NZ227758A

NZ227758A - Tricyclic diazepinone derivatives, preparatory processes and pharmaceutical compositions

Info

Publication number: NZ227758A
Application number: NZ227758A
Authority: NZ
Inventors: Wolfgang Eberlein; Wolfhard Engel; Gerhard Mihm; Gunter Trummlitz; Norbert Mayer; Henri Doods; Jonge Adriaan De
Original assignee: Thomae Gmbh Dr K
Priority date: 1988-01-27
Filing date: 1989-01-27
Publication date: 1991-09-25
Also published as: EP0326066A2; FI890380A; JPH01233284A; PT89540A; DK33389D0; IL89098A; KR890011886A; HUT49351A; IL89098A0; EP0326066A3; AU622887B2; PT89540B; AU2886289A; DE3802334A1; FI890380A0; IE890232L; HU203347B; DK33389A; ZA89659B; DD283391A5

Description

<div id="description" class="application article clearfix"> New Zealand Paient Spedficaiion for Paient Number £27758 22 7 7 5 8 Complete- Specification Filed: ..J.~l.r.l-J&Gy. Ciass: dO.TIlC5>.{4».($>"r7| .y^T) • <Z,OTn^44^^|ot^+ll^A(i)._lj<^xL/e5^. Pufriieatiors Date: .T.....^Jr.f. — W - - >niijr — 199T K'X Journftf; Patents Form No. 5 NEW ZEALAND PATENTS ACT 1953 COMPLETE SPECIFICATION CONDENSED DIAZEPINONES X^We, DR. KARL THOMAE GMBH, A Body corporate of the Federal Republic of Germany, of D-7950 Biberach an der Riss, FEDERAL REPUBLIC OF GERMANY hereby declare the invention, for which ¥/we pray that a patent may be granted to m*/us, and the method by which it is to be performed, to be particularly described in and by the following statement: - 1 - (followed by page la) - la- 22 7 7 5 8 OG 53 706 Condensed Diazepinones This invention relates to condensed diazepinones, and more particularly, to certain novel condensed diazepinones, processes for preparing them and pharmaceutical compositions containing them. Condensed diazepinones with anti-ulcerative properties and an inhibitory effect on the secretion of gastric juices have been described in EP-A-39519 and EP-A-57428 and in US Patents 3660380, 3691159, 4213984, 4213985, 4210648, 4410527, 4424225, 4424222 and 4424226. It is also known from EP-A-156191 that valuable pharmacological properties completely different from those of the compounds of the publications mentioned above can be induced by the introduction of new aminoacyl groups. We have now found that the certain new condensed diazepinones have superior properties when for use as vagal pacemakers for the treatment of bradycardia and bradyarrhythmia. Viewed from one aspect the invention thus provides compounds formula I (followed by page 2) - 2 - 22 7 7 5 8 wherein represents alkyl group and 2 R represents a straight-chained or branched C^_g alkyl group optionally substituted from the second carbon atom (i.e. at the beta, gamma, delta...carbons) by a hydroxy group, a C2_q cycloalkyl or (C3_g cycloalkyl)-methyl group in which the cycloalkyl moiety optionally is substituted by a methyl or hydroxy group, a phenyl (C-^_2 alkyl) group in which the phenyl moiety optionally is substituted by one or two substituents which may be the same or different selected from halogen atoms and methyl, methoxy and trifluoromethyl groups, or 1 2 R and R together with the intervening nitrogen atom represent a group of formula (CHJn , 2 n / \ 3 -N X (CV™ 2 m wherein n and m, which may be the same or different, each represents the integer 2,3 or 4, with the proviso that the sum of n and m is 4, 5 or 6, is a methylene group, an oxygen atom or a group of formula NR' where R' represents a hydrogen atom or a alkyl, phenyl alkyl) or phenyl group in which the phenyl nucleus is optionally substituted by one or two substituents selected 227758 - 3 - from halogen atoms and methyl, methoxy and trifluoromethyl groups; R3 represents a alkyl group or a hydrogen or chlorine atom; R4 represents a hydrogen atom or a methyl group; A represents a straight chain or branched C5_8 alkylene or alkenylene group, with the provisos that there are at least 5 carbon atoms in the carbon chain linking the semicyclic carbonyl group to the nitrogen atom of the N group, R and when A is a C5-alkylene group then -NR^2 is other than l-piperazinyl; ^b)represents a group of formulae fH3 N . R . R6 I I V R- (wherein R5 and R6, which may be identical or different, each represents a hydrogen, fluorine, chlorine or bromine atom or a C,_A alkyl group, R7 represents a methyl group or a chlorine atom or, if R3 represents a hydrogen atom or a alkyl group, R7 also may represent a hydrogen atom, R8 represents a hydrogen atom or a C.,_A alkyl group, 22 7 7 58 - 4 - 9 R represents a C1-4 alkyl group or a hydrogen or chlorine atom, and R1® represents a hydrogen atom or a methyl group); and i 2 X and X each represents a methine group or, if represents a group of formula ,8 cht h 3 \^N\ ft ,7 R10 1 2 X and X may each represent a nitrogen atom or i 2 one of X' and X may represent a methine group and ] 2 the other of X and X may represent a nitrogen atom), the isomers and acid addition salts thereof, especially for pharmaceutical use the physiologically acceptable salts. R\ The definition of the 0 N group R2/ given above includes, for example, (dimethylamino), (diethylamino), (dipropylamino), [[bis(methylethyl)]-amino], [(ethyl)butylamino], [(ethyl)methylamino], [(methylethyl)methylamino], [(butyl)methylamino], [(cvclobexyl)methylamino], trans-[(4-hydroxycyclo-hexyl)methylamino], [(phenylmethvl)methvlamino], (1-piperidinyl), (hexahydro-lH-l-azepinyl), (octahydro-1-azocinyl), (4-morpholinyl), (4-methyl-l-piper-azinyl), (4-hydroxy-l-piperidinyll, [4-(phenylmethyl)-1-piperazinyl], I 4-(2-phenylethyl)-1-piperazinyl], [4-(3-phenylpropyl)-1-piperazinyl], [(4-(4-chloro- 227758 2-methylphenyl)methyl)-1-piperazinyl], [4-(methylethyl) -1-piperazinyl], (4-ethyl-1-piperazinyl), [4-(4-methoxy-2-methylphenyl)-1-piperazinyl] and [4-[3-(trifluoromethyl)phenyl]-1-piperazinyl] groups. Examples of CO-A groups include 1-oxo-hexyl, 1-oxoheptyl, 1-oxooctyl, 1-oxononyl, 2-methyl-1-oxoheptyl, 2-ethyl-l-oxoheptyl, l-oxo-4-hexenyl, 1-oxo-5-heptenyl, l-oxo-6-octenyl, l-oxo-7-nonenyl, 2-methyl-l-oxo-4-hexenyl or 2-ethyl-l-oxo-4-hexenyl groups, which are substituted in the omega-position, and the 1-oxoheptyl and l-oxo-5-heptenyl group which are substituted in the 6-position by a 9 N group. R ^ Thus, for example, in addition to the compounds specified hereinafter in the Examples, the compounds of the invention include the compounds of formula I: 5,ll-dihydro-ll-[6-(dimethvlamino)-1-oxohexvl]-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one, 5,11-dihydro-11-[6-[(methylethyl)methylamino]-1-oxohexyl]-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one, 11-[7-(diethylamino)-1-oxoheptyl]-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one, 5,11-dihydro-11-[6-(4-methyl-1-piperazinyl)-1-oxohexyl] 6K-pyrido[2,3-b][1,4]benzodiazepin-6-one, 11-[6-[(cyclohexyl)methylamino]-1-oxohexyl]-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one, - 6 - 22 7 7 5 8 trans-5,ll-dihydro-ll-[6-[f 4-hydroxycvclohexyl)methylamino] -1-oxohexyl]-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one, 5,ll-dihydro-ll-[6-[(phenylmethyl)methylamino]-1-oxohexyl]-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one, 5,11-dihydro-11-[6-(1-piperidinyl)-1-oxohexyl]-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one, 5,11-dihydro-ll-[6-(4-hydroxy-1-piper idinyl)-1-oxohexyl]-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one, 5,ll-dihydro-ll-[6-(hexahydro-lH-l-azepinyl)-1-oxohexyl]-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one, 5,11-dihydro-ll-[6-[4-(phenylmethyl)-1-piperazinyl)-1-oxohexyl]-6H-pyrido[2,3-b][l,4]benzodiazepin-6-one, 5,11-dihydro-ll-[6-[4-(2-phenylethyl)-1-piperazinyl) -1-oxo-hexyl]-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one r 5,11-dihydro-ll-[6—[4—(3-phenylpropyl)-1-piperazinyl)- I-oxohexyl]-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one, II-[6-[(4-(4-chloro-2-methylphenyl)methyl]-1-piperazinyl) 1-oxohexyl]-6H-pyrido[2,3-b][1,4]benzodiazepin- 6-one, 5,11-dihydro-ll-[6—[4—(methylethyl)-1-piperazinyl]-l-oxohexvl]-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one, 22 7 7 5 8 5,11-dihydro-ll-[6-(4-ethyl-1-piperazinyl)-1-oxohexyl]-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one, 5,11-dihydro-ll-[6-[4-[3-(trifluoromethyl)phenyl]-1-piperazinyl)-1-oxohexyl]-6H-pyrido[2,3-b][1,4]benzo-diazepin-6-one, (Z) -5,11-dihydro-ll-[6-(1-piperidinyl)-l-oxo-4-hexenyl]-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one, (E)-5,11-dihydro-ll-[6-(1-piperidinyl)-l-oxo-4-hexenyl]-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one, (Z)-5,11-dihydro-ll-[7-(1-piperidinyl)-l-oxo-5- heptenyl]-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one, (E)-5,11-dihydro-ll-[7-(1-piperidinyl)-l-oxo-5-heptenyl]-6H-pyrido[ 2,3-b][1,4]benzodiazepin-6-one, 5,11-dihydro-ll-[6-[4-(4-methoxy-2-methylphenyl)-1-piperazinyl]-1-oxohexyl]-6H-pyrido[2,3-b][1,4]benzo-diazepin-6-one, 5,11-dihydro-ll-[2-methyl-6-(4-methyl-1-piperazinyl)-1-oxohexyl]-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one, (+)-5,11-dihydro-ll-[2-ethyl-6-(4-methyl-l-piperazinyl)-1-oxohexyl]-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one, (-)-5,11-dihydro-ll-[2-propyl-6-(4-methyl-1-piperazinyl)-1-oxohexyl]-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one, 22 7 7 5 8 - 8 - 5, ll-dihydro-ll-[ 3-methyl-6- (4-methyl-l-piperazinyl) -1-oxohexyl]-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one, 5,ll-dihydro-ll-[4-methyl-6-(4-methyl-l-piperazinyl)-1-oxohexyl]-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one, 5,ll-dihydro-ll-[5-methyl-6-(4-methyl-l-piperazinyl) -1-oxo-hexyl]-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one, 5,11-dihydro-ll-[6-(4-methyl-l-piperazinyl)-1-oxoheptyl]-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one, 5,11-dihydro-ll-[7-(1-piperidinyl)-1-oxoheptyl]-6H-pyrido[ 2,3-b] [ 1,4 ]benzodia7:epin-6-one, 6,11-dihydro-ll-[6-(1-piperidinyl)-1-oxohexyl]-5H-pyrido[2,3-b][1,5]benzodiazepin-5-one, 6,ll-dihydro-ll-[6-fhexahydro-lH-l-azepinyl)-1-oxohexyl]-5H-pyrido[2,3-b][1,5]benzodiazepin-5-one, 6,11-dihydro-ll-[6-(4-methyl-l-piperazinyl)-1-oxohexyl]-5H-pyrido[2,3-b][1,5]benzodiazepin-5-one, 5,ll-dihydro-8-methyl-11-[6-(1-piperidinyl)-1-oxohexyl]-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one, 5,ll-Dihydro-8-methyl-ll-[6-(hexahydro-lH-l-azepinyl)-1-oxo-hexyl]-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one. 5,ll-dihydro-8-methvl-ll-[6-(4-methyl-l-piperazinyl)-1-oxohexyl]-6H-pyrido[2,3-b][1,4]benzodiazepin- - 9 - 22 7 7 58 6-one, 5 , ll-dihydro-9-methyl-ll-[ 6- (1-piperidinyl) -1-oxohexyl] -6H-pyrido[2,3-b][1,4]benzodiazepin-6-one, 5,ll-dihydro-9-methyl-ll-[6-(hexahydro-lH-l-azepinyl)-1-oxo-hexyl]-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one, 5,ll-dihydro-9-methyl-ll-[6-(4-methyl-l-piperazinyl)-1-oxo-hexyl]-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one, 9-chloro-5,11-dihydro-ll-[6-(1-piperidinyl)-1-oxohexyl]-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one, 9-chloro-5,11-dihydro-ll-[6-(hexahydro-lH-l-azepinyl)-1-oxohexyl]-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one, 9-chloro-5,11-dihydro-ll-[6-(4-methyl-l-piperazinyl)-1-oxohexyl]-6H-pyrido[2,3-b][1,4]benzodiazepin -6-one, 4,9-dihydro-3-methyl-4-[6-(1-piperidinyl)-1-oxohexyl]-10H-thieno[3,4-b][1,5]benzodiazepin-10-one, 4,9-dihydro-4-[6-(hexahydro-lH-l-azepinyl)-1-oxohexyl]- 3-methyl-10H-thieno[3,4-b][1,5]benzodiazepin-10- one, 4,9-dihydro-3-methvl-4-[6-(4-methyl-l-piperazinyl) -l-oxohexvl]-10H-thieno[3,4-b][l,5]benzodiazepin- 10-one, 4,9-dihydro-l,3-dimethyl-4-[6-(4-methyl-1-piperazinyl)-1-oxo-hexyl]-lOH-thieno[3,4-b][1,5]benzodiazepin- 22 7758 - 10 - 10-one, 3-chloro-4,9-dihydro-4-[6-(4-methyl-l-piperazinyl)-1-oxohexyl]-10H-thieno[3,4-b][1,5]benzodiazepin-10-one, 1,3-dimethyl-4-[6-(1-piperidinyl)-1-oxohexyl]-1,4,9,10-tetrahydropyrrolot 3,2-b][1,5]benzodiazepin-10-one, 1,3-dimethyl-4-[6-(hexahydro-lH-l-azepinyl)-1-oxohexyl]-1,4,9,10-tetrahvdropyrrolo[3,2-b][1,5]benzodiazepin-10-one, 1,3-dimethyl-4-[6-(4-methyl-l-piperazinyl)-1-oxohexyl]-1,4,9,10-tetrahvdropyrrolo[3,2-b][1,5]benzodiazepin-10-one, 3-chloro-l-methyl-4-[6-(4-methyl-l-piperazinyl)-1-oxohexyl]-1,4,9,10-tetrahydropyrrolo[3,2-b][1,5]benzodiazepin- 10 -one , l-methyl-4-[6-(4-methyl-l-piperazinyl)-1-oxohexyl]-1,4,9,10-tetrahydropvrrolo[3,2-b][1,5]benzodiazepin-10-one, 1,3-dimethyl-4-[6-(1-piperidinyl)-l-oxohexvl]-1,4,9,10-tetrahydropyrazolof 4,3-b][l,5]benzodiazepin-10-one, 1,3-dimethyl-4-[6-(hexahydro-lH-l-azepinyl)-1-oxohexyl]-1,4,9,10-tetrahydropyrazolo[4,3-b][1,5]benzodiazepin-10-one, 1,3-dimethyl-4-[6-(4-methyl-l-piperazinyl)-1-oxohexyl]-1,4,9,10-tetrahydropyrazolof4,3-b][1,5]benzodiazepin-10-one and - 11 - 22 7 7 58 l-methyl-4-[ 6- (4-methyl-l-piperazinyl) -1-oxohexyl] -1,4,9,10-tetrahydropyrazolo[4,3-b][1,5]benzodiazepin-10-one, and the isomers and acid addition salts, especially physiologically acceptable acid addition salts, thereof. Preferred compounds according to the invention include those of formula I wherein R1 represents a methyl or ethyl group, 7 R" represents a C^_3 alkyl group or a cyclohexyl, trans-(4-hydroxycvclohexyl) or phenylmethyl group or 1 2 R and R together with the intervening nitrogen atom represent a 1-piperidinyl, 4-hydroxy-l-piperidinyl or hexahydro-lH-azepinyl group or a 1-piperazinyl group optionally substituted in the 4-position by a alkyl, phenyl (C-,^alkyl) or phenyl group wherein the phenyl nucleus itself is optionally substituted by one or two substituents, which may be identical or different, selected from methyl, methoxy and trifluoromethyl groups, 3 R represents a methyl group or a hydrogen or chlorine atom, 4 R represents a hydrogen atom or a methyl group, A represents a alkylene group optionally methyl-substituted in the alpha-position to the semicyclic carbonyl group and/or containing a double bond in the gamma-delta-position, - 12 - ^ represents a group of formula 5 or 6 ' 22 7 7 (wherein R represents a hydrogen atom, R^ represents a hydrogen, chlorine or bromine atom or a methyl or ethyl group in the 8 or 9-position of the heterocyclic ring system, g R represents a hydrogen atom and 9 R represents a hydrogen atom or a methyl group), X1 represents a methine group, and 2 X represents a methine group or a nitrogen atom, and the isomers and acid addition salts thereof. However, particularly preferred compounds according to the invention include the compounds of formula la (la) wherein 12 2 R , R , A and X are as hereinbefore defined and - 13 - 22 7 7 5 8 B)represents a qroup of formula or S CH 3 and the isomers and acid addition salts thereof. Viewed from a further aspect the invention also provides a process for preparing the compounds of the invention, said process comprising at least one of the following steps: (a) (to prepare compounds of formula I wherein 7 R represents a chlorine atom or a methyl group) reacting a compound of formula II H 0 (II) CO - A - Y (wherein 3 4 1 2 R , R , A, X and X are as hereinbefore defined represents a group of formula 8 R 10 wherein R^, R^ and R^ to R"*"^ are as hereinbefore defined 22 7 7 58 - 14 - and R represents a methyl group or a chlorine atom, and Y is a halogen atom, preferably a chlorine or bromine atom), with an amine of formula III H - N R Nr2 fill) (wherein 1 2 R and R are as hereinbefore defined); (b) (to prepare compounds of formula I wherein 7 R represents a chlorine atom or a methyl group) reacting a compound of formula IV (IV) (wherein R^, R^, X^" and X^ are as hereinbefore defined and By represents a group of formula R I CH_ t 3 N ^ R R 7' R" N or ?H3 N T I R wherein R5, R^ and R^ to R10 are as hereinbefore - 15 - 22 7 7 58 defined and 7 T R represents a methyl group or a chlorine atom) with a compound of formula V R s Nu - CO - A - N (V) \ 2 R (wherein 1 2 R , R and A are as hereinbefore defined and Nu represents a nucleofugic group); (c) catalytically hydrogenating a compound of formula VI 3 Ho R ■> ' // 1 N II A ^ (VI) ^ . x \ R1 ' 1 / CO - Z - N XR2 (wherein R^" to R^ and^B) are as hereinbefore defined and 7?' represents a straight-chained or branched Cc 0 D — O alkenylene or alkynylene group, preferably containing the double or triple bond in the 2,3-position relative to the 1 2 N group, * \ R with the proviso that the carbon chain linking the semicyclic carbonyl group to the nitrogen atom of the 22 77 5 9 N group is at least 5-membered); R (d) (to prepare compounds of formula I wherein R represents a hydrogen atom or a C, alkyl 7 group, R represents a hydrogen atom and A represents a saturated alkylene group) hydrogenolysing a compound of formula VII wherein Yb), 1 4 12 R to R , X and X are as hereinbefore defined and 2 Z represents a straight-chained or branched C,_ g alkylene, alkenylene or alkynylene group, with the proviso that the carbon chain linking the semicyclic carbonyl group to the nitrogen atom of the 9 N group is at least 5-membered and may R ^ contain a double or triple bond, preferably in the r1\ 2,3-position relative to the ~ N groups; R ^ (e) resolving a compound of formula I thus obtained into the diastereoisomers or enantiomers thereof; - 17 - 22 7 7 5 8 and (f) converting a compound of formula I thus obtained into an acid addition salt thereof or an acid addition salt of a compound of formula I into the free base. The amination of step (a) may conveniently be carried out in an inert solvent at temperatures of between -10°C and the boiling temperature of the solvent, preferably with, for each mole of the compound of formula II, either at least 2 moles of the secondary amine of formula III or 1 to 2 moles of a secondary amine of formula III and an auxiliary base. Suitable solvents include, for example, chlorinated hydrocarbons such as methylene chloride, chloroform or dichloroethane; open-chained or cyclic ethers such as diethylether, tetrahydrofuran or dioxan; aromatic hydrocarbons such as benzene, toluene, xylene, chlorobenzene or pyridine; alcohols such as ethanol or isopropanol; ketones such as acetone; acetonitrile, dimethylformamide or 1,3-dimethyl-2-imidazolidinone. Examples of auxiliary bases include tertiary organic bases such as triethyl-amine, ^-methylpiperidine, diethylaniline, pyridine and 4-(dimethylamino)pyridine or inorganic bases such as alkali metal or alkaline earth metal carbonates or hydrogen carbonates, hydroxides or oxides. If desired, the reaction may be accelerated by the addition of alkali metal iodides. The reaction times range from 15 minutes to 80 hours depending on the nature and quantity of the amine of formula III used. The reaction of step (b) of the compound of formula IV with the acid derivative of formula v may be carried out using conventional techniques. The leaving group Nu is a group which together with - 18 - 22 7 7 5 8 the carbonyl group to which it is bonded forms a reactive carboxylic acid derivative. Examples of reactive carboxylic acid derivatives include acid halides, esters, anhydrides or mixed anhydrides, such as are formed from salts of the corresponding acids (i.e. where Nu = OH) and acid chlorides such as phosphorus oxychloride diphosphoric acid tetrachloride or chloroformic acid esters or the N-alkyl-2-acyloxypyridinium salts formed when compounds of formula V (in which Nu = OH) are reacted with N-alkyl-2-halopvridinium salts. Preferably, the reaction of step (b) is carried out with the mixed anhydrides of strong inorganic acids, particularly dichlorophosphoric acid. The reaction is optionally carried out in the presence of an acid binding agent (proton acceptor). Examples of suitable proton acceptors include alkali metal carbonates or hydrogen carbonates, such as sodium carbonate or potassium hydrogen carbonate; tertiary organic amines such as pyridine, triethylamine, ethyl diisopropylamine, 4-(dimethylamino)pyridine or sodium hydride. The reaction is conveniently carried out at temperatures of between -25°C and 130°C, preferably in an inert solvent. Examples of inert solvents include chlorinated aliphatic hydrocarbons such as methylene chloride, 1,2-dichloro-ethane; open-chained or cyclic ethers such as diethyl-ether, tetrahydrofuran or 1,4-dioxan; aromatic hydrocarbons such as benzene, toluene, xylene, o-dichlorobenzene; polar aprotic solvents such as acetonitrile, dimethylformamide or hexamethyl-phosphoric acid triamide; or mixtures thereof. The reaction times range between 15 minutes and 80 hours depending on the nature and quantity of the acylating agent of formula V used. It is not necessary to prepare the compounds of formula V - 19 - 22 7 7 5 8 in pure form; rather, they may be produced iji situ in the reaction mixture using conventional techniques. The catalytic hydrogenation of step (c) is conveniently is carried out in the presence of catalysts based on metals of the Vlllth sub-group of the Periodic Table of Elements, for example palladium on animal charcoal, palladium on barium sulphate, Raney nickel or Raney cobalt, under hydrogen pressures of from 0.1 to 300 bar and at temperatures of from 0 to 130°C, preferably at ambient temperature, and in the presence of solvents, for example alcohols such as methanol or ethanol, ethers such as dioxan, diethylether or tetrahydrofuran, carboxylic acids such as acetic acid or tertiary amines such as triethylamine. Any halogen present in the starting materials of formula VI, with the exception of fluorine, is generally split off during the catalytic hydrogenation. In order to prepare compounds of formula I wherein A represents an alkenylene group starting from a compound of formula VI wherein Z ~ represents an alkynylene group the procedure used is preferably either to break off the catalytic hydrogenation after the uptake of 1 mole of hydrogen and/or to carry out the catalytic hydrogenation in the presence of a deactivated catalyst, e.g. palladium on calcium carbonate deactivated v?ith lead or cadmium (Lindlar catalyst), palladium on barium sulphate with the addition of quinoline or P2 nickel in the presence of ethylenediamine. Compounds of formula I characterised by Z geometry with regard to the olefinic double bond are predominantly formed. - 20 - 22 7 7 58 Obviously, a compound of formula I thus obtained wherein A represents an alkenylene group may subsequently, as described above, be further hvdrogenated to obtain a compound of formula I wherein A represents an alkylene group. The hydrogenolysis of step (d) is conveniently carried out in the presence of catalysts based on metals of the Vllith sub-group of the Periodic Table of Elements, for example palladium on animal charcoal, palladium on barium sulphate, Raney nickel or Raney cobalt, and under hvdroqen pressures of from 1 to 300 bar, and at temperatures of from 0°C to 130°C, in the presence of solvents, for example alcohols such as methanol or ethanol; ethers such as dioxan, tetrahydrofuran; carboxylic acids, e.g. acetic acid; or tertiary amines, for example triethylamine. If the operation is carried out in the absence of additional hydrogen chloride acceptors, for example sodium carbonate, potassium hydrogen carbonate, triethylamine or sodium acetate, the hydrochlorides of the desired compounds are formed directly and may be isolated after removal of the catalyst by evaporation of the reaction solution. If in the above hydrogenolysis reaction formic acid is used in place of hydrogen, the reaction will be successful in theory even under pressureless conditions. In this alternative embodiment, the reaction is preferably effected with formic acid in the presence of dimethylformamide as solvent and palladium on charcoal as catalyst at temperatures of between 70 and 110°C, and reduction with triethyl-ammonium formate in the presence of 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 of between 40 and 110°C, - 21 - 22 7 7 5 8 have proved particularly successful. Suitable acids for use in the preparation of addition salts include, for example, hydrochloric, hydrobromic, sulphuric, methylsulphuric, phosphoric, tartaric, fumaric, citric, maleic, succinic, gluconic, malic, p-toluenesulphonic, methanesulphonic and amidosulphonic acid. The compounds of the invention contain up to two independently chiral elements, and may, in certain circumstances, include an asymmetric carbon atom in the side chain. The second chiral element is the acylated tricyclic group itself, which may occur in two mirror-image forms. It depends on the nature of the tricyclic group whether the energy barrier for ring inversion is so high that the individual isomers are stable at ambient temperature and so are capable of isolation. The substituents in the peri positions adjacent to the aminoacyl side chain are of particular importance to the height of the inversion barrier. It has been found 2 that compounds of formula I wherein X is a methine group and B represents an o-phenylene group always occur in two diastereoisomeric forms which may be separated at ambient temperature. The individual diastereoisomers are totally stable in the crystalline state, but go into solution and, at ambient temperature, revert to the original mixture with a half-life of a few days. In compounds of formula I wherein 2 X represents a nitrogen atom and B represents an o-phenylene group, the activation energy required is reduced so much that at ambient temperature diastereoisomers can no longer be detected (except by complex "'"H-NMR spectra) , let alone preparatively separated. 22 7 7 5 8 - 22 - The compounds of formula I according to the invention thus contain, under certain circumstances, two chiral centres, one of which is not always configur-ationally stable at ambient temperature. These compounds may therefore occur in two diastereoisomeric forms or as enantiomeric (+) and (-) forms. Diastereo-meric cis/trans forms are also possible if A in the compounds of formula I claimed represents an alkenylene group. The invention includes the individual isomers as well as the mixtures thereof. The diastereomers may be separated on the basis of their different physico-chemical properties, e.g. by fractional recrystallisation from suitable solvents, by high pressure liquid chromatography, column chromatography or gas chromatography. The separation of any racemates of the compounds of formula I may be carried out by conventional methods, 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. According to a conventional method of separating isomers, the racemate of a compound of formula I is reacted with one of the optically active acids specified above in equimolar quantities in a solvent and the crystalline diastereoisomeric salts obtained are separated, using their different solubilities. This reaction may be carried out in any type of solvent provided that the latter exhibits sufficiently different solubilities for the salts. Preferably, methanol, ethanol or mixtures thereof, e.g. in a ratio by volume of 1:1, are used. Each of the - 23 - 22 7 7 5 8 optically active salts is then dissolved in water and neutralised with a base such as sodium carbonate or potassium carbonate and in this way the corresponding free compound is obtained in the (+) or (-) form. A single enantiomer or a mixture of two optically active diastereoisomeric compounds covered by formula I may also be obtained by carrying out the syntheses described above with only one enantiomer of formula II or V. In order to prepare the haloacyl compounds of formula II, the starting compounds of formula IV are reacted with compounds of formulae VIII or IX Hal-A-CO-Hal (VIII) [Hal-A-C0]20 (IX) wherein Hal represents a chlorine, bromine or iodine atom. This acylation is carried out without a solvent or preferably in an inert solvent at ambient temperature or elevated temperature, up to the boiling temperature of the solvent, optionally in the presence of an auxiliary base and/or an acylation catalyst. The acid halides of formula VIII are preferable to the acid anhydrides of formula IX. Examples of suitable solvents include aromatic hydrocarbons such as toluene, xylene and chlorobenzene; open chained or cyclic ethers such as diisopropylether and dioxan; chlorinated hydrocarbons such as dichloro-ethane; other solvents such as pyridine, acetonitrile and dimethylformamide. Examples of suitable auxiliary bases include tertiary organic bases such as triethylamine and ethyl diiso- - 24 - 227758 propylamine and pyridine; and inorganic bases such as anhydrous alkali metal and alkaline earth metal carbonates and hydrogen carbonates and alkaline earth metal oxides. Examples of acylation catalysts include imidazole, pyridine and 4-dimethylamino-pyridine. If in a compound of formula II Hal represents a chlorine atom, it may easily be exchanged for the more reactive iodine by reacting with sodium iodide in acetone or ethanol. The secondary amines of formula III are commercially obtainable or may easily be prepared by methods analogous to those known from the literature. The tricyclic groups of formula IV are known from the literature or may be synthesised from common starting materials by adhering closely to published methods. The starting compounds of formula V may be obtained via the corresponding esters, i.e. compounds of formula V wherein Nu represents an alkoxy group may be obtained by reacting secondary amines of formula III with carboxylic acid esters of formula X Hal-A-CC^R11 (X) wherein Hal and A are as hereinbefore defined and R"1 ~ represents a lov;er alkyl (e.g. group, optionally using additional auxiliary bases, e.g. triethylamine, or catalysts, e.g. Triton B. By saponification of the esters obtained, e.g. with barium hydroxide solution, the carboxylic acids of formula V are obtained which may be used to prepare derivatives with other nucleofugic groups. 22 7 7 5 8 - 25 - The starting compouncls of formulae VI and VII may be obtained by reacting a corresponding compound of formula II with a corresponding secondary amine of formula III. The compounds of formula I and the physiologically tolerable acid addition salts thereof have valuable pharmacological properties; in particular, whilst having excellent stability to hydrolysis, high selectivity and good resorption after oral administration, they have favourable effects on heart rate and, in view of their lack of mydriatic effects or inhibitory effects on the secretion of gastric acid or salivation, they are suitable for use as vagal pacemakers in the treatment of bradycardia and bradyarrhythmia in human as well as veterinary medicine; some of the compounds also exhibit spasmolytic properties on peripheral organs, particularly the colon and bladder. A favourable relationship between tachycardiac effects on the one hand and the undesirable effects on pupil size and the secretion of tears, saliva and gastric acid, on the other hand, which occur with therapeutic agents having an anticholinergic component, is of particular importance for the therapeutic use of the substances. The following tests show that the compounds according to the invention exhibit surprisingly favourable properties in this respect. 22 7 7 5 8 26 A. Studies of binding to muscarinic receptors: In vitro measurement of the IC^q value The organs were donated by male Sprague-Dawley rats weiqhing 180-220 g. After the heart and submandibular gland and cerebral cortex had been removed, all other steps were carried out in ice cold Hepes HCl buffer (pH 7.4; 100 millimolar NaCl, 10 millimolar MgCl2). The whole heart was cut up with scissors. All the organs were then homogenised in a Potter apparatus. For the binding test the homogenised organs were diluted in the buffer as follows: The homogenised organs were incubated in an Eppendorf centrifuge tube at 30°C at a given concentration of the radioligand and at a series of concentrations of the non-radioactive test substances. Incubation lasted 4 5 minutes. The radioligand used was 0.3 nanomolar 3 3 H-N-methylscopolamine ( H-NMS). Incubation was ended by the addition of ice cold buffer followed by vacuum filtration. The filters were rinsed with cold buffer and their radioactivity was determined. It represents the sum of specific and non-specific 3 binding of H-NMS. The proportion of non-specific binding was defined as the radioactivity which was bound in the presence of 1 micromolar cruinuclidinyl-benzylate. Each measurement was taken four times. The values of the non-labelled test substances were determined graphically. They represent that Whole heart Cerebral cortex Submandibular gland 1: 3000 1: 400 1: 400 22 77 5 - 27 - concentration of the test substance at which the specific binding of "H-NMS to the muscarinic receptors in the various organs was inhibited by 50%. The results are set forth in Table I. B. Investigation of functional selectivity of the antimuscarinic effect Substances with antimuscarinic properties inhibit the effects of agonists supplied exogenically or of acetylcholine, which is released from cholinergic nerve endings. The following is a description of some methods that are suitable for the detection of cardioselective antimuscarinic agents. "In vivo" methods The objective of the methods was to confirm the selectivity of the antimuscarinic effect. Those substances which had been selected on the basis of "in vitro" test results were tested for their 1. M^/M2 selectivity in the rat, 2. Salivation-inhibiting effect on the rat and 3. Inhibition of the acetylcholine effect on the bladder, bronchi and heart rate in the guinea pig. I. Mj/Mq selectivity in the rat The method used was that described by Hammer and Giachetti in Life Sciences 32., 2991-2998 (1982) . 5 minutes after intravenous injection of increasing doses of the test substance, either the right vagus was electrically stimulated (frecruency: 25 Hz; pulse width: 2ms; duration of stimulus: 30s; voltage: - 28 - 22 7 7 5 8 supramaximal) or 0.3 mg/kg of McN-A-343 were intravenously injected into male THOM rats. The bradycardia caused by vagus stimulation and the rise in blood pressure caused by McN-A-343 were determined. The dosage of the substances which reduced either the vagal bradycardia (M2) or the rise in blood pressure (M-j,) by 50% was determined graphically. The results are set forth in Table II. 2. Salivation-inhibiting effect in the rat Using the method of Lavy and Mulder (see Arch. int. Pharmacodyn. 178, 437-445, (1969H, male THOM rats anaesthetised with 1.2 g/kg of urethane were given increasing doses of the test substance by i.v. route. The secretion of saliva was initiated by subcutaneous administration of 2 mg/kg of pilocarpine. The saliva was absorbed with blotting paper and the surface area covered was measured every 5 minutes by planimetry. 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. 3. Inhibition of the effect of acetylcholine on the bladder, bronchi and heart rate in guinea pigs 5 minutes after the administration of the test substance, 10 microgram/kg of acetylcholine were simultaneously injected intravenously and intra-arterially into anaesthetised guinea pigs. The heart rate was recorded directly by extracorporeal derivation of the ECG, the expiration resistance according to Konzett-RftBler and contraction of the exposed bladder. In order to determine the inhibition of the acetylcholine activity on the organs under investigation, dosage/activity curves - 29 - 22 7 7 58 were recorded and from them -log ED^q values were determined. The results are set forth in Table III. The following compounds, by way of example, were investigated according to the procedures set forth above: A = 5,ll-dihydro-ll-[5-(1-piperidinyl)-1-oxohexyl]-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one, and as comparison substances B = ll-[[2-[(diethylamino)methyl]-1-piperidinyl]acetyl]-5,ll-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one (see US Patent No. 4550107), C = 5,11-dihydro-ll-[(4-methyl-l-piperazinyl)acetyl]-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one (see US Patent No. 3660380) and D = atropine. 227758 - 30 - Table It Receptor Binding Tests jji vitro: Results: Receptor Binding IC5Q[nmol 1~ Tests Substance Cortex Heart A 60 10 B 1200 140 C 100 1500 D 2 4 The information shown in Table I above shows that the compounds of the invention distinguish between muscarinic receptors in different tissues. This is clear from the substantially lower IC^q values when the test substances are investigated on preparations from the heart compared with those from the cerebral cortex. 22 7 7 5 8 - 31 - Table II: Mi/Mj selectivity and salivation-inhibiting activity on the rat: Results: Substance -log ED50 Heart [mol kg Blood pressure Salivation A 7.75 6.42 6.65 B 6.42 5.63 5.0 0 C 5.60 6.94 6. 22 D 7.94 7.34 7.60 22 7 7 5 - 32 - Table III Inhibition of acetylcholine activity on the bladder, bronchi and heart rate in the guinea pig: Results: Substance -log ED50 Heart [mol kg Bronchi Bladder A 6.88 7.49 6.20 B 5.84 5.58 4.73 C 5.58 6.57 5.36 D 7.70 7.96 7.03 The pharmacological data in Tables II and III above show - in total agreement with the receptor binding studies - that the heart rate is increased by the above-mentioned compounds even at dosages at which there is no restriction in the secretion of saliva. Moreover, the pharmacological data in Table III above indicate a surprisingly high power of selectivity between the heart and smooth muscle. The above-mentioned substances show a substantially improved effectiveness compared with the known compound E. At the same time, their therapeutically useful selectivity is retained. This results in a reduction in the Quantity of drug which needs to be administered to the patient without increasing the risk of muscarinic side effects. 227758 33 Furthermore, the compounds prepared according to the invention are well tolerated; even in the highest doses administered, no toxic side effects were observed in the pharmacological trials. For pharmaceutical use the compounds of the invention may be incorporated in known manner in conventional pharmaceutical preparations, e.g. solutions, suppositories, plain or coated tablets, capsules infusions, etc. The daily dosage is expected to be between approximately 0.02 and 5 mg/kg, preferably 0.02 and 2.5 mg/kg, in particular 0.05 and 1.0 mg/kg of body weight, optionally administered in the form of several, preferably 1 to 3, individual doses in order to achieve the desired results. Thus viewed from a further aspect the invention provides a pharmaceutical composition comprising a compound of formula I or a physiologically acceptable acid addition salt thereof together with one or more pharmaceutical carriers or excipients. Viewed from a still further aspect the invention provides the use of a compound of formula I or of a physiologically acceptable acid addition salt thereof for the manufacture of a pharmaceutical composition for use as a vagal pacemaker for treating bradycardia and bradyarrhythmia. Viewed from a yet still further aspect the invention also provides a method of treatment of the non-human animal body to combat bradycardia and bradyarrhythmia comprising the administration to said body of a compound of formula I or a physiologically acceptable acid addition salt thereof. I 22 7 7 5 8 - 34 - The following Examples are intended to illustrate the invention, without limiting its scope in any way. Percentages and ratios are by weight unless otherwise indicated. Satisfactory elemental, IR, UV and ^"H-NMR analyses are available for all the compounds and mass spectra are available for many of them. Example 1 5,ll-Dihydro-ll-[6-f1-piperidinyl)-1-oxohexyl]-6H-pyrido[2,3-b][l,4]benzodiazepin-6-one 0.9 g (2.317 mmol) of 5,ll-dihydro-ll-[6-(1-piperidinyl) -l-oxo-4-hexynvl]-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one (m.p.: 197°C) were dissolved in 45 ml of ethanol and after the addition of 0.3 g of 10% palladium on animal charcoal the mixture was hydro-genated under 3 bar of hydrogen pressure and at ambient temperature until the uptake of hydrogen had ceased. The mixture was filtered, the filtrate was evaporated down in a water jet vacuum and the oily residue was triturated with a few drops of diethylether. Crystallisation occurred. The precipitate was removed by suction filtering and recrystallised once more from ethyl acetate. 0.84 g (92% of theory) of colourless crystals were obtained, m.p. 168-170°C. Example 2 11-[6-[(Cyclohexyl)methylamino]-1-oxohexyl]-5,11-dihydro-SH-pyrido[2,3-b][1,4]benzodiazepin-6-one Prepared analogously to Example 1 from 11-f6-[(cyclo-hexyl)methylamino]-l-oxo-4-hexynyl]-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one (m.p.: n 7 7 58 - 35 - 162-163°C) by catalytic hydrogenation in the presence of palladium on animal charcoal in a yield of 56% of theory. Colourless crystals, m.p. 98-100°C (ethyl acetate). Example 3 Trans-5,11-dihydro-ll-[6-[(4-hydroxycyclohexyl)methylamino] -1-oxohexyl]-6H-pyrido[2,3-b][l,4]benzodiazepin-6-one Prepared analogously to Example 1 from trans-5,11-dihydro-ll- [ 6- [ (4-hydroxycyclohexyl)methylamino]-l-oxo-4-hexynyl]-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one (m.p.: 176-178°C) by catalytic hydrogenation in the presence of palladium on animal charcoal in a yield of 36% of theory. Colourless crystals, m.p. 178-179°C (ethyl acetate). Example 4 5,11-Dihydro-ll-[6-[(phenylmethyl)methylamino]-1-oxohexyl]-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one Prepared analogously to Example 1 from 5,11-dihydro-ll- [ 6- [ (phenylmethyl)methylamino]-l-oxo-4-hexynyl]-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one (m.p.: 204-206°C) by catalytic hydrogenation in the presence of palladium on charcoal in a yield of 47% of theory. Colourless crystals, m.p. 128°C (diethylether). 22 77 - 36 - Example 5 5,11-Dihydro-ll-[6-fhexahvdro-lH-l-azepinyl)-1-oxohexyl]-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one Prepared analogously to Example 1 from 5,11-dihydro-ll-[6-(hexahydro-lH-l-azepinyl)-l-oxo-4-hexvnyl]-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one (m.p.: 169-170°C) by catalytic hydrogenation in the presence of palladium on charcoal in a yield of 40% of theory. Colourless crystals, m.p. 140°C (ethyl acetate). Example 6 5,11-Dihydro-ll-[6-[4-(phenylmethyl)-1-piperazinyl]-1-oxohexyl]-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one Prepared analogously to Example 1 from 5,11-dihydro-11-—[ 6 — [ 4— (phenylmethyl) -l-piperazinyl]-l-oxo-4-hexynyl]-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one (m.p.: 157-158°C) by catalytic hydrogenation in the presence of palladium on animal charcoal in a yield of 50% of theory. Colourless crystals, m.p. 105-107°C (ethyl acetate). Example 7 5,ll-Dihvdro-ll-[2-methyl-6-(4-methyl-l-piperazinyl)-1-oxohexyl]-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one Prepared analogously to Example 1 from 5,11-dihydro-ll-[2-methyl-6-(4-methyl-l-piperazinyl)-l-oxo-4-hexynyl]-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one (m.p.: 212-214°C) by catalytic hydrogenation in the presence of palladium on charcoal in a yield of 52% of theory. Colourless crystals, m.p. 156°C (ethyl acetate./diethyl ether, 1:1 y/v) . - 37 - Example 8 227758 5,11-Dihydro-ll-[7-(1-piperidinyl)-1-oxoheptyl]-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one and (Z)-5,11-dihydro-ll-[7-(1-piperidinyl)-l-oxo-5-heptenyl]-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one 800 mg (1.988 mmol) of 5,ll-dihydro-ll-[7-(l-piper-idinyl)-l-oxo-5-heptynyl]-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one (m.p.: 166-167°C) were dissolved in 20 ml of methanol and after the addition of 100 mg of 10% palladium/charcoal catalyst the mixture was hydrogenated for 10 hours in a Parr autoclave at ambient temperature under a hydrogen pressure of 0.7 bar. The catalyst was filtered off, the filtrate was evaporated down Jji vacuo and the mixture of products obtained was separated by column chromatography on silica gel (30-60 micrometers) using ethyl acetate/methanol/cyclohexane/conc. ammonia (8:1:1:0.1 by volume) as eluant. Bv working up the corresponding fractions, 250 mg (31% of theory) of colourless crystals were obtained, m.p. 148-149°C (diisopropylether) which v;ere characterised by NMR spectroscopy as 5,ll-dihydro-ll-[7-(1-piperidinyl)- I-oxoheptyl]-6H-pyrido[2,3-b][1,4]benzodiazepin- e-one together with 100 mg (12% of theory) of colourless crystals, m.p. 125°C, (diisopropylether), which were assigned the structure of a (Z)-5,11-dihydro- II-[7-(1-piperidinyl)-l-oxo-5-heptenyl]-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one. Example 9 (2)-5,11-Dihydro-ll-[6-(1-piperidinyl)-l-oxo-4-hexenyl]-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one Prepared analogously to Example 1 from 5,11-dihydro- 22 77 58 - 38 - 11-[6-(1-piperidinyl)-l-oxo-4-hexvnyl]-6H-pyrido[2,3-b]-[1,4]benzodiazepin-6-one, but using palladium on calcium carbonate and contaminated with lead (Lindlar catalyst), instead of palladium on animal charcoal as catalyst, in a yield of 58% of theory. Colourless crystals, m.p. 184°C (ethvl acetate). Example 10 5,11-Dihydro-ll-[6-(dimethylamino)-1-oxohexyl]-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one a mixture of 6.0 g (17.45 mmol) of 11-(6-chloro- 1-oxohexyl)-5,ll-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin- 6-one (m.p.: 128-130°C [decomp.]), 2.3 g (57.7 mmol) of dimethylamine and 160 ml of anhydrous ethanol was heated for 5 hours to 100°C in a bomb tube. The mixture was then evaporated down _in vacuo, the oily residue obtained was purified by HPLC using silica gel as the stationary phase and dichloro- methane/cyclohexane/methanol/conc. ammonia/ethyl acetate (177.5:23:23:3:75.5 by volume) as the mobile phase. 0.2 g (3.3% of theory) of colourless crystals, m.p. 129-130°C (acetonitrile) "ere isolated from the suitable fractions. Example 11 5,11-Dihydro-ll-[6-(4-methyl-l-piperazinyl)-1-oxohexyl]-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one Prepared analogously to Example 10 from 11-(6-chloro-1-oxohexyl)-5,ll-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one and 1-roethylpiperazine in a yield of 8.4% of theory. Colourless crystals, m.p. 179-181°C (from ethyl acetate using activated charcoal). 22 7 7 58 - 39 - Example 12 5 f11-Dihydro-ll-[6-(4-hydroxy-l-piperidinyl)-1-oxohexyl]-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one Prepared analogously to Example 1 from 5,11-dihydro-ll-[6-(4-hydroxy-l-piperidinyl)-l-oxo-4-hexynvl]-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one (m.p.: 175-176°C) by catalytic hydrogenation in the presence of palladium on animal charcoal in a yield of 54% of theory. The colourless salt with 1 molar equivalent of fumaric acid melted at 145°C (decomp.) (from ethyl acetate/ethanol = 1:1 = v/v). Example 13 5,11-Dihydro-ll-[6—[4 —(methylethyl)-1-piperazinyl]-1-oxohexyl]-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one Prepared analogously to Example 1 from 5,11-dihydro-ll-[6-[4-(methylethyl)-l-piperazinvl]-l-oxo-4-hexynyl]-6H-pyr ido[2,3-b][1,4]benzodiazepin-6-one (m.p.: 124-126°C) by catalytic hydrogenation in the presence of palladium on animal charcoal in a yield of 66% of theory. Colourless crystals, m.p. 141-142°C (ethyl acetate). Example 14 5,11-Dihydro-ll-[6-(4-ethyl-l-piperazinyl)-I-oxohexyl]-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one Prepared analogously to Example 1 from 5,11-dihydro-11-[6-(4-ethyl-l-piperazinyl)-l-oxo-4-hexynyl] 22 7 7 58 - 40 - -6H-pyrido[2,3-b][l,4]benzodiazepin-6-one by catalytic hydrogenation in the presence of palladium on animal charcoal in a yield of 62% of theory. Colourless crystals, m.p. 161-162°C. (ethyl acetate) . Example 15 5,11-Dihydro-ll-[6-[4-[3-(trifluoromethyl)phenyl]- I-piperazinyl]-1-oxohexyl]-6H-pyrido[2,3-b][1,4]benzo-diazepin-6-one heroifuroarate Prepared analogously to Example 1 from 5,11-dihydro- II-[6-[ 4-[ 3-(trifluoromethyl)phenyl]-l-piperazinyl]-l-oxo-4-hexynyl]-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one by catalytic hydrogenation in the presence of palladium on animal charcoal in a yield of 11% of theory. The hemifumarate melted at 199-200°C (acetone). Example 16 4,9-Dihydro-4-[6-(hexahydro-lH-l-azepinyl)-1-oxohexyl]- 3-methyl-10H-thieno[3,4-b][1,5]benzodiazepin-10- one Prepared analogously to Example 1 from 4,9-dihydro-4 — [6—(hexahydro-lH-l-azepinyl)-l-oxo-4-hexynyl]-3-methyl-10H-thieno[3,4-b][1,5]benzodiazepin-10-one (m.p. 192-193°C) in a yield of 15% of theory. Colourless crystals, m.p. 103-104°C (diisopropyl ether). 22 7 7 - 41 - Example 17 5,11-Dihydro-ll-[6-(1-piperidinyl)-1-oxohexyl]-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one A mixture of 12.60 g (0.0632 mol) of 1-piperidine-hexanoic acid and 2.0 g of a 75% sodium hydride dispersion in paraffin oil was heated in 160 ml of anhydrous dimethylformamide at 50 to 80 °C until the liberation of hydrogen had ceased. To the resulting sodium salt of the entire acid were added 13.20 g (0.0625 mol) of 5,ll-dihvdro-6H-pyrido[2,3-b]-[1,4]fcenzodiazepin-6-one and at -10°C 9.9 a (0.0646 mol) of phosphorus oxychloride were added dropwise within 10 minutes. The mixture was stirred for 4 hours at -10°C, for 4 hours at 0°C and for 20 hours at ambient temperature. The mixture was stirred into 300 g of ice, adjusted to pF 9 with sodium hydroxide solution and extracted exhaustively with dichloro-methane. The combined organic Dhases were washed once with a little ice water, dried over sodium sulphate and concentrated by evaporation. The oily residue was triturated with a few drops of diethylether, whereupon crystallisation occurred. The precipitate was separated by suction filtering and recrystallised from ethyl acetate using activated charcoal. 5.15 g (21% of theory) of colourless crystals were obtained, m.p. 169-170°C, which were found to be totally identical to a sample obtained according to Example 1 when investigated by thin layer chromatography, mixed melting point, IR, UV and ~H-NMR spectra. 22 7 7 58 - 42 - The following Examples illustrate the preparation of some pharmaceutical administration forms: Example I Tablets containing 5 mg of 5/ll-dihydro-ll-[6-(1-piperidinyl)-1-oxohexyl]-6H-pyrido[2,3-b][1,41benzodiazepine -one 1 tablet contains: Active substance Lactose Potato starch Magnesium stearate Total 5.0 mg 148.0 mg 65.0 mg 2.0 mg Weight: 220.0 mg A 10% mucilage is prepared from potato starch by heating. The active substance, lactose and remaining potato starch are mixed together and granulated with the above mucilage through a 1.5 mm mesh screen. The granules are dried at 45°C, rubbed through the same screen again, mixed with magnesium stearate and compressed with a punch of diameter of 9 mm to form tablets weighing 220 mg. Example II Coated tablets containing 5 mg of 5,11-dihydro- ll- [ 6-(l-piperidinvl)-1-oxohexyl]-6H-pyrido[2,3-b][l,4]~ benzodiazepin-6-one The tablets prepared according to Example I are coated, by a known method, with a coating consisting essentially of sugar and talc. The finished coated tablets are polished with beeswax and weigh approximately 300 mg each. 22 77 58 - 43 - Example III Ampoules containing 10 mg of 5,11-dihydro-ll-[6-(1-piperidinyl)-1-oxohexyl]-6H-pyrido[2,3-b][1,4]benzodiazepine -one 1 ampoule contains: Active substance 10.0 mg Sodium chloride 8.0 mg Distilled water ad 1 ml The active substance and sodium chloride are dissolved in distilled water and then made up to the volume specified. The solution is sterile filtered and transferred into 1 ml ampoules. Sterilisation: 20 minutes at 120°C. Example IV Suppositories containing 20 mg of 5,11-dihydro- ll- [6-(1-piperidinyl)-1-oxohexyl]-6H-pyrido[2,3-b][1,4]- benzodiazepin-6-one 1 suppository contains: Active substance 20.0 mg Suppository mass (e.g. Witepsol W 45) 1 680.0 mg 1 700.0 mg The finely powdered active substance is suspended in the molten suppository mass which has been cooled to 40°C. The mass is poured at 37°C into slightly chilled suppository moulds. Weight of suppository: 1.7 g (Witepsol W45 is a registered trade mark). </div>

Claims

<div id="claims" class="application article clearfix printTableText"> 22 7 7 5 8 - 44 - Example V Drops containing 5,11-dihydro-ll-[6-(1-piperidinyl)-1-oxohexyl]-6H-pyrido[2,3-b][1,4jbenzodiazepin-6-one 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 substance 0. , 5 g Sodium cyclamate 1. .0 g Glycerol 15. .0 g Distilled water ad 100. ,0 ml The active substance and sodium cyclamate are dissolved in about 70 ml of water and glycerol is added. The p-hydroxybenzoates, aniseed oil and menthol are dissolved in ethanol and this solution is added with stirring to the aqueous solution. Finally, the solution is made up to 100 ml with water and filtered to remove any suspended particles. 227758 WHAT ^fWE CLAIM tS:- 45

1. Compounds of formula I R R 1 (I) CO - A - N \r2 (wherein R^" represents a alkyl group 2 R represents a straight-chained or branched C^_g alkyl group optionally substituted from the second carbon atom by a hydroxy group, a C3_g cycloalkyl or (C3_g cycloalkyl)methyl group in which the cycloalkyl moiety optionally is substituted by a methyl or hydroxy group, a phenyl (C-^_2 alkyl) group in which the phenyl group optionally is substituted by one or two substituents selected from halogen atoms and methyl, methoxy and trifluoromethyl groups, or 1 2 R and R together with the intervening nitrogen atom represent a a group of formula wherein n and m, which may be the same or different, 227758 - 46 - each represents the integer 2, 3 or 4, with the proviso that the sum of n and m is 4, 5 or 6, X3 is a methylene group, an oxygen atom or a group of formula NR' where R1 represents a hydrogen atom, or a Cv3 alkyl, phenyl (C^ alkyl) or a phenyl group in which the phenyl nucleus is optionally substituted by one or two substituents selected from halogen atoms and methyl, methoxy and trifluoromethyl groups; R3 represents a C.,.3 alkyl group or a hydrogen or chlorine atom; R4 represents a hydrogen atom or a methyl group; A represents a branched or straight chain C5_8 alkylene or alkenylene group, with the provisos that there are at least 5 carbon atoms in the carbon chain linking the semicyclic carbonyl group and the nitrogen atom of the R1 R' N group, and when A is a C5-alkylene group then -NR^2 is other than 1-piperazinyl; ^(b) represents a group of formula Yn 'kW . ?»3 N _ V or CH, '/ 3 N ^ N A . T E/v 10 18MAR/99I 0'/ /j // 22 77 58 - 47 - 5 fi (wherein R and R , which may be identical or different, each represents a hydrogen, fluorine, chlorine or bromine atom or a alkyl group, R represents a methyl group or a chlorine atom or, if R^ represents a hydrogen atom or a C, , 7 "" alkyl group, R may also represent a hydrogen atom, g R represents a hydrogen atom or a C^_4 alkyl group, 9 R represents a alkyl group or a hydrogen or chlorine atom; and >10 represents a hydrogen atom or a methyl group); 1 2 X and X each represent a methine group or, if B) represents one of the groups 5 R8 R R CH, t 3 or N ,10 R" 1 2 y and X may each represent a nitrogen atom or 1 2 one of v and X may represent a methine group and 1 2 the other of X and X may represent a nitrogen atom), the isomers and acid addition salts thereof.

2. Compounds as claimed in claim 1 being compounds of formula I wherein R^~ represents a methyl or ethyl group, 2 R represents a C^_^ alkyl group or a cyclohexyl, 227758 - 48 - trans-(4-hydroxycyclohexyl) or phenylmethyl group or 1 2 R and R together with the intervening nitrogen atom represent a 1-piperidinyl, 4-hydroxy-l-piperidinyl or hexahydro-lH-azepinyl group, or a 1-piperazinyl group optionally substituted in the 4-position by a C1-3 alkyl, phenyl (C1_3 alkyl) or phenyl group wherein the phenyl nucleus itself is optionally substituted by one or two substituents selected from methyl, methoxy and trifluoromethyl groups, R represents a methyl group or a hydrogen or chlorine atom, 4 R represents a hydrogen atom or a methyl group, A represents a C^_g alkylene group optionally methvl-substituted in the alpha-position to the semicyclic carbonyl group and/or containing a double bond in the gamma-delta-position, [b) represents a group of formula R8 % R9 5 (wherein R represents a hydrogen atom, represents a hydrogen, chlorine or bromine atom or a methyl or ethyl group in the 8 or 9-position of the heterocyclic ring system, I R5 or R6 22 77 58 - 49 - O R represents a hydrogen atom and R represents a hydrogen atom or a methyl group), X1 represents a methine group, and 9 X represents a methine group or a nitrogen atom, and the isomers and acid addition salts thereof.

3. Compounds as claimed in claim 1 being compounds of formula la (la) co - a - n wherei n 12 2 R , R , A and x are as defined in either of claims 1 and 2 and b) represents a group of formula or and the isomers and acid addition salts thereof.

4. A compound as claimed in claim 1 being 5,11-dihydro-ll-[6-(1-piperidinyl)-1-oxohexyl]-6h-pyrido[2,3-b]f1,4]benzodiazepin-6-one, 227758 - 50 - 5,11-dihydro-ll-[6-[4-[3-(trifluoromethyl)phenyl]-1-piperazinyl]-1-oxohexyl]-6H-pyrido[2,3-b][1,4]benzo-diazepin-6-one, or an isomer or acid addition salt thereof.

5. A compound as claimed in claim 1 being 5,11-dihydro-ll-[6-(1-piperidinyl)-1-oxohexyl]-6H-pyrido[ 2,3-b][1,4]benzodiazepin-6-one, or an isomer or acid addition salt thereof.

6. A compound as claimed in any one of claims 1 to 5 being a physiologically acceptable salt of a compound of formula I.

7. A pharmaceutical composition comprising a compound of formula I as claimed in any one of claims 1 to 5 or a physiologically acceptable acid addition salt thereof together with one or more pharmaceutical carriers or excipients.

8. A process for the preparation of the compounds claimed in any one of claims 1 to 6, said process comprising at least one of the following steps: 7 a) (to prepare compounds of formula I wherein R represents a chlorine atom or a methyl group) reacting a compound of formula II (wherein 3 4 1 2 R , R , A, X and X are as defined in any one - 51 - of claims 1 to 5; 22 7 7 58 y represents a group of formula „ 8 I J R" I CH, I 3 I \ -]J f R R" or T CH, I 3 N . N A R 10 wherein R^, R^ and R8 to R"10 are as defined in 7' any one of claims 1 to 5 and R represents a methyl group or a chlorine atom, and Y represents an halogen atom) with an amine of formula III ,1 R H - N ^ fill) V (wherein 1 2 R" and R are as defined in any one of claims 1 to 5) ; b) (in order to prepare compounds of formula I 7 wherein R represents a chlorine atom or a methyl group) reacting a compound of formula IV (wherein 22 7 7 5 - 52 - 3 4 1 2 R , R , X and X are as defined in any one of claims 1 to 5; and represents a group of formula N or ?H3 N N 1 wherein R , R and R to R are as defined in 7 ' any one of claims 1 to 5 and R represents a methyl group or a chlorine atom) with a compound of formula v Nu - CO - A - N / V (V) (wherein 1 2 R t R and A are as defined in any one of claims 1 to 5; and Nu represents a nucleofugic group); c) catalytically hydrogenating a compound of formula VI R (VI) 22 77 58 - 53 - (wherein R^" to R^ andj(B) are as defined in any one of claims 1 to 5 and Z"^ represents a straight-chained or branched C^_g alkenylene or alkynylene group, with the proviso that the carbon chain linking the semicyclic carbonyl group to the nitrogen atom of the r1\ 9 N group is at least five-membered); R ^ d) (to prepare compounds of formula I wherein R represents a hydrogen atom or a alkyl group, R^ represents a hydrogen atom and A represents a saturated alkylene group) hydrogenolysing a compound of formula VII (wherein 1 4 1 2 p to R , (B/'X and X are as defined in any one of claims 1 to 5; and 2 Z represents a straight chained or branched C5_g alkylene, alkenylene or alkynylene group, with the proviso that the carbon chain linking the semi-cyclic carbonyl group to the nitrogen atom of the ■■ ' u 227758 R1 - 54 - N group is at least five-membered); (e) resolving a compound of formula I thus obtained into the diastereoisomers or enantiomers thereof; and (f) converting a compound of formula I thus obtained into an acid addition salt thereof or an acid addition salt of a compound of formula I into the free base.

9. A process as claimed in claim 8 wherein the reaction is carried out in a solvent.

10. A process as claimed in claim 8 or 9 wherein the reaction of step (a) is carried out at temperatures of between -10°C and the boiling temperature of the solvent used.

11. A process as claimed in claim 8 or 9 wherein the reaction of step (b) is carried out at temperatures of between -25°C and 130°C.

12. A process as claimed in claim 8 or 9, wherein the catalytic hydrogenation of step (c) is carried out in the presence of a catalyst comprising a metal of the Vlllth subgroup of the Periodic Table of Elements, under hydrogen pressures of from 0.1 to 3 00 bar and at temperatures of between 0 and 130°C.

13. A process as claimed in claim 12 wherein (to prepare compounds of formula I wherein A contains a double bond) a compound of formula VI wherein Z1 contains * a triple bond is catalytically hydrogenated and the hydrogenation is broken off after the uptake of 1 molar ,equivalent of hydrogen. 14. A process as claimed in claim 13, wherein (to ^ 0 AUGJ99 £|PrePare compounds of formula I wherein A £ i v t.

V V >\\ 7.27758 55 m contains a double bond) a compound of formula VI wherein Z1 contains a triple bond is catalytically hydrogenated and hydrogenation is carried out in the presence of a deactivated catalyst.

15. A process as claimed in claim 8 or 9, wherein the hydrogenolysis of step (d) Ms carried out in the presence of a catalyst comprising a metal of the Vlllth subgroup of the Periodic Table of Elements, under hydrogen pressures of from 1 to 300 bar and at temperatures of between 0 and 130°C.

16. A process as claimed in claim 8 or 9, wherein the hydrogenolysis of step (d) is carried out in the presence of a catalyst comprising a metal of the Vlllth subgroup of the Periodic Table of Elements, in the presence of formic acid or a derivative thereof as the hydrogen source, and at temperatures of between 70 and 110°C.

17. Use of a compound of formula I as defined in claim 1 or of a physiologically acceptable acid addition salt thereof for the manufacture of a pharmaceutical composition for use as a vagal pacemaker for treating bradycardia and bradyarrhythmia.

18. A method of treatment of the non-human animal body to combat bradycardia and bradyarrhythmia comprising the administration to said body of a compound of formula I as defined in claim 1 or a physiologically acceptable acid addition salt thereof.

19. Compounds of formula I as defined in claim 1 and salts thereof substantially as herein disclosed in any one of the Examples. dr. karl thomae gmbh </div>