DD284014A5 - METHOD FOR PRODUCING CONDENSED DIAZEPINONES - Google Patents

Abstract

Condensed diazepinones of the general formula I <IMAGE> in which <IMAGE> is one of the divalent radicals <IMAGE> <IMAGE> <IMAGE> <IMAGE> or <IMAGE> X<1> and X<2> can be the =CH-group or, if <IMAGE> is the radical (S), (U) or (W), also nitrogen atoms, A is a C1 to C6-alkylene radical, R<1> and R<2> are lower alkyl radicals or R<1> and R<2> together with the nitrogen atom are also a saturated 4- to 7-membered heteroaliphatic ring, R<3> is lower alkyl or hydrogen or chlorine, R<4> and R<1><0> are hydrogen or methyl, R<5> and R<6> are hydrogen, fluorine, chlorine, bromine or lower alkyl, R<7> is hydrogen, chlorine or methyl and R<8> and R<9> are hydrogen or lower alkyl, R<9> is additionally halogen, are suitable for the treatment of bradycardias and bradyarrhythmias.

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 diazepinones and medicaments containing these compounds

Characteristic of the known state of the art

From EP-AO 039 519 and O 057 428 and from US-A 3,660,300; & «691 '« 159f 4, _β 213ί.984 | 4 * 213 * 985; 4.P.1O.648, 4,410 «527 | 4u424to225f... 424 ("222 and 418" 226 are already condensed oiazepinones known for ulcus hemorrhage and gastric secretion-enhancing properties.

In EP-AO 156 191 describes! ^"One that" valuable pharmacological properties can be induced by introducing novel Aroinoacylreete to the compounds of the above publications completely different * _»o

Object of the invention

The aim of the invention is the provision of new condensed Oiazepinonen «distinguished by comparable or improved selectivity and absorption after oral administration by a significantly enhanced action and pronounced hydrolytic stability ^

Explanation of the essence of the invention

The invention is based on the object ^ new Oiazepinone with the desired properties and processes for their preparation

- la -

ο ί 4

aufzufindend

According to the invention, novel condensed oiazepinones having improved pharmacological properties are provided

2 8 4 θ ί 4

The new condensed diazepinones have the general formula I,

, 4 'X ^

² ..

(I)

in the * 1 Cb) one of the divalent radicals

N,

¹ R

7 '

(S)

(T)

or

(V)

(W)

represents and

X ¹ , X ² , A, R ¹ to R ¹⁰ and Z have the following meanings:

X ¹ and X represent a = CH group or, if the meanings of the abovementioned divalent radicals (S), (U) or (W) assume both or only Χ- * X or only X can also represent a nitrogen atom,

2b 4 ο 1 4

A is a straight-chain, saturated alkylene radical having 1 to 6 carbon atoms;

R ^x and R are the same or different alkyl radicals having up to 6 carbon atoms or together with the intervening nitrogen atom denote a 4- to 7-membered, saturated, monocyclic, heteroaliphatic ring optionally substituted by an oxygen atom or by the N-Cl ^ - Group can be interrupted;

R is an alkyl group having 1 to 4 C atoms, a chlorine atom or a hydrogen atom;

R is a hydrogen atom or a methyl group;

R and R are each a hydrogen atom, a fluorine, chlorine or bromine atom or an alkyl group having 1 to 4 C atoms;

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

R ° is a hydrogen atom or an alkyl radical having 1 to 4 carbon atoms;

R is a hydrogen or halogen atom or an alkyl group having 1 to 4 carbon atoms and R is a hydrogen atom or a methyl group and Z is a single bond, an oxygen or sulfur atom, the methylene or 1,2-ethylene group.

In the case where "ifssj is the bivalent radical (T) and R is a hydrogen atom, k

and Z is not a sulfur atom.

and R is a hydrogen atom, R can not be a chlorine atom

Preferred compounds of the above general formula I are those in which

" ⁴ " 2840 ί 4

X ^{1 is} a = CH group,

X represents either a nitrogen atom and Ifβ) represents the Zv / sivalent radical (S), with the proviso that R, R and R are hydrogen atoms and R ^{6 represents} a hydrogen atom, a chlorine or bromine atom or a methyl or ethyl group in 8- or 9-position of the heterocycle is,

or a = CH group, when ΊCb ) takes on the meaning of the divalent radicals V or U, wherein R is a hydrogen atom and R is a methyl group;

A represents a straight chain, saturated alkylene chain of 1 to 5 carbon atoms;

R · * and R¹ represent the same or different alkyl radicals having 1 to 5 carbon atoms or together with the enclosed nitrogen atom represent a 4- to 7-membered, saturated, monocyclic, heteroaliphatic ring optionally substituted by an oxygen atom or by the N-CH ^ Group can be interrupted

Z is a single bond, an oxygen atom which is methylene or 1,2-ethylene group,

Very particular preference is given to those compounds of the general formula I in which

X ^{I is} a = CH group;

X ^{2 represents} a nitrogen atom and "1 (bj represents the bivalent radical (S), with the proviso that R, R ^q and R ^{3 are} hydrogen atoms and R represents a hydrogen atom, a chlorine or bromine atom or a methyl or ethyl group in 8- or 9-position of the heterocycle is,

A represents an unbranched, saturated alkylene chain having 1 to 5 carbon atoms,

R 1 and R 2 represent identical or different alkyl radicals having 1 to 5 carbon atoms or, together with the intervening nitrogen atom, a 5- to 7-membered, saturated, monocyclic, heteroaliphatic ring optionally substituted by an oxygen atom or by the ^ N-CH- j group can be interrupted

Z is a single bond, an oxygen atom which is methylene or 1,2-ethylene group.

The compounds of the general formula I may, after reaction with inorganic or organic acids, also be in the form of their physiologically tolerated salts. 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, amidosulphonic acid or cyclohexanesulphamic acid have proven suitable as acids, for example.

To illustrate the subject invention, the following compounds are given as examples:

11- [4- [2 ~ [ (diethylamino) methyl] -1-piperidinyl] -1-oxobutyl] -5, ll-dihydro-6H-pyrido [2,3-b] [1,4] benzodiazepine-6 one;

D, Ii-5,11-dihydro-II- [4- [2- [(dimethylamino) methyl] -1-piperidinyl] -1-oxobutyl] -6H-pyrido [2,3-b] [1,4] benzodiazepin-6-one;

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

5, ll-dihydro-ll- (4- [2 - [(dipcopylamino) methyl] -1-piperidinyl] -1-oxobutyl] -6H-pyrido [2,3-b] [1,4] benzodiazepin-6- one;

11- [4- [2 - [(diethylamino) methyl] -1-pyrrolidinyl] -1-oxobutyl] -5,11-dihydro-6H-pyrido [2 _/ 3-b] [1,4] benzodiazepine-6 one;

11- [4- [2 - [(diethylamino) methyl] -1-azetidinyl] -1-oxobutyl] -5,11-dihydro-6H-pyrido [2,3-b] [1,4-benzodiazepine-6 one;

D, L-Il- [4- [2- [2- (diethylamino) ethyl] -1-piperidinyl] -1-oxobutyl] -5, II-dihydro-6H-pyrido [ 2,3-b] [1, 4] benzodiazepin-6-one;

D, L-5,11-dihydro-II- [4- [2- [2- (4-morpholinyl) ethyl] -1-piperidinyl] -1-oxobutyl] -6H-pyrido [2,3-b] [1,4] benzodiazepin-6-one;

5,11-Dihydro-II- [4- [2- [2- (hexahydro-1H-1-azepinyl) ethyl] -1-piperidinyl] -1-oxobutyl] -6H-pyrido [2, 3-b] [ 1,4] benzodiazepine-6-one;

5,11-Dihydro-II- [4- [2- [2- (dimethylamino) ethyl] -1-piperidinyl] -1-oxobutyl] -6H-pyrido [2,3-b] [1,4] benzodiazepine 6-one;

D, L-Il- [4- [3 - [(diethylamino) methyl] -4-morpholinyl] -1-oxobutyl] -5, II-dihydro-6H-pyrido [2,3-b] [1,4] benzodiazepin-6-one;

D-II- [4- [3 - [(diethylamino) methyl] -4-morpholinyl] -1-oxobutyl] -5,11-dihydro-6H-pyrido-f2,3-b] [1,4] benzodiazepine-6 -one;

L-Il- [4- [3 - [(diethylamino) methyl] -4-morpholinyl] -1-oxobutyl] -5,11-dihydro-6H-pyrido [2,3-b] [1,4] benzodiazepine 6-one;

11- [4- [2- [ (diethylamino) methyl] -1-piperidinyl] -1-oxobutyl] -5,11-dihydro-9-methyl-6H-pyrido [2,3-b] [1,4] benzodiazepin-6-one;

- ⁷ - 29 / Io

11- (4- [2 - [(diethylamino) methyl] -1-piperidinyl] -1-oxobutylJ-5, ll-dihydro-8-methyl-6H-pycido [2,3-b] (1,4] benzodiazepine -6-one;

11- [4- [3 - [(diethylamino) methyl] -4-morpholinyl] -1-oxobutyl] -5, U-dihydro-8-ethyl-6 H -pyrido (2,3-b] [1,4] benzodiazepin-6-one;

9-Chloro-II- [4- [3 - ((diethylamino) methyl] -4-morpholinyl] -1-oxobutyl] -5,11-dihydro-6H-pyrido (2,3-b] [1,4] benzodiazepin-6-one;

8-Bromo-II- [4- [2 - [(diethylamino) methyl] -1-piperidinyl] -1-oxobutyl] -5,11-dihydro-6H-pyrido [2,3-b] [1, '] benzodiazepin-6-onmethansulfonat;

11- [4- [2- [(1-azetidinyl) methyl] -1-piperidinyl] -1'-oxobutyl] 5, ll-dihydro-6H-pyrido [2,3-b] [1,4] benzodiazepine 6-one;

11- [4- [4- (3- (Diethylamino) propyl] -1-piperidinyl] -1-oxobutyl] -5,11-dihydro-6H-pyrido [2,3-b] [1,4] benzodiazepine 6-one;

5,1-Dihydro-II- [4- [2 - [(1-pyrrolidinyl) methyl] -1-piperidinyl] -1-oxobutyl] -6H-pyrido [ 2,3-b] [1,4] benzodiazepine 6-one;

5,11-Dihydro-II- [4- [4- [4- (1-pyrrolidinyl) -butyl] -1-piperidinyl] -1-oxobutyl] -6H-pyrido [2,3-b] [1,4] benzodiazepin-6-one;

11- [4- [3- [4- (Diethylamino) butyl] -1-piperidinyl] -1-oxobutyl] -5,11-dihydro-6H-pyrido [2,3-b] (1,4] benzodiaz. ePIN-6-one;

5,1'-Dihydro-ll- (4- [3- [2- (1-pyrrolidinyl) ethyl] -1-piperidinyl] -1-oxobutyl] -6H-pyrido [2,3-b] [1,4] benzodiazepine -6-one;

5,11-Dihydro-II- [4- [3- (4- (1-pyrrolidinyl) -butyl] -1-piperidinyl] -1-oxobutyl] -6H-pyrido [2,3-b] [1,4] benzodiazepin-6-one;

2840 ί 4

11- [4- [3- [2- (diethylamino) ethyl] hexahydro-lH-1-azepinyl] -1-oxobutyl] -5, ll-dihydro-6H-pyrido [2,3-b] [1, 4] benzodiazepin-6-one;

11- [4- [2 - [(diethylamino) methyl] -1-piperidinyl] -1-oxobutyl] -6, ll-dihydro-5H-pyrido [2,3-b] [1,5] benzodiazepin-5- one;

11- [4- [2- [2- (diethylamino) ethyl] -1-piperidinyl] -1-oxobutyl] -6, ll-dihydro-5H-pyrido [2,3-b] [1,5] benzodiazepine 5-one;

11- [4- [3- [(diethylamino) methyl] -4-morpholinyl] -1-oxobutyl] -6,11-dihydro-5H-pyrido [2,3-b] [1,5] benzodiazepine-5 one;

II- [4- [4- [3- (Diethylamino) propyl] -1-piperidinyl] -1-oxobutyl] 6,11-dihydro-5H-pyrido [2,3-b] [1,5] benzodiazepine-5 -one;

11- [4- [3- [4- (diethylamino) butyl] -1-piperidinyl] -1-oxobutyl] -6, ll-dihydro-5H-pyrido [2,3-b] [1,5] benzodiazepine 5-one;

5- [4- [3- [2- (Diethylamino) ethyl] -hexahydro-1H-1-azepinyl] -1-oxobutyl] -5,10-dihydro-11H-dibenzo [b, e] [1,4] diazepin-11-one;

5- [4- [2- [(diethylamino) methyl] -1-piperidinyl] -1-oxobutyl] -5,10-dihydro-11H-dibenzo [b, e] [l, 4] diazepine-II-one;

5- [4- [2- [2- (diethylamino) ethyl] -1-piperidinyl] -1-oxobutyl] -5,10-dihydro-llh-dibenzo [b, e] [1,4] diazepin-11 one;

5- [4- [3- [(diethylamino) methyl] -4-morpholinyl] -1-oxobutyl] -5,10-dihydro-11H-dibenzo [b, e] [1,4] diazepin-11-one;

5- [4- [4- [3- (diethylamino) propyl] -1-piperidinyl] -1-oxobutyl] -5,10-dihydro-llh-dibenzo [b, e] [1,4] diazepin-11 one;

284 ο 4

5- [4- [3- [4- (diethylamino) butyl] -1-piperidinyl] -1-oxobutyl] -5,10-dihydro-llh-dibenzo [b, e] [1,4] diazepin-ll- one;

4,9-Dihydro-3-methyl-4- [4- [3- [2- (1-piperidinyl) ethyl] hexahydro-1H-1-azepinyl] -1-oxobutyl] -10H-thieno [3,4 b] (1,5] benzodiazepin-10-one;

4,9-Dihydro-3-methyl-4- [4- [2 - [(1-piperidinyl) methyl] -1-piperidinyl] -1-oxobutyl] -10H-thieno [3,4-b] (1, 5] benzodiazepin-10-one;

4,9-Dihydro-3-methyl-4- [4- [2- [2- (1-piperidinyl) ethyl] -1-piperidinyl] -1-oxobutyl] -10H-thieno [3,4-b] 1,5] benzodiazepin-10-one;

4,9-Dihydro-3-methyl-4- [4- [3 - [(1-piperidinyl) methyl] -4-morpholinyl] -1-oxobutyl] -10H-thieno [3,4-b] [1, 5] benzodiazepin-10-one;

3-chloro-4,9-dihydro-4- [4- [3 - [(1-piperidinyl) methyl] -4-morpholinyl] -1-oxobutyl] -10H-thieno [3,4-b] [1, 5] benzodiazepin-10-one;

4,9-dihydro-4- [4- [3 - [(diethylamino) methyl] -4-morpholinyl] -1-oxobutyl] -1,3-dimethyl-10H-thieno [3,4-b] [1, 5] benzodiazepin-10-one;

4,9-Dihydro-3-methyl-4- [4- [4- [3- (1-piperidinyl) propyl] -1-piperidinyl] -1-oxobutyl] -HL-thieno [3,4-b] [ 1,5] benzodiazepin-10-one;

4,9-Dihydro-3-methyl-4- [4- [3 - [(4- (1-piperidinyl) butyl] -1-piperidinyl] -1-oxobutyl] -10H-thieno [3,4-b] [1,5] benzodiazepin-10-one;

- 10 -

? Ö40? 4

1,3-Dimethyl-4- (4- [3 - [(1-piperidinyl) methyl] -4-morpholinyl] -1-oxobutyl] -1,4,9,10-tetrahydropyrrolo [3,2-b] [1,5] benzodiazepin-10-one;

3-chloro-1-methyl-4- [4- [3 - [(1-piperidinyl) methyl] -4-morpholinyl] -1-oxobutyl] -1,4,9,10-tetrahydropyrrolo [3,2-b ] [1,5] -benzodiazepine-10-one;

1-Methy1-4- [4- [2- [2- (1-piperidinyl) ethyl] -4-morpholinyl] -1-oxobutyl] -1,4,9,10-tetrahydropyrrolo [3,2-b] [ 1,5] benzodiazepin-10-one;

1-Methyl-4- [4- [3- [4- (1-piperidinyl) butyl] -1-piperidinyl] -1-oxobutyl] -1,4,9,10-tetrahydropyrrolo [3,2-b] [ 1,5] benzodiazepin-10-one;

1,3-dimethyl-4- [4- [3 - [(l-piperidinyl) methyl] -4-morpholinyl] -1-oxobutyl] -1,4,9,10-tetrahydro-pyrazolo [4,3-b] [ 1,5] benzodiazepin-10-one;

l-methyl-4- [4- [3 - [(1-piperidinyl) methyl] -4-morpholinyl] -1-oxobutyl] -1,4,9,10-tetrahydro-pyrazolo [4,3-b] [1, 5] benzodiazepin-10-one;

1,3-dimethyl-4- [4- [3- [4- (1-piperidinyl) butyl] -1-piperidinyl] -1-oxobutyl] -1,4,9,10-tetrahydro-pyrazolo [4,3-b ] [1,5] benzodiazepin-10-one;

l-methyl-4- [4- [2- [2- (1-piperidinyl) ethyl] -4-morpholinyl] -1-oxobutyl] -1,4,9,10-tetrahydro-pyrazolo [4,3-b] [ 1,5] benzodiazepin-10-one;

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

- 11 -

a) Basic substituted condensed diazepinones of general formula Ia,

- N

B '

(Ia)

in the

R, R, R, R, X, X, A and Z are as defined above and ^ (bO is one of the bivalent radicals (S), (U), (V), (W) or (T ') CH,

jl

(T ¹ )

where R 'is a chlorine atom or a methyl group,

is obtained by reacting haloacyl compounds of general formula II,

(II)

- 12 -

284 ο j 4

in the

3 4 ν / ^ \ 1 2 R, R, j (B *), X and X have the meanings indicated, and

Hal is a chlorine, bromine or iodine atom, with secondary amines of general formula III,

(III)

sit in the R ¹ , R ² .

1 2 R, R, A and Z have the meanings defined 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 carbon compounds 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. Examples of suitable auxiliary bases are 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,

- 13 -

2 8 * OI 4

called 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) Basicly substituted condensed diazepinones of the general formula Ia can also be prepared by reacting tricyclic compounds of the general formula IV

(IV)

in the

the radicals R ³ , R ⁴ , X ¹ , X ² and} (β ~ j) are as defined above, with carboxylic acid derivatives of the general formula V,

• R ¹ ·.

R ² .

(V)

1 2 R, R, A and Z have the meanings given above and Nu represents a nucleofugic group or leaving group acylated.

- 14 - 2 S 4 ο \ 4

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, 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 the 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 a 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 130 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, 1,3-dimethyl-2-imidazolidinone or hexamethylphosphoric triamide; or mixtures thereof. The reaction times are, depending on the amount and type of acylation used.

- 15 -

2840 ί 4

by the general formula V between 15 minutes and 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 manner.

c.) The novel pyrrolo-condensed diazepinones of the general formula Ib falling under the general formula I,

R ² ·

12 4 12 R, R, R, X, X and A are as defined above, Z has the meanings mentioned above with the exception of one sulfur atom,

R is an alkyl group having 1 to 4 carbon atoms or a hydrogen atom and

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

Tie hydrogenolysis is in the presence of catalysts of metals from the VIII. Subgroup of the Periodic Table c'.er elements, such as palladium on animal charcoal, palladium on barium sulfate, Raney nickel or Raney cobalt, and

- 16 -

284

at hydrogen pressures of 1 to 300 bar and temperatures of O ⁰ C to 13O ⁰ C in the presence of solvents, for example alcohols, such as methanol, ethanol; Ethers such as dioxane, tetrahydrofuran; Carboxylic acids, for example acetic acid; or tertiary amines, for example triethylamine. If you work in the absence of additional hydrogen chloride acceptors, such as sodium carbonate, potassium bicarbonate, triethylamine odar sodium, so the result directly hydrochlorides of the compounds sought, which can be isolated after removal of the catalyst by evaporation of the reaction solution. If, in the above hydrogenolysis reaction, the hydrogen is replaced by formic acid, the reaction is in principle possible even with pressureless working. In this variant, especially the reaction with formic acid in the presence of dimethylformamide as a solvent and of palladium on carbon as a catalyst at temperatures between 70 and 110 ⁰ C, and the reduction with triethylammonium in the presence of excess Triethy! Amine and of palladium on animal charcoal or of Palladium acetate and triarylphosphines, 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 up to two independent chiral elements, of which one asymmetric carbon atom in the side chain. The second chiral element is the acylated tricycle itself, which can be present in two mirror-image forms. It depends on the nature of the tricycle, whether the energy barrier for a

- 17 -

Inversion at this center is so high that the individual. Isomers are stable at room temperature and become isolable. It has been shown that such compounds of the

2 general formula I, in which X is the Cfl group and

the o-phenylene radical, always present in two diastereomeric forms, which can be separated at room temperature into the components. The individual diastereomers are completely stable in crystalline state, but go back in solution and at room temperature but with a half-life of a few days back to the original mixture, if space-filling peri-substituents such as chlorine or methyl, missing.

In the case of compounds of general formula I in which X ^{2 is} the N atom and Ί (bj is the o-phenylene group unsubstituted in the peri-positions, the required activation energy is so greatly reduced that diastereomers at room temperature - except by the complex H- NMR spectra - no longer proven let alone preparatively separated.

The aminoacylated condensed diazepinones of the general formula I according to the invention thus generally contain two chiral centers, one of which may not be configurationally stable at room temperature. Therefore, these compounds can exist in two diastereomeric forms, which in turn can each be separated into 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, eg. B. by fractional recrystallization from suitable solvents, by high performance liquid chromatography, column chromatography or gas chromatographic methods.

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28 4 O ί 4

The cleavage of possible 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 acid, (+) - or (-) - monomethyl tartrate or (+) - camphorsulfonic acid.

According to a conventional isomer separation method, the racemate of a 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 crystalline diastereomeric salts obtained 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 hydroxide or potassium hydroxide to thereby obtain the corresponding free compound in the (+) or (-) form.

In each case only one enantiomer or a mixture of two optically active diastereomeric compounds falling under the general formula I is also obtained by carrying out the above-described syntheses with only one Eirantiomeren of the general formulas III and V. ·

The starting materials of the formulas II, III, IV and V required for the synthesis of the condensed diazepinones of the general formula I are known or are prepared in analogy to described processes; see ζ B the specifications in the patents US Patent 4 550 107, EP-A-254 955 and DE-A-36 43 666.

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7.84 ο 1 4

The basic substituted condensed diazepinones of general formula I and their acid addition salts have valuable properties; In particular, they have pronounced hydrolysis stability, high selectivity and good absorption after oral administration beneficial effects on the heart rate and are in the absence of gastric acid secretion inhibition. ¹ , salivationshemmender and mydriatic influences as vaginal pacemaker for the treatment of bradycardia and bradyarrhythmias in human and also veterinary medicine suitable; some of the compounds also show spasmolytic properties on peripheral organs, especially colon and bladder.

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.

Binding Studies on Muscarinic Receptors: Determination of ICcn Value in Vitro

As an organ donor served male Sprague-Dawley rats with 180-220 g body weight. After removal of the heart, submandibularis and cerebral cortex, illegal further steps were taken in ice cold Hepes HCl buffer (pH 7.4, 100 mM molar NaCl, 10 mM molar MgCl ₂ ). The whole heart was crushed with scissors. All organs were finally homogenized in a Potter.

- 20 -

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

total heart 1: 400 cerebral cortex 1: 3000 submandibular 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 nonspecific binding of ^ H-NMS. The proportion of nonspecific binding was defined as the radioactivity bound in the presence of 1 μ molar quinuclidinylbenzilate. There were always fourfold determinations. The IC.sub.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.

B. Investigation of functional 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

- 21 -

reproduced, which are suitable for the detection of 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 / M ₂ selectivity in the rat

2. Salivary secretion-inhibiting effect on the rat and

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

examined.

1. M, - / M ₂ selectivity in the rat

The method used was described by Hammer and Giachetti (Life Sciences 11, 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: 2 ms, stimulation time: 30 s, voltage: supramaximal) or 0.3 mg / kg McN-A-343 in male .THOM Rats injected intravenously. Vagal stimulation-induced bradycardia and blood pressure increase caused by McN-A-343 were determined. The dose of the substances that reduced either the vagal bradycardia (M ₂ ) or the blood pressure increase (M-,) by 50% was graphically determined. Results see Table II.

" ²² " 2 8 4

2. Spoichelsekretionshemmende effect in the rat

According to Lavy and Mulder (Arch. Int Pharmacodyn., 178 , 437-445, (1969)), male THOH rats anesthetized with 1.2 g / kg urethane received increasing doses of the substance i.v. Salivary secretion was triggered by the 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 action on the bladder, bronchi and heart rate of the guinea pig

On anesthetized guinea pigs, 10 μg / kg of acetylcholine were injected intravenously and intra-intraperitoneally 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 acetylcholine effect on the investigated organs and from this -log ED ₅ Q values were determined. For results, see Table III.

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

A = II- [4- [3 - [(diethylamino) methyl] -4-morpholinyl] -1-oxobutyl] -5, II-dihydro-6H-pyrido [2,3-b] [1,4] benzodiazepine 6-one;

B = II- [4- [2 - [(diethylamino) methyl] -1-piperidinyl] -1-oxobutyl] -5,11-dihydro-9-methyl-6H-pyrido [2,3-b] [1, 4] benzodiazepin-6-one

- 23 -

8 4 0 14

C = 5, 11-dihydro-II- [4- [2 - [(1-pyrrolidinyl) methyl] -1-piperidinyl] -1-oxobutyl] -6H-pyrido [2,3-b] [1, 4] benzodiazepin-6-one

and as comparison substances

D = II- [[2 - [(diethylamino) methyl] -1-piperidinyl] acetyl] -5,11-dihydro-6H-pyrido [2,3-b] [1,4] benzodiazepin-6-one (see US Pat. No. 4,550,107),

E-5,1'-dihydro-II - [(4-methyl-1-piperazinyl) acetyl] -6 H -pyrido [2,3-b] [1,4] benzodiazepin-6-one (see US Pat. 3,660,380) and

F = atropine

- 24 -

Table I:

Receptor binding assays, in vitro:

Results :

substance

Receptor Binding Assays IC ₅₀ [nMl " ¹ ]

Cortex Heart Submandi (C) (H) bularis (SM)

A 100 40 100 B 30 6 60 C 20 4 40 D 1200 140 5000 e 100 1500 200 P 2 4 4

The data in Table I above prove that the new compounds of general formula I differentiate between muscarinic receptors of different tissues. This follows from the considerably lower IC ₅₀ values when tested on preparations from the heart over those from the cerebral cortex.

Table II;

Mi / M2 ~ Selectivity and Speialhelsekretionshemmung in the rat:

Results ;

substance -log heart ED ₅₀ [Mkg " ¹ ] blood pressure Salivationsheitunung A 7.29 6.26 5.96 B 7.21 6.30 5.95 C 7.33 6.66 5.78 D 6.42 5.63 5.00 e 5, 60 6.94 6.22 F 7.94 7.34 7.60

- 26 -

Table III:

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

Results:

-log ED ₅₀

substance heart bronchia bladder A 7,55 7.15 6.00 B 7.15 6.82 6.12 C 7.56 7.29 6.50 D 5.84 5.58 4.73 e 5.85 6.57 5.36 F 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 restriction of salivary secretion is observed.

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

- 27 -

28 4 ο ί 4

Dir. · Mentioned substances have over the already known compound D a significantly increased potency. The therapeutically usable selectivity is retained. This leads einerλ less substance burden of 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.

For pharmaceutical use, 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 administered to achieve the desired results.

Ausführunqabeiapiel

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

For all compounds, satisfactory elements are also often present in ionic spectra, IR-V UV-V H-NMR.

example 1

il- / 4- / 2- / (diethylamino) methyl / -l-piperidinyl / -l-oxobutyl / - si-dihydro-6H-PVrdo / 2y3-b / 7ltf4 / benzodJLazepin-6-one

The mixture of 9 & 5 g (0 ^ 03 mol) of 2- (4-chloro-J.-oxobutyl) -5-t-dihydro-6H-pyrido / 2 <3 ^M b // 1 ^ 4 / benzodiazepine-6 -one% 100 ml of anhydrous dimethylformamide ^ 5ί · # 6 g (O $ O33 mol) of 2 - / (diethylamino) methyl / piperidine and 0 ^ 5 g of sodium iodide for 7 days stirred at a ^ ealttionstemperatur of 50 ⁰ C ¹ '' It was concentrated in a water-jet vacuum, and the residue was found to be clearly natron-alkaline and to be exhaustively extracted with dichloromethane. The dichloromethane extracts were combined "evaporated dried over sodium sulfate un ^H The crude product (14 $ 0 g) thus obtained was chromatographed on silica gel as stationary phase and eluting with dichloromethane / ethyl acetate / cyclohexane / Methaol / conc;! 'Anmoniak $ 58' 5/25 ^ 1 / 7ν7 / 7 ^ 7/1 ^ Ο / (v / v / v / v / v) for eluting eäulenchromatographisch purified ₀ The corresponding evaporated eluates crystallized on trituration with t-Sutyl methyl ether * After your recrystallization from Eseigsäureethyi (53ter using charcoal to give 3 # 8 g (28% of theory) of colorless crystals, mp 143-144 ⁰ _# C;? R _fi 0.7 (Macherey-Nageltf Polygranr ^ SIL 6 / UV ₂₃₄ * pre-coated plastic sheets for TLC; superplasticizers: dichloromethane / cyclohexane / methanol / concentrated ammonia 67 ^ 6 / 151,2 / 15r * 2/2 (v / v / v / v) or ₀ Rp 0y3 (liquid dichloromethane / ethyl acetate / cyclohexane / methanol / conc _e Ammonik 58i5 / 25 * il / 7f _t 7/7,> 7 / Lt> O (v / v / v / v / v) _o!

- 29 -

C ₂₆ H ₃₅ N 5 ° 2 (449, 59) H 7, 85 N 15 58 Bsr. : C 69, 7, 80 15th 60 Gef .: 69; , 46 , 69

Example 2

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

Prepared analogously to Example 1 from 11- (4-chloro-1-oxobutyl) 5, 11-dihydro-6H-pyrido [2,3-b] [1,4] benzodiazepine-6-one and 2 - [(dimethylamines) methyl] piperidine in a yield of 33% of theory. Colorless crystals of mp. 157-158 ° C (acetonitrile).

Example 3

II- [4- (2- [2- (Diethylamino) ethyl] -1-piperidinyl] -1-oxobutyl] -5,11-dihydro-6H-pyrido [2,3-b] [1,4] benzodiazepine -6-on

Prepared analogously to Example 1 from 11- (4-chloro-l-oxobutyl) -5, 11-dihydro-6H-pyrido [2,3-b] [1,4] benzodiazepine-6-one and 2- [2- (2- Diethylamino) ethyl] piperidine in a yield of 31% of theory. Colorless crystals of mp. 86-88 ° C; R _p 0.55 (Macherey-Nagel, Polygram ^(R) SIL ^G / UV ₂₅₄ , pre-coated plastic sheets for TLC; flow agents: dichloromethane / cyclohexane / methanol / concentrated ammonia * 67.6 / 15.2 / 15, 2 / 2.0 (v / v / v / v).

C ₂₇ H ₃₇ N ₅ O ₂ (463.62)

Calc .: C 69.95 H 8.04 N 15.11

G .: 69.97 7.97 15.00

" ³⁰ '2 β 4 ο ί 4

Example 4

5, ll-dihydro-ll- [4- [2- [2- (dimethylamino) ethyl] -1-piperidinyl] -1-oxobutyl] -6H-pyrido [2,3-b] [1,4] benzodiazepine 6-one

Prepared analogously to Example 1 from 11- (4-chloro-l-oxobutyl) -5, 11-dihydro-6H-pyrido [2,3-b] [1,4] benzodiazepine-6-one and 2- [2- (2- Dimethylamine) ethyljpiperidin in a yield of 6% of theory. Colorless crystals of mp. 94-96 ⁰ C (diisopropyl ether / cyclohexane 1: 1 v / v), soluble in water.

Example 5

11- [4- [3-ί (Diethylamino) methyl] -4-morpholinyl] -1-oxobutyl] 5,1'-dihydro-6H-pyrido [2,3-b] [1,4] benzodiazepin-6-one

Prepared analogously to Example 1 from 11- (4-chloro-1-oxobutyl) -5, 11-dihydro-6H-pyrido [2,3-b] [1,4] benzodiazepin-6-one and 3 - [(diethylamino) methyl] morpholine in a yield of 8% of theory. Colorless crystals of mp. 108-110 ⁰ C (t-butyl methyl ether), slightly soluble in water. C ₂₅ H ₃₃ N ₅ O ₂ (451.57)

3rd: C 66.50 H 7,37 N 15,51

Gef .: 66,65 7,17 15,42

2 8 4 0 ί 4

Example 6

11- [4- [2- [(diethylamino) methyl] -1-piperidinyl] -1-oxobutyl] -5,11-dihydro-9-methyl-6H-pyrido [ 2,3-b] [1, 4] benzodiazepin-6-one

Prepared analogously to Example 1 from 11- (4-chloro-l-oxobutyl) -5, 11-dihydro-9-methyl-6H-pyrido [2,3-b] [1,4] benzodiazepin-6-one (mp. 178 ⁰ C [acetonitrile]) and 2 - [(diethylaraino) methyl] piperidine in a yield of 53% of theory. Colorless crystals of mp. 154-156 ⁰ C (acetonitrile). C ₂₇ H ₃₇ N ₅ O ₂ (463.62)

Calc .: C 69.95 H 8,04 N 15,11 F .: 70,00 8,14 15,14

Example 7

8-Bromo-II- [4- [2 - [(diethylamino) methyl] -1-piperidinyl] -1-oxobutyl] -5,11-dihydro-6H-pyrido [2,3-b] [1,4] benzodiazepin-6-one

Prepared analogously to Example 1 from 8-bromo-ll- (4-chloro-l-oxobutyl] -5, ll-dihydro-6H-pyr ^; do [2,3-b] [1,4] benzodiazepin-6-one and 2 - [(diethylamino) methyl] piperidine in a yield of 50% of theory Colorless, brittle, isooctane-sandable, water-sparingly soluble resin R _F 0.3 (Macherey-Nagel, Polygram) SIL 0 / UV ₂₅₄ , pre-coated plastic sheets for TLC, eluant: dichloromethane / ethyl acetate / cyclohexane / methanol / concentrated ammonia 58/25/8/8/1 (v / v / v / v / v).

C ₂₆ H ₃₄ BrN ₅ O ₂ (528.49)

Calc .: C 59.09 H 6.48 Br 15.12 N 13.25 F .: 58.99 6.42 15,30 13,13

Example 8

U- [4- [4- (3-diethylamino) propyl] -1-piperidinyl] -1-oxobutyl] 5,1'-dihydro-6H-pyrido (2,3-b] [1,4] benzodiazepine-6 on

Prepared analogously to Example 1 from 11- (4-chloro-l-oxobutyl) -5, 11-dihydro-6H-pyrido [2,3-b] [1,4] benzodiazepine-6-one and 4- [3- ( Diethylamino) propyl] piperidine in a yield of 4.2% of theory. Colorless crystals of mp. 164-165 ⁰ C (ethyl acetate); R _p 0.4 (Merck, TLC plates, silica gel 60F-254, eluent: dichloromethane / metharole / cyclohexane / concentrated ammonia 68/15/15/2 v / v / v / v).

Example 9

II- (4- [3- [3- (Diethylamino) propyl) -1-piperidinyl] -1-oxobutyl] -5,11-dihydro-6H-pyrido [2,3-b] [1,4] benzodiazepine 6-one

Prepared analogously to Example 1 from ll- (4-bromo-l-oxobutyl) -5, 11-dihydro-6H-pyrido [2,3-b] [1,4] benzodiazepin-6-one (mp 175-180 ⁰ C) and 3- [3- (diethylamino) propyl] piperidine in a yield of 14% of theory. Colorless crystals of mp. 103-105 ⁰ C (acetonitrile).

C ₂₈ H ₃₉ N ₅ O ₂ (477.65)

Calc .: C 70.41 H 8.23 N 14.66

F .: 70.26 8.16 14.55

Example 10

5,1'-Dihydro-ll- (4- (2 - [(1-pyrrolidinyl) methyl] -1-piperidinyl] -1-oxobutyl] -6 H -pyrido [2,3-b] [1,4] benzodiazepine 6-one

Prepared analogously to Example 1 from 11- (4-chloro-l-oxobutyl) -5, 11-dihydro-6H-pyrido [2,3-b] [1,4] benzodiazepine-6-one and 2 - [(1 Pyrrolidinyl) methyl] piperidine in a yield of 4.7% of theory. Colorless crystals, mp. 144-145 ⁰ C (acetonitrile)

C ₂₆ H ₃₃ N ₅ O ₂ (447.60)

Calc .: C 69.77 H 7.43 N 15.65 F .: 69.93 7.43 15.77

Example 11

5,11-dihydro-ll- [4- [4- [4- (1-pyrrolidinyl) butyl] -1-piperidinyl] -1-oxobutyl] -6H-pyrido [2,3-b] [1,4] benzodiazepin-6-one

Prepared analogously to Example 1 from 11- (4-chloro-l-oxobutyl) -5, 11-dihydro-6H-pyrido [2,3-b] [1,4] benzodiazepine-6-one and 4- [4- (4-chloro-1-one 1-pyrrolidinyl) -butyl] -piperidine in a yield of 36% of theory. Colorless crystals of mp. 152-154 ° C (from acetonitrile using activated carbon). C ₂₉ H ₃₉ N ₅ O ₂ (489.66)

Calc .: C 71.14 H 8.03 N 14.30

F .: 71.04 8.03 14.46

2 8 4 ο t 4

Example 12

II- (4- [3- [4- (Diethylamino) butyl] -1-piperidinyl] -1-oxobutyl] 5, ll-dihydro-6H-pyrido [2,3-b] [1,4] benzodiazepine-6 -one

Prepared analogously to Example 1 from 11- (4-chloro-l-oxobutyl) -5, 11-dihydro-6H-pyrido [2,3-b] [1,4] benzodiazepine-6-one and 3- [4- (4-chloro-1-oxobutyl) -5- Diethylamino) butyl] piperidine in a yield of 4.7% of theory. Colorless crystals of mp. 106-108 ⁰ C (acetonitrile).

C ₂₉ H ₄₁ N ₅ O ₂ (491.68)

Calc .: C 70.84 H 8,40 N 14,24 Found: 70,60 8,14 14,19

Example 13

5,1'-Dihydro-II- [4- [3- [2- (1-pyrrolidinyl) ethyl] -1-piperidinyl] -1-oxobutyl] -6H-pyrido [2,3-b] [1,4] benzodiazepin-6-one

Prepared analogously to Example 1 from 11- (4-chloro-l-oxobutyl) -5, 11-dihydro-6H-pyrido (2,3-b] [1,4] benzodiazepin-6-one and 3- [2- ( 1-pyrrolidinyl) ethyl] piperidine - but using acetonitrile in the presence of dimethylformamide as solvent - in a yield of 8.5% of theory Colorless crystals of mp 126-128 ° C (acetonitrile); R _p 0.47 ( Macherey-Nagel, Polygram® SIL ^G / ^uv ₂₅₄ # pre-coated plastic sheets for TLC, eluent: dichloromethane / methanol / cyclohexane / concentrated ammonia 68/15/15/2 v / v / v / v) C ₂₇ H ₃₅ N ₅ O ₂ (461.61)

Ber. : C 70.25 H 7.64 N 15.17 F: 69.95 7.80 15,08

Example 14

5,11-dihydro-ll- [4- [3- [4- (1-pyrrolidinyl) butyl] -1-piperidinyl] -1-oxobutyl] -6H-pyrido [2,3-b] [1,4] benzodiazepin-6-one

Prepared analogously to Example 1 from 11- (4-chloro-l-oxobutyl] -5, 11-dihydi: o-6H-pyrido [2, 3-b] [1, 4] benzodiazepine-6-one and 3- [4 - (1-pyrrolidinyl) butyl] piperidine in a yield of 15.5% of theory .. Colorless crystals of mp. 110-112 ⁰ C (acetonitrile).

C ₂₉ H ₃₉ N ₅ O ₂ (489.66)

Calc .: C 71.14 H 8.03 N 14.30 F .: 70.97 8.08 14.40

Example 15

11- [4- [3- [(diethylamino) methyl] -4-morpholinyl] -1-oxobutyl] 5,1'-dihydro-6H-pyrido [2,3-b] [1,4] benzodiazepin-6-one

A mixture of 16.33 g (0.0632 mol) of 3 - [(diethylamino) methyl] -4-morpholine butanoic acid and 2.0 g of a 75% sodium hydride dispersion in paraffin oil in 160 ml of anhydrous dimethylformamide was heated at 50-80 ⁰ C until the hydrogen evolution was completed. To the resulting sodium salt of the said acid was added 13.20 g (0.0625 mol) of 5,1'-dihydro-6H-pyrido [2,3-b] [1,4] benzodiazepine-6-one and added dropwise to -1O ⁰ C 9.9 g (0.0646 mol) of phosphorus oxychloride within 10 minutes. The mixture was stirred for 4 hours at -10 ⁰ C, 4 hours at ^{0 0} C and 20 hours at room temperature. The mixture was stirred into 300 g of ice, adjusted to pH 9 with sodium hydroxide solution and exhaustively shaken with dichloromethane. The combined organic phases were washed once with a little ice water, over sodium

- 36 -

sulphate dried and evaporated. The oily residue was triturated with a few drops of diisopropyl ether, whereupon crystallization occurred. The precipitate was filtered off with suction and recrystallized from t-butyl methyl ether. This gave 6.55 g (23% of theory) of colorless crystals of mp. 108-110 ⁰ C, by thin layer chromatography, mixed melting point, IR, UV and .H-NMR spectrum completely identical to a sample obtained according to Example 5.

- 37 -

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

Example I

Tablets containing 5 mg of 11- [4- [3 - [(diethylamino) methyl] -4-morpholinyl] -1-oxobutyl] -5,1-dihydro-6H-pyrido [2; 3-b] [1,4] benzodiazepin-6-one

Composition: 5, 0 mg 1 tablet contains: 148.0 mg active substance 65.0 mg lactose 2.0 mg potato starch 220.0 mg magnesium stearate Production method:

From potato starch is prepared by heating a 10% mucus. 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 Scrap: 9 mm

Example II

Dragees with 5 mg of 1- [4- [3 - [(diethylamino) methyl] -4-morpholinyl] -1-oxobutyl] -5,11-dihydro-6H-pyrido [2,3-b] (1,4) benzodiazepin-6-one

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

Example III

Ampoules containing 10 mg of 11- [4- [3 - [(diethylamino) methyl] -4-morpholinyl] -1-oxobutyl] -5,11-dihydro-6H-pyrido [2,3-b] [1,4] · Benzodiazepine-6-one

Composition:

1 ampoule contains:

Active substance 10.0 mg

Sodium chloride; id 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.

" ³⁹ " 2 β 4 O ί

Example IV

Suppositories containing 20 mg of 1- [4- (3 - [(diethylamino) methyl] -4-morpholinyl] -1-oxobutyl] -5,11-dihydro-6H-pyrido [2,3-b] -f1,4] benzodiazepin-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 Method of preparation :

The finely powdered active substance is suspended in the melted and cooled to 4O ⁰ C suppository mass. Pour the mass at 37 ⁰ C in slightly pre-cooled suppository forms. Suppository weight 1.7 g

Example V

Drops of II- [4- [3 - [(diethylamino) methyl] -4-morpholinyl] -1-oxobutyl] -5,11-dihydro-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

Ethanol pure 10.0 g

Active ingredient 0.5 g

- 40 -

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-hydroxybenzoic acid ester, anisole and menthol in ethanol and add this solution with stirring to the aqueous solution. Finally, it is made up to 100 ml with water and filtered with no suspended particles.

Claims (1)

-ΨΙ- 284 ο ι 4 Pa t e nt a η ep r e cn e I «Process for the preparation of condensed Oiazepinonen of the general formula I. (D in the
| (B) one of the divalent radicals 284o 1 4 (T) (V) (W) represents: and X ¹ , X ² , A, R ¹ to R ¹⁰ and Z have the following meanings: X · ¹ · and · X ² represent a = CH-group is or, if ") N3 j the meanings of the above-mentioned divalent groups (S), (U) or (W) assumes both or only X or only X also represent a nitrogen atom, A is a straight-chain, saturated alkylene radical having 1 to 6 carbon atoms; R and R are the same or different alkyl radicals having up to 6 carbon atoms or together with the intervening nitrogen atom denote a 4- to 7-membered, saturated, monocyclic, heteroaliphatic ring optionally substituted by a sour oxygen or by the N-Cl ^ Group may be interrupted; R is an alkyl group having 1 to 4 C atoms, a chlorine atom or a hydrogen atom; R is a hydrogen atom or a methyl group; 284Of 4 R and R are each a hydrogen atom, a fluorine- ⁴ , chlorine or bromine atom or an alkyl group having 1 to 4 carbon atoms; R iet is a hydrogen or chlorine atom or a methyl group ι R is a hydrogen atom or an alkyl radical having 1 to 4 carbon atoms) R is a hydrogen or halogen atom or an alkyl group with 1 to 4 carbon atoms and IO
R is a hydrogen atom or a methyl group and Z is a single bond wherein "* if j ^(ß J represents the divalent radical (T) and R is a Wasssrstoffatom ;, R can not represent a chlorine atom and Z is not a sulfur atom ι where appropriate their diastereomers or "enantiomeric forms," and thereby gekennzeichne of their salts with inorganic or organic acids and, if appropriate, their pharmaceutical Verabreichungsformeny t? that a>) for the preparation of basic substituted condensed oiazepinones of general formula Iav (Ia) in which R, R, R, R, X, X, A and Z have the meanings given above, ond Ί (βΊ has one of the bivalent radicals (S), (U), (V), (W) or (T ¹ ) CH ₃ jl where R 'is a chlorine atom or a methyl group, a haloacyl compound of the general formula II, (II) Shark in the 3 4> f ~ * \ 1 R, R, J (By, X and X have the meanings indicated and Hal is a chlorine, bromine or iodine atom, with a secondary amine of general formula III, ON f 1_ LJ in the 1 2 R, R, A and Z are as defined above, in an inert solvent, preferably in the presence of a • vs- ? β 4 ο i 4 Auxiliary base or an excess of the amine of general formula III, at temperatures between -1O ⁰ C and the boiling temperature of the reaction mixture is reacted or b.) for the preparation of basic substituted condensed diazepinones of general formula Ia with the abovementioned meaning, the substituents tricyclene of general formula IV, ? ο B ¹ (IV) in the the radicals R, R, Χ, X "" and 1 (BM are as defined above, with carboxylic acid derivatives of the general formula V, X ² and - N .R ¹ -. R ² 1 2
R, R, A and Z have the meanings given above and Nu represents a nucleofugic group or leaving group, in an inert solvent at temperatures between -25 and 130 ⁰ C, optionally in the presence of a proton acceptor, be reacted or - ^? 8 4 O f 4 c.) for the preparation of a pyrrolo-fused diazepinone of the formula Ib falling under the general formula I, (Ib) k "^ \" 2 .. · R ^ -, R ² , R ⁴ , X · ¹ ·, X ² and A are as defined above, Z have the meanings mentioned above with the exception of one 3 ' Sulfur atom, R is an alkyl group having 1 to 4 carbon atoms or a hydrogen atom and R represents a hydrogen atom, such a compound of general formula Ib, in which R is a chlorine atom, in a solvent either in the presence of catalysts of metals of VIII of the Periodic Table of the Elements at hydrogen pressures of 1 to 300 bar and temperatures of 0 ⁰ C to 13O ⁰ C or with formic acid in the presence of palladium on carbon as catalyst at temperatures between 70 and 110 ⁰ C or with triethylammonium in the presence of excess triethylamine and palladium on animal charcoal or by PaIJadiumacetat and triarylphosphines, at temperatures between 40 and 110 ⁰ C is hydrogenolyzed 28 4 0 ί 4 and optionally compounds of the general formula I thus obtained in their diastereomeric or enantiomeric
Separate forms and / or compounds thus obtained of the general formula I are preferably converted into their Salzet in their. Physiologically compatible salts with inorganic or organic acids ^ and optionally the compounds prepared by this method
Medicines for the treatment of bradycardia and bradyarrhythmias and, where appropriate, of spasms on the bladder and Process according to Claim IbV, characterized in that, as carboxylic acid derivatives of the general formula V, acid halides? »Esters» anhydrides or mixed acid anhydrides