DD299307A5 - CONDENSED DIAZEPINE, METHOD FOR THE PRODUCTION THEREOF, AND MEDICAMENT CONTAINING THESE COMPOUNDS - Google Patents

Abstract

Condensed diazepinones of the general formula * in which one of the bivalent radicals, X is a CH group or a nitrogen atom, R is a lower alkyl radical which may optionally be substituted by an optionally halogen, methyl or methoxy-bearing phenyl, R4 and R5 is hydrogen , Halogen or lower alkyl, R6 is hydrogen, chlorine or methyl, R7 and R8 are lower alkyl, R8 is additionally halogen and m, n, o and p represent the numbers 0, 1, 2 or 3 with the following restrictions: the sum from mn and the sum from op means respectively the numbers 1, 2 or 3, the sum of no and the sum of mp respectively the numbers 1, 2, 3, 4 or 5, whereby however the sum of mnop always be greater than 2 and A1, A2, A3, A4 are hydrogen or, in the case where m, n, o and p each represent the number 1, A1 and A2 together or A3 and A4 together represent an ethylene bridge, are suitable for the therapy of cholinergic Spasms and motilit In the gastrointestinal tract, in the area of the leading bile duct, for the symptomatic treatment of cystitis and spasms in Urelithiasis, for the treatment of relative incontinence, for the symptomatic treatment of bronchial asthma and bronchitis as well as for the treatment of ischemic heart disease. The compounds are characterized by a good selectivity. Formula (I)

Description

in the

X, R, m, n, o, p, A ¹ , A ² , A ³ and A ^{4 have} the meanings mentioned above, compounds of

general formula Ia, in which J (b 'J is the bivalent radical (T') CH.

6 '

in which R ^{6 represents} a chlorine atom, are subjected to a hydrogenolysis, and, if appropriate, subsequently, compounds of general formula I thus obtained are separated into their isomers and / or converted into their salts with inorganic or organic acids.

7. The method according to claim 6c, characterized in that the hydrogenolysis is carried out in the presence of catalysts of metals of VIII. Subgroup of the Periodic Table, at hydrogen pressures of 1 to 300 bar and temperatures of ^{0 0} C to 13O ⁰ C in the presence of solvents.

8. The method according to claim 6c, characterized in that the hydrogenolysis

a) with formic acid and a palladium-on-carbon catalyst at temperatures between 70 and 11O ⁰ C in the presence of a solvent or

b) with triethylammonium formate in the presence of excess triethylamine and of palladium on animal charcoal or

c) with palladium acetate and triarylphosphines at temperatures between 40 and 110 ⁰ C.

The invention relates to novel condensed diazepinones, processes for their preparation and compounds containing them Drug. From EP-A-0 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 condensed diazepinones with uicushemmenden and gastric juice secretion inhibiting

Properties known. _y EP-A-0156191 (U.S. Patent 4,550,107) describes for condensed diazepinones that by introducing novel Aminoacylreste compared to the compounds of the above publications completely different, valuable

pharmacological properties can be induced. Compared with the above-mentioned anti-microbial and anti-bradycardic condensed diazepinones mentioned above, the compounds of the present application

despite close structural kinship - surprisingly another effect quality differing from the above effects. The compounds according to the invention are suitable for the therapy of cholinergic spasms and dysmotility in the gastrointestinal tract and in the area of the laxative bile ducts, for the symptomatic treatment of cystitis and spasms in the case of urtithiasis by lowering the pathologically increased tone of the hollow organs, for the therapy of relative incontinence. which is based on a disproportion of sphincter and detrusor tonus, for the symptomatic treatment of bronchial asthma and bronchitis by suppressing the muscarinic mediated portion of bronchoconstriction, as well as for the treatment of ischemic heart disease by Herzfrequenzsenkuh (j with simultaneous suppression of parasympathetic coronary spasm and lowering of the basal Coronartohus The condensed diazepinones of the invention show the

 given effects with high selectivity and are especially in the therapeutically relevant dose range free of tachycardic side effects

 The new condensed diazepinones have the general formula I.

[A ¹ -CH) _m (CH-A ² J _n

(A-CH) (CH-A ^J )

in the

one of the divalent radicals

(S)

(V)

represents and

X, R, R ⁴ , R ⁶ , R ", R ⁷ , R ⁸ , m, η, ο, ρ and A ¹ , A ² , A ³ and A ^{4 have} the following meanings: X is a = CH group or a nitrogen atom, R is a straight-chain or branched alkyl radical having 1 to 4 carbon atoms, which may also be replaced by chlorine, Bromine, fluorine, methyl or methoxy mono- or disubstituted phenyl may be substituted, R ⁴ and R ⁵ , which may be the same or different, represent a hydrogen, fluorine, chlorine or bromine atom or

an alkyl group having 1 to 4 carbon atoms,

R ⁶ is a hydrogen or chlorine atom or a methyl group, R ⁷ and R ⁸ , which may be the same or different, represent hydrogen atoms or alkyl groups of 1 to

4 carbon atoms, but R ⁸ may additionally also denote a halogen atom,

m, η, ο and ρ are each the numbers 0,1,2 or 3 with the following restrictions:

the sum of m + η and the sum of ο + ρ means respectively the numbers 1,2 or 3,

the sum of η + ο and the sum of m + ρ are each the numbers 1,2,3,4 or 5,

However, where the sum of m + η + ο + ρ must always be greater than 2,

A ¹ , A ² , A ³ , A ^{4 are} hydrogen atoms; in the event that m, η, ο and ρ each represent the number 1, either A 'and A ² together or A ³ and A ⁴ together also represent an ethylene bridge. To illustrate the remainder of the general formula

(A ^ CH) (CH-A ² ) mn

(A ⁴ -CH) (CH-A ³

rι r

R may be mentioned the following structures:

-.rs.N-R

-N

NO

LJL-N-R

-N

NO

-N

NO

N-

NO

NO

-N

NO

NO

"-Ν

-N

NO

NO

NO

NO

NO

wherein in the individual ring systems, the bond to the carbonyl group on the tricycle of the one nitrogen atom can also be exchanged for the radical R of the other nitrogen atom, which, if they meet the criteria mentioned later, can exist as cis or trans isomers

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

X is a nitrogen atom and X is the = CH group and

the radical (S) or the radical (V) mean.

R is the methyl group, and

R ⁴ and R ⁵ , which may be the same or different, each represents a hydrogen, fluorine or chlorine atom representing methyl or ethyl group, and

m = 0, n = 2, O = O, p = 2 or m, η, ο and ρ are each equal to 1.

The compounds of general formula I can also be in the form of their physiologically acceptable salts after reaction with inorganic or organic acids. As 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-toluene sulphonic acid, methanesulphonic acid or amidosulphuric acid have proved to be suitable. To illustrate the subject invention, the following compounds may be mentioned as examples: 5,11-Dihydra-11 - [[7-methyl-3,7-diazabicyclo [3,3,0] oct-3-yl] carbonyl] -6H-pyrido [2,3-b] [1,4] benzodiazepin-6-one 9-chloro-5,11-dihydro-11 - [(7-methyl-3,7-diazabicyclo [3,3,0,1-oct-3 -yl) carbonyl] -6H-pyrido [2,3-b] [1,4] ben2-adiazepin-6-one 6,11-dihydro-11-I [7-methyl-3,7-diazabicyclo (3.3.0] oct-3-yl] carbonyl) -5H-pyrido [2,3-b] | 1,5) ben2odiazepin-5-one L-5,11-dihydro-11 - [[6-methyl-2,6- diazabicyclo [3,3,0Joct-2-ylcarbonyl-6H-pyridol2,3-b] [1,4-benzodiazepin-6-one L-5,11-dihydro-8-methyl-11 - [(6-methyl-2, 6-diazabicyclo- (3,3 ₍ 0) oct-2-ylcarbonyl-6H-pyrido [2,3-b] [1,4] benzodiazepin-6-one L-6,11-dihydro-11 - ([6 -methyl-2,6-diazabicyclo [3,3,0-octyl-2-yl] carbonyl] -5 H -pyrido [2,3-b] [1,5] benzodiazepin-5-one D-5,11-dihydroxy 11 - [(6-methyl-2,6-diazabicyclo [3,3,0-oct-2-yl) carbonyl] -6 H -pyrido (2,3-b] [1,4] benzodiazepin-6-one D-5 , 11-dihydro-8-ethyl-11 - ([6-methyl-2,6-diazabicyclo- [3.3.0 | oct-2-yl] carbonyl] -6H-pyrido (2,3-b] [ 1,4] benzodiaze pin-6-one D-6 _/ 11-dihydro-11 - [[6-methyl-2,6-diazabicyclo [3,3,0] oct-2-yl] carbonyl] -5H-pyrido [2,3- b) [1,5] benzodiazepin-5-one L-5,11-dihydro-11 - [(6-isopropyl-2,6-diazabicyclo [3,3,0] octa-2-yl] carbonyl] - 6H-pyrido [2,3-bj [1,4] benzodiazepin-6-one L-5,11-dihydro-11 - [[6-isobutyl-2,6-diazabicyclo [3,3,0] octane 2-yl) carbonyl] -6H-pyrido [2,3-b] | 1,4] benzodiazepin-6-one cis-5,11-dihydro-11 - [[8-methyl-2,8-diazabicyclo [4 _/ 4.0] -dec-2-ylcarbonyl] -6H-pyrido [2,3-b] [1,4] benzodlazepine-6-one trans-5,11-dihydro-11 - [[8-methyl-2 , 8-diazabicyclo [4,4,0J-dec-2-yl] carbonyl-6H-pyrido [2,3-bl [1,4-benzodiazepin-6-one 5,11-dihydro-11 - [[10-methyl] 4,10-diazatricyclo [5,2,1,1,0 * ^e j-dec-4-yl] carbonyll-6H-pyrido [2,3-bl [1,4) benzodiazepin-6-one 5.11 - dihydro-11 - [[10-methyl-4,10-diazatricyclo (5,2,1,0 ^'e j-dec-4-yl] carbonylj-6H-dibenzo [2,3-b) [1,4) diazepin-6-one

6,11-dihydro-11- | [2-methyl · 2,7-diazabicyclo [3.3 _/ oίoct-7-yl) · carbonyl] -5H-pyridol2,3 · b] _[1/5) bθnzodiazepin-5 -one

5,11-dihydro-11-j (7-methyl-2,7 'diazabicyclo [3,3,0] oct-2-yl] -carbonylj-6H-pyrido [2,3-b] [1,4] benzodiazepin-6-one

6,11-Dihydro-11 - [r ^ -methyl ^ J-diazabicyclo d.doioct ^ -yl] -carbonyl] -5H-pyrido [2,3-b] (1,5] -benzodiazepin-5-one

6,11-dihydro-11- [i3-methyl-3,6-diazabicycloi3,2,0] hept-e-YLJ-carbonyl] -5H-pyrido (2,3-b] [1,5] benzodiazepin-5 -one

5,11-dihydro-11 - [[3-methyl-3, e-diazabicyclo [3,2,0] hept-6-yl] carbonyl] -6H-pyrido [2,3-b] ii, 4Jbenzodiazepin- 6-one

5,11-Dihydro-11-I [6-methyl-3 _/ 6-diazabicyclo [3,2,0-hept-3-yl-carbonyl] -6 H -pyrido [2,3-b] [1,4] benzodiazepine 6-one

_{6/11-dihydro-11} - [[6-methyl-3,6-diazabicyclo [3,2,0 | hept-3-YLJ-carbonylj-5H-pyrido [2,3-b] [1,5] benzodiazepine -5-on5,11-dihydro-11 - [[3-methyl-3,8-diazabicyclo [4,2,0] oct-8-yl) carbonyl) -6H-pyrido [2,3-b] ( 1,4) benzodiazepin-6-ONTRANS-5,11-dihydro-11 - [[7-methyl-2,7-diazabicyclo [4,4,0] dec-2-yl] carbonyl] -6H-pyrido [ 2,3-b] [1,4] benzodiazepine-6-ontrans-6 _> 11-dihydro-11 - [[7-methyl-2,7-diazabicyclo [4,4,0] dec-2-yl-1-carbonyl ] -5H-pyrido [2,3-b) [1,5 | _{benzodiazepin-5-on5>} 11-dihydro-11 - [[8-methyl-3,8-diazabicyclo (4.2 _<0joct-3-yl ) -carbonylj-6H-pyrido [2,3-b] [1,4] benzodiazepin-6-one 5,11 -dihydro-11 - [[3-methyl-3,7-diazabicyclo [4,2,0, oct -7-yl] -carbonyll-6H-pyrido-2,3-b (] 1.4 | benzodiazepin-6-one

5,11 ^: dihydro-11-i (7-methyl-3,7-diazabicyclo [4,2, oxyct-3-yl-carbonyl-6 H -pyrido [2,3-bl [1,4-benzodiazepin-6-one 5, 11-dihydro-11 - [[3-methyl-3,8-diazabicyclo |! 4.3.0] non-8-yl] - carbonyl] -6H-pyrido [2,3-b] [1,4] benzodiazepine-6-on5,11-dihydro-11 - [[8-methyl-3,8-diazabicycloxy4,3,0] non-3-ylcarbonyl] -6H-pyrido [2,3-bl [1,4 ] benzodiazepine-6-one

4,9-dihydro-3-methyl-4 - [[7-methyl-3,7-diazabicyclo [3,3,0joct-3-yl] carbonyll-10H-thieno [3,4-bJ [1,5lbenzodiazepin- 10-one

3-chloro-1-methyl-4 - ([7-methyl-3,7-diazabicyclo [3,3,0] oct-3-yljcarbonylj-1,4,9,10-tetrahydropyrrolo [3,2-b] [1,5] benzodiazepine-1C-on

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

following procedures:

a) Basic substituted condensed diazepinones of the general formula Ia

H Q

(A-CH) (CH-A ")

(La)

(A ⁴ -CH) (CH-A ³ ) \ P y o

Ir

in the X, R, R ⁴ , R ⁶ , R ^e , R ⁷ , R ⁸ , m, n, o, p. A ¹ , A ² , A ³ , A ^{4 have} the meanings given above and

Radicals (S), (U), (V) or (T ') CH.

[B ¹ J one of the two-valued

'3

6 ¹

where R ⁶ 'is a chlorine atom or a methyl group,

is obtained by reacting carbonic acid derivatives of the general formula II

H O

I II

N -Cs

B ¹

(II)

Indians J (B M and X have the meanings given and

V represents a halogen atom, preferably the bromine or chlorine atom, or the radical OR ¹¹ , 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 araikyl radical containing 7 to 15 carbon atoms , with compounds of general formula III,

(A ^ CH) (CH-A ² ) mn

(A-CH) (CH-A ^J )

I R

in the

R, m, η, ο, ρ, A ¹ , A ² , A ³ , A ^{4 are} as defined above. The reaction is carried out without or preferably in the presence of solvents, such as. As of water, toluene or alcohols,

such as As methanol, ethanol or isopropanol, but most preferably in the presence of aprotic polar solvent, for. B. from

Tetrahydrofuran, 1,4-dioxane, acetonitrile, Ν, Ν-dimethylformamide, dimethyl sulfoxide, hexamethylphosphoric triamide, or

of mixtures thereof and at temperatures between -1O ⁰ C and the boiling point of the reaction mixture, preferably carried out between 40 and 100 ⁰ C. Has proven the use of additional inorganic or organic bases, eg. B.

of alkali or alkaline earth hydroxides, alcoholates or carbonates, such as sodium hydroxide, sodium methoxide, potassium tert-butoxide, sodium carbonate, potassium carbonate; of tertiary amines, eg of triethylamine, ethyldiisopropylamine, N ₁ N-

Dimethylaniline, pyridine or of 4- (dimethylamino) pyridine; and the reaction in the presence of an excess of a Compound of the general formula III. Using the bicyclic diamines of the more general. Formula III and the carbonic acid derivatives of the general formula II in

Equimolar proportions, we get - if Y is a halogen atom - directly the halogenic acid acids

Salts of the desired compounds of general formula I a. However, the reaction can also be carried out with a metal compound of the general formula IIIa,

(purple)

(A ^ CH) (CH-A ² ) m

(A.-CH) (CH-A-

in the

M represents an alkali metal atom or 1 equivalent of an alkaline earth metal atom. You can do that Metal compounds of general formula III a from III by reaction with alkali or alkaline earth metals, such as sodium, Potassium or barium, or with alkali or alkaline earth metal hydrides, such as sodium, potassium or calcium hydride, or by Reaction with alkali or fcrdalkaliorganylen, 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 tricyclene general formula IV

(IV)

in which X and Ί (β Λ are as defined above, with a Chlorkohlensä jrederivat of the general formula V

(V)

(A ⁴ -CH) (CH-A ³ )

wherein R, m, η, ο, ρ, A ¹ , A ² , A ³ , A ^{4 have} the meanings mentioned above.

The reaction is preferably carried out in inert orgar Ischen solvents, for example in aromatic hydrocarbons such as toluene, xylene, ethers such as diisopropyl ether in 1 etrahydrofuran or dioxane, ketones such as in 3-pentanone, in chlorinated aliphatic carbon arms " 's, such as 1,2- Dichloroethane or in other 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 reaction mixture, preferably at temperatures between 4-30 and + 100 ⁰ C, carried out, c ) The novel pyrrolo-condensed diazepinones of the general formula I b, which are covered by the general formula I,

(A ^ CH) (CH-A ² ) m

(Ib)

(A-CH) (CH-A "

IT

X, R, m, n, o, p, A ¹ , A ² , A ³ and A ^{4 have} the meanings mentioned above, can also be prepared by hydrogenolysis from those compounds of general formula Ia, in which R ⁶ 'is a chlorine atom means. The hydrogenolysis is carried out in the presence of catalysts of metals from the VIII. Subgroup of the Periodic Table of the Elements, for example of palladium on animal charcoal, palladium on barium sulfate, Raney nickel or Raney cobalt, and at hydrogen pressures of 1 to 300bar and temperatures of O ⁹ C. to 13O ⁰ C in the presence of solvents, for example alcohols, such as methanol, ethanol; Ethern such as dioxaii, tetrahydrofuran, carboxylic acids, such as acetic acid or tertiary amines, such as triethylamine performed. If you work in the absence of additional hydrogen chloride acceptors, such as sodium carbonate, potassium bicarbonate, triethylamine or sodium acetate, the result directly hydrochlorides of the compounds sought, which can be isolated after removal of the catalyst by evaporation of the reaction solution. If, 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, in particular the reaction with formic acid in the presence of dimethylformamide as solvent and of palladium on carbon as catalyst at temperatures between 70 and 110 ⁰ C, and the reduction with triethylammonium in the presence of excess triethylamine and of palladium on animal charcoal or of palladium acetate and Triarylphosphinen, such as triphenylphosphine, tris (o-tolyl) phosphine, tris (2,5-diisopropylphenyl) phosphine, at temperatures between 40 and 11O 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. If in the aminocarbonylated condensed oiazepinones according to the invention of the general formula I m, η, ο or ρ in each case have the value 1, these compounds are achiral, but in all other cases the compounds are chiral. These chiral compounds may therefore each occur as enantiomeric (+) and (-) forms. The invention includes the individual isomers as well as their racemates.

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

According to a conventional isomer separation method, the racemic compound of the general formula I is reacted with one of the above-mentioned optically active acids in an equimolar amount in a solvent, and the obtained crystalline diastereomeric salts are separated by utilizing their various solubilities. This reaction can be carried out in any kind of solvent as long as it has a sufficient difference in the solubility of the salts. Preferably, methanol, ethanol or mixtures thereof, for example in

oil ratio 50:50, 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 above-described syntheses with only one enantiomer of the general formula III or V. .

The preparation of the required as intermediates carbonic acid derivatives of the general formula II is described in detail in DE-37 26908-AI.

Intermediate compounds of the general formula III, some of which are new and not yet described above, are obtainable, for example, by the following methods:

a) The 2-substituted 2,6-diazabicyclo [3.3.0] octanes falling under the general formula III are obtained in accordance with the instructions of Cope, A.C., and Shen, T.Y., in J. Am. Chem. Soc. 1956,78,5916.

The 2-benzyl-2,6-diazabicyclo (3.3.0) octane described in this reference is then reacted with ethyl chloroformate to give the corresponding urethane, which is then reduced with lithium aluminum hydride to give 2-benzyl-e-methyl-1-diazabicyclo- cept.SO-octane The hydrogenolytic removal of the benzyl radical gives the desired 2-methyl-2,6-diazabicyclo [3.3.0] octane.

b) The 3-substituted 3,7-diazabicyclo [3.3.0] octanes falling under the general formula III can be prepared, for example, starting from pyrrole-3,4-dicarboxylic acid in complete analogy to the statements of Loftus, P., and Wong, JJ, in J. Heterocyclic. Chem. 1983, 20, 321.

Alternatively, starting from N-alkylated glycine derivatives, paraformaldehyde and maleimide and subsequent reduction of the bicyclic imide formed in this [3 + 2] cycloaddition with lithium aluminum hydride, the desired 3-substituted 3,7-diazabicyclo [3.3.0] octanes can be prepared.

c) The 2-substituted 2,7-diaza-bicyclo [3.3.0] octanes falling under the general formula III are obtainable according to the statements of Birkhofer L., and Feldmann H. in Annalen 1964, 677, 154.

d) The 10-methyl-4,10-di9zatricyclo [5.2.1.O '-' 1-decane covered by the general formula III is known, for example, from the literature (Bansal, RC, et al., Can. J. Chem , 47, 2391-4) N-ethoxycarbonyl-7-azabicyclo [2.2.1] hepta-2,5-diene-2,3-dicarboxylic acid dimethyl ester is obtainable. Alkaline saponification of both methyl ester groups followed by palladium-catalyzed hydrogenation gives N-ethoxycarbonyl-7-azabicyclo [2.2.1] heptane-2,3-dicarboxylic acid in very good yield. The dicarboxylic acid is cyclized with the aid of dicyclohexylcarbodiimide to the anhydride and this is then heated under reflux with excess benzylamine. The thus obtained in good yield 4-benzyl-10-ethoxycarbonyl-4,10-diazatricyclo [5.2.1.0 ^M ] decane-3,5-dione is reduced with lithium aluminum hydride and the benzyl protecting group finally cleaved by catalytically excited hydrogen.

e) The 8-substituted 2,8-diazabicyclo [4.4.0] decanes falling under the general formula III can be obtained, for example, starting from N-substituted 4-piperidones. This by reaction with z. B. pyrrolidine obtained enamine is first added to acrylonitrile and cyclized the addition product in sulfuric acid to 8-substituted A ^{1> e} -2,8-diazabicyclo [4.4.0] decene-3-ones. Hydrogenation of the double bond with catalytically excited hydrogen preferably gives cis-linked hydrogenation with triethylsilane, but preferably trans-linked ring systems. Reduction of the thus-obtained 8-substituted-2,8-diazabicyclo [4.4.0] decan-3-ones to the desired 8-substituted 2,8-diazabicyclo [4.4.0] decanes can be achieved smoothly with lithium aluminum hydride.

f) The trans ^ -methyl ^ -diazabicycloHAOldecan falling under the general formula IiI can be prepared, for example, starting from 1,5-naphthyridine. Reaction with sodium in amyl alcohol gives the trans-2,7-diazabicyclo [4.4.0] decane, which is converted with methyl chloroformate to monourethane (Arch, Immunol Ther. Exp. 1971, 19, 261). Treatment with lithium aluminum hydride gives the desired trans ^ -methyl-diazabicyclo ^ aldecane. Alternatively, the trans-2,7-diazabicyclo (4.4.0) decane can be reacted with formaldehyde and hydrogen with the addition of a catalyst directly into the trans-7-methyl-2,7-diazabicyclo [4.4.0] decane.

Another object of the invention are pharmaceutical compositions containing one or more basic substituted diazepinones of 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. When administered orally, the daily dose is generally between 0.01 and 10 mg / kg, preferably 0.02 and 5 mg / kg, in particular 0.05 and 2.5 mg / kg of body weight, optionally in the form of several, preferably 1 to 3 single doses administered to achieve the desired results.

The basic substituted condensed diazepinones of general formula I and their acid addition salts have valuable properties; As already mentioned at the outset, they show selective spasmolytic properties on peripheral organs, in particular the ileum and the bladder, and in view of the lack of a heart rate increase in the therapeutic dose range,

Gastric acid secretion inhibiting, salivationshemmender and the capacity of the eye impairing effects in human and veterinary medicine suitable for the treatment of cholinergic spasms and motility disorders in the gastrointestinal tract and in the area of the bile ducts, for the symptomatic treatment of cystitis and spasms in Urelithiasis by lowering the Pathologically increased tone of the hollow organs, for the treatment of relative incontinence, which is based on a disproportion of sphincter and detrusor Tonue, for the symptomatic treatment of bronchial asthma and bronchitis by suppression of muscarinic determined proportion of bronchoconstriction, as well as for the treatment of ischemic heart disease by lowering heart rate and at the same time suppression of parasympathetic coronary spasm and reduction of the coronal coronary tone.

A favorable relationship between spasmolytic effects on the one hand and the adverse effects on heart rate, pupil width, tear, salivary and gastric acid secretion occurring in Therapeutica 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. Investigation of the functional selectivity of the anticancer activity

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

In vitro Organ Preparations

Dissociation constants (Kg values) were determined "in vitro" on the lumbar and spontaneously beating guinea pig atria, and the ileum was removed and incubated in the organ bath in Krebs-Henselelt solution, so contractions were caused by increasing concentrations of methacholine (M) M was then washed out, the substance to be tested added and left in contact for 30 minutes, and again a concentration-response 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, 48, 1959).

In the 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 muscarinic receptors of the atria were obtained in the same manner as described above. The comparison of the dissociation constants determined in both tissues allowed the identification of selectively spasmolytic substances. The results are included in Table III.

"In 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" studies were reported

1. selectivity of guinea pig bronchospasmolytic activity,

2. Salivary secretion-inhibiting effect on the rat and

3. investigated in-south spasmolytic activity in guinea pigs.

1. Effect on M receptors of the bronchi, the heart and the bladder of anesthetized guinea pigs Method:

Guinea pigs of both sexes (550-600g body weight) were anaesthetized with urethane (1.4g / kg, i.p.). A cannula was inserted into the jugular vein to inject the drugs. 2201. U./kg of heparin were injected intravenously. A cannula was inserted into the trachea; The animals were artificially ventilated with oxygen-enriched air by means of a positive pressure pump (Braun-Melsungen) at a rate of 80 beats per minute. A branch of the tracheostomy tube was connected to a water manometer of 10cm height. The ventilation volume was adjusted so that the maximum intratracheal pressure during ventilation reached just the pressure of a 10 cm water column.

Apart from some modifications, the effect of the active ingredients on the bronchial tone was measured according to the method described by Konzett and Rössler (1940). The volume of the respiratory gas mixture generated by bronchoconstriction, which flowed through the water manometer, was measured by means of a tube pneumotachometer (FLEISCH, Model 1000) connected to an SP 2040D Differential Pressure Transducer (HSE). The values were registered with an IFD recorder. Prior to the experiment, the trachea was clamped for a short time to produce the maximum possible level of bronchoconstriction for calibration. A cannula was inserted into the left major carotid artery; Arterial blood pressure was measured using a pressure transducer (Bell and Howell, 4-3271) in conjunction with an IFD recorder. Heart rate was measured using a frequency meter triggered by arterial pulse waves.

A small median abdominal incision was made and the bladder was attached to a force transducer under a 1 gram rest tension.

The active substances to be tested were injected via the jugular vein, 5 minutes later bladder tension increase (in grams), bronchial resistance (%) and heart rate decrease (beats per minute) after administration of acetylcholine (50 μg / kg iv and ia) measured. Dose-dependent curves were plotted by plotting the percentage inhibition of bronchoconstriction, bradycardia and bladder tension increase versus the logarithm of the dose (mol / kg) of the drugs to be tested. The results are given as mean values (n = 4-6). For results see Table I.

2. Splechselsekretlonshemmende effect in the rat

According to Lavy and Mulder (Arch. Int Pharmacodyn., 178, 437-445, (1969)), male THOM rats anesthetized with 1.2 g / kg urethane received increasing doses of the substance iv. Salivary secretion was detected by sc administration of 2 mg / kg pilocarpine The saliva was aspirated with blotting paper, the area occupied by it was determined planimetrically every 5 minutes, and the dose of substance reducing the salivary volume by 50% was determined graphically, see Table II for results.

3. In-slut spasmolytic effect in guinea pigs

Male guinea pigs (500 to 600g body weight) were anaeathet with urethane (1.2g / kg, i.p.); cannulas were inserted into the trachea, jugular vein and left carotid artery. The animals were artificially ventilated with oxygen-enriched air by means of a positive pressure pump at a beat rate of 80 per minute. A 3 to 4cm long abdominal incision was made and about 15cm of a movable loop of the ileum was ligated distally to maintain blood circulation. The proximal part was filled with a Krebs-Ringer solution and a pressure gauge with a Millar microtip catheter (PC-450.6F) was inserted into the intestine. A glass tube was placed vertically in the abdomen and attached to the surrounding abdominal wall such that upon filling the glass tube with Krebs-Ringer's solution, the animal served as its own organ bath.

The glass tube was filled with Krebs-Ringer solution so far that the entire lower abdomen was immersed. The drugs to be tested were injected via the jugular vein; 5 minutes later, contractions were produced by methacholine (20pg / kg i.a.). By recording the percentage suppression of the methacholine-induced contractions versus the logarithm of the dose amount (mol / kg) of the active substance to be tested, dose-response curves were obtained. The results were given as mean values in = 4 to 8) (see Table II). For example, according to the above, the following compounds were investigated:

A = L-5,11-dihydro-11 - [(6-methyl-2,6-diazabicyclo [3.3.0] oct-2-yl) carbonyl] -6H-pyrido [2,3-b] [1 , 4] benzodiazepin-6-one B - D -6,11-dihydro-11 - [[6-methyl-2,6-diazabicyclo [3.3.0] oct-2-ylcarbonyl] -5H-pyrido [2, 3-b] [1,5] benzodia-7-quin-5-one C = 5,11-dihydro-11 - [[7-methyl-3,7-diazabicyclo [3.3.0] oct-3-yl] carbonyl ] -6H-pyrido [2,3-b] [1,4] benzodiazepin-6-one D - 4,9-dihydro-3-methyl-4 - (! 7-methyl-3,7-diazabicyclo- [3.3 .0] oct-3-yl] carbonyl] -10H-thieno [3,4-bl (1,5] benzodiazepine-10-one and as comparative substances

χ = n.l ^ -H-diethylamino-methyll-i-piperidinyl-acetyl-S-II-dihydro-eH-pyridol ^ S-bJH ^ benzodiazepine-e-one (see US Pat. No. 4,550,107)

Y = 5,11-dihydro-11 - ((4-methyl-1-pioerazinyl) acetyl] -6H-pyrido [2,3-b] (1,4] benzodiazepin-6-one (pirenzepine, see US Pat No. 3660380) and Z = atropine.

Table I Selectivity of guinea pig bronchospasmolytic activity: Acetylcholln-Antagonlsmus

Sub bronchia bladder heart relationship punching • log ED ₆₀ -log EDgo -log EDm influencing (mol χ kg " ¹ ) (mol χ kg " ¹ ) (mol χ kg " ¹ ) of bradycardia iv iv i.v. to broncho- constriction

A 7.31 6.31 5.98 21 B 7.35 6.09 5.71 44 C 6.20 5.52 5.32 8th, D 7.05 5.80 6.13 8th X 5.58 4.93 5.84 0.5 Y 6.57 5.84 5.90 5 Z 8.09 7.28 7.57 3

Table II Selectivity of in-vivo spasmolytic activity in relation to saliva-secretory activity

Sub In situ Spasmolysis Speichelsekre relationship punching Guinea pig- tion inhibition Speichelsekre ileum rat tion inhibition -log EDso • log ED ₆₀ zurspasmolyti- (mol χ kg " ¹ ) (mol x kg " ¹ ) activity i.v. iv

6.93 6.15

6.08 7.28

6,70 5,53

6,42 7,60

0.5 0.5

Table III Dissociation constants (K _B values) on the ileum and spontaneously beating guinea pig atria

Substance heart Kelmol / Il lleum Selectivity Kb heart to K _B ileum A 2,09-10- ' 3.02 · 10- " 6.9 B 1.45 -10 " ⁷ 6,03-10- " 2.4 X 1,05-10- ' 6.17 to 10 '' 0.17 Y 1.23 to 10 '' 1.94 to 10 '' 0.63 Z 1,41-10- ' 8,13-10- '° 1.7

Discussion of the results: The substances of the general formula I inhibit the effects of exogenously supplied acetylcholine in low dosages

or methacholine on the smooth muscles of the bronchi, bladder or small intestine, without the agonistic effect on the

Heart rate (Table I and III). For example, substances A and B show a very pronounced Smooth muscle selectivity; 21- and 44-fold lower doses are necessary to those triggered by acetylcholine Bronchoconstriction compared with acetylcholine-induced bradycardia (Table I). The substances of

General formula I not only show selectivity for smooth muscle compared to effects produced by cardiac

Muscarinic receptors are triggered, but higher dosages are required to induce pilocarpine To inhibit salivary secretion (Table II). The observed in vivo selectivity of the smooth muscle substances is consistent with in vitro studies. The substances have a higher affinity for muscarinic receptors of the ileum compared to cardiac muscarinic receptors

(Table IC).

The data show that the substances of general formula I the effects of muscarinic agonists on the smooth Musculature, z. As bronchi, bladder and ileum inhibit, in dosages that have no effect on the heart rate or the Have saliva secretion. The comparison substances Y (pirenzepine) and Z (atropine) show no selectivity and influence the

above-mentioned effects in the same dose range. Comparative substance X shows a higher cardial activity

Muscarinic receptors. All substances of general formula I are characterized by a pronounced hydrolysis stability. It will

possible to prepare storage-stable solutions for parenteral administration.

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

"Mp" means "melting point", "Z." means "decomposition". For all compounds are satisfactory elemental analyzes,

IR, UV, ¹ H NMR, often also mass spectra. Percentages are always, unless otherwise stated Weight. example 1

5,11-dihydro-1V [[7-methyl-3,7-dlazablcyclo [3.3.0] oct-3-yl] carbonyl] -6H-pyrldo [2,3-b] [1,4] benzodlazepin -6-on

The mixture of 4,9 g (18 mmol) of 11- (chlorocarbonyl) -5,11-dihydro-6 H -pyrido [2,3-b] [1,4] benzodiazepine-6-one and 2,3 g of 3-methyl-

3,7-diazabicyclo (3.3.0) octane in 75 ml of dry dimethylformamide was stirred for 20 hours at room temperature

The reaction mixture was concentrated in vacuo, the residue partitioned between 1N hydrochloric acid and methylene chloride. The

organic phase was washed twice more with 1N hydrochloric acid and once with water. The combined aqueous phases were basified with potassium carbonate and extracted with methylene chloride (3 × 150 ml). The United

Methylene chloride phases were dried over magnesium sulfate, concentrated, and the crude material was acetonitrile

recrystallized. This gave 2.9 g (41% of theory) of colorless crystals of mp. 157-159 ⁰ C.

C ₂₀ H ₂₁ N ₅ O ₂ (363.43)

Calc .: C, 65.75, H, 5.68, N, N, 19.7

Example 2

9-chloro-5,11-dihydro-11 - [[7-methyl-3,7-diazabicyclo [3.3.0] oct-3-yl] carbonyl] -6H-pyrldo [2,3-b] [1 , 4] benzodiazepin-6-one Prepared analogously to Example 1, dechloro-H-chloro-chloro-D-SH-dihydro-eH-pyridozoate.S-bHM-benzodiazepine e-one undabicyclo [not] olOctane in a yield of 67% of theory. Colorless crystals of mp. 216-217 ° C (acetonitrile).

7.87)

Calcd .: C 60.38 H 5.07 N 17.50 Cl 8.91 Found: C 59.73 H 5.02 N 17.28 Cl 8.90

Example 3

6,11-dihydro-11 · [[7-methyl-3,7diazablcyclo [3.3.0] oct · 3 · yl] carbonyl] -5H-pyr [do [2,3-bJ _[1/5] benzodiazθpln-5 -one

Prepared analogously to Example 1 from 11- (chlorocarbonyl-8,11-dihydro-5H-pyrido [2,3-b] [1,5] benzodiazepin-5-one and 3-methyl-3,7-

diazabicyclo [3.3.0] octane in a yield of 7% of theory. Colorless crystals of mp 115-120 ° C (ethyl acetate /

Diisopropyl ether).

Prepared as in Example 1 from 4- (chlorocarbonyl) -4,9-dihydro-3-methyl-10H-thieno [3,4-bl [1, S) benzodiazepine-10-one and 3-methyl-3,7-diazabicyclo3. 3.0) octane In a yield of 13% of theory. Colorless crystals of mp. 220-222T (ethanol).

Example 5

3 · chlorine · 1 · · mθthyl 4 - [[7 · methyl · 3.7 · dlazablcyclo [3.3.0] oct-3 · yl] carbonyll-1.4.9.10 · tθtrahydropyrrolo [3,2 · b] [1,5 ] bβnzodiazβρln-

Prepared analogously to Example 1 from S-chloro-1-chlorocarbonyl-1-methyl-1-hydroxy-1-methyl-1-α-tetrahydropyrrolol (S) -blH.S] ·

benzodiazepine-10-one and 3-methyl-3,7-diazabicyclo [3.3.0] octane in a yield of 24% of theory. Colorless crystals of

Mp> 280 ^e C (ethanol / water).

Example β

a) L · 2-Bβnzyl · 6 · ethoxycarbonyl · 2.6 · dlazablcyclo [3.3.0] octane

To the mixture of 5.7 g (28.2 mmol) L -benzyl-1-diazabicycloS.O.octoctane, 3.1 g (31, OmMoI) triethylamine in 0.5 L of ether was added ethyl chloroformate (3.7 g. 33.8 mmol) was added dropwise and stirred overnight. The resulting solid material was filtered off and the filtrate was concentrated. The crude product (6.0 g, 81% of theory) was used without further purification in the following step

Rf = 0.7 (Merck, TLC plates, Kieselgel 60 F] C ₄ , eluent: dichloromethane / methanol / concentrated ammonia 90/10/1, v / v / v).

b) L-6-methyl-2,6-diazacyclo [3.3.0] octane

The mixture of 6.0 g (22.8 mmol) of L-2-benzyl-6-ethoxycarbonyl-2,6-diazabicyclo [3.3.0] octane and 0.87 g (22.8 mmol) of aluminum hydride in 200 ml of ether became 5 Heated under reflux for hours. With ice cooling, 5 ml of 30% aqueous sodium hydroxide solution were then added dropwise and decanted from the white precipitate. The ethereal ether solution was dried and concentrated, leaving the residual oily L-benzyl-e-methyl-1-diazazaclicyclic S.S.Octane (4.8 g, 97% of theory) by TLC (R f = 0.35 (Merck. TLC plates, Kieselgel 60 F ₂ M, eluent: dichloromethane / methanol / concentrated ammonia 90/10/1, v / v / v)] and was autoclaved with the addition of 0.5 g of palladium on carbon (10%). and hydrogenated in ethanol for 5 hours at 6O ⁰ C. the reaction mixture was concentrated under reduced pressure and the crude product (3.3 g) used for the further reactions.

c) L-5,11-Dlhydro-11 - [[6-methyl-2, e-dlazablcyclo [3.3.0-oct-2-yl] carbonyl] -eH-pyridine [2,3-b] [1,4] benzodlazepln-6-one

The mixture of 0.95 g (3.5 mmol) of 11- (chlorocarbonyl) -5,11-dihydro-6H-pyrido (2,3-b] (1,4) benzodiazepine-6-one and 0,40 g (3, Solctane was stirred in 50 ml of acetonitrile for 3 hours, then concentrated under reduced pressure, the residue was partitioned between water and ethyl acetate, in which previously 0.4 g (3.5 mmol) of maleic acid The aqueous phase was further extracted twice more with ethyl acetate and made alkaline by addition of 0.5 g of potassium carbonate The aqueous phase was exhaustively extracted with dichloromethane and the combined organic extracts were dried and concentrated by evaporation 63-200pm, eluent: dichloromethane / methanol / concentrated ammonia 1200/50/5, v / v / v) to give 0.44 g (38% of theory) of m.p. 220-222 ° C (acetonitrile). ,

Example 7

L-5,11-dihydro-8-methyl-11 - [[6-methyl-2 _I 6-diazablcyclo [3.3.0] oct-2-yl] carbonyl] -6H-pyrido [2,3-b] [1,4] benzodiazepine-6-one Prepared analogously to Example 6c from 2.0 g (7, OmMoI) 11- (chlorocarbonyl) -5,11-dihydro-8-methyl-6H-pyrido [2,3-b ] (1,4] benzodiazepin-6-one, 0.8 g (6.3 mmol) of L, 3-methyl-1-diazabicyclodyl, o-octane and 100 ml of acetonitrile in a yield of 25% colorless crystals of mp. 165 ⁰ C.

Example 8

L-6,11-dihydro-11 - [[6-methyl-2,6-diazablcyclo [3.3.0] oct-2-yl] carbonyl] -5H-pyrldo [2,3-b] [1,5] benzodiazepine-5-one Prepared analogously to Example 6c from 1.9g (7, OmMoI) IHChlorocarbonyD-eH-dihydro-SH-pyridozoate.S-bHi.Slbenzodiazepine-S-oi., 0.8g (6.3moles) L-methyl ^ e-diazabicyclo-ß.d.Oloctan and 100 ml of acetonitrile in a yield of 54% of theory. [a] g ° = + 314 °.

Example 9

D-5,11-Dlhydro-11 - [[6-methyl-2,6-diazablcyclo [3.3.0] oct-2-yllcarbonyl] -6H-pyrldo [2,3-b] [1,4] benzodiazepln- 6-on Prepared analogously to Example 6c from 0.95 g (3.5 mmol) of 11- (chlorocarbonyl) -5.11 • dihydro-6H-pyrido (2,3-b] [1,4] benzodiazepine-6-one, 0 , 40g (3.2 mmol) D ^ -Moethyl ^ e-diazabicyclo-ß.SOJoctan in 50ml acetonitrile .. Colorless crystals of mp 160-165 ⁰ C in a yield of 38% of theory.

Example 10 D-5,11 -dihydro-8-ethylm 1 • [[6-methyl-2,6-diazacyclo [3.3.0] oct-2-yl] carbonyl] -6H-pyrido [2,3-b ] [1,4] benzodiazepin-6-one Prepared analogously to Example 6c from 1.6 g (5.3 mmol) of 8-ethyl-11- (chlorocarbonyl) -5,11-dihydro-6H-pyrido [2,3-b] [1,4] benzodiazepine

6-one, 0.67 g (5.3 mmol) of D 1 -methyl-1-diazabicyclo-β-d-octoctane in 67% yield.

Colorless crystals of mp. 162-165 "C. Example 11

D-6 _/ 11-Dlhvdro-11 - [[6-methyl-2, e-dlazablcvclo [3.3.0] oct-2-vl] carbonyl] -5H-pyrldo [2,3-b] [1,5] benzodla2epln-5-one Prepared analogously to Example 6c from 0.95 g (3.5 mmol) of 11- (chlorocarbonyl) -6,11-dihydro-5H-pyrido [2,3-bl (1,5] benzodiazepin-5-one, 0.40 g (3.2 mmol) of D 1 -methyl-e-diazabicyclo-β-S-o-octane in a yield of 42%, colorless crystals of melting point 172-174 ° C., [ag ⁰ = + 284 °.

Example 12 L-5,11-Dlhydro-11 - [[e-isopropyl-2, e -dlazablcyclo [3.3.0] oct-2-yl] carbonyl-6H-pyrldo [2,3-b] [1,4 ] benzodlazepln-e-on

The mixture of 10.0 g (34 mmol) of L ^ .e-dibenzyl-e-dlazabicyclodyl, S.Oloctan, 10.0 g of acetone (172 mmol) and ethanol (1.0 liter).

(10%) was hydrogenated at 6O ⁰ C for 20 hours with addition of 1 g of palladium on carbon. The catalyst was filtered off and the reaction mixture was concentrated. The residue was purified by column chromatography (silica gel 60-200 μιη;

Dichloromethane / methanol / conc. Ammonia 100/10/1, v / v / v). 1.2 g (26% of theory) of L-2-isopropyl-2,6-

diazabicyclo [3.3.0] octane and 1.5 g (45% of theory) of 2,6-diazabicyclo (3.3.0) octane elucidated.

L ^ ^ -lsopropyl .e diazabicycloß.S.Oloctan. Rf = 0.2 (Merck, DC precast plates, silica gel 60 F ₂₆₄ , eluent: dichloromethane / methanol / concentrated ammonia 150/50/5, v / v / v). Prepared analogously to Example 6c from 2.1 g (7.8 mmol) of 11- (chlorocarbonyl) -5,11-dihydro-6H-pyrido [2,3-b] [1,4] benzodiazepine-6-one

and 1.2 g (7.8 mmol) of L-1-isopropyl-1-diazabicyclo-β-S-octoethane in 50 ml of dry dimethylformamide in a yield of 56% of theory.

Rf = 0.2 (Merck, DC precast plates, silica gel 60 F ₂₆₄ , eluant: dichloromethane / methanol / concentrated ammonia 140/10/1, v / v / v).

Calcd .: C, 67.50, H, 6.44; N, 17.89, Found: C, 67.66, H, 6.65, N, N, N, 17.36

Example 13

The mixture of 1.64 g (5, OmMoI) H -chloro-carbonyl-D-II-dihydro-eH-pyrido-1-yl-S-benzodipaze-e-one, 0.8 g (5.2 mmol) 8-methyl-2, 8-diazabicyclo (4.4.0) decane and 0.85 ml (6, OmMoI) triethylamine in 20 ml of tetrahydrofuran was stirred at room temperature for 3 hours The reaction mixture was concentrated in vacuo and the residue was partitioned between ethyl acetate and dilute aqueous potassium carbonate solution separated, dried and concentrated in vacuo The chromatographic purification was carried out on silica gel (30-60 .mu.m) with the solvent mixture ethyl acetate / methanol / concentrated ammonia 70/30/1, v / v / v. The two main fractions were concentrated, triturated with acetonitrile 'and the resulting precipitate filtered off. from the first eluted main fraction was obtained 100 mg (5% of theory) of crystals of mp. 230-233 ⁰ C, which was identified by spectroscopic methods as trans-compound. the following main fraction contained 200 mg ( 10% of theory) of k crystalline cis compound with mp 160-161 ⁰ C.

Example 14

5 _> 11-Dlhydro-11 - [[10-methyl-4,10-dlazatrylcyclo [5.2.1.0 ^M ] dec-4-yl] carbonyl] -6H-pyrldo [2,3-b] [1,4 ] bonzodlazepin-6-one The mixture of 1.44 g (S) SmMoDII-chlorocarbonyD-SH-dihydro-eH-pyrido-1-yl-benzyl-benzodiazepine-e-one, 0.8 g (5.25 mmol) 10-methyl-1-one 4,10-diazatricyclo [5.2.1.0 ^2e ldecane and 0.73 ml (5.2 SmMoI) triethylamine was stirred for 8 hours at room temperature in 80 ml acetonitrile The suspension was filtered off with suction from the solid and the filtrate obtained was concentrated by evaporation, the residue was recrystallized from ethyl acetate, The organic phase was separated and the aqueous phase was extracted twice more with methylene chloride, the combined organic phases were dried over sodium sulphate, filtered and concentrated in vacuo.The residue was finally passed through a silica gel column ( Silica gel 30-60pm, eluent: cyclohexane / ethyl acetate / methanol / concentrated ammonia 2/2/10/1, v / v / v / v) and then recrystallized again from ethyl acetate. This gave 0.53 g (26% of theory) of white crystals, mp. 218-220 ⁰ C.

C ₂₂ H ₂₃ N ₅ O ₂ (389.46)

Ben: C 67.85 H 5.95 N 17.98 Found: C 67.98 H 6.10 N 18.18

Example 15

5 _/ 10-D-hydro-5 - [[10-methyl-4,10-diazatrylcyclo [5.2.1.0 ² - '] - dec-4-yl] carbonyl] -11H-dibenzo [b, e] [1, 4.ldiazepln-11-one

Prepared analogously to Example 14 from 1.40 g (5.1 mmol) of 5- (chlorocarbonyl) -5,10-dihydro-11H-dibenzo [b, e) [1,4] diazepin-11-one, 0.78 g

(5.12 mmol) 1-O-methyl-4,10-diazatricyclo- [5.2.1.0 ^M Jdecan, 0.7 mL (5.1 mmol) triethylamine and 60 mL acetonitrile in a yield of 30% of theory. Colorless crystals of mp. 230-233 ⁰ C.

C ₂₂ H ₂₄ N ₄ O ₂ (388.47)

Calc .: C, 71.11, H, 6.23; N, 14.42, Found: C, 70.75, H, 6.34, N, 14.42

Example 16 Prepared analogously to Example 6caus4- (chlorocarbonyl) -4,9-dihydro-3-methyl-HMT-thieno | 3,4-b) [1,5) benzodiazepine-10-one and S.S.Octan in a yield of 37% of theory. Colorless crystals of mp. 9 & -100% (acetonitrile). Example 17 Prepared analogously to Example 6c from S-chloro-t-chlorocarbonyl-D-i-methyl-IAS / IO-tetrahydropyrrolois-bHi.bluezodiazepine-IO-

on and L ^ -Methyl ^ e-diazabicyclodie.SOloctan in a yield of 56% of theory. Colorless crystals of mp 20O-203 ° C.

Example 18

a) trans-2,7-dlazabicyclo [4.4.0] decane

1,5-naphthyridine (5.0 g, 38.4 mmol) was heated to reflux in 450 mL of amyl alcohol and sodium (21.3 g, 0.92 mol) was added portionwise to the reaction mixture over a period of 30 minutes. Subsequently, 84 ml of concentrated hydrochloric acid were added. The organic phase was separated, washed twice with water and the combined aqueous extracts extracted twice more with ether. The ether phases were'verworfen, the aqueous phase basified with sodium hydroxide solution under ice cooling and the desired product extracted by repeated extraction with dichloromethane. The combined dichloromethane phases were dried and concentrated under reduced pressure. Quantitative yield (5.8 g) of crystals of mp. 174-176 ⁰ C (ethyl acetate).

b) trans-2-methyl-2,7-diazablcyclo [4.4.0] decane

A mixture of trans-2,7-diazabicyclo [4.4.0ldecane (1.4g, 10mMoI), 37% aqueous formaldehyde solution (0.6ml, 8mmol) and 0.5g palladium on carbon (10%) was stirred at 60 ° for 10 hours ⁰ C hydrogenated under a pressure of 3 to 4bar. After addition of another 0.3 ml of 37% aqueous formaldehyde solution was further hydrogenated under the above conditions, the reaction mixture was then concentrated and digested with petroleum ether. The petroleum ether solution was concentrated under reduced pressure and the oily residue (1.2 g) without further purification used for the further reactions.

c) trans-5 _/ 11 · dihydro-11 · [[7 · mθthyl · 2,7 · dlazablcyclot4.4.0l · dθc · 2 · yl] carbonyl} · 8H · pyrido [2,3 · b] [1,4 ] bθnzodlazβpln · 6 · on The mixture of 0.84 g (3.1 mmol) H-HCl chlorocarbony D-SH-dihydro-eH-pyrido ^. S-bKi ^ benzodiazepine e-one and 0.43 g (2.8 mmol) trans ^ -MethyWJ-diazabicyclo ^ aldecane was stirred for 24 hours in 80 ml of acetonitrile and then concentrated under reduced pressure. The residue was partitioned between water and ethyl acetate, in which 0.3 g of maleic acid had previously been dissolved. The aqueous phase was again extracted with ethyl acetate, made alkaline by the addition of potassium carbonate and then extracted exhaustively with dichloromethane. The combined organic extracts were dried, concentrated by evaporation and purified by column chromatography (silica gel 63-200 μm, mobile phase: dichloromethane / methanol / concentrated ammonia 90/10/1, v / v / v). This gave 0.2 g of the title compound (18% of theory).

Example 19

trans-6,11-Dlhydro-11 - [[6-methyl-2,6-dlazablcyclo [4.4.0] dec-2-yl] carbonyll-5H-pyrldo [2,3-b] [1,5] benzodlazepln-5-one Prepared analogously to Example 18c from 0.84 g (3.1 mmol) of 11- (chlorocarbonyl) -6,11-dihydro-5H-pyrido [2,3-b] [1,5] benzodiazepine-5 on, 0.43 g (2.8 mmol) of trans-2-methyl-2,7-diazabicyclo [4.4.0] decane in 37% yield.

Example 20 L-5,11-Dihydro'-11- [t6-methyl-2,6-d! Azablcyclo [3.3.0] oct-2-yl] carbonyl] -6H-pyrldo [2,3-b] [1, 4] benzodlazepln-6-one In a mixture consisting of 11.2 ml of a 20% solution of phosgene in toluene, 50 ml acetonitrile and 2.4 g (0.023 mol)

Anhydrous sodium carbonate was added dropwise with ice cooling with ice 2.6 g (0.021 mol) of L ^ -methyl ^. -diazabicyclold.SOctanzugetropft. After 60 minutes, 4.5 g (0.021 mol) of 5,11-dihydro-6H-pyrido [2,3-b] [1,4] benzodiazepin-6-one was added and refluxed for 4 hours. The hot mixture was filtered, the precipitate washed three times with 10 mL each of hot acetonitrile, and the combined filtrates concentrated in vacuo to a total volume of 15 mL. The solution was cooled in an ice bath and the resulting crystal slurry was sucked off. Recrystallization from acetonitrile gave 2.1 g (27% of theory) of colorless

Crystals of mp. 220-222 ⁰ C, according to mixed melting point and spectroscopic data identical to that of Example 6c

prepared preparation.

Accordingly, one received:

5,11-dihydro-11 - [[7-methyl-3,7-diazabicycloI3.3.0] oct-3-yllcarbonyl) -6H-pyrido [2,3-bJ [1,4] benzodiazepin-6-onvom

Mp. 157-159 ⁰ C (acetonitrile)

5,11 -dihydro-11 - [[10-methyl-4,10-diazatricyclo [5.2.1.0 ^M ] -dec-4-yl] carbonyl] -6H-pyrido [2,3-b] [1,4] benzodiazepine-6-one from

Mp 218-22O ⁰ C (ethyl acetate). The following describes the preparation of pharmaceutical applications by means of a few examples: Example I Tablets containing 5 mg of D-6,11 -dlhydro-11 • [[6-methyl-2,6-dlazablcyclo [373.0] oct-2-yl] carbonyl] -5H> pyrido [2 _l 3-b] [1, 5] benzodiazepln-

Composition: 5.0 mg 1 tablet contains: 148.0 mg active substance 65.0 mg lactose 2.0 mg potato starch 220.0 mg Magnosiumstearat

Production method: Potato starch is used to produce a 10% slime by heating. The active substance, lactose and the rest Potato starch is mixed and granulated with the above mucus through a sieve of mesh size 1.5mm. The granules

is dried at 45 ⁰ C, rubbed again through the above sieve, mixed with magnesium stearate and compressed into tablets.

Tablet weight: 220mg

Stamp: 9mm

Example Il The tablets prepared according to Example I are coated by a known method with a shell which substantially

consists of sugar and talc. The finished dragoes are polished using beeswax.

Dragoe weight: 300 mg Example III Ampoules of 10 mg of D-6,11-dihydro-11 - [[6-methyl-2, e-dlazablcyclo [3.3.0] oct-2-yl] carbonyl] -5H-pyridot2,3-b]

[1,5] benzodiazepln-5-one

Composition:

1 ampoule contains:

Active substance 10.0 mg Sodium chloride 8.0 mg Dest. Water ad 1 ml Production method: The active substance and sodium chloride are dissolved in dist. Dissolved water and then filled to the given volume. The solution is sterile filtered and filled into 1 ml ampoules. Sterilization: 20 minutes at 12O ⁰ C. Example IV Suppositories with 20 mg of D-6,11-dihydro-11 - [[e-mothyl-2, e-dlazablcyclot3.3.0] oct-2-yl] carbonyl] -5-pyrido [2,3-b] [1, 5] -

bonzodiazopin-5-one

Composition: 1 suppository contains:

Active ingredient 20.0 mg Suppository mass (eg Witepsol W 45) 1 680.0 mg

1700.0 mg

Production method: The finely powdered active substance is suspended in the melted and cooled to 4O ⁰ C suppository mass. You pour

the mass at 37 ⁰ C in slightly pre-cooled suppository forms.

Suppository weight 1.7g Example V Drops of D-6,11-Dlhydro-11 - [[6-methyl-2,6-dlazablcyclo [3.3.0] oct-2-yl] carbonyl] -5 H -pyrido [2,3-b] [1 , 5] benzodlazepln-5-one

Composition: 0.035 g 100 ml drip solution contain: 0.015 g p-hydroxybenzoate 0.050 g p-hydroxybenzoate 0.060 g anisole 10,000 g menthol 0.500 g Pure ethanol 1,000 G active substance 15,000 g sodium ad 100,000 ml glycerin Dest. Water

Production method:

The active substance and sodium cyclamate are dissolved in about 70 ml of water and glycerol is added. Dissolve p-hydroxybenzoate, anisole and menthol in ethanol and add this solution while stirring the aqueous solution. Finally, it is made up to 100 ml with water and filtered with no suspended particles.

Claims (6)

Claims: in one of the divalent radicals CH. ¹ -XX-X) - (T! (U: (V) represents and X, R, R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , m, n, o, p, A ¹ , A ² , A ³ and A ^{4 have} the following meanings: X is a = CH group or a nitrogen atom, R is a straight-chain or branched alkyl radical having 1 to 4 carbon atoms, which may optionally be substituted by a phenyl mono- or disubstituted by chlorine, bromine, fluorine, methyl or methoxy, R ⁴ and R ⁵ , which may be the same or different, represent a hydrogen, fluorine, chlorine or bromine atom or an alkyl group having 1 to 4 carbon atoms, R ⁶ is a hydrogen or chlorine atom or a methyl group, R ⁷ and R ⁸ , which may be the same or different, represent hydrogen atoms or Alkyl groups having 1 to 4 carbon atoms, but R ⁸ may also additionally be a halogen atom, m, η, ο and ρ are each the numbers 0,1,2 or 3 with the following limitations: the sum of m + η and the sum of ο + ρ means respectively the numbers 1,2 or 3, the sum of η + ο and the sum of m + ρ is the numbers 1,2,3,4 or 5, However, where the sum of m + η + ο + ρ must always be greater than 2, A ¹ , A ² , A ³ , A ^{4 are} hydrogen atoms; in the event that m, η, ο and ρ each represent the number 1, either A ¹ and A ² together or A ³ and A ⁴ together also an ethylene bridge represent their isomers and their physiologically acceptable salts with inorganic or organic acids. 2. Condensed diazepinones of general formula I according to claim 1, in which either X is a nitrogen atom and ΊΓβ) is the radical (S) or
X is the = CH group and 100 is the radical (V), R is the methyl group, R ⁴ and R ⁵ , which may be the same or different, each represents a hydrogen, fluorine or chlorine atom representing methyl or ethyl, and m = 0, n = 2, o = 0, p = 2 or
m, η, ο and ρ are each equal to 1, their isomers and their physiologically acceptable salts with inorganic or organic acids. 3. As condensed diazepinones of the general formula I according to claim 1, the compounds b] [1,4] benzodiazepin-6-one D-6,11-dihydro-11 - ([6-methyl-2 _l 6-diazabicyclo (3.3.0] oct-2-yl] carbonyl] -5H-pyrido _[2/3 b] [1,5] benzodiazepin-5-one 4. Medicaments containing one or more compounds according to claims 1 to 3 in addition to the usual carriers and / or excipients. 5. Use of compounds according to claim 1 to 3 for the preparation of medicaments for the treatment of cholinergic spasms and dysmotility in the gastrointestinal tract and in the area of the laxative bile ducts, for the therapy of cystitis and spasms in Urelithiasis, for the therapy of relative incontinence, for the treatment of asthma brochiale and bronchitis and for the treatment of ischemic heart disease. 5,11-dihydro-11 - [(7-methyl-3,7-diazabicyclo [3.3.0j-oct-3-yl) carbonyl] -6H-pyrido [2,3- b] [1,4] benzodiazepin-6-one their isomers and their physiologically acceptable salts with inorganic or organic Acids. 6. A process for the preparation of condensed diazepinones of the general formula I. (A-CH) _m (CH-A ') _n (I) (A ⁴ -CH) br in the ^ Cb) one of the divalent radicals represents and (S) (T) R ⁸ (U) (V) X, R, R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , m, n, o, p, A \ A ² , A ³ and A ^{4 have} the following meanings: X is a = CH group or a nitrogen atom, R is a straight-chain or branched alkyl radical having 1 to 4 carbon atoms, which may also be a phenyl which is monosubstituted or disubstituted by chlorine, bromine, fluorine, methyl or methoxy may be substituted R ⁴ and R ⁶ , which may be the same or different, represent a hydrogen, fluorine, chlorine or bromine atom or an alkyl group having 1 to 4 carbon atoms, R ⁶ is a hydrogen or chlorine atom or a methyl group, R ⁷ and R ⁸ , which may be the same or different, represent hydrogen atoms or alkyl groups having 1 to 4 carbon atoms, but R ⁸ may additionally have a halogen atom mean, m, η, ο and ρ are each the numbers 0,1,2 or 3 with the following restrictions: The sum of m + η and the sum of ο + ρ means respectively the numbers 1,2 or 3, the sum of η + ο and the sum of m + ρ means respectively the numbers 1,2,3,4 or 5, where However, the sum of m + η + ο + ρ must always be greater than 2, A ¹ , A ² , A ³ , A ^{4 are} hydrogen atoms; in the event that m, η, ο and ρ each represent the number 1, either A ¹ and A ² together or A ³ and A ⁴ together also represent a Ethyienbrücke, their isomers and their salts with inorganic or organic acids, characterized characterized in that a) for the preparation of basic substituted condensed diazepinones of general formula I a (La) (A ⁴ -CH) (CH-A ³ ) in the X, R, R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , m, n, o, p, A ¹ , A ² , A, A have the meanings given above, and (U), (V) or (T ') CH-, C ^ \ one of the divalent radicals (S), (τ ¹ ) wherein R ⁴ , R ⁵ , R ⁷ and R ^{8 are} as defined above and R ⁶ 'represents a chlorine atom or a methyl group, a carbonic acid derivative of the general Formula Il H (ID in the [B ¹ J and X are as defined above and Y represents a halogen atom or the radical -OR ^{11 in} which R ^{11 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, with a compound of the general formula III H ι (A-CH) (CH-A *) m η (III) (A ⁴ -CH) (CH-A ³ ) or with their metal compound of general formula III a / N \ (A ¹ -CH) _1n (CH-A ² J _n (IIIa) (A ⁴ -CH) (CH-A ³ ) in which R, m, η, ο, ρ, A ¹ , A ² , A ³ , A ^{4 are} as defined above and M is an alkali metal atom or 1 equivalent of an alkaline earth metal atom, optionally in the presence of a solvent, at temperatures between -1O ⁰ C and the boiling point of the reaction mixture, optionally in the presence of a base or an excess of the compound of general formula III, or b) for the preparation of basic substituted condensed diazepinones of vorgenannton general formula I a a tricycle of general formula IV (IV) in the X and ^) (βί are as defined above, with a chlorocarbonic acid derivative of the general formula V Cl o (V) (A-CH) (CH-A ^J )
\ ^P / ° in the R, m, η, ό and p, A ¹ , A ² , A ³ and A ^{4 have} the meanings mentioned above, are reacted in inert solvents, preferably in the presence of bases, at temperatures between 30 and 100 ⁰ C, or c) for the preparation of falling under the general formula I pyrrolo-fused diazepinones of the general formula Ib C = O (A ^ CH) _1n (CH-A ² J _n (Ib) (A ⁴ -CH) (CH-A ³ )