ο

In addition, the pharmacological data of Table III above indicate a surprisingly large discernment between heart and smooth muscle.

The substances mentioned have compared to the already known compound E a significantly increased potency. The therapeutically usable selectivity is retained. This leads to a lower substance burden on the patient without increasing the risk of muscarinic side effects.

Furthermore, the compounds according to the invention are well tolerated, so no toxic side effects were observed even at the highest applied doses in the pharmacological studies.

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2840

Ausführungsbeiepiel

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

"Fp ₀ " means "melting point", "ZV means" decomposition "» For all compounds there are satisfactory elemental analyzes, IR, UV, H-NMR, often also mass spectra ο

example 1

5, ll ~ Dihydro-II - /// 2- (1-methyl-2-piperidinyl) ethyl / methylamino / acetyl / -6H-pyrido / 2'3-b // l »4 / benzodiazebin-6-one

To a solution of 5.7 g (0.02 mol) of 2- (chloroacetyl) -5, 1-dihydro-6H-pyrido / 2,3-b // 1, 4 / benzodiazepin-6-one and 2.8 ml of triethylamine in 50 ml of dimethylformamide, 3.1 g (0.02 mol) of 1-methyl-2- / 2- (methylamino) ethyl / piperidine were added dropwise and the mixture was stirred for 0.5 hours at room temperature After distilling off the solvent using silica gel column chromatographed (Mobile Phases methylene chloride / methanol 9 »1 v / Vo the concentrated eluates were taken up in potassium carbonate solution and extracted with ethyl acetate After distilling off the solvent, the resulting crystals from diisopropyl ether / Essigsäureethyleeter were recrystallized _o yield: 3.0 g (37 % of theory) Fp ₀ J 143-144 ⁰ C (diisopropyl ether / ethyl acetate) «

Example 2

II - [[(2- (1-methyl-2-piperidinyl) ethyl] methylamino] acetyl] -6H-pyrido [2,3-b] [1,4] benzodiazepin-6-one

Prepared analogously to Example 1 from 9-chloro-ll (chloroacetyl) 5, 11-dihydro-6H-pyrido [2,3-b] [1,4] benzodiazepine-6-one and 1-methyl-1-2- (2- (methylamino) ethyl) piperidine.

Yield: 12.5% of theory.

Mp: 183-184 ° C (ethyl acetate).

Example 3

5,11-Dihydro-II- [[(2- (1-methyl-2-piperidinyl) ethyl] amino] acetyl] -6H-pyrido (2,3-b] [1,4] benzodiazepin-6-one

Prepared analogously to Example 1 from 11- (chloroacetyl) -5,11-dihydro-6H-pyrido [2,3-b] (1,4) -benzod: .azepin-6-one and 2- (2-aminoethyl) -1 methylpiperidine.

Yield: 28% of theory.

M.p .: 123-125 ⁰ C (cyclohexane).

Example 4

5,11-Dihydro-II - [[[2- (1-ethyl-2-piperidinyl) ethyl] methylamino] acetyl] -6H-pyryl.do [2, 3-b] [1,4] benzodiazepine 6-one

A solution of 2.9 g (0.01 mol) of 11- (chloroacetyl) -5,11-dihydro-6H-pyrido [2,3-b] (1,4] benzodiazepin-6-one, 1.75 g (0.01 mol) of 1-ethyl-2- [2- (methylamino) ethyl] piperidine and 3 g of potassium carbonate in 100 ml of acetonitrile was added during 2 hours

- 24 - 3 8 4 0 15

6O ⁰ C stirred, the solvent was distilled off in vacuo, the residue stirred with water and extracted with methylene chloride. After purification by column chromatography on silica gel (mobile phase: ethyl acetate / methanol / ammonia 70/30/3 v / v / v /) and evaporating the eluates crystals were recrystallized from diisopropyl ether / ethyl acetate.

Yield: 1.26 g (30% of theory) M.p .: 138-14O ⁰ C (diisopropyl ether / ethyl acetate).

Example 5

5,1'-Dihydro-8-methyl-II - [[ [2- (1-methyl-2-piperidinyl) ethyl] methylamino] acetyl] -6H-pyrido (2,3-b] [1,4] benzodiazepine 6-one

Prepared analogously to Example 4 from 11- (chloroacetyl) -5,11-dihydro-8-methyl-6H-pyrido [2,3-b] [1,4] benzodiazepine-6-one and 1-methyl-2- [2 - (methylamino) ethyljpiperidine as an amorphous solid.

Yield: 46% of theory.

R "= 0.25 (Merck precoated plates, silica gel F 254, eluant: ethyl acetate / methanol / ammonia 8: 2: 0.3 v / v / v).

Example 6

5, 11-Dihydro-II- [4- [[2- (1-methyl-2-Pipe I: idynyl) ethyl] methylamino] butyryl] -6 H -pyrido [2,3-b] [1,4Jb

Prepared analogously to Example 4 from 11- (4-chlorobutyryl) -5,11-dihydro-6H-pyrido [2,3-b] [1,4] benzodiazepin-6-one and 1-methyl-2- [2- (2- methylamino) ethyl] piperidine.

- 25 -

Yield: 4.3% of theory.

Mp: 118 ° C (diisopropyl ether / ethyl acetate).

example ~>

9-Chloro-5,1'-dihydro-II- [[[2- (1-ethyl-2-piperidinyl) ethyl] -methylamido] acetyl] -6H-pyrido [2,3-b] [1,4] benzodiazepine -6-on

Prepared analogously to Example 4 from 9-chloro-ll (chloroacetyl) -5, ll-dihydro-6H-pyrido [2,3-b] fl, 4] benzodiazepine-6-one and

l-ethyl-2- [2- (methylamino) ethyl] piperidine.

Yield: 15% of theory.

Mp: 164 ° C (diisopropyl ether / acetone).

Example 8

5, 11-Dihydro-II - [[[3- (1-methyl-2-piperidinyl) propylmethylamino] acetyl] -6H-pyrido [2,3-b] [1,4] benzodiazepine-6-one

Prepared analogously to Example 4 from 11- (chloroacetyl) -5,11-dihydro-6H-pyrido [2,3-b] [1,4] benzodiazepine-6-one and 1-methyl-2- [3- (methylamino) propyl] piperidine.

Yield: 23% of theory.

Mp .: 145-146 ⁰ C (diisopropylether / Essigsäureethylcster)

- 26 - _Λ

284 0 t

1 9

6,11-Dihydro-11 - [[[3- (1-methyl-2-piperidinyl) propyl] methylamino] acetyl] -5H-pyrido (2,3-b] [1,5] benzodiazepin-5-one

Prepared analogously to Example 4 from 11- (chloroacetyl) -6,11-dihydro-5H-pyrido [2,3-b] [1,5] benzodiazepin-5-one and 1-methyl-2- [3- (methylamino) propyl] piperidine.

Yield: 24% of theory.

Mp .: 132-133 ⁰ C (diisopropyl ether / ethyl acetate).

Example 10

5,10-Dihydro-5 - [([3- (1-methyl-2-piperidinyl) propyl] methylamino] acetyl] -III-dibenzo [b, e] [1,4] diazepine-II-one

Prepared analogously to Example 4 from 5- (chloroacetyl) -5,10-dihydro-11H-dibenzo [b, e] [1,4] diazepin-11-one and 1-methyl-2- [3- (methylamino) propyl! piperidine

 Yield: 43% of theory

 Mp: 124-126 ° C (diisopropyl ether / ethyl acetate).

Example 11

5, 11-Dihydro-II - [[[2- (1-methyl-hexahydro-1H-2-azepinyl) ethyl] methylamino] acetyl] -6H-pyrido [2,3-b] [1,4] benzodiazepine -6-on

Prepared analogously to Example 4 from 11- (chloroacetyl) -5,11-dihydro-6H-pyrido [ 2,3-b] [1,4] benzodiazepin-6-one and 1-methyl-2- [2- (methylamino) ethyχ] hexahydro-lH-azepine.

- 27 -

Yield: 30% dfjr theory.

M.p .: 139-14O ⁰ C (ethyl acetate)

Example 12

9-chloro-5, ". 1-dihydro-II- [[[2- (1-methyl-hexahydro-1H-2-azepinyl) ethyllmethylamino] acetyl] -6H-pyrido [2,3-b] [1, 4] benzodiazepine-6-one hydrochloride

Prepared analogously to Example 4 from 9-chloro-ll (chloroacetyl) 6H-pyrido [2,3-b] [1,4] benzodiazepine-6-one and 1-methyl-2- (2- (methylamino) ethyl] hexahydro -lH-azepine.-The base was converted into the hydrochloride with concentrated hydrochloric acid, with the result being 4.5% of the theory

Mp .: 258-259 ⁰ C (ether / ethyl acetate).

Example 13

5, ll-dihydro-8-methyl-ll - [([2- (l-methyl-hexahydro-lH-2-azepinyl) ethyllmethylamino] acetyl] -6H-pyrido [2,3-b] [1,4] benzodiazepin-6-one

Prepared analogously to Example 4 from 11- (chloroacetyl) -8-methyl-6H-pyrido [2,3-b] [1,4] benzodiazepine-6-one and 1-methyl-2- [2- (methylamino) ethyl] hexahydro-lH-azepine.

Yield: 17% of theory.

Mp .: 132-134 ⁰ C (ethyl acetate).

- ²⁸ - 2 8 4 0 j ξ

Example 14

5, 10-Dihydro-5 - [[[2- (1-methyl-hexahydro-1H-2-azepinyl) echyl] methylamino] acetyl] -III-dibenzo [b, e] [1,4] diazepine on

Prepared analogously to Example 4 from 5- (chloroacetyl) -5,10-dihydro-11H-dibenzo [b, e] [1,4] diazepin-11-one and 1-methyl-2- [2- (methylamino) ethyl] hexahydro-lH-azepine. Yield: 53% of theory

Mp .: 112-114 ⁰ C (diethyl ether).

Example 15

6,1-Dihydro-II - [[[2- (1-methyl-hexahydro-lH-2-azeoinyl) ethyl] methylamino] acetyl] -5H-pyrido [2,3-b] [1,5] benzodiazepine. 5-one

Prepared analogously to Example 4 from 11- (chloroacetyl) -6,11-dihydro-5H-pyrido [2,3-ü] (1,5] benzodiazepin-5-one and 1-methyl-2- [2- (methylamino) etnyl] hexahydro-lH-azepine.

Yield: 27% of theory.

Mp .: 120-122 ⁰ C (Uiisopropylether / Essigsdureethylester).

- 29 -

2840 IS

The following describes the preparation of pharmaceutical applications by means of a few examples:

Example I

Tablets containing 5 mg of 5,1'-dihydro-II - [[(2- (1-methyl-hexahydro-1H-2-azepinyl) ethyl-methylamino] -acetyl] -6H-pyrido [2,3-b] - [1,4 ] benzodiazepine-6-one

Composition: 5.0 mg 1 tablet contains: 14 8.0 mg active substance 65.0 mg lactose 2,0 mq potato starch 220.0 mg Magnesium tearat 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

Dragees with 5 mg 5,11-dihydro-II - [[[2- (1-methyl-hexahydrolH-2-azepinyl) ethyl] methylamino] acetyl] -6H-pyrido [2,3-b] - [1,4 ] benzodiazepine-6-one

The tablets prepared according to Example I are coated by a known method with a shell consisting essentially of sugar and talc. The finished dragees are polished using beeswax. Drageegewicnt: 300 mg

Example III

Ampoules containing 10 mg of 5,11-dihydro-II- [[[2- (1-methyl-hexahydrolH-2-azepinyl) ethyl-1-methylamino] -acetyl] -6H-pyrido [2,3-b] - [1,4] benzodiazepine -6-on

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.

" ³¹ " 2 8 4 O

Example IV

Suppositories containing 20 mg 5,11-dihydro-II - [([2- (1-methylhexahydro-1H-2-azepinyl) ethyl] methylamino] acetyl] -6H-pyrido (2,3-b] [1,4] benzodiazepine 6-one

Composition: 1 suppository contains:

Active ingredient 20.0 mg

Suppository mass (eg Witepsol W 45 ^) 1 680.0 mg

1 700.0 mg

Production method:

The finely pulverized active substance is suspended in the melted and cooled to 40 ⁰ C suppository mass. Pour the mass at 37 ° C in slightly pre-cooled suppository forms

 Suppository weight 1.7 g

Example V

Drops of 5,11-dihydro-II - [[[2- (1-methyl-hexahydro-1H-2-azepinyl) ethyl-methylamino] -acetyl] -6H-pyrido [2,3-b] [1,4] -benzodiazepine 6-one

Composition: 100 ml dropping solution contain:

p-hydroxybenzoic acid methyl ester 0.035 g

propyl p-hydroxybenzoate 0.015 g

Anisole 0.05 g

Menthol 0.06 g

32 - 28 4

Ethanol pure 10.0 g

Active ingredient 0.5 g

Sodium cyclamate 1.0 g

Glycerol 15.0 g

Dest. Water ad 100.0 ml

Production method;

The active substance and sodium cyclamate are dissolved in about 70 ml of water and glycerol is added. Dissolve p-hydroxybenzoate, anisole and menthol in ethanol and add this solution while stirring the aqueous solution. Finally, it is made up to 100 ml with water and filtered without suspended particles.

Claims (1)

claims Process for the preparation of fused Oiazeplnonen the general formula (D in the B 1 one of the bivalent radicals (S) (T) (V) only then by assuming that Jf BJ can be the bivalent radical (V) if X represents the «CH- or» = C ~ C1 group ^ X is a "CH group, a" C-Cl group or a nitrogen atom, 1 2
A and A are straight-chain or branched, saturated alkylene are radicals with 1 to 4 carbon atoms, Z is an oxygen atom or an alkylene chain having 1 to 3 carbon atoms, R is a branched or unbranched alkyl radical having 1 to 7 carbon atoms, a cycloalkyl or (cycloalkyl) alkyl radical having a total of up to 8 carbon atoms or a hydrogen atom, R 1 is a branched or unbranched alkyl group having 1 to 6 carbon atoms or a cycloalkyl group having up to 7 carbon atoms, R and R, which may be the same or different, represent a hydrogen, fluorine, chlorine or bromine atom or an alkyl group having 1 to 4 carbon atoms, R is a hydrogen or chlorine atom or a methyl group, R ⁶ and R, which can be identical or different, denote hydrogen atoms or alkyl groups having 1 to 4 carbon atoms, R additionally also a halogen atom, and of their possible isomers dzw. Enantiomers and of their acid addition salts with inorganic or organic acids, characterized in that a.) For the preparation of basic substituted condensed diazepinones of general formula Ia -35Γ- O = C- A ^A -NA- / (Ia) in the 12 1 2
X, Z, Ά, A, R and R are as defined above andj (βί is one of the bivalent radicals (S), (U), (V) or (T ¹ ) H. where R is a chlorine atom or a methyl group, Haloacyl compounds of the general formula II (II) _{= c} - A ¹ - shark in the A, X and j (bO have the abovementioned meanings and Hai is a chlorine, bromine or iodine atom, with secondary amines of the general formula III, 264015 , (III) .A, Z, R ^x and R have the abovementioned meanings, in a solvent at temperatures between -1O ⁰ C and the boiling temperature of the reaction mixture, preferably in the presence of an auxiliary base or an excess of the amine of general III, implemented or b.) for the preparation of basic substituted diazepinones of general formula Ia, Diazepinones of general formula IV, (IV) wherein X and J (bM have the meanings given above, with carboxylic acid derivatives of the general formula V -cj wherein Z, A ¹ , A ² , R ¹ and R ^{2 are} as defined above and Nu represents a nucleofugic group or leaving group, are reacted in an inert solvent at temperatures between -25 ° C and 13O ⁰ C, or c.) for the preparation of falling under the general formula I pyrrolo-fused diazepinones of general formula Ib , (Ib) 12 1 2
X, Z, A, A, R and R have the abovementioned meanings and R ^{5 represents} a hydrogen atom, compounds of the general formula Ib, in which R ^{5 is} a .Chloratom, in the presence of a solvent at temperatures between 0 ⁰ C and 13O ⁰ C and in the presence of catalysts of the metals of the VIII. Subgroup of the Periodic Table at hydrogen pressures of 1 to 300 bar, or, if the hydrogen is replaced by formic acid or Triethylammoniumformiat in the presence of triethylamine are subjected to hydrogenolysis, the resulting compounds of the general formula I are then optionally separated into their isomers or enantiomers and / or the resulting salts are converted into the free bases and / or the bases obtained in their physiologically acceptable salts with inorganic or organic acids. 2 _e ) Process according to claim Ib, characterized in that as reactive carboxylic acid derivatives of the general formula V whose acid halides, esters, anhydrides or mixed anhydrides, in particular their mixed anhydrides are used with strong mineral acids, the reaction is carried out in the presence of acid-binding Mittbin and as etherified solvents chlorinated aliphatic hydrocarbons, open-chain or cyclic ethers, aromatic hydrocarbons or polar aprotic solvents or mixtures of these solvents are used « 3o) Process according to claim Ic, characterized in that the hydrogenolysis a ₀ ) with palladium on animal charcoal or on barium sulfate, with Raney nickel or Raney cobalt as catalysts and in the presence of alcohols, ethers, carboxylic acids or tertiary amines as solvents or b) with formic acid, if appropriate in the presence of dimethylformamide as solvent, and of palladium on carbon as catalyst at temperatures between 70 and 110 ^° C., or C ₀ ) is carried out with triethylammonium formate in the presence of excess triethylamine and of palladium on animal charcoal or of palladium acetal and triarylphosphines at temperatures between 40 and 110 ^° C. 4o) Process according to claims 1 to 3, characterized in that as condensed Oiazepinone the compounds 264 0 15 5, ll-dihydro-ll - /// 2- (l-methyl-2-piperidinyl) ethyl / methylamino / ac8tyl / 6H-pyrido / 2 _f 3-b // l, 4 / benzodiazepine "6-one 5 _# II-Dihydro-II - /// 2- (1-methyl-hexahydro-.lH-2-azepinyl) -ethyl / methylamino / acetyl / -6H-pyrido / 2,3- b // l, 4 / benzodiazepine "6-one 9-Chloro-5,1,2-dihydro-II - /// 2- (1-methyl-hexahydro-1H-2-azepinyl) ethyl / methylamino / acetyl / 6H-pyrido / 2 _# 3 ~ b // l > 4 / «« benzodiazepine-6-one and 5 _# II-dihydro-8-methyl-II-2/2 (1-methyl-8-hydroxy-1H-2-azepinyl) -ethyl-methylamino-acetyl-6H-pyrido-2,3-b. 1, 4 / benzodiazepine-6-one and whose pharmacologically compatible salts can be prepared with inorganic or organic acids. 5.) Use of the condensed Oiazepinone according to claim 1 and 4 and their physiologically acceptable salts, characterized »that they are used for the preparation of medicaments for the treatment of bradycardia urH bradyarrhythmias and of spasms on colon» bladder and bronchi »