DD282226A5 - METHOD FOR PRODUCING CONDENSED DIAZEPINONE - Google Patents

Abstract

Condensed diazepinones of the general formula I <IMAGE> in which <IMAGE> represents one of the divalent radicals <IMAGE> and X<1>, X<2>, A, R<1> to R<1><0> and Z have the following meanings: X<1> and X<2> represent a = CH-group or, if <IMAGE> assumes the meanings of the abovementioned divalent radicals (S), (U) or (W), both or only X<1> or only X<2> can also represent a nitrogen atom; A is an alkylene radical having two to seven carbon atoms; which can also be interrupted by an oxygen or sulphur atom or by the methylimino or ethylimino group; Z is a single bond, an oxygen or sulphur atom, the methylene or 1,2-ethylene group; R<1> is a lower alkyl radical or the benzyl group; R<2> is an alkyl radical having 1 to 7 carbon atoms, which can optionally be further substituted by a hydroxyl group on its 2nd to 7th carbon atom, a cycloalkyl or a cycloalkylmethyl radical, where the cycloalkyl ring can optionally be further substituted by a hydroxyl group; R<1> and R<2>, however, together with the nitrogen atom lying in between, can also form a 4- to 7-membered saturated, monocyclic heterocyclic ring which can optionally be interrupted by an oxygen atom or by the N-CH3 group; R<2> can, however, also be linked to A via an alkylene bridge such that, together with the group NR<1>, a saturated, 5 to 7-membered heterocyclic ring system is formed; R<3> is a lower alkyl group, a chlorine atom or a hydrogen atom; R<4> is a hydrogen atom or a methyl group; R<5> and R<6> each denote a hydrogen atom, a fluorine, chlorine or bromine atom or a lower alkyl group; R<7> is a hydrogen or chlorine atom or a methyl group; R<8> is a hydrogen atom or a lower alkyl radical; R<9> is a hydrogen or halogen atom or a lower alkyl group and R<1><0> is a hydrogen atom or a methyl group, where in the case in which <IMAGE> represents the divalent radical (T) and R<7> is hydrogen, R<3> cannot be chlorine and Z cannot be sulphur. Processes for their preparation and medicaments which contain these compounds are also described. In view of the lack of gastric acid secretion-inhibiting, salivation-inhibiting and mydriatic influences, the novel diazepinones are suitable as vagal pacemakers for the treatment of bradycardias and bradyarrhythmias in human and veterinary medicine.

Description

in the (Bj one of the divalent radicals

7 '

(S)

(T)

(V)

(W)

represents and

X ¹ , X ² , A, R ¹ to R ' ⁰ and Z have the following meanings:

X 'and X ² represent a = CH group or, if (BJ the meanings of the abovementioned, divalent radicals (S),

(U) or (W), both or only X 'or only X ^{2 may} also represent a nitrogen atom; A is a straight-chain or branched saturated alkylene radical having two to seven carbon atoms; which may also be interrupted by an oxygen or sulfur atom or by the methylimino or ethylimino group; Z is a single bond, an oxygen or sulfurato, the methylene or 1,2-ethylene group; R ^{1 is} a branched or unbranched alkyl radical having 1 to 4 carbon atoms or the benzyl group; R ^{2 is} a branched or unbranched alkyl radical having 1 to 7 carbon atoms, which may still be on its 2 nd to

7. carbon atom may be substituted by a hydroxy group, a cycloalkyl or a cycloalkylmethyl radical having 3 to 7 carbon atoms in the ring, where the cycloalkyl ring may optionally be substituted by a hydroxy group; However, R ¹ and R ² may also form, together with the intervening nitrogen atom, a 4- to 7-membered saturated monocyclic heterocyclic ring which may be optionally interrupted by an oxygen atom or by the iso-CH ₃ group;

However, R ² can also be linked to A via an alkylene bridge in such a way that together with the group NR ¹ a saturated, 5-, 6- or 7-membered heterocyclic ring system is formed;

R ³ is an alkyl group having 1 to 4 C atoms, a chlorine atom or a hydrogen atom; R ^{4 is} a hydrogen atom or a methyl group;

R ⁵ and R ⁶ each represent a hydrogen atom, a fluorine, chlorine or bromine atom or an alkyl group having 1 to 4 C atoms; R ^{7 is} a hydrogen or chloro: om or a methyl group;

R ^{8 represents} a hydrogen atom or an alkyl radical having 1 to 4 carbon atoms;

R ^{9 is} a hydrogen or halo atom or an alkyl group having 1 to 4 carbon atoms and R ' ^{0 is} a hydrogen atom or a methyl group.

In the event that Γ BJ represents the bivalent radical (T) and R ^{7 is} a hydrogen atom, R ^{3 can} not chlorine atom and

Z is not a sulfur atom.

Preferred compounds of the above general formula I are those in which either X ^{1 is} a = CH group,

X ^{2 represents} a nitrogen atom and I ( B ) represents the bivalent radical (S), with the proviso that R ³ , R ⁴ and R ^{5 are} hydrogen atoms

and R ^{6 is} a hydrogen atom, a chlorine or bromine atom or a methyl or ethyl group in the 8- or 9-position of the heterocycle,

or X ¹ and X ² = CH groups and (B) assumes the meaning of the bivalent radical (U), wherein R ^{8 is} a

Is hydrogen atom and R ^{9 is} the methyl group, or the radical (V), where at least one of the radicals R ³ and R ^{4 is} a hydrogen atom,

A is a two- to four-membered alkylene chain in the 3- or 4-position of the saturated heterocyclic ring, Z is the methylene group and

R 'and R ^{2 are} alkyl groups having 1 to 4 carbon atoms or together with the enclosed nitrogen atom, the 1-pyrrolidinyl, 1-piperidinyl, 4-morpholinyl or hexahydro-1H-1-azepinyl radical.

The compounds of general formula I can also be in the form of their physiologically acceptable salts after reaction with inorganic or orgic 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.

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

6,11-dihydro-11 - [[3- [3- (1-piperidinyl) propyll-1-piperidinyl) carbonyl | benzodiazepin-5-one -5H-pyrido [2,3-b] [1,5] 11 - [[3- [2- (cyclopentylmethylamino) ethyl] -1-piperidinyl] carbonyl-6,11-dihydro-5 H -pyrido [2,3-b] [1,5-benzodiazepin-5-one 6,11-dihydroxy] 11 - [[3- [3- (1-pyrrolidinyl) propyl] -1-piperidinyl-carbonyl] -5H-pyrido [2,3-b] [1,5-benzodiazepine-5-yne 6,11-dihydroxy] ! 11 - [[3- [2- (hexahydro-1H-1-azepinyl) -1-ethyl piperidinyllcarbonyl] -5H-pyrido [2,3-b | [1,5] benzodiazepin-5-onmethansulfonat

D, L-6,11-dihydro-11 - [[3- [2- (1-piperidinyl) ethyl] -1-piperidinyl | carbonyl] -5H-pyrido [2,3-b] [1,5 | benzodiazepine -5-one

(-) - 6,11-dihydro-11 - [[3- [2- (1-piperidinyl) ethyl] -1-piperidinyl | carbonyl] -5H-pyrido [2,3-b] [1,5 | benzodiazepine -5-one 11 - [(3- [2- (diethylamino) ethyl] -1-] piperidinylcarbonyl-6,11-dihydro-5H-pyrido [2,3-b] [1,5-benzodiazepin-5-one 11 - [[3- (3-diethylamino) propyl] -1-piperidinylcarbonyl) -6,11-dihydro-5H-pyrido [2,3-b] [1,5] benzodiazepin-5-one 6,11-dihydro-11 - [[4- [4- (1-pyrrolicinyl) butyl-1-piperidinyl] carbonyl-5H-pyrido [2,3-b] [1,5] benzodiazepin-5-one hydrochloride 6,11-dihydro- 11 - [[3- [3- (4-morphrilinyl) propyl-1-piperidinyl] carbonyl] -5H-pyrido [2,3-bl (1,5-benzodiazepin-5-one 11 - [[2 - [(3 - (diethylamino) propyl; methylaminoJmethyll-1-piperidinyljcarbonyl) -6,11-dihydro-5 H-pyrido [2,3-b] [1,5lbenzodiazepin-5-one dihydrochloride

11 - [[2- [2 - [[3- (diethylamino) propyl] methylamino] ethyl] -1-piperidinyllcarbonyl] -6,11-dihydro-5H-pyrido [2,3-b] [1,5] benzodiazepine -5-one

6,11-Dihydro-11 - [[3- [3- (1-piperidinyl) propyl] -1-pyrrolidinyl] carbonyl-5H-pyrido (2,3-b] [l, 5) benzodiazepin-5-one 6 , 11-Dihydro-11 - [[3- [3- (1-piperidinyl) propyl-hexahydro-1H-1-azepinylcarbonyl) -5H-pyrido [2,3-bl [1,5] benzodiazepin-5-one 11 - [[3- [2 - [(cyclopentyl) ethylamino] ethyl) -1-pyrrolidinyl] carbonyl] -6,11-dihydro-5H-pyrido [2,3-b] [1,5-benzodiazepin-5-one H- KS - ^ - dCyclobutylmethyDmethylaminolethyll-i-pyrrolidinyllcarbonyll E.II-dihydro-SH-pyrido ^ S-blli.Blbenzodiazepin-S-on

-7- 2S2

6,11-DihvJro-11 - [[(1-pyrrolidinyl) butyl] -1-pyrrolidinyllcarbon / ll-5H-pyr'do [2,3-b 3-I4- | [1,5] benzocliazepin-5-one 6,11-dihydro-11 - [[3- (2- (1-pyrrolidinyl) ethyl] hexahydro-1H-1-azepinyl) carbonyl) -5H-pyrido [2,3-b) [1,5) benzodiazepine -5-one 6,11-dihydro-11 - [[3- [2- (hexahydro-1H-1-azepinyl) ethyl] -1-pyrrolidinyl) carbonyl!] - 5H-pyrido [2,3-b] [ 1,5-benzodiazepin-5-one 6,11-dihydio-11 - [[3- [2- (hexahydro-1H-1-azepinyl) ethyl] -hexahydro-1H-1-azopinyl-carbonyl] -5H-pyridol2,3 bl (1,5] benzocJiazepin-5-one

HI? [2- (Diethylamino) ethyl] -1-pyrrolidinylcarbonyl-6,1l-dihydro-5H-pyrido [2,3-b] [1,5-benzodiazepin-5-one 11 - [[3- [2- (3-one) Diethylamino) ethyl 1-hexahydro-1H-1-azepinyl] carbonyl-6,11-dihydro-5H-pyrido [2,3-b] [1,5] benzodiazepine-b-one 6,11-dihydra-11 - [(3 (4- (dimethylar, iino) butyl) -1-piperidinyl-1-carboxylate-5H-pyrido [2,3-b! [1,5-benzodiazepin-5-one - [[3- [2- (butylethylamino) ethyl 1-piperidinyl] carbunyl) -6,11-dihydro-5 H -pyrido [2,3-b] | 1,5) benzodiazepin-5-one 6,11-dihydro-11- [3- [3- (dipropylamino) propyl] -1-piperidinylcarbonyl-5H-pyrido (2,3-bl [1,5-benzodiazopin-5-one 11 - [(3- [2- (dibutylamino) ethyl] -1-piperidinyl] carbonyl) -6, 11-dihydro-5H-pyrido [2,3-b] [1,5] benzodiazepin-5-one e.ii-dihydro-H-ILS-IKI-methyl ^ -piperidinyl-dimethylaminol-methyl-1-piperidinyl-carbonyl-BH-pyrido ^. sb] [1,5] benzodiazepin-5-one

6,11-dihydro-11 - benzodiazepin-5-one [(2 [[(1-methyl-4-piperidinyl) methylaminolmethyll-4-morpholinyl) carbonyll-5H-pyrido [2,3-b] [1,5]

6,11-dihydro-11- [| 4- | 3- (1-piperidinyl) prcpyl] -1-piperidinyl] carbonyl) -5H-pyrido [2,3-b] | 1,5] benzodiazepin-5-one 11 - [[4- [3- (Diethylamino) propyl) -1-piperidinyl] carbonyl-6,11-dihydro-5H-pyriclo [2,3-b] [1,5-benzodiazepin-5-one 11- [[4- (4- (Diethylamino) butyl] -1-piperidinyl] carbonyl] -6,11-dihydro-5H- ^r ) yridoI2,3-b] [1,5] benzodiazepin-5-one 5,11- Dihydro-11- [4- [3- (1-piperidinyl) propyl] -1-piperidinyl) carbonyl-6H-pyrido [2,3-b] [1,4] benzodiazepin-6-one 5,11-dihydro -11 - [[- 3- [3- (1-piperidinyl) propyl) -1-piperidinyl] carbonyl] -6H-pyrido [2,3-bl | 1,4] benzodiazepin-6-one 5,11-dihydro -11 - [[4- [4- (1-piperidinyl) butyl] -1-piperidinyl] carbonyl-6H-pyrido [2,3-b] | 1,4] benzodiazepin-6-one 11- [3] [2 - [(Cyclopentyl) methylaminolethyl] -1-piperidinyl] carbonyl] -5,11-dihydro-6H-pyrido [2,3-b] [1,4] benzodiazepin-6-one 5,11-dihydro- ' i1 - [[3- [3- (1-pyrrolidinyl) prynyl] -1-piperidinylcarbonyl) -6H-pyrido [2,3-b] [1,4] benzodiazepin-6-one 5,11-dihydro-11- | [4- [4- {1-oyrrolidinyl) butyl] -1-piperidinyl | carbonyll-6H-pyrido (2,3-bl | 1,4] benzodiazepin-6- on 5,11-dihydro-11 - [[3- [4- (1-, -) -rolidinyl) butyl] -1-piperidinyl] carbonyl] -6H-pyrido [2,3-b] [1,4-benzodiazepine-6 -on B.II-dihydro-H-KS-IS-d-pyrrolidinylpropyl-hexahydro-IH-i-azepinyl-carbonyl-eH-pyrido ^. -silylbenzodiazepine-e-one

(-) - 5,11-dihydro-11 - [[3- [2- (1-piperidinyl) ethyl] -1-piperidinyl] carbonyl] -6H-pyrido | 2,3-b) [1,4] benzodiaiepin -6-one 5,11-dihydro-11 - [[3- [2- (hexahydro-1H-1-azepinyl) ethyl] -1-piperidinyl] carbonyl-6H-pyrido [2,3-b] [1, 4lbenzodiazepin-6-onmethansulf ^ nat

11 - [[3- (2-Ethyl) -1-piperidinyl] carbonyl] -5,11-dihydro-6H-pyrido [2,3-b] [1,4] benzodiazepin-6-one 11- [[3- [3- (Diethylamino) propyl] -1-piperidinyl] -carbonyi-5,11-dihydro-6H-pyrido [2,3-bl [1,4] ben7odiazepin-6-one 11- [2 [3- (diethylamino) propyl] -4-morpholinyl] carbonyl) -5,11-dihydro-6H-pyrido [2,3-b] [1,4] benzodiazepin-6-one 11 - ([4- [ 3- (Diethylamino) propyl] -1-piperidinyl] carbonyl] -5,11-dihydro-6H-pyrido [2,3-b] [1,4] benzodiazepin-6-one 8-Chloro-5,11-dihydro -11 - [[3- [2- (1-piperidinyl) ethyl] -1-piperidinyl] carbonyl] -6H-pyrido [2,3-b] [1,4] benzodiazepin-6-one 9-chloro-5 , 11-dihydro-11 - [(3- [2- (1-piperidinyl) ethyl) -1-piperidinyllcarbonyl) -6H-pyrido [2,3-bl [1,4] benzodiazepin-G-on

5,11-Dihydro-8-ethyl-11 - [[3- [2- (1-piperidinyl) ethyl] -1-piperidinyl] carbonyl-6 H -pyrido [2,3-b] (1,4) benzodiazepine-6 -on 5,11-dihydro-9-methyl-11 - [[3- [2- (1-piperidinyl) ethyl] -1-piperidinylcarbonyl] -6H-pyrido [2,3-b] [1,4] benzodiazepine -6-one 5,11-dihydro-11 - [[3- [3- (4-morpholinyl) propyl] - '1-piperidinyl] carbinyl) -6H-pyrido [2,3-b] [1,4 benzodiazepin-6-one 11 - [[2 - [[3- (diethylamino) propyl) methylaminolmethyl] -1-piperidiryl] carbonyl] -5,11-dihydro-6H-pyridol2,3-b) [1,4] benzodiazepin-6-one dihydrochloride

5,11-dihydro-11 - [[3- | 2- (dipropylamino) ethyl] -1-piperidinyl] carboi; yl] -6H-pyrido [2,3-b] [1,4] benzodiazepin-6-one hydrochloride 5,11-dihydro-11- [3- [2 - [(2-methylpropyl) methylamino] ethyl] -1-piperidinyl] carbonyl] -6H-pyrido [2,3-b] [1,4] benzodiazepin-6-one hydrochloride

5,11-Dihydro-11 - [(3- [2 - [(methylethyl) methylaminolethyl] -1-piperidinyl] carbonyl] -6H-pyrido [2,3-b] [1,4] benzodiazepin-6-one 5 , 10-Dihydro-5 - [[3- [2- (1-piperidinyl) ethyl] -1-piperidinyl] carbonyl-11H-dibenzo | b, el (1,4) diazepine-11-one

e-Chloro-S.-di-O-dihydro-O-IO-Ud-piperidinyl-ethyl-1-piperidinyl-carbonyl-D-IIH-dibenzolb.eli-ldiazepine-H-one 4,9-dihydro-3-methyl-4 - [[3- (3-one] 2- (1-piperidinyl) ethyl] -1-piperidinyl] carbonyl] -10H-thienol3,4-b] [1,5] benzodiazepin-10-one 1,3-dimethyl-4 - [(3- [4- (1-piperidinyl) but "1" -1-piperidinyl] carbonyl! -1,4,9,10-tetrahydropyrero [3,2-b) [1,5] benzodiazepin-10-one S-chloro-i -methyl ^ -DS Md piperidinyDbytyll-i-piperidinyllcarbonyll IAg.iO-tetrahydropyrroloIS ^ -bld.Slbenzodiazepin IO

1-methyl-4 - [[3- [4- (1-piperidinyl) butyl] -1-piperidinyl) carbonyl] -1,4,9,10-tetrahydropyrrolo | 3,2-b] [1,5] benzodiazepine -10-one 4 - [(3- [3- (Diethylamino) propyl] -1-piperidinyl] carbonyl] -1,3-dimethyl-1-1,4,9,10-tetrahydropyrazolo [4,3-b] 1,5] benzodiazepine-10

4 - [[3- [3- (Diethylamino) propyl] -1-piperidinyl] carbonyl] -1-methyl-1,4,9,10-tetrahydropyrazolo [4,3-b] [1,5] benzodiazepine-10 -on 4 - [(3- [3- (Diethylamino) propyl] 1-piperidinyl] carbonyl) -1-methyl-1,4,9,10-tetrahydropyrazolo [4,3-e] pyrido [3,2-b ) [1,4) diazepin-10

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

a) Basic substituted condensed Diazepi.ione the general formula la H ₀

(La)

"R '

in the

R ¹ , K ', R ³ , R ⁴ , Χ', X ² , A and Z have the meanings given above and (V), (W) or (T ')

B ') one of the bivalent radicals (S), (U),

7 '

where R ^{7 is} a chlorine atom or a methyl group,

is obtained by reaction of carbonic acid derivatives of the general formula I.

(II)

X ¹ , X ^{2 have} the meanings indicated and

Y is a halogen atom, preferably the bromine or chlorine atom, or the radical OR ", where R" represents an optionally halogen-substituted alkyl radical having 1 to 5 carbon atoms, a phenyl radical optionally substituted by halogen atoms or nitro groups or an aralkyl radical having 7 to 15 carbon atoms Compounds of the general formula HI,

ON'

(III)

-R '

in the

R ¹ , R ² , A and Z are as defined above.

The reaction is carried out without or preferably in the presence of solvents, such as. B. of water, toluene or alcohols, such as. As methanol, ethanol or isopropanol, but most preferably in the presence of aprotic polar solvent, for. Example of tetrahydrofuran, 1,4-dioxane, acetonitrile, Ν, Ν-dimethylformamide, dimethyl sulfoxide, hexamethylphosphoric triamide, or mixtures thereof and at temperatures between -10 ° C and the boiling point of the reaction mixture is preferred

carried out between 40 and 100 ⁰ C. It has proven useful to use additional inorganic or organic bases, ζ. Β of alkali or alkaline earth metal hydroxides, alcoholates or carbonates, such as sodium hydroxide, sodium methoxide, potassium tert-butoxide, sodium carbonate, potassium carbonate; tertiary amines, for example triethylamine, ethyldiisopropylamine, Ν, Ν-dimethylaniline, pyridine or of 4- (dimethylamino) pyridine; and the reaction in the presence of an excess of a compound of general formula III.

If the amines of the general formula III and the carbonic acid derivatives of the general formula II are used in equimolar proportions, if Y is a halogen atom, the hydrochloric acid salts of the desired compounds of the general formula Ia are obtained directly.

However, the reaction can also be carried out with a metal compound of the general formula Ml a,

J A - NC

(purple)

in the

M represents an alkali metal atom or 1 equivalent of an alkaline earth metal atom. In this case, metal compounds of general formula IIIa from III by reaction with alkali or alkaline earth metals, such as sodium, potassium or barium, or with alkali or Erdalkalihydriden, such as sodium, potassium or calcium hydride, or by reaction with alkali or Erdalkaliorganylen, z. B. with n-butyl lithium or phenyllithium, easily prepared in situ.

b) Basicly substituted condensed diazepinones of the general formula Ia can also be prepared by reaction of tricycles of the general formula IV

(IV)

in the

the radicals R ³ , R ⁴ , X ', X ² and

as defined above, with a chlorocarbonic acid derivative of the general formula V

A -

(V)

wherein the radicals R ¹ , R ² , A and Z have the meanings mentioned above.

The reaction is preferably carried out in inert organic solvents, for example in aromatic hydrocarbons such as toluene, xylene, in ethers such as diisopropyl ether, tetrahydrofuran or dioxane, in ketones such as 3-pentanone, in chlorinated aliphatic hydrocarbons, such as 1,2-dichloroethane or in others Solvents, such as acetonitrile or dimethylformamide or in mixtures thereof, optionally in the presence of tertiary organic bases such as pyridine, and at temperatures up to the boiling point of the Reaktionsgernisches, preferably at temperatures between + 3O ⁰ C and + 100 ⁰ C performed.

c) The under the o !! c; ° meiris form! covered by novel pyrrolo-conjugated diazepinones of general formula Ib,

^R .. 2

(Ib)

R ¹ , R ² , R ⁴ , X ', X ² , A and Z have the meanings mentioned above, for Z except for a sulfur atom, 7 "have a hydrogen atom and

R ^{3 represents} an alkyl group having 1 to 4 C atoms or a hydrogen atom, can also dutch hydrogenolysis from those compounds of the general formula I b are prepared, in which R ^{7 represents} a chlorine atom.

The hydrogenolysis is carried out in the presence of catalysts of metals from subgroup VIII of the Periodic Table of the Elements, for example palladium on animal cabbage, palladium on barium sulfate, Raney nickel or Raney cobalt, and at hydrogen pressures of 1 to 300 bar and temperatures from O ⁰ C to 130 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 presence 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 by evaporation of the reaction solution after removal of the catalyst. 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 11O ⁰ C, and the reduction with triethylammonium in the presence of excess triethylamine and of palladium on animal charcoal or of palladium acetate and Triarylphcsphinen, such as Tripheny! Phosphine, tris (o-tolyl) phosphine, tris- (2,5-diisopropylphenyl) phosphine, proven at Ί emperaturen between 40 and 11O ⁰ C, proven.

Bases of the general formula I obtained in this way can subsequently be converted into their acid addition salts or acid addition salts obtained into the free bases or other pharnocyanologically acceptable acid addition salts.

The aminoacylated condensed diazepinones of the general formula I according to the invention contain, in part, an asymmetric carbon atom in the side chain. These compounds can therefore each occur as enantiomeric (+) and (-) forms. The invention includes the individual isomers as well as their racemates.

The cleavage of any 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 (+ j-oderf- l-diacetyltartaric acid, (+) - or (-) - monomethyl tartrate or (+) - Camphersull 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 hydroxide or potassium hydroxide to thereby obtain the corresponding free compound in the (+) or (-) form.

In each case only one enantiomer is also obtained by carrying out the syntheses described above with only one enantiomer of the general formula III or V.

The carbonic acid derivatives of the general formula II required as intermediates are obtained in analogy to DE-A-3204169, DE-A-3204158 and DE-A-3204401 by reacting tricycles of the general formula IV,

(IV)

in the

the radicals R ³ , R ⁴ , X ¹ , X ² and iβ M are as defined above, with a halocarbonic acid derivative of the general formula V ¹ ,

Hal-CY ^(VI >

in the

Hal is the bromine or chlorine atom, preferably the chlorine atom, and i has the meanings given above. The reaction is carried out in inert organic solvents, for example aromatic hydrocarbons, such as toluene, chlorobenzene or xylene; open-chain or cyclic ethers, such as diisopropyl ether, tetrahydrofuran or dioxane; open-chain or cyclic aliphatic ketones, for example 3-pentanone; chlorinated aliphatic hydrocarbons, such as 1,2-dichloroethane or other solvents, such as acetonitrile or dimethylformamide or in mixtures thereof and preferably in the presence of tertiary organic bases, preferably of pyridine, and at temperatures up to at most the boiling point of the solvent or solvent mixture used between +30 and +80 ⁰ C, performed. Intermediates of the general formula III which have an alkylene radical A interrupted by a heteroatom in the β-position to the saturated heterocycle can be synthesized in analogy to the methods discussed in detail in WO-3626095.

Intermediate compounds of the general formula III, in which Z represents a methylene group, are expediently based on appropriately substituted pyridines, for example by catalytic hydrogenation in an ethanolic-hydrochloric acid solution and using platinum (IV) oxide as catalyst (cf. also: FF Blicke et al. J. Org. Chemistry 26, 3258 (1961)) or in glacial acetic acid and in the presence of platinum (IV) oxide (see also WF Minor et al., J.Med.Pharm.Chem.5, 96, 105 ff. (1962) and AHSommers et al , J.Amer.Chem.Soc.75, 57, 58ff. (1953]). The substituted pyridines in turn can be readily synthesized by methods known to those skilled in the art, for example by addition of appropriate secondary amines, dialkylaminoalkanols or dialkylaminoalkane thiols to vinylpyridines by reduction of suitable Pyridinalkansäureamiden with lithium aluminum hydride, by alkylation of picolines with Dialkylaminoalkylhalogeniden in the presence of lithium diisopropylamide or sodium amide (see also AETschits chibabin, Bull. Soc. Chim. France 1938, 436) or else by reacting (cü-haloalkyl) -pyridines with dialkylaminoalkanols, dialkylaminoalkanethiols or secondary amines (see also L.Rondahl, Acta Pharm. Succ.13, 229-234 [1975]) or their metallated derivatives , A generally applicable method for the synthesis of amines of the general formula III consists in the reduction of suitable heterocyclic substituted and optionally interrupted in the alkylene by heteroatoms Alkancarbonsäuredialkylamide, for example by Lithiumaluminiumhydi id. Protecting groups which may still be present on the nitrogen function of the saturated heterocycle from the precursors may be cleaved off in a conventional manner, a benzyl radical, for example. By hydrogenolysis in the presence of palladium / animal charcoal. For example, 5-oxo-2-pyrrolidineacetic acid (GLEvansu. A., J. Amer. Chem. Soc., 72, 2727 (195O)) can be sequentially reacted with thionyl chloride and a dialkylamine of interest and so prepared. N-dialkyl-5-oxo-2-pyrrolidineacetamide can then be reduced with lithium aluminum hydride to the desired 2- (2- (dialkylamino) ethyl) pyrrolidine, or the tus 4-benzyl-3- (hydroxymethyl) -morpholine (GRBrown et al. J. Chem. Soc. Perkin Trans. 1198, 2577) convert 4-benzyl-3- (chloromethyl) -morpholine hydrochloride obtainable by the action of thionyl chloride by chain extension in customary manner into (4-benzyl-3-morpholinylalkanoic acids and thus for the synthesis of The tricyclics of the general formula IV are known from the patent literature or can be synthesized from common starting materials in close accordance with published procedures

 Halocarboxylic acid derivatives of the general formula VI are known.

Compared with the known condensed diazepinones, the condensed diazepinones prepared according to the invention are characterized by a significantly enhanced action and marked hydrolytic stability with comparable or improved selectivity and resorption after oral administration.

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

For this purpose, the compounds of the general formula I can be prepared in a manner known per se in the usual pharmaceutical preparation forms, for. B. in solutions, suppositories, tablets, dragees, capsules or tea preparations. The daily dose is generally between 0.01 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 individual doses to Achieving the desired results is administered.

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 η ydriatischer influences as vagale Schrittmacner 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 colon and bladder. A favorable relation between tachycardic effects on the one hand, and the adverse 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. Screening for Functional Selectivity of the Antimuscarinic Effect Substances having antimuscarinic properties inhibit the effects of exogenously added agonists or acetylcholine releasing allergy-endolipid nerve endings. The following is a description of vr-n methods suitable for detecting cardioselective antimuscarinica.

-12-282,226 in vitro "organ preparations

Dissociation constants (K _B values) were determined "in vitro" on the ileum and spontaneously beating atrium dos guinea pig. The ileum was removed ^and! Incubated m organ bath in Krebs-Henseleit solution. Contractions were induced in such a way by steigenda concentrations of Mothacholin (M) that full concentration-response curves could be recorded, then M was washed out, the substance to be tested was added and left in contact for 30 minutes, and again a concentration-activity curve was recorded with M.

From the dose ratio (DR), which is the extent of the shift in the concentration-activity curve, the dissociation constant was calculated according to Arunlakshana and Schild (Brit. J. Pharmacol., 14, 8, 1859).

At the more isolated, spontaneously beating right atrium, M reduced the heart rate in a concentration-dependent manner. By adding an antimuscarinic this effect was reversed. Dissociation constants for the auricle muscarinic receptors were obtained in the same manner as described above. The comparison of the dissociation constants determined in both tissues allowed the identification of cardioselective substances. The results are included in Table III.

ln vivo "methods

The methods used were to confirm the selectivity of the antimuscarinic effect. Those substances which had been selected on the basis of in vitro tests were tested for their

1. M, - / M ₂ selectivity in the rat,

2. Salivary antisecretory effect in 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 31, 1992-2998 [1982]). Five minutes after intravenous injection of increasing doses of the substance, either the right vagus was electrically stimulated (frequency: 25Hz, pulse width: 2ms, stimulation time: 30s, voltage: supramaximal), or 0.3mg / kg McN-A-343 in male THOM rats intravenously injected. 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 (M2) or the blood pressure increase (M ₁ ) by 50% was graphically determined

 Results see Table II.

2. Salivary secretion-inhibiting effect on the rat

According to Lavy and Mulder (Arch. Int Pharmacodyn., 178, 437-445, [19691] male THOM rats anesthetized with 1.2 g / kg urethane received increasing doses of the i.V. substance. Salivary secretion was replaced 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 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 simultaneously intraarterially 5 minutes after administration of the test substance. The heart rate was recorded by extakorporale derivation of the ECG, the exhalation resistance of Konzett-Rößler and the contraction of the exposed bladder directly. Dose-response curves were recorded for the inhibition of the acetylcholine effect on the organs examined, and from this, the EDso values were determined. Results see Table V.

B Educational studies on muscarinic receptors:

1.) in vitro: Determination of the IC 50 value

As an organ donor served male Sprague-Dawley rats with 180-22Og body weight. After removal of heart and submandibularis, all further steps were carried out in ice-cold Hepes-HCl (pH7.4, 100 mM molar NaCl, 10 mM molar MgCl ₂ ). The whole heart was scissors small. All organs were finally homogenized in a Potter.

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

Total heart 1: 400

Submandibularis 1: 400

The incubation of the organ homogenates was carried out at a certain concentration of radioligand and a series of concentrations of nonradioactive test substances in an Eppendorf centrifuge tubes at 3O ⁰ C. The incubation time was 45 minutes. The radioligand used was 0.3 nmolar ³ HN-methylol scopolamine ( ³ H-NMS). The incubation was terminated by the addition of ice cold buffer followed by vacuum filtration. The filters were rinsed with cold buffer and their radioactivity determined. It represents the sum of specific and unspecific binding of ³ H-NMS. The proportion of nonspecific binding was defined as the radioactivity bound in the presence of 1 μmol of quinclidinylbenzilate. There were always fourfold determinations. IC 50 values of unlabeled test substances were determined graphically. They represent that concentration of the test substance at which the specific binding of ³ H-NMS to the muscarinic receptors in the various organs was inhibited by 50%. The results are shown in Table 1.

2.) in vivo: determination of the ID _S0 values

For these experiments, female rats weighing about 200 g were used. Before starting the experiment, the animals were anesthetized with a dose of 1.25 g / kg urethane. The animals were each given the intended dose of the test substance by iv injection. At the end of 15 minutes, 113ng / kg ³ HN-methylscopolamine ( ³ H-NMS) was added in the same manner. After another 15 minutes, the animals were sacrificed, the heart, bronchi and lacrimal glands removed. These organs were dissolved in Soluene R and the radioactivity determined. These measurements were as

Total commitment accepted. The proportion of non-specific binding was defined as that radioactivity that was not displaceable by administration of 2 mg / kg atropine. From these experiments IDw values were determined for the individual organs. The IDso values are doses of the test substances that inhibited 50% of the specific binding of ³ H-NMS to the muscarinic receptors of the respective organs. The results are contained in Table IV.

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

A = 5,11-dihydro-11-I (3- [3- (1-piperidinyl) propyl] -1-piperidinyl-carbonyl-6H-pyrido [2,3-bl [1,4] benzodiazepin-6-one B = 5,11-dihydro-11 - [[3- [3- (1-pyrrolidinyl) propyl) -1-piperidinyl] carbonyl] -6H-pyrido [2,3-b] [1,4- |

benzodiazepine-6-one hydrochloride C = 5,11-dihydro-11 - [[3- [2- (1-piperidinyl) ethyl-1-piperidinylcarbonyl) -6 H -pyrido [2,3-bl (1,4] benzodiazepin-6-one

methanesulfonate D = 5,11-dihydro-11 - [(3- [2- (1-pyrrolidinyl) ethyl-1-piperidinyl] carbonyl] -6H-pyrido [2,3-b] [1,4] -benzodiazepine 6-one hydrochloride

E = 11 - ([3- [2 - [(Cyclopentyl) methylamino] ethyl] 1-1-piperidinylcarbonyl] -5,11-dihydro-6H-pyrido [2,3-b] [1,4] -F = benzodiazepine [[3- (2- (hexahydro-1H-1-azepinyl) -ethyl-1-piperidinyl] carbonyl) -6H-pyrido [2,3-b) [1,4] - 5,11-dihydro-11 6-on-hydcrochlorid

G = 6,11-dihydro-11- [I3- [2- (1-piperidinyl) ethyl] -1-piperidinyl] carbonyl-5H-pyrido [2,3-b] (1,5] benzodiazepin-5-one and as reference substances X - 11 - [[2 - [(diethylamino) methyll-1-piperidinyl-acetyl] -5,11-dihydro-6H-pyrido [2,3-b] [1,4] benzodiazepin-6-one

(see U.S. Patent No. 4,550,107) Y = 5,11-dihydro-11 - [(4-methyl-1-piperazine) acetyl] -6H-pyrido [2,3-bl | 1,4] benzodiazepine-6 on

(Pirenzepine, see US Pat. No. 3,660,380) and

Z = atropine The following tables contain the results found:

Table I: Receptor binding assays, in vitro:

Substance Receptor Binding Log IC ₆₀ InMr ¹ ] Heart -Tests submandibularis Selectivity factor: ratio of IC ₅₀ submandibular to IC ₆₀ heart A 8.70 7.70 10 B 8.00 7.40 4 C 8.52 7.52 10 D 8.22 7.30 8.3 e 8.52 7.52 10 F 8.52 7.52 10 G 8.40 7.40 10 X 6.82 5.30 33 Y 5.82 6.70 0.13 Z 8.40 8.40 1

Tabellell:

M | / M ₂ selectivity and salivary secretion-inhibiting activity in the rat:

Sub M ₂ activity M, activity Speichelse relationship punching (Rat) (Rat) kretionshemmung Saliva- ED ₆₀ [MgAgI EDüofog / kg] (Rat) secretory iv iv ED ₆₀ [pg / kg | TION iv hemmungzu M ₂ activity A 6.9 49 35 5 C 7.6 39 58 7.6 G 8.13 7.16 6.83 20.00 X 160 988 4215 26.3 Y 883 40 84 0.1 Z 4 16 9 2.2

Table III:

Dissociation constants (Kg values) in the ileum and spontaneously beating. Guinea pig atrium:

substance heart K _B (mol / l) ileum A 3.47 χ 10 "'° 3,23 χ 10 " ⁹ X 1.05 x 10 " ⁷ 6.17 x 10 " ⁷ Y 2.4 x 10 " ⁷ 1.55 χ 10 " ⁷

1.41 χ 10 " ⁹

8,13 χ 10 "'°

Table IV: Receptor binding assays, in vivo:

substance

heart

Atrium

ventricles

ID ₆₀ (mg / kg) I tears relationship bronchia glands the ID ₆₀ lachrymal gland ToID ₆₀ of the atrium

A 0.01 0.005 0.06 0.2 20 X 1.0 0.6 15.0 > 30.0 > 30 Y 5.0 1.0 10.0 10.0 2 Z 0.08 0.03 0.1 0.2 1.5

Table V:

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

-log ED ₅₀ [Molkg- ¹ ] substance heart bronchia bladder A 7.06 6.93 5.87 B 7.18 7:06 6.16 C 7.37 7.38 6.45 D 7.32 7.49 6.15 e 7.09 7.01 6.05 F 7.79 7.40 6.42 G 7.83 7.58 6.52 X 5.84 5.58 4.73 Y 5, œ5 6.57 5.36 Z 7.70 7.96 7.03

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 _M values when tested on preparations from the heart versus those from the submandibularis. From the pharmacological data of Table II above results - 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. The ratio of ED50 of the salivary secretion inhibition ZuED _{50 of} the M ₂ activity shows a sufficient safety margin to the side effect dry mouth for the compounds A to G. Thus it is proved that the substances A to G with increasing the effectiveness (see Table IV) a sufficient having substance X comparable therapeutically useful selectivity. In addition, the pharmacological data of Table III above indicate a surprisingly large discernment between heart and smooth muscle. A is significantly more potent than X and Y, with clear selectivity to the heart being evident and compound A having clear efficacy advantages over X and Y. Atropine (= Z) is a known non-selective antimuscarinic and exhibits a reverse selectivity ratio under these model conditions. The compounds mentioned are excellently absorbed because they have a small dose ratio po to iv. The smaller the ratio ED ₆₀ po to ED ₅₀ i · v. is, the better the absorbability of the active substance.

Table IV shows the preferred binding to receptors of the heart (atrium / ventricle). Substance A shows a significant improvement in the potency against the substances X and Yam hearts. This is an important therapeutic benefit for the creation of a vaginal pacemaker. This increase in efficiency was achieved while maintaining the usable selectivity distance to the effects on the exocrine glands, as is also evident from the ratio of the ID ₅₀ values of the lacrimal gland to the ID ₅₀ values of the atrium. The atropine (= Z), on the other hand, is not selective.

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.

All substances of general formula I are characterized by a pronounced hydrolysis stability. This makes it possible to produce storage-stable solutions for parenteral administration.

The following examples soller, explain the invention in more detail:

"Mp" means "melting point", "Z." means "decomposition". For all compounds there are satisfactory elemental analyzes, IR, UV, 'H-NMR, often also mass spectra. Percentages are, unless expressly stated otherwise, always by weight.

embodiment

The invention is explained in more detail below with reference to some examples.

example 1

To the suspension of 2.6 g (9.5 oM mol) of 1-chlorochloro-1-1-dihydro-6H-pyrido [2,3-b] [1,4] benzodiazepin-6-one in 30 ml of dimethylformamide was added dropwise Room temperature and with stirring, the solution of 2.00 g (9.51 mmol) of 3- [3- (1-piperidinyl) propyl-piperidine in 10 ml of dimethylformamide The initially clear solution re-turbid within a few minutes After stirring for half an hour at room temperature, the colorless The resulting solid colorless monohydrochloride of the desired compound of melting point> 26O ⁰ C was dissolved in 10 ml of water, treated with a saturated aqueous potassium carbonate solution until a clearly alkaline reaction and then filtered The solid is washed thoroughly with water and then dried in a vacuum drying oven at 50 ^° C. and over di-phosphorus pentoxide to give 3.0 g (71% of theory) of the desired 5.1-i-dihydro-11- ([3- [ 3- (1-pip eridinyl) propyl |. -1-piperidinyl) -carboiiyll-6H-pyrido [2,3-b) [1,4) benzodiazepin-6-one, mp 123-135 ⁰ C, Ri 0.41 (Merck TLC plates Silica gel 60 F ₂₆₄ ; Eluant: dichloromethane / methanol / aqueous conc. Ammonia 90/10/1, v / v / v)

For conversion into the hydrochloride, 500 mg of the base were dissolved in a mixture of 70 ml of ethyl acetate and 3 ml of ethanol, and 1.12 ml of an ethereal 1 molar hydrogen chloride solution were added. The resulting precipitate was dissolved in a mixture of 50 ml of methanol and 2 ml of water, then evaporated to a total volume of 10 ml in vacuo and mixed with 30 ml of acetone. After trituration, colorless crystals were obtained which were dried and melted at> 260 ° C. The solubility in water was about 0.2%.

C ₂₆ H ₃₄ CIN ₅ O ₂ (484.04)

Calc .: C 64.52 H 7.08 Cl 17.32 N 14.47

Gef .: 63.99 7.13 7.21 14.3G

Analogously, 300 mg of 5,11-dihydro-11 - [[3- [3- (1-piperidinyl) -propyl] -1-piperidinyl] carbonyl] -6H-pyrido [2,3-b] [1,4] benzodiazepine Dissolved in 100 ml of warm ethyl acetate and converted into the corresponding salt by treatment with 60 mg of methanesulfonic acid. Colorless crystals of mp. 183-187 ⁰ C, slightly soluble in water.

C ₂₆ H ₃₃ N ₅ O ₂ CH ₃ SO ₃ H (543.68)

Calc .: C 59.65 H 6.86 N 12.88 S 5.90

F .: 59.42 6.75 12.33 5.91

The salt with N-Cyclohexylsufamidsäure melted at 204-208 ⁰ C and was in the water to about! % soluble.

C ₃₂ H ₄₆ N ₆ O ₅ S (611.80)

Calc .: C 61.32 H 7.40 N 13.41 S 5.11

Gef .: 60.83 7.44 13.08 5.16

Example 2

Prepared analogously to Example 1 from 11- (chlorocarbonyl) -5,11-dihydro-6H-pyrido [2,3-b] - [1,4] benzodiazepine-6-one and 2- [2- (Diethyfamino) ethyllpiperidine in one Yield of 37% of theory. Colorless crystals of melting point 100 ^° C. (Z.) (from acetonitrile), Rt 0.25 (Macherey-Nagel, Polygram ") SIL G / UV ₂₅₄ , pre-coated plastic sheets for TLC;

Dichloromethane / ethylacetate / cyclohexane / methanol / conc. Ammonia 57/25/8/8/1, v / v / v / v / v) C ₂₄ H ₃₁ N ₅ O ₂ (421.54)

Calc .: C 68.38 H 7.41 N 16.61

Gef .: 68.18 7.47 16.80

Example 3

5,11-Dihydro-11 - [[2- [2- (dimethylamino) ethyl] -1-piperidinyl-1-carbonyl] -6H-pyrido [2,3-b] [1,4] benzodiazepin-6-one Prepared by analogy Example 1 of 11- (Chlorocarbonyl) -5,11-dihydro-6H-pyrido [2,3-b] [1,4] benzodiazepin-6-one and 2- [2- (dimethylamino) ethyl-piperidine in 37% yield % of theory. Colorless crystals, mp 188-19O ⁰ C (from acetonitrile), Ri 0.6 (Macherey-Nagel, Polygram "" SIL G / UV _254, pre-coated plastic sheets for TLC; eluant:. Dichloromethane / cyclohexane / methanol / conc Ammonia 68/15/2, v / v / v / v)

C22H27 N «, 0 ₂ (393,49) H 6.92 N 17.80 Calc .: C 67,15 6.63 17.83 Found .: 66.97

Example 4

11 - [[2- [4- (Diethylamino) -butyl] -1-piperidinyl] carbonyl] -5,11-dihydro-6H-pyrido [2,3-b] [1,4] benzo-ciocin-j-on The mixture of 4.5 g (0.0164 mol) of 11- (chlorocarbonyl) -5-, 11-dihydro-6H-pyrido (2,3-bl [1,4-benzcdiazepin-6-one, 2,2 g (0,02 mol) of anhydrous sodium carbonate , 4.3 g (0.0202 mol) of 2- [4- (diethylamino) butyllpiperidine and 100 ml of acetonitrile were refluxed with stirring for 1 hour, the solvent was then distilled off in vacuo, the remaining highly viscous residue was taken up in 30 ml of water, sodium-alkaline and extracted exhaustively with dichloromethane.

The combined dichloromethane layers were dried over sodium sulfate and evaporated, the residue on silica gel (35-70 mesh) using dichloromethane / ethyl acetate / cyclohexane / methanol / conc. Ammonia 58/25/8/3/1, v / v / v / v / v, purified by chromatography for elution. This gave 4.0 g (56% of theory) of a colorless resin which could not be crystallized.

C ₂₆ H ₃₅ N ₆ O ₂ (449.59)

Calc .: C 69.46 H 7.85 N 15.58

G .: 69.42 7.96 15.51

The water-soluble dihydrochloride melted at 174-175 ° C (Z) C ₂₆ H ₃₇ Cl ₂ N ₆ O ₂ (522.51)

Calc .: C 59.77 H 7.14 Cl 13.57 N 13.40

Gef .: 60.13 7.07 13.50 13.45

Example 5

5,11-Dihydro-11 - [[2- [4- (dimethylamino) butyl] -1-piperidinyl] carbonyl] -6 H -pyrido [2,3-b] [1,4] benzodiazepin-6-one analogously to Example 4 from 11- (chlorocarbonyl) -5,11-dihydro-6H-pyrido [2,3-b] [1,4-benzodiazepin-6-one and 2- [4- (dimethylamino) butyl] piperidine in a yield of 55% of theory. Colorless crystals, mp 145-147 ⁰ C (from Essigsä'ureethylester), R, 0.1 (Macherey-Nagel, Polygram "" SIL G / UV _2; ,, pre-coated plastic sheets for TLC; eluant:. Dichloromethane / Ethyl acetate / cyclohexane / methanol / concentrated ammonia 08/25/8/8/1, v / v / v / v / v) C ₂₄ H ₃₁ N ₆ O ₂ (421.54)

Calc .: C 68.38 H 7.41 N 16.61

Gef .: 68.40 7.53 16.45

Example 6

11 - [[2- [3- (Diethylamino) propyl] 1-piperidinyl] carbonyl-5,11-dihydro-6H-pyrido [2,3-b] [1,4] benzodoazepine · 6-one Prepared analogously to Example 4 11 - (Chlorocarbonyl) -5,11-dihydro-6H-pyrido [2,3-b] (1,4] benzodiazepin-6-one and 2- [3- (diethylamino) propyl] piperidine in a yield of 70% of theory . Colorless crystals, mp 125-128 ⁰ C (ethyl acetate), R, 0.15 (Macherey-Nagel, Polygram ^{1 "1} SIL G / UV _254, pre-coated plastic sheets for TLC; eluant.:

Dichloromethane / ethylacetate / cyclohexane / methanol / conc. Ammonia 58/25/8/8/1, v / v / v / v / v) C ₂₆ H ₃₃ N ₆ O ₂ (435.57)

Calc .: C 68.94 H 7.64 N 16.08

G .: 69.00 7.66 15.90

Example 7

5,11- (dihydro-11 - [[2- [3- (dimethylamino) propyl] -1-piperidinyl] carbonyl] -6H -pyrido [2,3-b] [1,4] benzodiazepin-6-one analogously to Example 4 from 11- (chlorocarbonyl) -5,11-dihydro-6H-pyrido [2,3-b] [1,4] benzodiazepine-6-one and 2- [3- (diethylamino) propyl] piperidine in a yield of 51% of theory. Colorless crystals, mp. 142-144 ⁰ C _((from acetone and ethyl acetate), R 0.7 (Macherey-Nagel, Polygram '^"1 SIL G / UV _264, pre-coated plastic sheets for TLC;

Dichloromethane / cyclohexane / methanol / conc. Ammonia 68/15/15/2, v / v / v / v) C ₂₃ H ₂₉ N ₆ O ₂ (407.51)

Calc .: C 67.79 H 7,17 N 17,19

Gef .: 67.80 7.27 16.99

Examples

5,11 (dihydro-11 - [[4- [2- (1-piperidinyl] ethyl] -1-piperidinyl] carbonyl] -6 H-pyrido [2,3-b] [1,4] benzodiazepin-6 Prepared analogously to Example 4 from 11- (chlorocarbonyl) -5,11-dihydro-6H-pyrido [2,3-b] [1,4-benzodiazepin-6-one and 4- [2- (1-piperidinyl) ethyl) piperidine in a yield of 47% of theory colorless crystals of mp. 178-18O ⁰ C.

Example 9

5,11-dihydro-11 - [[4- (1-methyl-4-piperidinyl] -1-piperidinyl] -i; arbonyl] -6H-pyrido [2,3-b] [1,4] benzodiazepin-6 -on-hydrochloride Prepared analogously to Example 4 from 11- (chlorocarbonyl) -5,11-dihydro-6H-pyrido [2,3-b] [1,4] benzodiazepine-6-one and 4- [1-methyl-4 piperidinyl piperidine in a yield of 21% of theory. Colorless crystals of mp. 254-255 ° C.

Example 10

[1,4] benzodiazepin-6-one

Prepared analogously to Example 1 from II-chloro-carbonyl-SJI-dihydro-eH-pyridote.S-bHMlbenzodiazepine e-one and 2- | 2 - [[1- (phenylmethyl) -4-piperidinylmethylamino] ethyl) pyrrolidine in a yield of 13 % of theory. Amorphous, resinous, colorless substance, Rf 0.06 (Merck TLC plates, silica gel 60 (F ₂ M, eluent: dichloromethane / methanol / concentrated ammonia 90/10/1, v / v / v)

Cj ₂ H ₃₈ N ₆ O; (538.69)

Calc .: C 71.35 H 7.11 N 15.60

Gef .: 70,80 7,34 15,31

Example 11

5,11-Dihyclro-11 - benzodiazepin-6-one [[4- [3- (1-pipuridinyl) propyl] -1-piperidinyl] carbonyl] -6 H-pyrido [2,3-b] [1,4] Prepared analogously to Example 4 from 11- (chlorocarbonyl) -5,11-dihydro-6H-pyrido [2,3-bis [1,4] benzodiazepine-6-one and 4- [3- (1-piperidinyl) propyl] piperidine in a yield of 81% of theory. Colorless crystals of mp. 200 ⁰ C.

Example 12

11 - [[3- [3- (diethylamino) propyl] -1-piperidinyl] carbonyl] -5,11-dihydro-6H-pyrido [2,3-b] [1,4] benzodiazepin-6-one hydrochloride Prepared analogously to Example 1 from 11- (chlorocarbonyl) -5,11-dihydro-6H-pyrido [2,3-b] [1,4] benzodiazepine-6-one and 3- (3- (diethylamino) propyl] piperidine in a yield of 84% of theory Colorless crystals of mp 257-258 ⁰ C (ethanol / -iisopropyl ether).

C ₂₅ H ₃₄ CIN ₅ O ₂ (472.03)

Calcd .: C, 63.61, H, 7.26, Cl, 7.51, N, 14.84

Gef .: 64.00 7.35 7.44 14.88

Example 13

Prepared analogously to Example 1 from 11- (chlorocarbonyl) -5,11-dihydro-6H-pyridc [2,3-b] [1,4] benzodiazepine-6-one and 3- [3- (dimethylamino) propyl] piperidine in a yield of 71% of theory. Colorless crystals, mp. 115-117 ⁰ C (ethanol / ether 1:30, v / v), R | 0.35 (Merck DC precast plates, silica gel 60 F ₂₅₄ , eluent: dichloromethane / methanol / concentrated ammonia 90/10/1, v / v / v)

The monohydrochloride melted at 222-224X.

C ₂₃ H ₃₀ CIN ₅ O ₂ (443.98)

Calc .: C 62.22 H 6.81 Cl 7.99 N 15.77

Gef .: 62.00 7.07 7.79 15.58

Example 14

5,11-dihydro-11 - [[3- [3- (4-morpholinyl) propyl] -1-piperidinyl] carbonyl] -6H-pyrido. {, 3-b] [1,4] benzodiazepine-6-one hydrochloride Prepared analogously to Example 1 from 11- (chlorocarbonyl) -5,11-dihydro-6H-pyrido [2,3-bi | 1,4-benzodiazepine -6-one and 3- [3- (q-morpholinyl) propyl] piperidine in a yield of 61% of theory. Colorless crystals of mp> 26O ⁰ C (from ethanol / water / acetone).

C ₂₅ H ₃₂ CIN ₅ O ₃ (486.01)

Bee: C 61.78 H 6.64 Cl 7.29 N 14.41

F .: 61.41 6.68 7.26 14,18

Example 15 S.II-dihydro-H-ttS-tS-lhexahydro-IH-i-i-azepinyllpropylJ piperidinylJcarbonylJ-t'H-pyrido ^ .S ^ blfi lbenzodiazepin-e-one

hydrochloride

Prepared analogously to Example 1 from 11- (chlorocarbonyl) -5,11-dihydro-6H-pyrido [2,3-b] [1,4] benzodia-7-quin-6-one and 3- [3- (hexahydro-1H-1 azepinyl) propyl] piperidine in a yield of 60% of theory. _(Colorless crystals, mp> 260 C ^c, R 0.4 (Merck, DC-Fertigplatten, Kieselgel 60 F _254; eluent:.. Dichloromethane / methanol / concentrated ammonia 90/10/1, v / v / v) C ₂₇ H ₃₆ CIN ₅ O ₂ (498.07)

Calc .: C 65.11 H 7.28 Cl 7.12 N 14.06

Gaf .: 65.51 7.21 7.18 13.92

Example 16

SH-Dihydro-H-ItS-fS-d-pyrrolidinylpropyl-i-piperidinyl-carbonyl-eH-pyrido ^ .S-bli ^ Jbenzodiazepine e-on hydrochloride Prepared analogously to Example 1 from 11- (chlorocarbonyl) -5,11-dihydro 6H-pyrido [2,3-b] [1,4lbonzodiazepin-6-one and 3- [3- (1-PyrrolidinyDpropyllpiperidin in a yield of 56% of theory. Faiblose crystals of mp.> 260 ^c C (from water / Acetone), water solubility: about 0.3%.

C ₂₅ H ₃₂ CIN ₅ O ₂ (470.01)

Calc .: C 63.89 H 6.86 Cl 7.54 N H90

G .: 63.90 6.92 7.25 14.86

Example 17

Prepared analogously to Example 4 - H-chloro-carbonyU-BH-dihydro-eH-pyrido ^ S-bHMIbenzodiazepine e-on and 2- [4- (i-piperidinyl) butyl] piperidine in a yield of 41% of theory. Colorless crystals, mp. 199-201 ⁰ C, (after two recrystallizations from ethanol using charcoal).

C ₂₇ H ₃₅ N ₅ O ₂ (461.61)

Calc .: C 70.25 H 7.64 N 15.17

Found: '70.07 7.58 15.02

Example 18

5.11 Dlhydro-11 - [[3 · [2- (dipropylamino) θthyll-1-piperylnyl] carbonyl] .6H.pyrido [2,3-b] [1,4] bethzodiazepine .6on hydrochloride analogously to Example 1 from 11- (chlorocarbonyl) -5,11-dihydro-6H-pyrido [2,3-b] [1,4-benzodiazepine-6-one and 3- [2- (dipropylamino) ethyl] piperidine in a yield of 67% of theory. Colorless crystals of mp. 202-205 ⁰ C (ethanol).

C ₂₆ H ₃₆ CIN ₆ O ₂ (486.06)

Calc .: C 64.25 H 7.46 Cl 7.29 N 14.41

Gef .: 64.00 7.39 7.41 14.25

Example 19

B.II-dihydro-ii-ttS - ^ - ldimethylaminolbutyl-i-piperidinyl-carbonyl-eH-pyrido ^^ - benzylbenzodiazepine-e-on-hydrochloride Prepared analogously to Example 1 from 11- (chlorocarbonyl) -5,11- dihydro-6H-pyrido [2,3-b] [1,4] benzodiazepine-6-one and 3- [4- (dimethylamino) butyllpiperidine in a yield of 69% of theory. Colorless crystals of mp. 234-235 ° C (isopropanol).

C ₂₄ H ₁₂ CIN ₅ O ₂ (458.0)

Calc .: C, 62.94; H, 7.04; Cl, 7.74, N, 15.29

Gef .: 63.03 6.90 7.90 14.89

Example 20

S.II-dihydro-H-lO-Wd-pyrrolidinyldbutyl-i-piperidinyl-1-carbonyl-eH-pyridota.S-bi-benzodiazepine e-one Prepared analogously to Example 1 from 11- (chlorocarbonyl) -5,11-dihydro- 6H-pyrido [2,3-b] [1,4-benzodiazepin-6-one and 3- (4- (1-pyyrolidinyl) -butyl] -piperidine in a yield of 50% of theory Colorless crystals of mp 153-156 ° C (Ethyl acetate / diethyl ether 1/1, v / v), R ₁ 0.25 (Merck TLC plates, silica gel 60 F ₂₆₄ , eluant: dichloromethane / methanol / concentrated ammonia 90/10/1, v / v / v ).

C ₂₆ H ₃₃ N ₅ O- '447.58)

Calc .: C 69.77 H 7.43 N 15.65

Gef .: 69.72 7.27 15.25

Example 21

6,11-dihydro-11 - [[3- [3- (1-piperidinyl) propyl] -1-piperidinyl] carbonyl] -5H-pyrido [2,3-b] [1,5] benzodiazepin-5- on Prepared analogously to Example 4 from 11- (chlorocarbonyl) -6,11-dihydro-5H-pyrido [2,3-bl [1,5] benzotliazepin-5-one and 3- [3- (1-piperidinyl) propyl] piperidine in a yield of 58% of theory. Colorless crystals of mp. 165.5-167.0 ° C (acetonitrile).

C ₂₆ H ₃₃ N ₅ O ₂ (447.58)

Calc .: C 69.77 H 7.43 N 15.65

Gfef .: 69.65 7.44 15.50

Example 22

11 - [[3- [2 - [(cyclopentyl) methylamino] ethyl] -1-piperidinyl] carbonyl] -6,11-dihydro-5H-pyrido [2,3-b] [1,5-benzodiazepin-5- on Prepared analogously to Example 4 from 11- (chlorocarbonyl) -6,11-dihydro-5H-pyrido [2,3-b] [1,5] benzodiazepin-5-one and 3- [2 - [(cyclopentyl) methylaminolethyl] piperidine in a yield of 61% of theory. Colorless crystals of mp. 148-15O ⁰ C (Acetronitrii).

C ₂₆ H ₃₃ N ₅ O ₂ (447.58)

Calc .: C 69.77 H 7.43 N 15.65

Gef .: 69.75 7.55 15.76

Example 23

5,11-dihydro-11 - [[3- [2- (1-piperidinyl) ethyl] -1-piperidinyl] carbonyl] -6 H-pyrido [2,3-b] [1,4] benzodiazepin-6- on-methanesulfonate Prepared analogously to Example 1 from 11- (chlorocarbonyl) -5,11-dihydro-6H-pyrido [2,3-b] [1,4] benzodiazepine-6-one and 3- [2- (1-piperdinyl ) ethyl] piperidine in a yield of 66% of theory. Colorless crystals of mp. / 31-234 ° C (ethanol).

C ₂₆ H ₃₆ N ₅ O ₅ S (529.65)

Calcd .: C, 58.96, H, 6.66, N, 13, 22, S, 6.05

Gef .: 58.84 6.69 13.07 6.26

Example 24

!! • [[SW-f-diethylaminol-butyl-i-piperidinyl-carbonyl-SH-dihydro-eH-pyridota.S-bKi] benzodiazepine-e-on-hydrochloride Prepared analogously to Example 1 from 11- (chlorocarbonyl) -5,11-dihydro-6H -pyrido [2,3-b] [1,4] benzodiazepine-6-one and 3- | 4- (diethylamino) butyllpiperidine in a yield of 90% of theory. Colorless crystals of mp. 182-184 ⁰ C (ethanol).

C ₂₆ H ₃₆ CIN ₆ O ₂ (486.06)

Calc .: C 64.25 H 7.46 Cl 7.29 N 14.41

Gef .: 63,80 7,62 7,35 13,49

Example 25

Prepared analogously to Example 1 from 9-chloro-11- (chlorocarbonyl) -5,11-dihydro-6H-pyrido (2,3-b) [1,4] benzodiazepin-6-one and 3- [2- (1 Pyrrolidinyl) ethyl] piperidine in a yield of 42% of theory. Colorless crystals, mp 136-139 ⁰ C, R ₁ 0.25 (Merck TLC plates, silica gel 60 F _254; eluent: dichloromethane / methanol / concentrated ammonia 90/10/1, v / v / v.)..

C ₂₄ H ₂₈ CIN ₅ O ₂ (453.97)

Calc .: C 63.50 H 6.22 Cl 7.81 N 15.43

F .: 63.41 6.43 7.70 15.52

Example 26

5,11-Dlhydro-11 - [(3- [2- (methylethylmethylamino) othyl] -1-plperldinyl] carbonyl] -6H-pyrldo [2,3-b] [1,4] benzodlazepin-6-onhydrochloric!

Prepared analogously to Example 1 from 11- (chlorocarbonyl) -5,11-dihydro-6H-pyrido [2,3-b] [1,4] benzodiazepine-6-one and 3- (2- (methylethylmethylamino) ethyl] piperidine in a yield of 38% of theory Colorless crystals of mp 196-198 ⁰ C (Z.), R ₁ 0.21 (Merck DC precast plates, silica gel 60 F ₂₅₄ , eluent: dichloromethane / methanol / concentrated ammonia 90 / 10/1, v / v / v).

C ₂₅ H ₃₄ CIN ₅ O ₂ (472.03)

Calcd .: C, 63.61, H, 7.26, Cl, 7.51, N, 14.84

F .: 63.55 7.37 7.61 14.61

Example 27

Prepared analogously to Example 4 from 11- (chlorocarbonyl) -5,11-dihydro-6H-pyrido [2,3-b] | 1,4-benzodiazepine-6-one and 4- [2- (diethylamino) ethyl] piperidine in a yield of 34% of theory. Colorless crystals of mp. 154 ⁰ C (ethyl acetate).

Example 28

Prepared analogously to Example 1 from 11- (chlorocarbonyl) -5,11-dihydro-6H-pyrido [2,3-b] [1,4] benzodiazepine-6-one and 3- [2- (1-PyrrolidinyDethyljpiperidin in a yield of 58% of theory Colorless crystals of R, 0.25 (Merck DC precast plates, silica gel 60F ₂₅₄ , eluent: dichloromethane / methanol / concentrated ammonia 90/10/1, v / v / v).

C ₂₄ H ₃₀ CIN ₅ O ₂ (455.99)

Calc .: C 63.22 H 6.63 Cl 7.78 N 15.36

Gef .: 63.10 6.76 7.63 15.21

Example 29

H-il - ^ - nCyclopentyDmethylaminoJethyll-i-piperidinyllcarbonyll B.II-dihydro-eH-pyrido ^ .a ^'m lbenzodiazepin-e-one hydrochloride

Prepared analogously to Example 1 from ii-chlorophenyl D-O, H-dihydro-eH-pyrido ^, S-bHi ^ benzodiazepine e-one and 3- [2 - [(cyclopentyl) methylamino] ethyl] piperidine in a yield of 54% the theory. Colorless crystals of mp 244-246T (ethanol), Ri 0.31 (Merck DC precast plates, silica gel 60F ₂₅₄ , eluant: dichloromethane / methanol / concentrated ammonia 90/10/1,

C ₂₆ H ₃₄ CIN ₅ O ₂ (484.04)

Calc .: C 64.52 H 7.08 Cl 7.32 N 14.47

F .: 64.33 7.11 7.53 14.39

Example 30

B.II-Dihydro-tia-H - ^ - lhexahydro-IH-i-i-azepinyDethyll piperidinylJcarbonylJ-eH-pyrido ^ .S ^ BLTi lbenzodiazepin-e-one hydrochloride

Prepared analogously to Example 1 from H-chlorocarbonyU-SJI-dihydro-eH-pyridoss.S-bHMlbenzodiazepine e-on and 3- [2- (hexahydro-1H-1-azepinyl) ethyl] piperidine in a yield of 78% of theory , Colorless crystals, mp 255-257 ⁰ C (ethanol / water / acetone 45/5/50, v / v / v), R, 0.27 (Merck TLC plates, silica gel 60 F _254; eluent:. Dichloromethane / methanol / concentrated ammonia 90/10/1, v / v / v).

C ₂₆ H ₃₄ CIN ₅ O ₂ (484.04)

Calc .: C 64.52 H 7.08 Cl 7.32 N 14.47

Gef .: 64,39 7,17 7,50 14,29

Example 31

B.II-dihydro-ii-lta-1-methylmethylethylaminoethyl-i-piperidinyl-carbonyl-eH-pyrido ^, -S-bKi-1-benzodiazepine e-on hydrochloride

Prepared analogously to Example 1 from 11- (chlorocarbonyl) -5,11-dihydro-6H-pyrido [2,3-bl (1,4) benzodiazepine-6-one and 3- (2- (methylethylethylamino) ethyl) piperidine in one Yield of 43% of theory. Colorless crystals, mp 228-230 ° C, R, 0.39 (Merck DC Finished Plates, Silica Gel 60F ₂₅₄ , eluant: dichloromethane / methanol / concentrated ammonia 90/10/1, v / v / v).

C ₂₆ H ₃₄ CIN ₅ O ₂ (472.03)

Calcd .: C, 63.61, H, 7.26, Cl, 7.51, N, 14.84

F .: 63.27 7.40 7.81 14.80

Example 32

6,11-dihydro-11 - bonzodiazopin-5-one [[3- [3- (1-pvrrolidinyl) propyl] -1-piperidinyl] carbonyl] -5H-pyrido [2,3-b] [1,5] Prepared analogously to Example 4 from 11- (chlorocarbonyl) -6,11-dihydro-5H-pyrido [2,3-bis [1,5] benzodiazepin-5-one and 3- [3- (1-pyrrolidinyl) propyl) piperidine in a yield of 56% of theory. Colorless crystals, front: mp 174-176 ° C (acetonitrile), R ₍ 0.65 (Macherey-Nagel, Polygram), SIL G / UV ₂₅₄ , pre-coated plastic sheets for TLC, eluent: dichloromethane / cyclohexane / methanol / conc Ammonia 68/15/15/2, v / v / v)

C ₂₅ H ₃ IN ₅ O ₂ (433.55)

Ber .: C '69,26 H 7,2-1 N 16,15

Gef .: 69.20 7.19 16.45

Example 33

6,11-dihydro-11 - [[3- [2- (hexahydro-1H-1-azepinyl) ethyl] -1-piperidinyl] carbonyl] -5H-pyrido [2,3-b] [1,5] benzodiazepine -5-one Prepared analogously to Example 4 from H-chloro-carbonyl-e.ii-dihydro-δ-H-pyrido ^. S-bKI.S-benzodiazepine-S-one and 3- (2- (hexahydro-1H-1-azepinyl) -ethyl] in a yield of 58% of theory, colorless crystals of mp 152-154'C (acetonitrile), R ₍ 0.64 (Macherey-Nagel, Polygram '''SIL G / UV ₂₅₄ , pre-coatod plastic sheets for TLC, eluent: dichloromethane / cyclohexane / methanol / concentrated ammonia 68/15/15/2, v / v / v)

C ₂₆ H ₃₃ N ₅ O ₂ (447.58)

Calc .: C 69.77 H 7.43 N 15.65

F .: 69.74, 7.51, 15.64

Example 34

6,11-dihydro-11 - [[4- [4- (1-pyrrolidinyl) butyl] -1-piperidinyl] carbonyl] -5H-pyrido [2,3-b] [1,5] benzodiazepin-5- on Prepared analogously to Example 4 from 11- (chlorocarbonyl) -6,11-dihydro-5H-pyrido [2,3-bl (1,5-benzodiazepin-5-one and 4- [4- (1-PyrrolidinyDbutylJpiperidin in a yield of 72 % of theory Colorless crystals of mp 193-195 ° C (ethanol).

C ₂₆ H ₃₃ N ₅ C ₂ (447.58)

Calc .: C 69.77 H 7.43 N 15.65

G .: 69.97 7.45 15.78

Example 35

4 - [[3 '[3- (diethylamino) propyl] -1-piporidinyl] carbonyl] -4,9-dihydro-3-methyl-10H-thieno [3,4-b] [1,5] benzodiazepin-10 Prepared analogously to Example 4 from 4- (chlorocarbonyl) -4,9-dihydro-3-methyl-10H-thieno [3,4-b] [1,5] benzodiazepine-10-oii and 3- [3- ( Diethylamino) propyl) piperidine in a yield of 34% of theory. Colorless crystals of mp. 136.0-137.5 ⁰ C (diisopropyl ether).

Example 36

4 _< 9-dihydro-4 - [[3- [3- (dimethylamino) propyl] -1-piperidinyl] carbonyl] -3-methyl-10H-thieno [3,4-b] [1,5] benzodiazepine 10-on Prepared analogously to Example 4, 4- (chlorocarbonyl) -4,9-dihydro-3-methyl-10H-thieno [3,4-b] [1,5] benzodiazepine-10-one and 3- [3- (dimethylamino ) propyl] piperidine in a yield of 35% of theory. Colorless crystals of mp. 137-139 ⁰ C (acetonitrile).

C ₂₃ H ₃₀ N ₄ O ₂ S (426.58)

Calc .: C 64.76 H 7.09 N 13.13 S 7.52

Gef .: 64.77 7.25 13.07 7.75

Example 37

e ^ i-Dihydro-H-IlS-d-piperidinylpropyl-i-piperidinyl-carbonyl-SH-pyrido ^ S-blti.Bluezodiazepine-S-one In a mixture consisting of 22.5 ml of a 20% solution of phosgene in Toluene, 100 ml of acetonitrile and 4.75 g (0.045 mol) of anhydrous sodium carbonate were added dropwise, with external cooling with ice, 8.94 g (0.0425 mol) of 3- [3- (1-piperidinyl) propyl] piperidine. The mixture was stirred at room temperature for a further 60 minutes, then 9.0 g (0.0428 mol) of 6,11-dihydro-5H-pyrido [2,3-bl (1,5] benzodiazepin-5-one in the reaction mixture and boiled The mixture was then refluxed for 4 hours, and the precipitate was thoroughly washed with three times 10 ml of hot acetonitrile and the combined filtrates were concentrated in vacuo to a total volume of 50 ml, allowed to cool and held with a glass rod 2 with occasional stirring Hours at 0 to 5 ⁰ C, filtered off the resulting crystal slurry, recrystallized again from acetonitrile and gave colorless crystals of mp. 166-167 ⁰ C, after Mischschmelzpunkt, IR and 'H-NMR spectrum identical to one of Example 21 prepared preparation

 Yield: 6.2 g (33% of theory)

 Accordingly, one received:

SJI-dihydro-ii-KS-IS-d-piperidinylipropyl-i-piperidinyl-carbonyl-eH-pyrido ^ .S-bKi) -benzodiazepine-e-one of m.p. 123.5-125.5'C (acetonitrile);

11 - [[3- [3- (Diethylamcino) propyl] -1-piperidinyl) carbonyl] 5,11-dihydro-6H-pyrido [2,3-b] [1,4] benzodiazepin-6-one, which was prepared according to the conversion into monohydrochloride at 257.5-259.0 ° C (ethanol) melted;

11 - [[3- (2-t (cyclopentyl) methylamino] ethyl] -1-piperidinyl) carbonyl] -6,11-dihydro-5H-pyrido [2,3-b) | 1,5] benzodiazepin-5 of the m.p. 149-15O ⁰ C (acetonitrile);

5,11-dihydro-11 - [[3- [2- (1-piperidinyl) ethyl | -1-piperidinyl) carbonyl) -6H-pyrido [2,3-b] [1,4] benzodiazepin-6- on, which melted after conversion to methanesulfonate at 233-234 ° C (ethanol).

Example 38

Prepared analogously to Example 4 from 11- (chlorocarbonyl) -5,11-dihydro-6H-pyrido [2,3-b] (1,4] benzodiazepine-6-one and 3- [2- (1-piperidinyl) ethyllpyrrolidine in a yield of 75% of theory Colorless crystals of mp 234-236X (methanol).

C ₂₄ H ₂₉ N ₅ O ₂ (419.53)

Calc .: C 68.71 H 6.97 N 16.69

Gef .: 68.38 7.05 16.70

Example 39

8,11-Dlhydro-11-t [3- (4-morpholinyl) propyl] -1-piperidinyl) carbonyl] -5 H -pyrido [2,3-b] [1,5] benzodiazepin-5-one Prepared by analogy Example 4 from 11- (Chlorocarbonyl) -6,11-dihydio-5H-pyrido [2,3-b] (1,5) benzodiazepin-5-one and 3- | 3- (4-morpholinylpropyl-piperidine in a? yield of 43% of theory. Färblose crystals of mp. 161-163 ⁰ C (acetonitrile).

C ₂₅ H ₃₁ N ₅ O ₃ (449.55)

Calc .: C 66.79 H 6.95 N 15.58

Gef .: 66.21 6.99 15.63

The monohydrochloride melted at 221-223 ⁰ C.

Example 40

6,11-dihydro-11 - [[3- [2- (1-piperidlnyl) ethyl] -1-pip3ridinyl] carbonyl] -5H-pyrido [2,3-b] [1,5] benzodiazepin-5- on Prepared analogously to Example 4 from II-IChlorcarbonyD-e.ii-dihydro-SH-pyridoss.S-blli.S) benzodiazepin-5-one and 3- [2- (1-piperidinyl) ethyl] piperidine in a yield of 50 % of theory. Colorless crystals of mp. 168-16P ⁰ C (acetonitrile).

C ₂₅ H ₃₁ N ₅ O ₂ (433.55)

Calc .: C 69.26 H 7,21 N 16,15

F .: 69.22 7,20 16,04

Example 41

Prepared analogously to Example 4 from 11- (chlorocarbonyl) -6,11-dihydro-5H-pyrido [2,3b] [1,5] benzodiazepin-5-one and 3- [2- (diethylaminol) ethyl] piperidine in a yield of 54 % of theory. Colorless crystals of mp. 110-113 ⁰ C (acetonitrile).

C ₂₄ H ₃₁ N ₅ O ₂ (421.54)

Calc .: C 68.38 H 7.41 N 16.61

G .: 69.00 7.73 16.56

Example 42

H-tP-iS-Idiethylaminolpropyl-i-piperidinylcarbonyl-eH-dihydro-SH-pyrido ^ .S-blti.Slbenzodiazepine-S-one Prepared analogously to Example 4 from 11- (chlorocarbonyl) -6,11-dihydro-5H-pyrido [2,3-b] [1,5-benzodiazepin-5-one and 3- [3- (diethylaminol) propyl] piperidine in a yield of 38% of theory. Colorless crystals of mp. 123-125 ⁰ C (acetonitrile).

C ₂₅ H ₃₃ N ₅ O ₂ (435.57)

Calc .: C 68.94 H 7.64 N 16.08

Gef .: 68.80 7.64 15.79

Example 43

11 - [[4- (4- (Diethylamino) butyl] -1-piperidinyl] carbonyl] -5,11-dihydro-6H-pyrido [2,3-b] [1,4] benzodiazepin-6-one Prepared by analogy Example 4 from H-chloro-carbonyl-O-H-dihydro-eH-pyrido ^. S-n-kiylbenzodiazepine-e-one and 4- [4- (diethylamino) -butyl-piperidine in a yield of 62% of theory. Colorless crystals of mp. 126-127 ° C.

C ₂₆ H ₃₅ N ₅ O ₂ (449.59)

Calc .: C 69.46 H 7.85 N 15.58

Gef .: 69.18 7.86 15.70

Example 44

9-chloro-11 - [[4- [4- (diethylamino) butyl] -1-piperidinyl] carbonyl] -5,11-dihydro-6H-pyrido [2,3-b] [1,4] benzodiazepin-6 Prepared analogously to Example 4 from 9-chloro-11- (chlorocarbonyl) -5,11-dihydrc-6H-pyrido [2,3-b] [1,4-benzodiazepin-6-one and 4- (4- (diethylamino) buty !! piperidine in a yield of 38% of theory. Colorless crystals, mp. 126-127 ⁰ C.

C ₂₆ H ₃₄ CIN ₅ O ₂ (484.04)

Bar .: C 64.52 H 7.08 N 14.47 Cl 7.32

Gef .: 64.12 7.23 14.53 7.37

Example 45

Prepared analogously to Example 4 from 4- (chlorocarbonyl) -4,9-dihydro-3-methyl-10H-thieno [3,4-b] [1,5] benzodiazepin-10-one and 4- [4- (1- Piperidinyl) butyllpiperidine in a yield of 31% of theory. Colorless crystals of mp. 209-210 ⁰ C (ethyl acetate).

Example 46

11 - [-2- [2- | [3- (diethylamino) propyl] methylamino] ethyl] -1-piperidinyllcarbonyll5,11-clihydro-6H-pyrido | 2,3-bl (1,4) -benzodiazepine-6- on

Prepared analogously to Example 4 from 11- (chlorocarbonyl) -5,11-dihydro-6H-pyrido-2,3-b] (1,4) benzodiazepine-10-one and 2- (2 - ((3- (diethylamino) propyl] m-3thylamino] ethyl) piperidine (bp. _olmlT, n _g 130-134 ⁰ C) in a yield of 80% of theory. Colorless crystals, mp. 123-125 ⁰ C (acetonitrile).

C ₂₈ H ₄₀ N ₆ O ₂ (492.66)

Calc .: C 68.26 H 8,18 N 17,06 Found: 68,08 8,30 17,34

Example 47

11 - [! [2- [2- [2- (Dlethylamino) ethcxy] 9thyl] -1-p poridinyl] corbonyl] -5,11-dihydro ^ H-pv, ido [2,3-b] [1 , 41benzodia2epin-B-one Prepared analogously to example 4 from 1-liter (chlorocarbonyl) -5,11-dihydro-6H-pyrido ^{[2,3! j>} l (1,4] benzodiazepin-6-one and 2- (2- [2- (Diethylamino) ethoxylethyl] piperidine (bp ₀ , _4r , niHa 95-99 ° C) in a yield of 79% of theory.

134-136T (acetonitrile).

C ₂₆ H ₃₅ N ₅ O ₃ (465.59)

Calc .: C 67.07 H 7.58 N 15.04

Found: - 67.14 7.64 15.16

Example 48

4 - [[2- [2 - [[2- (Dlethylamino) ethyl] methylam no] ethyl] -1-piperidinyl] carbonyl!] -4,9-dihydro-3-methyl-10H-thleno- [3,4- -b] [1,5] benzodiazepine-10-one Prepared analogously to Example 4, but using dichloromethane instead of acetonitrile as solvent, from 4- (chlorocarbonyl) -4, S dihydro-3-methyl-10H-thierio- 3,4-bl (1,5] benzodiazpin-10-one and 2- (2 - [[2- (diethylamino) ethylmethylamino] ethyl] piperidine (bp _{o 3mmHg} 92-95 "C) in 22 % yield Theory: Colorless Ki is all of Fp.

C ₂₇ H ₃₉ N ₅ O ₂ S (497.70) H 7.90 N 14.07 S 6.44 Re: C 65.16 7.70 14.00 6, C3 Gef .: 65,00

Example 49

4 - [[2 · [2- [2- (diethylamino) ethoxy] θthylJ · 1-piperidinylcarbonyl · Ⓒ dihydro-3-methylthio · 10H → hiβno [3,4 · b] [1,5'-benzodiazepine

Prepared analogously to Example 4 from 4- (0-η-θ-θ3-οηνΙ) -3-ηηβΐΙινΙ-10Η-η6ηο [3,4-ω] [1,5-β-βα-α-β-βρίη-10-one and 2- [Z- [2- (diethylamino) -ethoxy] ethyl] piperidine in a yield of 53% of theory. Colorless crystals of mp. 105-107 ° C (diisopropyl ether).

C ₂₆ H ₃₆ N ₄ O ₃ S (484.66)

Calc .: C 64.43 H 7.49 N 11.56 S 6.62

Gef .: 64.00 7.44 11.70 6.6i

Example 50

11 - [[2- [2 - [[3- (diethylamino) propyl] methylamino] ethyl] -1-piperidinyl] ca, boron, vl] -6,11-dihydro-5H-pyrido [2,3-b] [1,5] · benzodiazepine B-on dihydrochloride hydrate Prepared analogously to Example 4 from II-chlorocarbonyl-eH-dihydro-SH-pyridoU.'S-bHI.Salbenzadiazepine-Son and 2- (2 - [3] (Diethylamino) propyl] methyl! Amino] ethyl] piperidine in 46% yield of theory The colorless HCl hydrochloride melted at 145-15O ⁰ C (Z.).

C ₂₈ H ₄₀ N ₆ O ₂ χ 2HCl χ H ₂ O (583.60;

Calc .: C 57.63 H 7, oo Cl 12.15 N 14.40

Gef .: 57.64 7.80 -2 05 14.49

Example 51

11 - [(3- [2- (Diethylamino) ethyl] -1-pyrrolidinyl] carbonyl] -5,11-dihydro-6H -pyrido [2,3-b] [1,4] benzodiazepin-6-one Prepared by analogy Example 4 from 11- (chlorocarbonyl) -5,11-dihydro-6H-pyrido [2,3-b] [1,4-benzodiazepin-6-one and 3- [2- (diethylamino) ethyl] pyrrolidine in a yield of 13 % of theory Colorless crystals of mp 137-138 ° C, from ethyl acetate / methanol 98/2 v / v.).

C ₂₃ H ₂₉ N ₆ O ₂ (407.51)

Calc .: C 67.79 H 7,17 N 17,19

Gef .: 67.19 7.05 17.15

Example 52

5,11-Oihydro-11-t [4- [3- (4-methyl-1-piperazii ^{</ l} i-propyl] -1-piperidinyl] carbonyl] -6H-pyrido [2,3-bJ [1,4 ] benzodiazepine-6-pn Prepared analogously to Example 4 from H-chlorocarbonyl-SJI-dihydro-δ-H-pyridol Z.S-bHi ^ benzodiazepine e-one and 4- [3- (4-methyl-1-piperazinyl) propyl] piperidine in one Yield of 17% of theory Colorless crystals of melting point 213-214 ° C, R ₁ 0.25 (Merck, DC precast plates, silica gel 60 F ₂₅₄ , eluent: ethyl silicate / methanoi / cyclohexane / concentrated ammonia 80 / 10/10/1 v / v / v / v).

Example 53

4 - [[4- [2- [2- (diethylamino) ethoxy] ethylj-1-piperidinyl] carbonyl] -4,9-dihydro-3-me {hyl-10H-ih eno [3,4-b]! [1,5] benzodiazepine-10

Prepared analogously to Example 4 from 4- (chlorocarbonyl) -4,9-dihydro-3-methyl-10H-thieno [3,4-b] [1,5] benzodiazepin-10-one and 4- [2- [ 2- (Diethvlamino) ethoxy] ethyl] piperidine (Sdp.o.oogmmHg 101-102 ° C) in a yield of 71% of theory. Colorless crystals of mp. 125-126 ⁰ C (diisopropyl ether).

C ₂₆ H ₃₆ N ₄ O ₃ S (484.66)

Calc .: C 64.43 H 7.49 N 11.56 S 6.62

Gef .: 6Ί..50 7,27 11,80 f, 52

Example 54

11 - [[4- [2- [2- (diethylamino: io | uthoxy] ethyl] -1-piparidinyl] carbonyl] -b, 11-dihydro-6H-pyrido [2,3-b] [1,4] bonzodiflEopin-6-one Prepared a.Aog Example 4 from 11- (chlorocarbonyl) -5,11-dihydro-6H-pyrido [2,3-b] [1,4] benzodiazepin-6-one and 4- [ 2- [2- (diethylamino) ethoxy] ethyl) piperidine in a yield of 71% of theory. Colorless crystals, mp 119-120 ° C (cyclohexane), R ₍ 0.43 (Macherey-Nagel, Polygram® SIL G / UV ₂₅₄₎ , pre-coated plastic sheets for TLC, eluant: ethyl acetate / methanol / concentrated ammonia 100 / 30/3, v / v / v).

Example 55 -

9-Clilor-11 - [[4- [2- [2- (diethylamino) ethoxy] ethyl] -1-piperidinyl] carbonyl] -5,11-dihydro-6H-pyrido [2,3-b] [1, 4] benzodiazepin-6-one

Prepared analogously to Example 4 except = 9-chloro-1-chlorocarbonyl-O,! 1-dihydro-6H-pyrido [2,3-bj [1,4] benzodiazepin-6-one and 4- (2- [2- (2H) Diethylamino) ethoxy] ethyl] piperidine in a yield of 43% of theory Colorless crystals of mp 145-146 ° C (acetonitrile), Rf 0.39 (conditions as in Example 54).

C ₂₆ H ₃₄ CINsO ₃ (500.04)

Calc .: C, 62.45, H, 6.85; Cl, 7.09; N, 14.01

F .: 62,16 6,97 7,30 14,12

Example 56

11-t [4- [2- [2-diethylamino) ethoxy] ethyl] -1-piperidinyl-1-carbonylJ-6,11-dihydro-5H-pyrido [2,3-b] [1,5] benzodiazepin-5-one analogously to Example 4 from 11- (chlorocarbonyl) -6,11-dihydro-5H-pyrido (2,3-b] [1,5] benzodiazepin-5-one and 4- [2- (2- (diethylamino) ethoxylethyl] piperidine a yield of 83% of theory The colorless hydrochloride melted at 148-150 ° C (ethyl acetate).

C ₂₆ H ₃₆ CIN ₆ O ₃ (502.05)

Calc .: C 62.20 H 7.23 Cl 7.06 N 13.95

Gef .: 61.96 7.37 7.20 13.77

Example 57

5,11-Dihydro-11 - [[2- [2- (1-piperidinyl) othyl] -4-m orpholinyl] carbonyl] -6H-pyrido [2,3-b] [1,4] bonzodiazopin-6 Prepared analogously to Example 4 from 11- (chlorocarbonyl) -5,11-dihydro-6H-pyrido [2,3-b] [1,4-benzodiazepin-6-one and 2- (2- (1-piperidinyl) Jmorpholin (R _f 0.4 [Macherey-Nagel, Polygram® SIL G / UV _2M , pre-coated plastic sheets for TLC;

Dichloromethane / methanol / cyclohexane / conc. Ammonia 68/15/15/2, v / v / v / v]) in a yield of 79% of theory. The colorless hydrochloride melted at 274-275 ° C.

C ₂₄ H ₃₀ CIN ₅ O ₃ (471.99)

Calc .: C, 61.07, H, 6.41, Cl, 7.51, N, 14.81

Gef .: 60.86 6.37 7.69 15.08

Example 58

, R-dihydro-11 6 - [[2-t2- (1-piperldinyl) ethyl] -4-morphollnyl] benzodiazepin-5-one -carbonyl] -5H-pyrido [2,3-b] [1,5] Prepared analogously to Example 4 from H-IChlorcarbonyO-ei 1-dihydro-5H-pyrido [2,3-b] (1,5] benzodiazepine-5-one and 2- [2- (1-piperidinyl) ethyl] morpholine in one yield of 78% of theory Colorless crystals, mp 136-138 ⁰ C (diisopropyl ether), H, 0.46 (Macherey-Nagel, POLYGRAM® SILGZUV _254, pre-coated plastic sheets for TLC; eluant:.. ethyl acetate / methanol / concentrated ammonia 100/30/3, v / v / v).

C ₂₄ H ₂₉ N ₅ O ₃ (435.52)

Calc .: C 66.19 H 6.71 N 16.08

Gef .: 66.01 6.64 16.10

Example 59

5,11-Dihydro-8 · methyl-11 - [[2 · [2- (1-piperidinyl) ethyll. 4-morpholinyl] carbonyl] -6H · pyrido [2,3b] [1,4] benzodiazepine · 6 Prepared analogously to Example 4 from 11- (chlorocarbonyl) -5,11-dihydro-8-methyl-6H-pyrido [2,3-bI (1,4] benzodiazepin-6-one and 2- [2- (1 Piperidinyl) ethyl] morpholine in a yield of 79% of theory R ₁ 0.43 (conditions as in Example 58) The colorless hydrochloride melted at 272-273 ° C with decomposition.

Cj ₅ H ₃₂ CIN ₅ O ₃ (486.01)

Calc .: C 61.78 H 6.64 Cl 7.29 N 14.41

Results: 61.49 6.65 7.43 14.50

Example 60

11 - [[2- [2- [2- (diethylamino) ethoxy] ethyl] -1-piperidinyl] carbonyl] -6,11-dihydro-5H-pyrido [2,3-b] [1,5] benzodiazepine 5-one Prepared analogously to Example 4 from 11- (chlorocarbonyl) -6,11-dihydro-5H-pyrido [2,3-bl-1,5-benzodiazepin-5-one and 2- [2- [2- (diethylamino) ethoxy] ethyl] piperidine in a yield of 86% of theory. The colorless hydrochloride melting at 186-187 ⁰ C.

C ₂₆ H ₃₆ CIN ₅ O ₃ (502.05)

Calc .: C 62.20 H 7.23 Cl 7.06 N 13.95

Gef .: 61.91 7.13 7.09 13.90

Example 61

4,9-Dihydro-3-methyl-4- [L2- [2- (1-piperidinyl) ethyl] -4-morpholinyl] carbonylM0H-thieno [3,4-b] [1,5] benzodiazepin-10-one Prepared analogously to Example 4 from 4- (chlorocarbonyl) -4,9-dihydro-3-methyl-10H-thieno [3,4-b] [1,5] benzodiazepine-10-one and 2- [2- (2- 1-piperidinyl) ethyl] morpholine in a yield of 74% of theory. R, 0.48 (conditions as in Example 58). The colorless hydrochloride melted at 254-256X (Z.).

C ₂₄ H ₃₁ CIN ₄ O ₃ S (491.05)

Calcd .: C 58.70 H 6.36 Cl 7.22 N 11.41 S6.53

Gef .: 58.51 6.38 7.31 11.56 6.71

The following examples illustrate the preparation of pharmaceutical formulations:

Example I

Tablets containing 5 mg 5,11-dihydro-11 - [[3- [3- (1-piperidinyl) propyl] -1-piperidinyl] carbonyl-6H-pyrido [2,3-bl [1,4] benzodiazepine-6 on

Composition: 5.0 mg 1 tablet contains: 148.0 mg active substance 65.0 mg lactose 2,0 m potato starch 220.0ng magnesium stearate

Production method:

Potato starch is made into a 10% mucus by heating. The active substance, milk sugar 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 Il

Drag6esmit5mg5,11 · Dihydro-11 · [[3 [3- (1-piperidinyl) propyll-1-piperidinyl] carbonyl] · 6H-pyrido [2,3 · b] [1,4] benzodiazθpin · 6 on Die nach Beispiel I prepared tablets are coated by a known method with a shell consisting essentially of sugar and talc. The finished Dragoes are polished using beeswax. Dragee weight: 300mg

Example III Ampoules containing 10 mg of 5,11-dihydro · 11 - [[3 · [3- (1-piperidinyl) propyl) -1-piperodinyl] carbonyl] · 6H · pyrido [2,3-b] [1,4] benzodiazepine 6 -

one methanesulfonate

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

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 poured into 1 ml. Sterilization: 20 minutes at 120 ^° C.

BaImage IV

Suppositories containing 20mg5 _> 11-dihydro-11 - [[3- [3- (1-piperidinyl) propyl] -1-piperidinyl] carbonyl] -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 ^s 1 680.0 mg

1 700.0 mg

Production method:

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

Suppository weight 1.7 g

Example V Drops with S.II-dihydro-H-tp-O-d-piperidinylpropylM-piperidinyl-1-carbonyl-E-pyrido ^ S -blti ^ benzodiazepine-e-one

methanesulfonate

Composition 100 ml dropping solution contain:

p-hydroxybenzoic acid methyl ester 0.035 g

p-hydroxybenzoic acid propyl ester 0.015 g

Anisole 0.05 g

Menthol 0.06 g

Ethanol pure 10.0 g

Active ingredient 0.5 g

Sodium cyclamate 1.0 g

Glycerol 15.0 g of water, ad 100.0 ml

Production method:

The active substance and sodium cyclamate are dissolved in about 70 ml of water and added to glycerol. Dissolve p-Hydroxybenzoesäuieester, 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 with no suspended particles.

Claims (2)

claims: X ¹ and X ² represent a = CH group or, if 1 (εμ the meanings of the above-mentioned, divalent radicals (S), (U) or (W), both or only X ¹ or only X ² also represent a nitrogen atom; A is a straight-chain or branched saturated alkylene radical having two to seven Carbon atoms: also by an oxygen or sulfur atom or by the Methylimino- or Ethylimino group may be interrupted; Z is a single bond, an oxygen or sulfur atom, the methylene or 1,2-ethylene group; R 'is a branched or unbranched alkyl radical having 1 to 4 carbon atoms or the benzyl; R ^{2 is} a branched or unbranched alkyl radical having 1 to 7 carbon atoms, which may optionally be substituted by a hydroxy group at its 2 to 7 carbon atom, a cycloalkyl or a cycloalkylmethyl radical having 3 to 7 carbon atoms in the ring, wherein the cycloalkyl ring is optionally may be substituted by a hydroxy group; But R ¹ and R ² can also be used together with the intervening nitrogen atom 4- to Form a 7-membered saturated, monocyclic, heterocyclic ring which may optionally be interrupted by an oxygen atom or by the N-CHa group; However, R ² can also be linked to A via an alkylene bridge in such a way that, together with the group NR ^1, a saturated, 5-, 6- or 7-membered heterocyclic ring system is formed; R ³ is an alkyl group having 1 to 4 C atoms, a chlorine atom or a hydrogen atom; R ^{4 is} a hydrogen atom or a methyl group; R ⁵ and R ⁶ each represent a hydrogen atom, a fluorine, chlorine or bromine atom or a Alkyl group having 1 to 4 C atoms; R ^{7 is} a hydrogen or chlorine atom or a methyl group; R ^{8 is} a Wasserstoffatrr.i or an alkyl radical having 1 to 4 carbon atoms; R ^{9 is} a hydrogen or halogen atom or an alkyl group having 1 to 4 carbon atoms and R ^{10 represents} a hydrogen atom or a methyl group, provided that when I [Bj represents the bivalent radical (T) and R ^{7 represents} a hydrogen atom, R ^{3 has} the abovementioned meanings except for a chlorine atom and Z has the abovementioned meanings, with the exception of Have sulfur atom and of their optically active isomers and physiologically acceptable salts with inorganic or organic acids, characterized in that a) for the preparation of basic substituted, condensed diazepinones of the general formula Ia (La) in the R ¹ , R ² , R ³ , R ⁴ , X ¹ , X ² , A and Z have the meanings given above and J (β ί bivalent radicals (S), (U), (V), (W) or ( T ') CH. one of the where R ^{7 is} a chlorine atom or a methyl group, carbonic acid derivatives of the general formula II, (II) in the R ³ , R ' ¹ , JQ ^ y, X ¹ , X ^{2 have} the meanings indicated and Y is a halogen atom, preferably the bromine or chlorine atom, or the radical OR ¹¹ , where R ^{11 is} an optionally halogen-substituted alkyl radical having 1 to 5 Carbon atoms, a phenyl radical optionally substituted by halogen atoms or nitro groups, or an aralkyl radical having 7 to 15 carbon atoms, with compounds of general formula III, / (III) ON- or the corresponding metal compounds of the general formula IIIa M
I / ("Ia) wherein in the general formulas III and purple M is an alkali metal atom or an equivalent of an alkaline earth metal atom, and R ^1, R ^2, A and Z are as defined above, at temperatures between -10 ⁰ C and + 100 ⁰ C, if appropriate in the presence of bases or an excess of a compound of general formula III and a solvent, or b) for the preparation of basic substituted, condensed diazepinones of general formula Ia (La) in which R ¹ , R ² , R ³ , R ⁴ , X ¹ , X ² , A and Z have the meanings given above, and one of the bivalent radicals (S), (U), (V), (W) or (T ') f ^H 3 where R ⁷ 'is a chlorine atom or a methyl group, -4- 282 226 a tricyclic compound of general formula IV, in which the radicals R ³ , R ⁴ , X ¹ , X ² and J \ ^ J are as defined above, r.it a chlorocarbonic acid derivative of the general formula V O. Cl a - ^r1 (V) wherein R ¹ , R ² , A and Z have the meanings mentioned above, is reacted at temperatures up to the boiling point of the reaction mixture, optionally in the presence of an organic solvent and / or a base, or
c) for the preparation of a pyrrolo-fused diazepinone of the general formula I b R ¹ , R ² , R ⁴ , X ¹ , X ² , A and Z have the meanings mentioned above, for Z except for a sulfur atom, R ⁷ 'have a hydrogen atom and R ^{3 is} an alkyl group having 1 to 4 carbon atoms or represent a hydrogen atom, a compound of general formula I b in which R ^{7 is} a chlorine atom, is hydrogenolyzed either with hydrogen in the presence of catalysts and solvents at temperatures between 0 and 130 ⁰ C with hydrogen pressures of 1 to 300 bar or with formic acid in Presence of solvents and palladium or palladium acetate as catalyst at temperatures between 40 and 110 ⁰ C, and optionally obtained compounds of general formula I in their acid addition salts with inorganic or organic acids, or acid addition salts obtained, are converted into the free bases and / or racemates obtained If desired, they are separated into their isomers by means of optically active acids. A method according to claim 1, characterized in that the reaction in the presence of at temperatures between 40 and 100 ⁰ C in the presence of alkali or alkaline earth metal hydroxides, alcoholates or carbonates or aprotic polar solvent is performed by tertiary amines. 3. The method according to claim 1, characterized in that the reaction in the presence of aromatic hydrocarbons, in ethers, in ketones, in chlorinated aliphatic hydrocarbons, in acetonitrile or dimethylformamide or in mixtures thereof Solvent and in the presence of tertiary amines at temperatures between 30 and 100 ⁰ C is performed. 4. The method according to claim 1, characterized in that the hydrogenolysis in the presence of metals of VIII. Subgroup of the Periodic Table of the Elements, optionally in the presence of hydrogen chloride acceptors or Hiire of formic acid in the presence of dimethylformamide and palladium on carbon or with the aid of Triethylammoniumformiat in the presence of excess triethylamine and palladium on animal charcoal or palladium acetate and triarylphosphines at temperatures between 40 and 110 ° C is sensed. 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-A 039519 and 0057428 and from US A 3,660,380; 3,691,159; 4,213,984; 4,213,985; 4,210,648; 4,410,527; 4,424,225; 4,424,222 and 4,424,226 are already known condensed diazepinones with ulcushemmenden and gastric juice secretion-inhibiting properties. In EP-A0156191 it is described that completely different, valuable pharmacological properties can be induced by introducing novel Aminoacrylreste over the compounds of the above-mentioned publications. Object of the invention The aim of the invention is the provision of novel condensed diazepinones with valuable pharmacological properties. Explanation of the essence of the invention The invention has for its object to find new condensed diazepinones with the desired properties and processes for their preparation. The new condensed diazepinones have the general formula I,