CA2025006A1 - Condensed diazepinones, processes for their preparation and medicaments containing these compounds - Google Patents

Abstract

Abstract Condensed diazepinones Compounds of formula I

(I) (in which ] ? represents one of the qroups (S) (T) (U)

Description

55884.5~2 Condensed dia~epinones The invention relates to novel condensed diazepinones, processes for their preparation and pharmaceutical compositions containing these compounds.

Condensed diazepinones having ulcer-inhibiting and gastric secretion-inhibiting properties are known from EP-A-239519, EP-A-57428, US-A-3660380, US-A-3619159, us-A-42l3s84~ US-A-4213985, US-A-4210648, US-A-4410527, US-A-4424225, US-A-4424222 and US-A-4424226.

EP-A-156191 (and the corresponding United States Patent Number 4550107~ discloses condensed diazepinones which, compared to the compounds of the abovementioned publications, achieve completely different, valuable pharmacological properties through the introduction of novel aminoacyl radicals.

We have however now found that certain novel condensed diazepinones, despite their close structural relationship, surprisingly possess a further different active quality, compared to those of the abovementioned ulser-inhibiting condensed diazepinones and the antibradycardiac condensed diazepinones. More specifically the novel compounds are suitable for the treatment of cholinergically induced spasms and motility disorders in the gastrointestinal tract and in the region of the outwardly leading bile ducts, for the symptomatic treatment of cystitis and of spasms from ~ ~2 ~

urelithiasis by reducing the pathologically increased tone of the hollow organs, for treatment of relative incontinence which is caused by disordered correlation between sphincter and detrusor tone, for the symptomatic treatment of bronchial asthma and bronchitis by suppressing the muscarine-induced portion of bronchoconstriction, and for the treatment of ischaemic heart diseases by reducing the heart rate and suppressing parasympathetically caused coronary spasms while at the same time reducing the basal coronary tone. The novel condensed diazepinones show these effects with greater selectivity, and in particular are free of tachycardiac side-effects within the therapeutically useful dosage range.

-Thus viewed from one aspect the present invention provides compounds of formula I.
O ~
H N

[~N~O

~AI-CH)m~CH A2) (~J'-CH~p ~CH-A3)o N
R

(wherein ] ~ represents one of the divalent groups ` 3 ;

:`

R ~_ ( U ) ~ ( Y ) :``
~ . .

;` X repr~sents a =CH- group or a nitrogen atom;
`~:
R represents a straight-chained or branched C14 alkyl group optionally substituted by a phenyl group itself optionally mono or disubstituted by chlorine, bromine or fluorine .
atoms or methyl or methoxy groups;

R4 and R5, which may be the same or different, each represents a hydrogen, fluorine, chlorine or bromine atom or a C~ 4 alkyl group;

R6 represents a hydrogen or chlorine atom or a methyl group;

R7 and R8, which may be the same or different, each represents a hydrogen atom~or a C14 alkyl group and R8 may also represent a halogen:atom;

m, n, o and p independently r-pr~sent the numbers 0, 1, 2 ' ,~: ~ . ' : ' ~' -'~

;

~2~ 3 or 3, where the sum of m-~n and the sum of o+p are each 1, 2 or 3, the sum of n+o and the sum of m+p are each 1, 2, 3, 4 or 5, and the sum of m-~n+o+p is greater than 2; and A1, A2, A3 and A4 each represent hydrogen atoms, and where m, n, o and p each is 1, either Al and A2 together or A3 and A4 together may also represent an ethylene group) and the isomers and acid addition salts thereof.

In the compounds of the invention, the moiety of formula I
~N~
( A I -C\H )m ( CH-A2) n ( A4-CU~p ( CH-d3 ) O
N
I

may for example have one of the following structures:

~ liN\ ~N~ 8N

8 ~N~ NQ>

Q N? ~a ~N~
N N J I~J
;

[~ N ~/ \ ~

wherein group R may be bound to either of the two ring nitrogens shown. These divalent moieties may be present in cis and trans configurations.

Preferred compounds according to the invention include those of formula I are wherein either X represents a nitrogen atom and ] ~ represents a group (S) or X represents a =CH- group and ] ~ represents group (V~;

:

~ '3~J

R represents a methyl group, R4 and R5 each independently represents a hydrogen, fluorine or chlorine atom or a methyl or ethyl group, and m, n, o and p are each 1 or m and o are each zero and n and p are each 2, and the isomers and salts thereof.

Especially preferred compounds according to the invention include 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;

D-6,11-dihydro-11-[[6 methyl-2,6-diazabicyclo[3.3.0]oct-2-yl]carbonyl]-5H-pyrido[2~3-b][l~5]benzodiazepin-5-one; and 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; and the isomers and salts thereof.

As indicated above, the compounds of formula I may be present in the form of their acid addition salts, preferably of course the physiologically acceptable salts.
Suitable e~amples of salt-forming inorganic or organic acids include hydrochloric acid, h~drobromic acid, sulphuric acid, methylsulphuric acid, phosphoric acid, tartaric acid, fumaric acid, citric acid, maleic acid, succinic acid, gluconic acid, malic acid, p-toluenesulphonic acid, methanesulphonic acid and amidosulphonic acid.
;

The following compounds may be mentioned as examples of compounds according to the invention:

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 9-chloro-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 6,11-dihydro-11-[[7-methyl-3,7-diazabicyclo[3.3.0]oct-3-yl]
-car.bonyl]-5H-pyrido[2,3-b][1,5]benzodiazepin-5-one L-5,11-dihydro-11-[[6-methyl-2,6-diazabicyclo[3.3.0]oct-~-yl]-carbonyl]-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one L-5,11-dihydro-8-methyl-11-[[6-methyl-2,6-diazabicyclo [3.3.0]oct-2-yl]-carbonyl]-6H-pyrido[2/3-b][1,4]-benzodiazepin-6-one L-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 D-5,11-dihydro-11-[[6-methyl-2,~-diazabicyclo[3.3.0]oct-2-yl]-carbonyl]-6~-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]-6~-pyrido[2,3-b][1,4]
benzodiazepin- 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]oct-7~2~

2-yl]-carbonyl]-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one L-5,11-dihydro-11-[[6-isobutyl-2,6-diazabicyclo[3.3.0]oct-2 -yl]-carbonyl]-6~-pyrido[2,3-b][1,4]benzodiazepin-6-one cis-5,11-dihydro-11-[[8-methyl-2,8-diazabicyclo[4.4.0]dec-2 -yl]-carbonyl]-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one trans-5,11-dihydro-11-[[8-methyl-2,8-diazabicyclo[4.4.0]dec -2-yl]-carbonyl]-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one 5,11-dihydro-11-[[10-methyl-4,10-diazatricyclo~5.2.1O o2,6]
dec-4-yl]-carbonyl]-6H-pyrido[2,3-b][1,4]-benzodiazepin-6-one 5,11-dihydro-11-[[10-methyl-4,10-diazatricyclo[5.2.1. o2,6]
dec-4-yl]-carbonyl]-6H-dibenzo[2,3-b][1,4]diazepin-6-one 5,11-dihydro-11-[[2-methyl-2,7-diazabicyclo[3.3.0]oct-7-yl]
-carbonyl]-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one , 6,11-dihydro-11-[[2-methyl-2,7-diazabicyclo[3.3.0]oct-7-yl]
-carbonyl]-5H-pyrido[2,3-b~[1,5]benzodiazepin-5-one 5,11-dihydro-11-[[7-methyl-2,7-diazabicyclo[3.3.0]oct-2-yl]
-carbonyl]-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one 6,11-dihydro~ [7-methyl-2,7-diazabicyclo[3.3.0]oct-2-yl]
-carbonyl]-5H-pyrido[2,3-b][1,5]benzodiazepin 5-one 6,11-dihydro-11-[[3-methyl-3,6-diazabicyclo[3.2.0]hept-6-yl]-carbonyl]-5H pyrido[2,3-b][1,5]benzodiazepin-5-one 5,11-dihydro-11-[[3-methyl-3,6-diazabicyclo[3.2.0]hept-6-.

. ' ' ' ~2~
, . ..

carbonyl]-6H-pyrido[2,3-b]~1,4Jbenzodiazepin-6-one 5,11-dihydro-11-[[6-methyl-3,6-diazabicyclo[3.2.0]hept-3-yl ]- carbonyl]-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one 6,11-dihydro-11-[[6-methyl-3,6-diazab.icyclo[3.2.0]hept-3-yl]-carbonyl]-5H-pyrido[2~3-b][1~5]benzodiazepin-5-one 5,11-dihydro-11-[[3-methyl-3,8-diazabicyclo[4.2.0]oct-8-yl]
-carbonyl]-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one trans-5,11-dihydro-11-[[7-methyl-2,7-diazabicyclo[4.4.0~dec -2-yl]-carbonyl]-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one trans-6,11-dihydro-11-[[7-methyl-2,7-diazabicyclo[4.4.0]dec -2-yl]-carbonyl]-5H-pyrido[2,3-b][1,5]benzodiazepin-5-one 5,11-dihydro-11-[[8-methyl-3,8-diazabicyclo[4.2.0]oct-3-yl]
-carbonyl]-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]
-carbonyl]-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one 5,11-dihydro-11-[[7-methyl-3,7-diazabicyclo[4.2.0]oct-3-yl]
-carbonyl]-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one 5,11-dihydro-11-t[3-methyl-3,8-diazabicyclo[4.3.0]non-8-yl]
-carbonyl]-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one .
5,11-dihydro-11-[[8-methyl-3,8-diazabicyclo[4.3.0]non-3-yl]
-carbonyl]-6H-pyridot2,3-b][1,4]benzodiazepin-6-one L-4,9-dihydro-3-methyl-4~[~6-methyl-2,6-diazabicyclo[3.3.0]
oct-2-yl~-carbonyl]-lOH-thieno[3,4-b][1,5]benzodiazepin-10-10one 4,~-dihydro-3-methyl-4-[[7 methyl-3,7-diazabicyclo[3.3.0]
oct-3-yl]-carbonyl]-lOH-thieno[3,4-b][1,5]benzodiazepin-10-one L-3-chloro-1-methyl 4-[[6-methyl 2,6-diazabicyclo[3.3.0]oct -2-yl]-carbonyl]-1,4,9,10-tetrahydropyrrolo[3,2-b]
[1,5]benzodiazepin-10-one 3-chloro-1 methyl-4-[[7-methyl-3,7 diazabicyclo[3.3.0]oct-3 -yl]-carbonyl]-1,4,9,10-tetrahydropyrrolo[3,2-b][1,5]
benzodiazepin-10-one and the isomers and salts thereof.

Viewed from a further aspect, the invention also pro~ides a process for the preparation of the compounds of the in~ention, said process comprising at least one of the following steps:

a) (to prepare basic substituted compounds of formula Ia ~2~

o~

H--N
,~N~pO

~(AI-CH~)," ~CH~A2)n ~ I a ) ~ A4 -C H~ p,~ C H-~3 ~ -: N

;. -wherein R R4 R5 R6 R7 R8 m n o, p, A1, A2, A3 and A are as hereinbefore defined and ] ~ represents a group (S), (U) or (V) as hereinbefore defined or a group (T') f H3 N~

~ (T ' ) ; ~ R6 wherein R6 represents a chlorine atom or a methyl group)) reacting a carbonic acid derivative of formula II
H ~ O

y~O

. . , (wherein ] ~ nd X are as hereinbefore defined and Y
represents a halogen atom, preferably a bromine or chlorine atom, or a group OR~1 in which R11 represents an optionally halogen-substituted C15 alkyl group, a phenyl group optionally substituted by halogen atoms or nitro groups, or a C715 aralkyl group) with a compound of formula III
H

~Al-CH)m ~H-A2~n h (~
C H~p t C H- A 3 ) o N

(wherein R, m, n, o, p, A1, A2, A3 and A4 are as hereinbe~ore defined) or an organometallic compound of formula IIIa M

c~ c S A -CH~p (CH-~3)~ ~ I i Ia) N

R

(wherein M represents an alkali metal atom or 1 equivalent of an alkaline earth metal atom and Al, A2, A3, A4, R, m, n, o and p are as hereinbefore defined);

,, 2 ~

b) (to prepare basic substituted compounds of formula Ia) reacting a tricyclic compound of formula IV
H ~ O

(wherein X and ] ~ are hereinbefore defined) with a chlorocarbonic acid derivative of formula V
Cl ~ ~

(A1_CI~ ~CH_A2)~ ~ y ) ( A ~ - C H~p ( C N -A 3 ) o R

:~ (wherein R, m, n, o, p, A1, A2, A3 and A4 are as hereinbefore defined);

:: ~ c) (to prepare compounds of formula Ib .

H3C~

H -N~
~N~ (Ib) (Al-CH)~CU-A2~
' ~

~ CH~ ~¢H~AS)~
I
R
.
(wherein X, R, m, n, o, p, A1, A2, A3 and A4 are as hereinbefore defined for formula I) hydrogenolysing a ; compound of formula Ia in which R6 represents a chlorine atom;
. .
d) converting a compound of formula I into an acid addition salt thereof or an acid addition salt of a compound of formula I into the free base; and e) separating a compound o* formula I into the isomers thereof.

The reaction of step (a) is carried out without or preferably in the presence of a solvent, such as for example water, toluene, or an alcohol, such as for example methanol, ethanol or isopropanol, but most preferably in the presence of an aprotic polar solvent, for example tetrahydrofuran, 1,4-dioxane, acetonitrile, N,N-dimethylformamid~, dimethylsulphoxide, hexamethylphosphoric acid triamide, or mixtures thereof, and at temperatures between -lO~C and the boiling point of the reaction mixture, preferably between 40 and 100C. The use of additional inorganic or organic bases, for example alkali metal or alkaline earth metal hydroxides, alkoxides or carbonates, for example sodium hydroxide, sodium methoxide, potassium tert.butoxide, sodium carbonate, potassium carbonate, tertiary amines, ~or example triethylamine, e~hyldiisopropylamine, N,N-dimethylaniline, pyridine and 4-(dimethylamino)pyridine, and reaction in the presence of an e~cess of a compound of formula III, have proved to be advantageous.

If the bicyclic diamine oE formula III and the carbonic acid derivative of formula II are used in equimolar amounts, then where Y represents a halogen atom the hydrohalic acid salts of the desired compounds of formula Ia are obtained directly.

For reaction step (a) metal compounds of formula IIIa can be easily prepared in situ from compounds of formula III by reaction with alkali metals or alkaline earth metals, for example with sodium, potassium or barium, or with alkali metal or alkaline earth metal hydrides, for example with sodium, potassium or calcium nydride, or by reaction with alkali metal or alkaline earth metal organometallic compounds for example with n-but~l lithium or phenyl lithium.

The reaction of step (b) is preferably carried out in an inert organic solvent, ~or example in an aromatic hydrocarbon ~such as toluene and xylene), in an ether (such as diisopropylether, tetrahydrofuran or dioxane), in a ketone (such as 3-pentanone), in a chlorinated aliphatic hydrocarbon (such as 1,2-dichloroethane), or in another ~ ~ 2 ~

solvent (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 +30 and +100C.

The hydrogenolysis of reaction step (c) may be carried out in the presence of a catalyst based on a metal from the VIIIth sub-group of the Periodic Table of elements, ~or example palladium on animal charcoal, palladium on barium sulphate, Raney nickel or ~aney cobalt, and at hydrogen pressures of 1 to 300 bar and temperatures of 0C to 130C, conveniently in the presence of a solvent, for example an alcohol (such as methanol or ethanol), ether (such as dioxane or tetrahydrofuran), carboxylic acid ~for example acetic acid) or tertiary amine (for example triethylamine).
If the process is carried out in the absence of an additional hydrogen chloride acceptor, for example sodium carbonate, potassium hydrogen carbonate, triethylamine or sodium acetate, the hydrochlorides of the desired compounds, which may be obtained by evaporating the reaction solution after removing the catalyst, are produced directly. If in the hydrogenolysis reaction formic acid is used in place of hydrogen, thP reaction will theoretically proceed even under pressureless conditions. Reaction with formic acid in the presence of dimethylfoxmamide as solvent and palladium on charcoal as catalyst at temperatures between 70 and 110C, and reduction using triethylammonium formate in the presence o~ excess triethylamine and palladium on animal charcoal or palladium acetate and triarylphosphines, such as triphenylphosphine, tris-(o-tolyl)phosphine, tris-(2,5-diisopropylphenyl)phosphine, at temperatures between 40 and 110C, have proved to be particularly advantageous ways of ~ 3~ ~3 effecting this process Bases of formula I thus obtained may then be converted to their acid addition salts or the acid addition salts obtained may be converted into the free bases or other pharmacologically acceptable acid addition salts using conventional procedures.

If in the condensed diazepinones of formula I m, n, o or p each have the value 1 these compounds are achiral; however, in all other cases the compounds are chiral. These chiral compounds may therefore occur in each case as (+) and (-) enantiomers. The scope of the invention includes the individual isomers as well as their racemates.

The separation of possible racemates of the compounds of formula I may be carried out using conventional processes, for example using an optically active acid, such as (+) or (-) tartaric acid, or a derivative thereof, such as (+) or (-) diacetyltartaric acid, (+) or (-) monomethyltartrate or (+) camphorsulphonic acid.

Thus for isomer separation, the racemate of a compound of formula I may be reacted with one of the above-mentioned optically active acids in equimolar quantities in a solvent in accordance with a conventional process, and the crystalline diastereomeric salts obtained are separated by utilising their differing solubilities. This reaction may be carried out in any type of solvent, as long as it has a sufficient difference in the solubility of the salts.
Methanol, ethanol or mixtures thereof, for example in volume ratio 50:50, are preferably used. Each of the diastereomeric salts is then dissolved in water, neutralised using a base, such as sodium hydroxide or potassium hydroxide, and thus the corresponding free compound is obtained in the (+) or (-) form.

In reaction steps (a) and (b) only one enantiomer will be obtained if the reaction is carried out using only one enantiomer of the reagent of formula III, IIIa or V.

The preparation of the carbonic acid derivatives of formula II used as starting compounds is described in detail in DE-A-3726908.

Starting compounds of formula III, some of which are novel and have not yet been previously disclosed, can be obtained, for example by the following methods:

a) 2-substituted 2,6-diazabicyclo[3.3.0~octanes of formula III may be obtained using a process as described by or analogous to that described by Cope A.C. and Shen T.Y. in J. Am. Chem. Soc. 78: 5gl6 (1956).

Thus for~example, the 2-benzyl-2,6-diazabicyclo[3.3.0]
octane disclosed by Cope and Shen ~supra) may be reacted with ethyl chloroformate to give the corresponding urethane, which is then reduced using lithium aluminium hydride to give 2-benzyl-6-methyl-2,6-diazabicyclo [3.3.0]octane. Hydrogenolytic removal of the benzyl groups yields the desired 2-methyl-2,6-diaæabicyclo[3.3.0]octane.

b) 3-substituted 3,7-diaæabicyclo[3.3.0]octanes of formula III can be prepared, for example, starting from pyrrole-3,4-dicarboxylic acid completely analogously to the procedure described by Loftus P. and Wong J.J. in J.
Heterocyclic. Chem. 20: 321 ~1983).

~2~

Alternatively, the desired 3~substituted 3,7-diazabicyclo[3.3.0~octanes may be prepared starting from N-alkylated glycine derivatives, paraformaldehyde and maleic acid imide with the bicyclic imide produced in this [3+2]
cycloaddition subsequently being reduced using lithium aluminium hydride.

c) 2-substituted 2,7-diazabicyclo[3.3.0]octanes of formula III can be obtained in accordance with the procedure described by Birkhofer L. and Feldmann H. in Annalen 677:
154 (1964).

d) 10-methyl-4,10-diazatricyclo[5.2.1. o2,6~ decane ~of formula III) can be obtained, for example from dimethyl N-ethoxycarbonyl-7-azabicyclo[2.2.1]hepta-2,5-diene-2,3-dicarboxylate which is known from literature (see Bansal i R.C. et al., Can. J. Chem. 47: 2391-4 (1969)). Alkaline saponification of both methyl ester groups followed by palladium-catalysed hydrogenation produces a very good yield of N-ethoxycarbonyl-7-azabicyclo[2.2.1]heptane-2,3-dicarboxylic acid. The dicarboxylic acid is cyclised with the aid of dicyclohexylcarbodiimide to the anhydride which is then heated under reflux with excess benzylamine. The 4-benzyl-10-ethoxycarbonyl-4,10-diazatricyclo[5.2.1. o2,6] _ decane-3,5-dione thus obtained in good yield is reduced using lithium aluminium hydride and the benzyl protective group is then split off by means of catalytically activated hydrogen.

e) 8-substituted 2,8-diazabicyclo~4.4.9]decanes of formula III may be obtained, for example starting from N-substituted 4-piperidones. The enamine obtained by reaction with, for example, pyrrolidine, is initially added ~2~

to acrylonitrile and the addition product is cyclised in sulphuric acid to give 8-substituted Q1~6-2,8-diazabicyclo[4.4.0]decen-3-ones. Hydrogenation of the double bond using catalytically activated hydrogen preferentially produces cis- linked ring systems, however, hydrogenation using triethylsilane preferentially produces trans-linked ring systems. Reduction of the 8-substituted 2,8-diazabicyclo[4.4.0]decan 3-ones thus obtained to give the desired 8-substituted 2,8-diazabicyclo[4.4.0]decanes proceeds smoothly using lithium aluminium hydride.

f) trans-7-methyl-2,7-diazabicyclo[4.4.0]decane (of formula III) may be prepared, for example starting from 1,5-naphthyridine. Reaction with sodium in amyl alcohol produces trans-2,7-diazabicyclo[4.4.0]decane which may be reacted with methyl chloroformate to give the monourethane (see Arch. Immunol. Ther. Exp. 19: 261 (1971)). Treatment with lithium aluminium hydride produces the desired trans-7-methyl-2,7-diazabicyclo[4.4.0]decane.
Alternatively, the trans-2,7-diazabicyclo[4.4.0]decane may be converted directly to the trans-7-methyl-2,7-diazabicyclo[4.4.0]decane using formaldehyde and hydrogen with addition of a catalyst.

The condensed diazepinones of formula I and their acid addition salts have valuable properties; as already mentioned in the introduction, they show selective spasmolytic properties on peripheral organs, in particluar ileum and bladder, and in view of the absence of any effect of increasing heart rate, inhibiting gastric acid secretion, inhibiting salivation or affecting the accomodation ability of the eye in the therapeutic dosage range, they are suitable in human and veterinary medicine for the treatment of cholinergically induced spasms and ~ J~

motility disorders in the gastrointestinal tract and in the region of the outwardly leading ~ile ducts, for the symptomatic treatment of cystitis and of spasms from urelithiasis by reducing the pathologically increased tone of the hollow organs, for the treatment of relative incontinence which is caused by disordered correlation between sphincter and detrusor tone, for the symptomatic treatment of bronchial asthma and bronchitis by suppressing the muscarine-induced portion of bronchoconstriction, and for the treatment of ischaemic heart diseases by reducing the heart rate and simultaneously suppressing parasympathetically caused coronary spasms and reducing the basal coronary tone.

Thus viewed from a further aspect the invention provides a method of treatment of the human or non-human (preferably mammalian) body to combat cholinergically induced spasms and motility disorders in the gastrointestinal tract and in the region of the outwardly leading bile ducts, or cystitis and spasms from urelithiasis, or relative incontinence, or bronchial asthma and bronchitis or ischaemic heart diseases, said method comprising administering to said body a compound of formula I or a physiologically acceptable acid addition salt thereof.

Viewed from a still further aspect the invention also provides use of a compound of formula I or a physiologically acceptable acid addition salt thereof for the manufacture of a therapeutic agent for use in a method of treatment of the human or non-human (preferably mammalian) body to combat cholinergically induced spasms and motility disorders in the gastrointestinal tract and in the region of the outwardly leading bile ducts, or cystitis and spasms from urelithiasis, or relative incontinence, or s~ ~

bronchial asthma and bronchitis or ischaemic heart diseases.

Viewed from a still further aspect the invention provides a pharmaceutical composition comprising a compound of formula I or a physiologically acceptable acid addition salt thereof together with at least one pharmaceutical carrier or exclplent.

The compounds of formula I or salts thereof can be presented for this purpose in conventional phaxmaceutical administration forms, for example in solutions, suppositories, tablets/ coated tablets, capsules or infusions (tisanes). The daily dosage of the compound or salt will generally be 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, for oral administration, which daily dosage is optionally administered in the form of several, preferably 1 to 3, individual doses, to achieve the required results.

A favourable correlation between spasmolytic effects on the one hand and the undesirable effects on the heart rate, pupil size, and the secretion of tears, saliva and gastric acid on the other hand which occurrs with therapeutic agents having anticholinergic activiky is particularly important for the thexapeutic use of the substances. The following tests show that the compounds of the invention have surprisingly favourable correlations in this regard.

A. Investigation of functional selectivit~ of the antimuscarinic effect Substances having anti-muscarine properties inhibit the v~ ~

effects of exogenously supplied agonists or of acetylcholine released ~rom cholinergic nerve endings. A
description of methods which are suitable for determining spasmolytically active anti-muscarine agents is given below.

"In vitro" orqan preparations:

Dissociation constants (KB values) were determined in vitro on the ileum and spontaneously beating attrium of the guinea pig. The ileum was removed and incubated in an organ bath in Krebs-Henseleit solution. Contractions were induced by increasing concentrations of methacholine (M) such that complete concentration-activity yraphs could be plotted. M
was then washed out, the test substance was added and incubated for 30 minutes, and once again a concentration-activity graph was plotted using M.

The dissociation constant according to Arunlakshana and Schild (see Brit. J. Pharmacol. 14: 48 (1959)) was calculated from the dosage ratio (DR) which is the measure of the displacement of the concentration-activity graph.

M reduced the heart rate as a function of concentration in ~'4 the isolated spontaneously beating right attrium. This effect was cancelled again by adding an anti-muscarinic agent. Dissociation constants for the muscarinic receptors of the attrium were obtained in the same manner as described above. The comparison of the dissociation constants determined in both tissues permitted tha identification of selectively spasmolytically active substances. The results are shown in Table III below.

~j ~ ?~

"In vivo" methods .
The methods used had the aim of confirming the selectivity of the anti-muscarinic effect. Any substances which had been selected on the basis of in vitro investigations were investigated for 1. selectivity of the bronchospasmolytic activity in the guinea pig, 2. saliva secretion-inhibiting effect in the rat, and 3. in situ spasmolytic activity in the guinea pig.
.; .

ffect on M-receptors of the bronchii, heart and bladder of anaesthetised guinea pigs -:
Method Male and female guinea pigs (550-600 g bodyweight) were anaesthetised using urethane (1.4 g/kg intraperitoneally).
A cannu]a was introduced into the jugular vein to inject the active agents. 220 I.U./kg of heparin were injected intravenously. A cannula was introduced into ~he trachea, the animals were artificially respirated by means of a positive pressure pump (Braun-Melsungen) using oxygen-enriched air at a rate of ~0 beats per minute. A
branch of the tracheal cannula was connected to a water manometer 10 cm high. The respiration volume was set such that the maximum intratracheal pressure during respiration just reached the pressure of a 10 cm water column.
;

~ ~ ~ r ~

Apart from a few modifications, the effect of the active agents on the bronchial tone was measured in accordance with the method described by Konzett and R~ssler (1940).
The volume of respiration gas mixture (overflow) p~oduced by bronchoconstriction which flowed through the water manometer was measured by means of a tube-type pneumotachometer (FLEISCH, Model lO00), which was connected to an SP 2040D differential pressure transducer (HSE). The values were recorded using an IFD recording apparatus. The trachea was clamped for a short time before the test to produce the maximum possible degree of bronchoconstriction for calibration. A cannula was introduced into the left large carotid artery; the arterial blood pressure was measured with the aid of a pressure transducer (Bell and Howell, 4-327 I) in conjunction with an IFD recording apparatus. The heart rate was measured using a rate detector triggered by arterial pulse waves.

A small median abdominal incision was made and the bladder was connected to a power transducer under a resting tension of 1 gram.

The active substances to be tested were injected via the jugular vein and 5 minutes later the increase in tension of the bladder (in grams) the bronchial resistance (in %) and the decrease in heart rate (beats per minute) were measured after administration o~ acetylcholine (50 ~g/~g intravenously and intraarterially). Dosage-dependency graphs were drawn by plotting the percentage inhibition of bronchoconstriction, bradycardia and the increase in tension of the bladder against the logarithm of the dosage (mole/kg~ of the active substances being investigated. The results are given as average values (for 4 to 6 animals) and are set forth in Table I below.

2. Saliva secretion-inhibitinq effect in the rat Male THOM rats anaesthetised using 1.2 g/kg of urethane received increasing dosages of the test substances intravenously in accordance with the procedure of Lavy and Mulder (see Arch. int. Pharmacodyn. 178: 437-445, (1969)).
The secretion of salivà was triggered by subcutaneous administration of 2 mg/kg of pilocarpine. The saliva was absorbed using blotting paper, the area taken up by it was determined planimetrically every 5 minutes. The dosage of the test substance which reduced the volume of saliva by 50 % was determined graphically. The results are set forth in Table II below.
~`
3. In situ spasmolytic effect in guinea pigs .
:
Male guinea pigs (500 to 600 g bodyweight) were anaesthetised using urethane (1.2 g/kg intraperitoneally);cannulae were introduced into the trachea, jugular vein and the left carotid artery. The animals were artificially respirated by means of a positive pressure pump using oxygen-enriched air at a beat frequency of 80 per minute. A 3 to 4 cm long abdominal incision was made and about 15 cm of a movable loop of the ileum was tied o~f at the distal end while the blood circulation was maintained. The proximal part was filled with a Krebs-Ringer solution and a pressure meter was introduced into the intestine using a Millar micro-tip catheter (PC-450, 5F). A glass tube was placed vertically in the abdomen and attached to the surrounding abdominal wall such that the animal served as its own organ bath when the glass tube was filled with Krebs-Ringer solutionO

The glass tube was filled with Krebs-Ringer solution until the whole of the lower abdomen was immersed. The test substances were injected via the jugular vein; 5 minutes later contractions were produced by means of methacholine (20 ~g/kg intraarterially). Dosage-activity graphs were obtained by plotting the percentage suppression o~
contractions produced by methacholine against the logarithm of dosage amount (mole/kg) o~ the test substance.

The results are given as average values (for 4 to 8 animals) and are set forth in Table II below.

The following compounds were investigated by way of example in accordance with the methods above:

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-yl]carbonyl]-5H-pyrido[2,3-b][1,5]benzodiazepin-5-one C = 5,11-dihydro-11-[[7-methyl-3,7-diazabicy~lo[3.3.0]-oct-3-yl]carbonyl]-6H-pyrido[2~3-b][l~4]benzodiazepin-6-one D = 4,9-dihydro-3-methyl-4-[[7-methyl-3,7-diazabicyclo-[3.3.0]-oct-3-yl]carbonyl]-lOH-thieno[3,4-b][1,5]benzodiaze pin-10-one and as comparison substances X = 11-[[2-[(diethylamino)methyl]-1-piperidinyl]acetyl]-5,11- dihydro-6H pyrido[2,3-b][1,4]benzodiazepin-6-one (see United States Patent No. 4550107) , Y = 5,11-dihydro-11-[(4-methyl-1-piperazinyl)acetyl]-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one ~Pirenzepine, see United States Patent No. 3660380) and Z = atropine.

Table I

Selectivity of the bronchospasmolytic activity in the guinea pig:

Acetylcholine - antagonism Tesl Bronchii Bladder Heart ~atio of Substance log ED50 Ir~g EDso - log EDso Wluence of (mol kg ) (mol kg-1) (mol kg 1) bradycardia i.v.i.v. i.v.to broncho-constfiction ., ..
A . 7,31 6.315.98 21 B 7.35 6.095.71 44 ¦ :
C 6.20 5.525.32 _8 D 7.05 5.806.13 X 5.58 4. 93 5 = 0 5 Y 6.57 ~i.84 5.90 5 Z 8.09 7.28 7.57 3 .... -.~ _ Table II

Selectivity of the in situ spasmolytic activity in relation to the saliva secretion-inhibiting effect.

¦ Tsst Subslance In situ spasmolysls Salivalion inhibibon ilalio ol salivalion guinca pig ilcum rat inhibition to the log ED50 - log ED spasmolytic activity _ (mol kg 1) (mol kg 1) ¦ A 6.05 6.70 2 ¦ C 6.15 5.53 4 . I Y 6.08 _ 6.42 0.5 .~ ~ 7.28 7.60 0.5 J _ . _ .

..
Table III

Dissociation constants (KB values) in the ileum and spontaneousl beating attrium o~ the guinea pig:

¦Tost Subs~anco ~oart lloum Solac~ivity ¦ _ KB ~mol/l] KB Imol/ll KB Heart to ¦ A 209 x ~0 7 3.02 x 10 8 6.9 l I .
I B _ 1.45x1~7 6.03x108 æ4 l I _ _ I X 1.05 x 1~7 6.17 x 10 7 0.17 l I _ Y 1.23x1~7 1.94x10~ 0.~3 _ 1.41 x 10 9 8.13 x 10 10 1.7 Discussion of the results The compounds according to the invention inhibit the effects of exogenously introduced acetylcholine or methacholine on the smooth muscle o~ bronchii, bladder or small intestine in low dosages, without this agonistic effect altering the heart rate (see Tables I and III). For example, substances A and B show a very marked smooth muscle selectivity; 21 to 44 times lower dosages are necessary to inhibit the bronchoconstriction triggered by acetylcholine compared to acetylcholine-induced bradycardia (see Table I). The compounds according to the invention not only show selectivity ~or thQ smooth muscle compared to effects which are triggered by cardiac muscarine receptors, but higher dosages are also required to inhibit the pilocarpine- induced saliva secretion (see Table II).

2 ~
", ~

The observed in vivo selectivity for the smooth muscle agrees with the in vitro investigations. The compounds according to the invention have a higher affinity to muscarine receptors in the ileum than for cardiac muscarine receptors (see Table III).

The data show that the compounds according to the invention inhibit the effects of muscarine agonists on the smooth muscle, for example bronchii, bladder and ileum, in dosages which do not have any influence on the heart rate or saliva secretion. The comparison substances Y (pirenzepine) and Z
(atropine) show no selectivity and influence the abovementioned effects in the same dosage range. The comparison substance X shows a higher effectiveness on cardiac muscarine receptors.

The compounds of formula I are characterised by a excellent stabilty to hydrolysis. It is thus possible to prepare storage-stable solutions for parenteral administration.

The following non-limiting Examples are provided to illustrate the invention further.

"M.p." denotes "melting point", "D." denotes "Decomposition".
Satisfactory elemental analyses, IR, UV and 1H-NMR spectra, and often mass spectra as well, exist for all compounds.
Percentages, parts and ratios are by weight, unless otherwise statedO

Example 1 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 A mixture of 4.9 g (18 mmol) of ~1-(chlorocarbonyl)-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-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 ambient temperature. The reaction mixture was concentrated in vacuo, the residue was divi~ed between lN hydrochloric acid and methylene chloride. The organic phase was washed two further times using lN hydrochloric acid and once using water. The combined aqueous phases were rendered basic using potassium carbonate and extracted using methylene chloride (3 x 150 ml). The combined methylene chloride phases were dried over magnesium sulphate, concentrated and the crude material was recrystallised from acetonitrile.
2.9 g (41 % of theory) of colourless crystals of m.p.
157-159C were obtained.
C20H21N52 (363-43) Calculated: C 66.10 H 5.82 N 19.27 Found: 65.75 5.68 19.17 ;

~2~

Example 2 9-Chloro-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 -Prepared analogously to Example 1 from 9-chloro-11-(chlorocarbonyl)-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodia zepin- 6-one and 3-methyl-3,7-diazabicyclo[3.3.0]octane in a yield of 67 % of theory. Colourless crystals of m.p.
216-217C (acetonitrile~.

C20H20ClN5O2 (397.87) Calculated: C 60.38 H 5.07 N 17.50 Cl 8.91 Found: 5~.73 5.02 17.28 8.90 Example 3 6,11-Dihydro-11-[[7-methyl-3,7-diazabicyclo[3.3.0]oct-3-yl]carbonyl]-5H-pyrido[2,3-b][1,5]benzodiazepin-5-one _ Prepared analo~ously to Example 1 from 11-(chlorocarbonyl)-6,11-dihydro-5H-pyrido[2,3-b][1,5]bengo diazepin-5-one and 3-methyl- 3,7-diazabicyclo[3.3.0]octane in a yield of 7 % of theory. Colourless crystals of m.p.
115-120C (ethyl acetate/diisopropyl ether).

~2~

Example 4 4,9-Dihydro-3-methyl-4-[[7-methyl-3,7-diazabicyclo[3.3.0]
oct-3-yl]carbonyl]-lOH-thieno[3,4-b][1,5]benzodiazepin-10-one Prepared analogously to Example 1 from 4-(chlorocarbonyl)-4,9-dihydro-3-methyl-lOH-thieno[3,4-b][1,5]benzodiazepin-lO
-one and 3-methyl-3,7-diazabicyclo-[3.3.0]octane in a yield of 13 % of theory. Colourless crystals of m.p. 220-222C
(ethanol).

Example 5 3-Chloro-l-methyl-4-[t7-methyl-3,7-diazabicyclo[3.3.0]oct-3 yl]carbonyl]-1.4.9.10-tetrahydropyrrolo[3,2-b][1,5]
benzodiazepin-10-one Prepared analogously to Example l from 3-chloro-4-(chlorocarbonyl)-4,9-dihydro-1-methyl-1.4.9.10-tetrahydropyrrolo[3,2-b][1,5]benzodiazepin-lO-one and 3-methyl-3,7-diazabicyclo~3.3.0]octane in a yield of 24 %
of theory. Colourless crystals of m.p. >280C
(ethanol/water).

Example 6 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 a) L~2-Benzyl-6-ethoxycarbonyl-2,6-diazabicyclo[3.3.0]-octane Ethyl chloroformate (3.7 g, 33.8 mmol) was added dropwise to a mixture of 5.7 g (28.2 mmol) of L-2-benzyl-2,6-diazabicyclo[3.3.0]octane, 3.1 g (31.0 mmol) of triethylamine in 0.5 litre of ether and was 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 in the following step without further purification.
Rf = 0.7 (Merck, thin-layer chromatography prepared plates, silica gel 60 F254; eluting agent:
dichloromethane/methanol/concentrated ammonia 90/10/1, v/v/v ) .

b) L-6-Methyl-2,6-diazabicyclo[3.3.0~octane A mixture of 6.0 g (~2.8 mmol) of L-2-benzyl-6-ethoxycarbonyl-2,6-diazabicyclo[3.3.0]octane and 0.87 g (22.8 mmol) of lithium aluminium hydride in 200 ml of ether was heated for 5 hours under reflux~ 5 ml of 30 % strength aqueous caustic soda were then added dropwise while cooling with ice and the solution was decanted off from the white precipitate. The ether solution was dried and concentrated, the remaining oily L-2-benzyl-6-methyl-2,6-diaza~icyclo[3.3.0]octane (4.~ g, 97 % of theory~ was uniform according to thin-layer chromatographic analysis [Rf = 0.35 (Merck, thin-layer chromatography prepared plates, silica gel 60 F254; el~ting agent:
dichloromethane/methanol/concentrated ammonia 90/10/1, v/v/v~] and was hydrogenated for 5 hours at 60C in an autoclave with addition of O . 5 g of palladium on charcoal (10 %) and in ethanol. The reaction mixture was concentrated under reduced pressure and used as the crude ~ 2 ~

product (3.3 g) for further reactions.

c) L-5,11-Dihydro~ll-[[6-methyl-2,6-diazabicyclo[3.3.0]-oct-2-yl]carbonyl]-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one A mixture of 0.95 g (3.5 mmol) of ll-(chlorocarbonyl)-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one and 0.40 g (3.2 mmol) of L-2-methyl-2,6-diazabicyclo-[3.3.0]octane was stirred for 3 hours in 50 ml of acetonitrile, then concentrated under reduced pressure. The residue was divided between water and ethyl acetate, in which 0.4 ~ (3.5 mmol) of maleic acid had previously been dissolved. The aqueous phase was extracted a further two times using ethyl acetate and rendered alkaline by adding 0.5 g of potassium carbonate. The aqueous phase was extracted exhaustively using dichloromethane and the combined organic extracts were dried and concentrated. The residue was purified using column chromatography (silica gel 63-200 ~m; mobile phase:
dichloromethane/methanol/concentrated ammonia 1200/50/5, v/v/v). 0.44 g (38 % of theory) of crystals of m.p.
220-222C (acetonitrile) were obtained.

Example 7 L-5,11-Dihydro-8-methyl-11-[[6-methyl-2,6-diazabicyclo[3.3.
O]oct-2-yl]carbonyl]-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one Prepared analogously to Example 6c from 2.0 g ~7.0 mmol) of ll-(chlorocarbonyl)-5,11 dihydro-8-methyl-6H-pyrido-~2,3-b][1,4]benzodiazepin-6-one, 0.~ g (6.3 mmol) of f~

L-2-methyl-2,6- diazabicyclo[3.3.0]octane and 100 ml of acetonitrile in a yield of 25 %. Colourless crystals of m.p. 160-165C.

Example 8 L-6,11-Dihydro-11-[[5-methyl-2,6-diazabicyclo[3.3.0]oct-2-yl]carbonyl]-5H-pyrido[2r3-b][l~5]benzodia2epin-5-one Prepared analogously to Example 6c from 1.9 g (7.0 mmol) of ll-(chlorocarbonyl)-6,11-dihydro-5H-pyrido [2,3-b][1,5]benzodiazepin-5-one, 0.8 g (6.3 mmol) of L-2-methyl-2,6- diazabicyclo[3.3.0]octane and 100 ml of acetonitrile in a yield of 54 % of theory.

[~320 = -~ 314.

Example 9 D-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 ~, Prepared analogously to Example 6c from 0.95 g (3.5 mmol) of ll-(chlorocarbonyl)-5,11-dihydro-6H-pyrido [2,3-b][1,4~benzodiazepin-6-one, 0.40 g (3.2 mmol) of D-2-methyl-2,6- diazabicyclo[3~3.0]octane in 50 ml of acetonitrile. Colourless crystals of m.p. 160-165C in a yield of 38 ~ of theory.

.~

Example 10 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]-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]benzodiazepin-6-one, 0.67 g (5.3 mmol) of D-2-methyl-2,6-diazabicyclo[3.3.0]octane in 67 ~ yield.
Colourless crystals of m.p. 162-165C.

ExamPle 11 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 :

Prepared analogously to Example 6c from 0.95 g (3.5 mmol) of 11-(chlorocarbonyl)-6,11-dihydro-5H-pyrido [2,3-b][1,5]benzodiazepin-5-one, 0.40 g (3.2 mmol) of D-2-methyl-2,6-diazabicyclo[3.3.0]octane in a yield of ~2 %. Colourless crystals of m.p. 172-17~C, [~]2D0 = + 284.

Example 12 ' L-5,11-Dihydro~ [[5-isopropyl 2,6-diazabicyclo[3.3.0]oct-2- yl]carbonyl-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one _ a) L-2-Isopropyl-2,6-diazabicyclo[3.3.0]octane A mixture of 10.0 g t34 mmol) of L-2,6-dibenzyl-2,6-diazabicyclo[3.3uO]octane, 10.0 g of acetone ~172 mmol) and ethanol (1.0 litre) was hydrogenated for 20 hours at 60~C
with addition of 1 g of palladium on charcoal ~10 %). The catalyst was filtexed off and the reaction mixture was concentrated. The residue was purified by means of column chromatography (silica gel 60-200 ~m; mobile phase:
dichloromethane/methanol/concentrated 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 were eluted~

Rf = 0.2 (Merck, thin-la~er chromatography prepared plates, silica gel 60 F254; eluting agent:
dichloromethane/methanol/concentrated ammonia 150/50/5, v/v/v ) -b)L-5,11-Dihydro-ll-[t6-isopropyl-2,6-diazabicyclo[3.3.0~oct-2-yl]carbonyl]-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one Prepared analogously to Example 6c from ~.1 g (7.8 mmol) of ~s ll-(chlorocarbonyl)-5,11-dihydro-6H-pyrido[2~3-~¦ b]tl,4]benzodiazepin-6-one and 1.2 g (7.8 mmol) of L-2-isopropyl-2,6-diazabicyclo[3.3.0]octane in 50 ml of dry dimethylformamide in a yield of 56 % of theory.

Rf = 0.2 (Merck, thin-layer chromatography prepared plates, silica gel 60 F2s4; eluting agent:
dichloromethane/methanol/concentrated ammonia 140/10~1, v/v/v ) .
:

Calculated: C 67.50 H 6.44 N 17.89 Found: 67.66 6.65 17.36 ExamPle 13 cis-5,11-Dihydro-11-[[8-methyl-2,8-diazabicyclo[4.4.0]dec-2 -yl]carbonyl]-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one and trans-5,11-dihydro~ [[8-methyl-2,8-diazabicyclo[4.4.0]dec -2-yl]carbonyl]-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one A mixture of 1.64 g (5.0 mmol) of 11 (chlorocarbonyl)-5,11-dihydro-6H-pyrido[2,3-b][1,4]
benzodiazepin-6-one, 0.8 g (5.2 mmol) of 8-methyl-2,8-diazabicyclo[4.4.0~decane and 0.85 ml (6.0 mmol) of triethylamine in 20 ml of tetrahydrofuran was stirred for 3 hours at ambient temperature. The reaction mixture was concentrated in vacuo and the residue was divided between ethyl acetate and dilute aqueous potassium carbonate solution. The organic phase was separated off, dried and concentrated in vacuo. Chromatographic purification took place on silica gel (30-60 ~m) using the solvent mixture ethyl acetate/methanol/concentrated ammonia 70/30/1, v/v/v. The two main fractions were concentrated, ground with acetonitrile and the resulting precipitate was filtered off. 100 mg (5 % of theory) of crystals of m.p.
230-233C, which were identified as the trans compound using spectroscopic methods, were obtained from the main fraction eluted initially. The subsequent main fraction contained 200 mg (10 % of theory) of the crystalline cis compound of m~p. 160~161~C.

Example 14 5,11-Dihydro-ll-[[10-methyl-4,10-diazatricyclo[5.2.1.02~6]
dec-4-yl]carbonyl]-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one -A mixture of 1.44 g (5.25 mmol) of ll-(chlorocarbonyl)-5,11-dihydro-6H-pyrido[2,3-b][1,4]
benzodiazepin~6-one, 0.8 g (5.25 mmol) of 10-methyl-4,10-diazatricyclo[5.2~1~02~6]decane and 0.73 ml (5.25 mmol) of triethylamine was stirred in 80 ml of acetonitrile for 8 hours at ambient temperature. The suspension was filtered free from solids under suction and the filtrate obtained was concentrated. The residue was recrystallised from ethyl acetate, the crystals were taken up in methylene chloride and treated with aqueous sodium carbonate solution. The organic phase was then separated off and the aqueous phase was extracted a Eurther two times using methylene chloride. The combined organic phases were dried over sodium sulphate, filtered and concentrated in vacuo. The residue was then purified over a silica gel column (silica gel 30-60 ~m; mobile phase:
cyclohexane/ethyl acetate/methanol/concentrated ammonia 2/2/10/1, v/v/v/v) and then recrystallised once again from ethyl acetate. 0.53 g (26 % of theory) of white crystals of m.p. 218-220C was obtained.
C2Z~23Nso2 (389-46) Calculated: C 67.85 H 5.95 N 17.98 Found: 67.98 6.10 18.18 ,f~ ~:

Exam le 15 5,10-Dihydro-5-[[10-methyl-4,10-diazatricyclo[5.2.1. o2,6] dec -4-yl]carbonyl]~llH-dibenzo[b,e][1,4]diazepin-11-one Prepared analogously to Example 14 from 1.40 g (5.1 mmol) of 5-(chlorocarbonyl)-5,10-dihydro-llH-dibenzo [b,e][1,4]diazepin-11-one, 0.78 g (5.12 mmol) of 10-methyl-4,10- diazatricyclo[5.2.1.02~6]decane, 0.7 ml (5.1 mmol) of triethylamine and 60 ml of acetonitrile in a yield of 30 % of theory.
Colourless crystals of m.p. 230~233C.
C22H24N402 (388.47) Calculated: C 71.11 H 6.23 N 14.42 Found: 70.75 6.34 14.42 Example 16 L-4,9-Dihydro-3-methyl-4-[[6-methyl-2,6-diazabicyclo[3.3.0]
oct-2-yl]carbonyl]-lOH-thieno[3,4-b][1,5~benzodiazepin-10-one Prepared analogously to Example 6c from 4-(chlorocarbonyl)-4,9- dihydro-3-methyl-lOH-thieno [3,4-b][1,5]benzodiazepin-lo-one and L-2-methyl-2,6-diaza-bicyclo[3.3.0]octane in a yield of 37 % of theory.
Colourless crystals of m.p. 95-100C (acetonitrile).

~ ~ 2 ~ ~ ~ f3 ; 44 Example 17 L-3-Chloro-1-methyl-4-[[6-methyl-2,6-diazabicyclo[3.3.0]oct -2-yl]carbonyl]-1,~,9,10-tetrahydropyrrolo[3,2-b][1,5]benzo diazepin- 10-one Prepared analogously to Example 6c from 3-chloro-4-(chlorocarbonyl)-1-methyl-1,4,9,10-tetrahydropyrrolo [3,2-b][1,5]benzodiazepin-10-one and L-2-methyl-2,6-diazabicyclo[3.3.0]octane in a yield of 56 % of theory.
Colourless crystals of m.p. 200-203C

Example 18 trans-5,11-Dihydro-11-[[7-methyl-2,7-diazabicyclo[4.4.0]dec -2-yl]carbonyl-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one a) trans-2,7-Diazabicyclo[4.4.0]decane 1,5-Naphthyridine (5.0 g, 38.4 mmol) in 450 ml of amyl i alcohol was heated under re~lux and sodium (21.3 g, 0.92 mol) was added in portions to the reaction mixture over a period of 30 minutes. 84 ml of concentrated hydrochloric acid were then added. The organic phase was separated off, washed twice using water and the combined aqueous extracts were extracted a further two times using ether. The ether phases were discarded, the aqueous phase was rendered basic using caustic soda while cooling with ice and the desired product was removed by repeated extraction using dichloromethane. The combined dichloromethane phases were dried and concentrated under reduced pressure. Quantitative yield (5.8 g) of crystals of m.p. 174-176C (ethyl acetate).

b) trans-2~Methyl-2,7-diazabicyclo[4.4.0]decane A mixture of trans-2,7-diazabicyclo[4.4.0]decane (1.4 g, 10 mmol)j 37 ~ aqueous formaldehyde solution (0.6 ml, 8 mmol) and 0.5 g of palladium on charcoal (10 %) was hydrogenated for 10 hours at 60C under a pressure of 3 to 4 bar.
Hydrogenation under the conditions given above was continued after adding a further 0.3 ml of the 37 % aqueous formaldehyde solution, the reaction mixture was then concentrated and digested with petrol ether. The petrol ether solution was concentrated under reduced pressure and the oily residue (1.2 g) was used for further reactions without further purification.

c)trans-5,11-Dihydro-11-[[7-methyl-2,7-diazabicyclo[4.4.0]d ec-2-yl]carbonyl-6H-pyrido[2,3-b~[1,4]benzodiazepin-6-one A mixture of 0.84 g (3.1 mmol) o~ ll-(chlorocarbonyl)-5,11-dihydro-6H-pyrido[2,3-b][1,4] benzodiazepin-6-one and 0.43 g (2.8 mmol) of trans-2-methyl-2,7-diazabicyclo[4.4.0]decane was stirred in 80 ml of acetonitrile for 24 hours and then concentrated under reduced pressure. The residue was divided between water and ethyl acetate, in which 0.3 g of maleic acid had been previously dissolved. The aqueous phase was extracted once again using ethyl acetate, rendered alkaline by adding potassium carbonate and then extracted exhaustively using dichloromethane. The combined organic extracts were dried, concentrated and purified by means of column chromatography (silica gel 63-200 ~m, mobile phase:
dichloromethane/methanol/concentrated ammonia 90/10/1, v/v/v). 0.2 g of the title compound (18 % of theory) was obtained.

Bxample 19 trans-6,11-Dihydro-11-[[6-methyl-2,6-diazabicyclo[4.4.0]dec -2-yl]carbonyl]-5H-pyrido[2,3-b]~1,5]benzodiazepin-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]benzodiazepin-5-one, 0.43 g (2.8 mmol) of trans-2-methyl-2,7-diazabicyclo[~.4.0]decane in a yield of 37 %.

Exam~le 20 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 .

2.6 g (0.021 mol) of L-2-methyl-2,6-diazabicyclo [3.3.0Joctane were added dropwise to a mixture consistiny of 11.2 ml of a 20 % strength solution of phosgene in toluene, 50 ml of acetonitrile and 2.4 g (0~023 mol) of anhydrous sodium carbonate while externally cooling witX
ice. A~ter 60 minutes, 4.5 g (0.021 mol) of 5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-~-one were added and the mixture was heated under reflux for 4 hours.
The hot mixture was filtered, the precipitate was washed three times using 10 ml of hot acetonitrile each time and the combined filtrates were concentrated in vacuo to a total volume of 15 ml. The solution was cooled in an ice bath and the resulting crystal paste was filtered under suction. ~ecrystallisation from acetonitrile produced 2.1 g (27 % of theory) of colourless crystals of m.p. 220-222C, identical to the material of Example 6c according to mixed melting point and spectroscopic data.

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 of m.p. 157-159C (acetonitrile) 5,11-dihydro 11-[[10-methyl-4,10-diazatricyclo~5.2.1.02~6]
dec-4- yl]carbonyl]-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one of m.p. 218-220C (ethyl acetate) were obtained analogously.

The preparation of pharmaceutical formulations is described below using some examples:

Example I

Tablets containing 5 mg of 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 , Composition:
1 tablet contains:
~ctive ingredient 5.0 mg Lactose 148.0 mg Potato starch 65.0 mg ~2~

Magnesium stearate 2.0 mg 220.0 mg A 10 ~ strength mucilage is prepared from potato starch by heating. The active substance, lactose and the remaining potato starch are mixed and granulated with the above mucilage through a sieve of mesh width 1~5 mm. The granules are dried at ~5C, rubbed once again through the above sieve, mixed with magnesium stearate and pressed to give tablets.
Tablet weight: 220 mg Punch: 9 mm Example II

- Coated tablets containing 5 mg of D-6,11-dihydro-11-[[6-methyl-2,6-diazabicyclo[3.3.0]oct-2-yl]carbonyl]-5H-pyrido[2,3-b]
tl,5]benzodiazepin-5-one Tablets prepared according to Example I are coated with a shell consisting essentially of sugar and talc in accordance with conventional processes. The finished coated table~s are polished with the aid of beeswax.
' Coated tablet weight: 300 mg Example III
:`
Ampoules containing 10 mg of 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 :
' ' Composition: -1 ampoule contains:
Active ingredient 10.0 mg 5Odium chloride 8.0 mg Distilled water ad1 ml The active substance and sodium chloride are dissolved in distilled water and the solution is then made up to the given volume. The solution is sterile filtered and poured into 1 ml ampoules.
Sterilisation: 20 minutes at 120C.

.
Example IV

Suppositories containing 20 mg of 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 Composition:
1 suppository contains:
Active ingredient 20.0 mg Suppository substance (for example Witepsol W 45 ~) 1,680.0 mg 1,700.0 mg Finely powdered active substance is suspended in the molten suppository substance cooled to 40C. The substance is poured at 37C into slightly pre-cooled suppository moulds.
Suppository weight 1.7 g ~2~

~xample V

Drops containing 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 -Composition:
100 ml of drops solution contain:
Methyl p-hydroxybenzoate 0.035 g Propyl p-hydroxybenzoate 0.015 g Aniseed oil 0.05 g Menthol 0.06 g Pure ethanol 10.0 g Active ingredient 0.5 g Sodium cyclamate 1.0 g Glycerol 15.0 g Distilled water ad100.0 ml The active substance and sodium cyclamate are dissolved in approximately 70 ml of water and glycerol is added. p-Hydroxybenzoates, aniseed oil and menthol are dissolved inethanol and this solution is added to the aqueous solution with stirring. The solution is then made up to 100 ml with water and filtered free of suspended particles.

Claims (13)

1. Compounds of formula I

(I) (wherein ] ? represents one of the divalent groups (S) (T) (U) (V) X represents a =CH- group or a nitrogen atom;

R represents a straight-chained or branched C1-4 alkyl group optionally substituted by a phenyl group itself optionally mono or disubstituted by chlorine, bromine or fluorine atoms or methyl or methoxy groups;

R4 and R5, which may be the same or different, each represents a hydrogen, fluorine, chlorine or bromine atom or a C1-4 alkyl group;

R6 represents a hydrogen or chlorine atom or a methyl group;

R7 and R8, which may be the same or different, each represents a hydrogen atom or a C1-4 alkyl group and R8 may also represent a halogen atom;

m, n, o and p independently represent the numbers 0, 1, 2 or 3, where the sum of m+n and the sum of o+p are each 1, 2 or 3,the sum of n+o and the sum of m+p are each 1, 2, 3, 4 or 5, and the sum of m+n+o+p is greater than 2; and A1, A2, A3 and A4 each represent hydrogen atoms, and where m, n, o and p each is 1, either A1 and A2 together or A3 and A4 together may also represent an ethylene group) and the isomers and acid addition salts thereof.

2. Compounds of formula I as claimed in claim 1 wherein either X represents a nitrogen atom and ] ? represents a group (S) or X represents a =CH- group and ] ? represents group (V), represents a methyl group, R4 and R5 each independently represents a hydrogen, fluorine or chlorine atom or a methyl or ethyl group; and m, n, o and p are each 1 or m and o are each zero and n and p are each 2, and the isomers and salts thereof.

3. A compound as claimed in claim 1 being 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, D-6,11-dihydro-ll-[[6-methyl-Z,6-diazabicyclo[3.3.0]oct-2-yl]carbonyl]-5H-pyrido[2,3-b][1,5]benzodiazepin-5-one, or 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, or an isomer or salt thereof.

4. A pharmaceutical composition comprising a compound of formula I as claimed in any one of claims 1 to 3 or a physiologically acceptable salt thereof together with at least one pharmaceutical carrier or excipient.

5. A process for the preparation of compounds as claimed in claim 1, said process comprising at least one of the following steps a) (to prepare basic substituted compounds of formula Ia (Ia) (wherein X, R, R4, R5, R6, R7, R8, m, n, o, p, A1, A2, A3 and A4 are as defined in any one of claims 1 to 3 and ] ?
represents a group (S), (U) or (V) as hereinbefore defined or a group (T') (T') wherein R6' represents a chlorine atom or a methyl group)) reacting a carbonic acid derivative of formula II

(II) (wherein ] ? and X are as hereinbefore defined and Y repressents a halogen atom or a group OR11 in which R11 represents an optionally halogen-substituted C1-5 alkyl group, a phenyl group optionally substituted by halogen atoms or nitro groups, or a C7-15 aralkyl group) with a compound of formula III

(III) (wherein R, m, n, o, p, A1, A2, A3 and A4 are as hereinbefore defined) or an organo-metallic compound of formula IIIa (IIIa) (wherein M represents an alkali metal atom or 1 equivalent of an alkaline earth metal atom and A1, A2, A3, A4, R, m, n, o and p are as hereinbefore defined);

b) (to prepare basic substituted compounds of formula Ia) reacting a tricyclic compound of formula IV

(IV) (wherein X and ] ? are hereinbefore defined) with a chlorocarbonic acid derivative of formula V

(V) (wherein R, m, n, o, p, A1, A2, A3 and A4 are as hereinbefore defined);

c) (to prepare compounds of formula Ib (Ib) (wherein X, R, m, n, o, p, A1, A2, A3 and A4 defined in any one of claims 1 to 3 for formula I)) hydrogenolysing a compound of formula Ia in which R6' represents a chlorine atom;

d) converting a compound of formula I into an acid addition salt thereof or an acid addition salt of a compound of formula I into the free base; and e) separating a compound of formula I into the isomers thereof.

6. A process as claimed in claim 5 wherein process step (a) is effected in the presence of a solvent, at temperatures between -10°C and the boiling point of the reaction mixture, and optionally in the presence of a base or an excess of the compound of formula III.

7. A process as claimed in claim 5 wherein process step (b) is effected in an inert solvent, optionally in the presence of a base, and optionally at a temperature between 30 and 100°C.

8. A process as claimed in claim 5 wherein process step (c) is effected in the presence of a catalyst based on a metal of the VIIIth sub-group of the Periodic Table, at a hydrogen pressure of 1 to 300 bar, at a temperature of 0°
to 130°C and in the presence of a solvent.

9. A process as claimed in claim 5 wherein process step (c) is effected:

using formic acid and a palladium-on-charcoal catalyst at a temperature of between 70 and 110°C and in the presence of a solvent; or using triethylammonium formate in the presence of excess triethylamine and palladium on animal charcoal: or using palladium acetate and a triarylphosphine at a temperature of between 40 and 110°C.

10. The use of a compound of formula I as defined in any one of claims 1 to 3 or a physiologically acceptable salt thereof for the manufacture of a therapeutic agent for use in combatting cholinergically induced spasms and motility disorders in the gastrointestinal tract and in the region of the outwardly leading bile ducts, or cystitis and spasms from urelithiasis, or relative incontinence, or bronchial asthma and bronchitis or ischaemic heart diseases.

11. A method of treatment of the human or non-human animal body to combat cholinergically induced spasms and motility disorders in the gastrointestinal tract and in the region of the outwardly leading bile ducts, or cystitis and spasms from urelithiasis, or relative incontinence, or bronchial asthma and bronchitis or ischaemic heart diseases, said method comprising administering to said body a compound of formula I as defined in any one of claims 1 to 3 or a physiologically acceptable salt thereof.

12. Compounds of formula I as defined in claim 1 substantially as herein disclosed in any one of the Examples.

13. Each and every novel compound, composition, method, process and use herein disclosed.