NZ229409A

NZ229409A - Substituted diazepinones and pharmaceutical compositions

Info

Publication number: NZ229409A
Application number: NZ229409A
Authority: NZ
Inventors: Wolfhard Engel; Wolfgang Eberlein; Gerhard Mihm; Gunter Trummlitz; Norbert Mayer; Henri Doods; Jonge Adriaan De
Original assignee: Thomae Gmbh Dr K
Priority date: 1988-06-08
Filing date: 1989-06-06
Publication date: 1990-12-21
Also published as: DD284014A5; HU203754B; EP0345629B1; DE3819444A1; IL90549A0; ZA894297B; GR3006558T3; DE58902273D1; AU612851B2; HUT50470A; KR900000366A; EP0345629A3; DK277589D0; JPH0232074A; EP0345629A2; ATE80630T1; CA1320198C; DK277589A; AU3613789A

Abstract

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

Description

<div class="application article clearfix" id="description"> New Zealand Paient Spedficaiion for Paient Number £29409 22 94 n MO DRAwmrjg Priority Date(s): 3.-.!*. Complete Specification Filed: Q>.'.*9.'WX. Class: Wf?\(qV\-iQ&iAV^/... £C?7) j. Pkf.l S&JP. kO./aU i i.%; Publication Date: D.EC.]??? P.O. Journal, Mo: , ...A330.-. Class Cont: 'v.QTI .QaT? DM&?J {?Zi.\ZiZZj. 9S£VfSSfe&..tel3.9i; Patents Form No. 5 Class Cont: At*. \ )f^2x \.[ S£? ./3&/.. • f/i f Si(i '■ i ( > ■ I ■ ■ ■ • I I ■ I NEW ZEALAND PATENTS ACT 1953 COMPLETE SPECIFICATION CONDENSED DIAZEPINONES i L... _ }j£/We, DR KARL THOMAE GMBH, a body corporate organized under the laws of the FEDERAL REPUBLIC OF GERMANY, of D-7950 Biberach an der Riss, FEDERAL REPUBLIC OF GERMANY, hereby declare the invention, for w.hich X/we pray that a patent may be granted to i^/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) * \ \- " ' fv," - la -Condensed Diazepinones 22 9 4 0 9 r-t € 10 The invention relates to certain new condensed diazepinones, processes for preparing them and pharmaceutical compositions containing these compounds. Condensed diazepinones with the properties of inhibiting both ulcer formation and the secretion of gastric acid are described in EP-A-39519, EP-A-57428, US-A-3660380, US-A-3691159, US-A-4213984, US-A-4213985, US-A-4210648, US-A-4410527, US-A-4424225, US-A-4424222 and US-A-4424226. EP-A-156191 describes how the introduction of certain aminoacyl groups may lead to valuable pharmacological properties completely different from those' of the 15 compounds disclosed in the above-mentioned publications. We have now found that certain new condensed diazepinones, compared with the compounds of EP-A-156191, are distinguished by a substantially increased activity and marked resistance to hydrolysis, 20 whilst having comparable or better selectivity and resorption after oral administration. O1 25 30 35 Thus, viewed from one aspect the invention provides a compound of formula I (wherein ^ Z (I) represents one of the groups (S) , (T) , (U) , (V) and (W) (followed by Page 2) 22 9 4 0 9 T J (S) CH, I 3 .N (T) R" (0) N ^ (V) CH-I • •N v N II X 10 (W) 10 o X1 and X2 each represents a methine group or, where represents a group (S), (U) or (W), both or either of X1 and X2 may alternatively represent a nitrogen atom; 15 A represents a straight-chained alkylene group; R1 and R2, which may be the same or different, each represents a c^s alkyl group or R1 and R2 together with the intervening nitrogen atom represent a 4- to 7-membered, saturated, monocyclic, heteroaliphatic ring 20 25 optionally interrupted by an oxygen atom or by a^N-CH3 group; R3 represents a alkyl group or a chlorine or hydrogen atom; O 30 35 Ra represents a hydrogen atom or a methyl group; R5 and R6, which may be the same or different, each represents a hydrogen, fluorine, chlorine or bromine atom or a alkyl group; R7 represents a hydrogen or chlorine atom or a methyl group; Rs represents a hydrogen atom or a Cj_4 alkyl group; R9 represents a hydrogen or halogen atom or a Calkyl _ < ?29409 io - 3 - group; R10 represents a hydrogen atom or a methyl group; and Z represents a single bond, an oxygen or sulphur atom or a methylene or 1,2-ethylene group; with the proviso that where represents a group (T) and R7 represents a hydrogen atom, then R3 represents a hydrogen atom or a C.,_4 alkyl group and Z represents other than a sulphur atom) or an isomer or acid addition salt thereof. Preferred compounds according to the invention include compounds of formula I wherein: X1 represents a methine group; X2 represents a nitrogen atom, 30 represents a group S, R3, R4 and R5 represent hydrogen atoms and R6 represents a hydrogen atom or a chlorine or bromine atom or a methyl or ethyl group in the 8- or 9- position of the tricyclic moiety, or X represents a methine group, epresents a group 0 <v> or (U) , R8 represents a hydrogen atom and R9 represents a methyl group; A represents an unbranched, saturated alkylene group; u R1 and R2, which may be the same or different, each represents a C.,_5 alkyl group or .R1 and R2 together with the intervening nitrogen atom represent a 4- to J7-membered, saturated, monocyclic, heteroaliphatic ring N optionally interrupted by an oxygen atom or a^N-CH group; and Z represents a single bond, an oxygen atom or a methylene or 1,2-ethylene group; / I 4 22 9 4 0 9 and isomers and salts, especially physiologically acceptable acid addition salts, thereof. Particularly preferred compounds according to the invention include compounds of formula I wherein: X1 represents a methine group; X2 represents a nitrogen atom, represents a divalent group (S), R3, R4 and R5 represent hydrogen atoms and R6 represents a hydrogen atom or a chlorine or bromine atom or a methyl or ethyl group in the 8- or 9-position of the tricyclic moeity; A represents an unbranched, saturated alkylene group; R1 and R2, which may be the same or different, each represents a alkyl group or R1 and R2 together with the intervening nitrogen atom represent a 5- to 7-membered, saturated, monocyclic, heteroaliphatic ring . , N optionally interrupted by an oxygen atom or a ^N-CH3 group; and Z represents a single bond, an oxygen atom or a methylene or 1,2-ethylene group; and isomers and salts thereof. The compounds of formula I, after reaction with inorganic or organic acids, may be converted into their physiologically acceptable salts. Examples of acids which have proved suitable are hydrochloric, hydrobromic, sulphuric, methylsulphuric, phosphoric, tartaric, fumaric, citric, maleic, succinic, gluconic, malic, p-toluenesulphonic, methanesulphonic, amidosulphonic and cyclohexanesulphaminic acids. 22 9 4 0 5 The following compounds will be mentioned by way of example to illustrate the invention: 11-[4-[2-[(diethylamino)methyl]-1-piperidiny1]-1-oxobutyl]-5,ll-dihydro-6H-pyrido[2,3-b][1,4] benzodiazepin-6-one; D,L-5,11-dihydro-ll-[4-[2-[(dimethylamino)methyl]-1-piperidinyl]-1-oxobutyl]-6H-pyrido[2,3-b][1,4] benzodiazepin-6-one; 5,11-dihydro-ll-[4-[2-[(ethylmethylamino)methyl]-1-piperidiny1]-1-oxobutyl]-6H-pyrido[2,3-b][1,4] benzodiazepin-6-one; 5,ll-dihydro-ll-[4-[2-[(dipropylamino)methyl]-1-piperidinyl]-1-oxobutyl]-6H-pyrido[2,3-b][1,4] benzodiazepin-6-one? 11-[4-[2-[(diethylamino)methyl]-1-pyrrolidiny1]-1-oxobutyl]-5,ll-dihydro-6H-pyrido[2,3-b][1,4] benzodiazepin-6-one; 11-[4-[2-[(diethylamino)methyl]-1-azetidinyl]-1-oxobutyl]-5,ll-dihydro-6H-pyrido[2,3-b][1,4] benzodiazepin-6-one; D,L-ll-[4-[2-[2-(diethylamino)ethyl]-1-piperidinyl]-1-oxobutyl]-5,ll-dihydro-6H-pyrido[2,3-b][1,4] benzodiazepin-6-one; D,L-5,11-dihydro-ll-[4-[2-[2-(4-morpholinyl)ethyl]-1-piperidinyl]-1-oxobutyl]-6H-pyrido[2,3-b][1,4] benzodiazepin-6-one; 5,11-dihydro-ll-[4 — [2 — [2-(hexahydro-lH-1-azepinyl)ethyl]-1-piperidinyl]-1-oxobutyl]-6H-pyrido[2,3-b][l,4]benzodiazepin-6-one; 6 229409 5,11-dihydro-ll-[4-[2-[2-(dimethylamino)ethyl]-1-piperidinyl]-1-oxobutyl]-6H-pyrido[2,3-b][1,4] benzodiazepin-6-one; D,L-ll-[4-[3-[(diethylamino)methyl]-4-morpho1iny1]-1-oxobutyl]-5,ll-dihydro-6H-pyrido[2,3-b][1,4] benzodiazepin-6-one; D-ll-[4-[3—[(diethylamino)methyl]-4-morpholinyl]-1-oxobutyl]-5,ll-dihydro-6H-pyrido[2,3-b][1,4] benzodiazepin-6-one; L-ll-[4-[3-[(diethylamino)methyl]-4-morpholinyl]-1-oxobutyl]-5,ll-dihydro-6H-pyrido[2,3-b][1,4] benzodiazepin-6-one; 11-[4-[2-[(diethylamino)methyl]-1-piperidinyl]-1-oxobutyl]-5,ll-dihydro-9-methyl-6H-pyrido[2,3-b][1,4] benzodiazepin-6-one; 11-[4-[2-[(diethylamino)methyl]-1-piperidinyl]-1-oxobutyl]-5,ll-dihydro-8-methyl-6H-pyrido[2,3-b][1,4] benzodiazepin-6-one; 11-[4-[3-[(diethylamino)methyl]-4-morpholinyl]-1-oxobutyl]-5,ll-dihydro-8-ethyl-6H-pyrido[2,3-b][1,4] benzodiazepin-6-one; 9-chloro-ll-[4-[3-[(diethylamino)methyl]-4-morpholinyl]-1-oxobutyl]-5,ll-dihydro-6H-pyrido[2,3-b][1,4] benzodiazepin-6-one; 8-bromo-ll-[4-[2-[(diethylamino)methyl]-1-piperidinyl]- I-oxobutyl]-5,ll-dihydro-6H-pyrido[2,3-b][1,4] benzodiazepin-6-one methanesulphonate; II-[4-[2-[(1-azetidiny1)methyl]-1-piperidinyl]-1-oxobutyl]-5,ll-dihydro-6H-pyrido[2,3-b][1,4] n o 10 122 9 4 0 9 benzodiazepin-6-one; 11-[4-[4-[3-(diethylamino)propyl]-1-piperidinyl]-l-oxobutyl]-5,ll-dihydro-6H-pyrido[2,3-b][1,4] benzodiazepin-6-one; 5,11-dihydro-ll-[4-[2-[(1-pyrrolidinyl)methyl]-1-piperidiny1]-1-oxobutyl]-6H-pyrido[ 2,3-b][1,4] benzodiazepin-6-one; 5,11-dihydro-ll-[4-[4-[4-(1-pyrrolidinyl)butyl]-1-piperidinyl]-1-oxobutyl]-6H-pyrido[2,3-b][1,4] benzodiazepin-6-one; * 15 11-[4-[3-[4-(diethylamino)butyl]-1-piperidinyl]-1-oxobutyl]-5,ll-dihydro-6H-pyrido[2,3-b][1,4] benzodiazepin-6-one; 5,11-dihydro-ll- [ 4-[3- [ 2- (1-pyrrc.lidinyl) ethyl] -1-2 0 piperidinyl]-1-oxobutyl]-6H-pyrido[2,3-b][1,4] benzodiazepin-6-one; 5,11-dihydro-ll-[4-[3-[4-(1-pyrrolidinyl)butyl]-1-piperidinyl]-1-oxobutyl]-6H-pyrido[2,3-b][1,4] 25 benzodiazepin-6-one; 11—[4—[3—[2—(diethylamino)ethyl]-hexahydro-lH-1-azepinyl]-1-oxobutyl]-5,ii-dihydro-6H-pyrido[2,3-b][1,4] (^) benzodiazepin-6-one; 30 11-[4-[2-[(diethylamino)methyl]-1-piperidinyl]-1-oxobutyl]-6,ll-dihydro-5H-pyrido[2,3-b][1,5] benzodiazepin-5-one; 35 11-[4-[2-[2-(diethylamino)ethyl]-1-piperidinyl]-1-oxobutyl]-6,ll-dihydro-5H-pyrido[2,3-b][1,5] benzodiazepin-5-one; 8 22 9 4 0 9 ll-[4-[3-[(diethylamino)methyl]-4-morpholinyl]-1-oxobutyl]-6,ll-dihydro-5H-pyrido[2,3-b][1,5] benzodiazepin-5-one; 11-[4-[4-[3-(diethylamino)propyl]-1-piperidinyl]-1-oxobutyl]-6,ll-dihydro-5H-pyrido[2,3-b][1,5] benzodiazepin-5-one; 11-[4-[3-[4-(diethylamino)butyl]-1-piperidinyl]-1-oxobutyl]-6,ll-dihydro-5H-pyrido[2,3-b][1/5] benzodiazepin-5-one; 5-[4-[3-[2-(diethylamino)ethyl]-hexahydro-lH-l-azepinyl] -1-oxobutyl]-5,10-dihydro-llH-dibenzo[b,e][1,4] diazepin-ll-one; 5-[4-[2-[(diethylamino)methyl]-1-piperidinyl]-1-oxobutyl]-5,10-dihydro-llH-dibenzo[b,e][l/4] diazepin-ll-one; 5-[4-[2-[2-(diethylamino)ethyl]-1-piperidinyl]-1-oxobuty1]-5,10-dihydro-llH-dibenzo[ b, e][1,4]diazepin-ll-one ; 5-[4-[3-[(diethylamino)methyl]-4-morpholinyl]-l-oxobutyl]-5,10-dihydro-llH-dibenzo[b,e][1,4]diazepin-ll-one ; 5-[4-[4-[3-(diethylamino)propyl]-1-piperidinyl]-1-oxobutyl]-5,10-dihydro-llH-dibenzo[ b, e j[1,4]diazepin-ll-one; 5-[4-[3-[4-(diethylamino)butyl]-1-piperidinyl]-1-oxobutyl]-5,10-dihydro-llH-dibenzo[b, e][1,4]diazepin-ll-one ; 4,9-dihydro-3-methyl-4-[4-[3-[2-(1-piperidinyl)ethyl-hexahydro-lH-l-azepinyl]-1-oxobutyl]-10H-thieno[3,4- 9 22 9 4 0 9 b][1,5]benzodiazepin-10-one; 4,9-dihydro-3-methyl-4-[4-[2-[(1-piperidinyl)methyl]-1-piperidinyl]-1-oxobutyl]-lOH-thieno[3,4-b][1,5]benzo-diazepin-10-one; 4,9-dihydro-3-methyl-4-[4-[2-[2-(1-piperidinyl)ethyl]-1-piperidinyl]-1-oxobutyl]-lOH-thieno[3,4-b][1,5]benzo-diazepin-10-one; 4,9-dihydro-3-methyl-4-[4-[3-[(1-piperidinyl)methyl]-4-morpholinyl]-1-oxobutyl]-lOH-thieno[3,4-b][1,5]benzo-diazepin-10-one;. 3-chloro-4,9-dihydro-4-[4-[3-[(1-piperidinyl) methyl]-4-morpholinyl]-1-oxobutyl]-lOH-thieno[3,4-b][1,5]benzo-diazepin-10-one; 4,9-dihydro-4-[4-[3-[(diethylamino)methyl]-4-morpholinyl]-1-oxobutyl]-1,3-dimethyl-lOH-thieno-[3,4-b][1,5]benzodiazepin-10-one; 4,9-dihydro-3-methyl-4-[4-[4-[3-(l-p iperidiny1)propyl]-1-piperidinyl]-1-oxobutyl]-lOH-thieno[3,4-b][1,5]benzo-diazepin-10-one; 4,9-dihydro-3-methyl-4-[4-[3-[(4-(1-piperidinyl)butyl]-1-piperidinyl]-1-oxobutyl]-lOH-thieno[3,4-b][l,5]benzo-diazepin-10-one; 1,3-dimethyl-4-[4-[3-[(1-piperidinyl)methyl]-4-morpholinyl]-1-oxobutyl]-l,4,9,10-tetrahydropyrrolo-[3,2-b][1,5]benzodiazepin-10-one; 3-chloro-l-methyl-4-[4-[3-[(l-piperidinyl)methyl]-4-morpholinyl]-1-oxobutyl]-1,4,9,10-tetrahydropyrrolo-[3,2-b][1,5]benzodiazepin-10-one; 10 22 9 4 0 9 l-methyl-4-[4-[2-[2-(1-piperidinyl)ethyl]-4-morpholinyl]-1-oxobutyl]-l,4,9,10-tetrahydropyrrolo-[3,2-b][1,5]benzodiazepin-10-one? l-methyl-4-[4-[3-[4-(1-piperidinyl)butyl]-1-piperidinyl]-1-oxobutyl]-1,4,9,10-tetrahydropyrrolo-[3,2-b][1,5]benzodiazepin-10-one; 1,3-dimethyl-4-[4-[3-[(1-piperidinyl)methyl]-4-morpholinyl]-1-oxobutyl]-1,4,9,10-tetrahydropyrazolo-[4,3-b][1,5]benzodiazepin-10-one; l-methyl-4-[4-[3-[(1-piperidinyl)methyl]-4-morpholinyl] 1-oxobutyl]-l, 4, 9,10-tetrahydr'opyrazolo[4, 3-b][1,5]-benzodiazepin-10-one; 1,3-dimethyl-4-[4-[3-[4-(1-piperidinyl)butyl]-1-piperidinyl]-1-oxobutyl]-1,4,9,10-tetrahydropyrazolo-[4,3-b][1,5]benzodiazepin-10-one; and l-methyl-4-[4-[2-[2-(1-piperidinyl)ethyl]-4-morpholinyl]-1-oxobutyl]-1,4,9,10-tetrahydropyrazolo-[4,3-b][1,5]benzodiazepin-10-one. Viewed from another aspect, the invention provides a process for the preparation of the compounds according to the invention, said process comprising at least one of the following steps: (a) (to prepare compounds of formula la (la) " V1**- 11 22 9 4 0 9 o 10 15 (wherein R1, R2, R3, Ra, X1, X2, A and Z are as hereinbefore defined and ^)(sj) represents a group (S) , (U), (V) or (W) as hereinbefore defined or a group (T1) CH. N (T») wherein R7' represents a chlorine atom or a methyl group)) reacting a compound of formula II 0 20 25 Hal (II) 30 (wherein R3, R4, X1 and X2 are as hereinbefore defined and Hal represents a chlorine, bromine or iodine atom) with a compound of formula III 35 H I I N- A - N • R1. R?.-" (Ill) '-rM- 22 9 4 09 (wherein R1, R2, A and Z are as hereinbefore defined) 7 5 (b) (to prepare compounds of formula la as hereinbefore defined) reacting a compound of formula IV 10 R 1 >V- N—»' © (IV) 15 (wherein R3, R4, X a carboxylic acid derivative of formula V R3, R4, X1, X2 and are as hereinbefore defined) with 0 20 25 Nu (V) C>* - "■ R2. •' (wherein Rx, R2, A and Z are as hereinbefore defined and Nu represents a nucleofugic group or a leaving group); C 3 0 (c) (to prepare compounds of formula lb, ,3 35 H ch r3'x2 L » 1 X - ^-N— ^ N >s. > 4/ X" N- r"' N A - N ,1.. R2-*' (Ib) 13 229409 n 10 (wherein R1, R2, R4, X1, X2 and A are as hereinbefore defined, Z represents a single bond, an oxygen atom or a methylene or 1.,2-ethylene group, R3' represents a Cx.4 alkyl group or a hydrogen atom, and V - J 7 R represents a hydrogen atom)), hydrogenolysmg a compound of formula lb wherein R7 represents a chlorine atom; 15 (d) converting a compound of formula I into an acid addition salt thereof or converting an acid addition salt of a compound of formula I into a free base or another salt, e.g. a pharmacologically acceptable acid addition salt; 20 (e) separating a compound of formula I into the enantiomers and/or diastereomers thereof. 0 The amination of step (a) is conveniently carried out in 25 an inert solvent, at temperatures of between -10"C and the boiling temperature of the solvent, preferably either with at least 2 moles of a secondary amine of formula III per mole of the haloacyl compound of formula f~~-- II or with 1 to 2 moles of a secondary amine of formula 3 0 III and an auxiliary base. Examples of suitable solvents include chlorinated hydrocarbons such as methylene chloride, chloroform and dichloroethane; open-chained or cyclic ethers such as diethyl ether, tetrahydrofuran and dioxan; aromatic hydrocarbons such 3 5 as benzene, toluene, xylene, chlorobenzene and pyridine; alcohols such as ethanol and isopropanol; ketones such as acetone; acetonitrile, dimethylformamide and 1,3-dimethyl-2-imidazolidinone. Examples of auxiliary bases 22 9 4 0 include tertiary organic bases such as triethylamine, N-methyl-piperidine, 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 necessary, the reaction may be accelerated by the addition of alkali metal iodides. The reaction times will generally 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 in a conventional manner. The leaving group Nu is conveniently a group which forms a reactive carboxylic acid derivative together with the carbonyl group to which it is bound. Examples of reactive carboxylic acid derivatives include acid halides, esters, anhydrides or mixed anhydrides, such as those formed from salts of the corresponding acids (wherein Nu represents 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 general formula V (wherein Nu represents OH) are reacted with N-alkyl-2-halopyridinium salts. The reaction of step (b) is preferably carried out with the mixed anhydrides of strong mineral acids, particularly dichlorophosphoric acid. The reaction is optionally effected in the presence of an acid binding agent (a proton acceptor). Examples of suitable proton acceptors include alkali metal carbonates and hydrogen carbonates such as sodium carbonate and potassium hydrogen carbonate; tertiary organic amines such as pyridine, triethylamine, ethyl diisopropylamine, 4-dimethylaminopyridine and sodium hydride. The reaction of step (b) may conveniently be carried out 15 22940 at temperatures of between -25°C and 130'C in an inert solvent. Examples of suitable inert solvents include chlorinated aliphatic hydrocarbons such as methylene chloride and 1,2-dichloroethane; open-chained or cyclic 5 ethers such as diethyl ether, tetrahydrofuran and 1,4-dioxan; aromatic hydrocarbons such as benzene, toluene, xylene or o-dichlorobenzene; polar aprotic solvents such as acetonitrile, dimethylformamide, 1,3-dimethyl-2-imidazolidinone and hexamethylphosphoric acid triamide; 10 or mixtures thereof. The reaction times generally range from 15 minutes to 80 hours, depending on the nature and quantity of the acylating agent of formula V used. Xt is not necessary to produce the compounds of formula V in pure form; instead, they can be prepared in situ in 15 the reaction mixture, in a Known manner. The hydrogenolysis of step (c) is conveniently carried out in the presence of catalysts of metals of the VIXIth sub-group of the periodic table, for example palladium 20 on animal charcoal, palladium on barium sulphate, Raney nickel or Raney cobalt, and under hydrogen pressures of from 1 to 3 00 bar, and at temperatures of from O'C to 130°C, in the presence of solvents, for example alcohols such as methanol and ethanol; ethers such as dioxan and 25 tetrahydrofuran; carboxylic acids, e.g. acetic acid; or tertiary amines, for example triethylamine. If the reaction is carried out in the absence of additional hydrogen chloride acceptors, for example sodium carbonate, potassium hydrogen carbonate, triethylamine 30 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 hydrogenolysis reaction the hydrogen is replaced by formic acid, the reaction will 35 in principle be successful even under pressureless conditions. In this alternative embodiment, reaction with formic acid in the presence of dimethylformamide as solvent and palladium on charcoal as catalyst at r-> c © 16 22 9 4 09 temperatures of between 7 0 and 110°C, and reduction with triethylammonium formate in the presence of excess triethylamine, and palladium on animal charcoal or palladium acetate and triarylphosphines such as 5 triphenylphosphine, tr is-(o-tolyl)-phosphine, tris-(2,5-diisopropylphenyl)-phosphine, at temperatures of between 40 and 110°C, have proved particularly successful. The compounds of formula I according to the invention 10 contain up to two independently chiral elements, which may 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 15 the energy barrier for ring inversion at this centre is so high that the individual isomers are stable at ambient temperature and capable of isolation. It has been found that compounds of formula I wherein X2 is methine group and represents an o-phenylene group 20 always occur in two diastereoisomeric forms which may be separated into the components at ambient temperature. The individual diastereoisomers are totally stable in the crystalline state but, in solution and at ambient temperature, revert to the original mixture with a half-25 life of a few days if there are no space-filling substituents in the peri position, such as a chlorine or a methyl group. In compounds of formula I wherein X2 represents a 30 nitrogen atom and represents an o-phenylene group unsubstituted in the peri positions, the activation energy required is so low that at ambient temperature diastereoisomers can no longer be detected (except by complex ^-NMR spectra), let alone preparatively 3 5 separated. The compounds of formula I according to the invention thus contain, as a rule, two chiral centres, one of r^, n O 17 229409 which is not always configurationally stable at ambient temperature. These compounds may therefore occur in two diastereoisomeric forms which may in turn be separated into enantiomeric (+) and (-) forms. 5 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 10 recrystallisation from suitable solvents, by high pressure liquid chromatography, column chromatography or gas chromatography. The separation of any racemates of the compounds of 15 formula I may be carried out by known 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. 20 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 25 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 diastereoisomeric salts. 3 0 Preferably, methanol, ethanol or mixtures thereof, e.g. in a 1:1 ratio by volume, are used. Each of the diastereoisomeric salts is then dissolved in water, neutralised with a base such as sodium hydroxide or potassium hydroxide and in this way the corresponding 35 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 22 9 4 0 9 also be obtained by carrying out the syntheses described above with only one enantiomer of formula III or V. The starting materials of formulae II, III, IV and V needed to synthesise the condensed diazepinones of formula I are known or may be prepared by methods analogous to known methods - see for example US-A-4550107, EP-A-254955 and DE-A-3643666. The base-substituted condensed diazepinones of general formula I and the physiologically acceptable acid addition salts thereof have valuable 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 saliva, 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 correlation between, on the one hand, tachycardiac effects and, on the other hand, the undesirable effects on pupil size and the secretion of tears, saliva and gastric acid which occur with therapeutic agents having an anticholinergic component, is of particular importance in the therapeutic use of such substances. The following tests show that the compounds according to the invention exhibit surprisingly favourable correlations in this respect. 22 9 4 0 9 19 A. Studies of binding to muscarinic receptors: In vitro measurement of the IC50 value The organs were donated by male Sprague-Dawley rats weighing 18 0-220 g. After the heart, 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 by volume as follows: Whole heart 1: 400 Cerebral cortex 1: 3000 Submandibular gland 1: 400 The homogenised organs were incubated at a certain concentration of the radioligand and at a series of concentrations of the non-radioactive test substances in Eppendorf centrifuge tubes at 30°C. Incubation lasted 45 minutes. The radioligand used was 0.3 nanomolar 3H-N-methylscopolamine (3H-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. This represents the sum of specific and non-specific binding of 3H-NMS. The proportion of non-specific binding was defined as the radioactivity which was bound in the presence of 1 micromolar quinuclidinylbenzylate. Each measurement was taken four times. The IC50 values of the non-labelled test substances were determined graphically. They represent that concentration of test substance at which the specific binding of 3H-NMS to the muscarinic receptors in the various organs was inhibited by 50%. 22 9 4 09 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" tests were tested for their 1. Mx/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. 1. M1/M2 selectivity in the rat The method used was described by Hammer and Giachetti (Life Sciences 3JL, 2991-2998 (1982)). 5 minutes after the intravenous injection of increasing doses of the substance, either the right vagus was electrically stimulated (frequency: 25 Hz; pulse width: 2ms; duration of stimulus: 3 0s; voltage: supramaximal) or 0.3 mg/kg of McN-A-34 3 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 o 35 22 9 4 0 9 21 determined. The dosage of the substances which reduced either the vagal bradycardia (Mz) or the rise in blood pressure (Mx) by 50% was determined graphically. The results are set forth in Table II. • 5 2. Salivation-inhibiting effect in the rat Using the method of Lavy and Mulder (Arch. Int. Pharmacodyn. 178. 437-445, (1969)) male THOM rats 10 anaesthetised with 1.2 g/kg of urethane were given increasing doses of the 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 15 covered was measured every 5 minutes by planimetry. The dosage of the substance which reduced the volume of saliva by 50% was determined graphically. The results are set forth in Table II. 20 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 25 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-Ro/31er and contraction of the exposed bladder. 3 0 In order to determine the inhibition of the acetylcholine activity on the organs under investigation, dosage/activity curves were recorded and from them -log ED50 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: 22 9 4 0 9 O G © A = 11-[ 4-[3-[(diethylamino)methyl]-4-morpholinyl]-1 oxobutyl]-5,1l-dihydro-6H-pyrido[2,3-b][l,4]benz diazepin-6-one; 5 B = ll-[4-[2-[(diethylamino)methyl]—1-piperidinyl]—1 oxobutyl]-5,ll-dihydro-9-methyl-6H-pyrido[2,3-b] [l,4]benzodiazepin-6-one; and 10 C= 5,11—dihydro—11-[4-[2-[(1-pyrrolidinyl)methyl]—1 piperidinyl]-1-oxobutyl]-6H-pyrido[2,3-b][1,4]-benzodiazepin-6-one; 15 and as comparison substances D = 11-[[2-[(diethylamino)methyl]-l- piperidinyl]acetyl]-5,ll-dihydro-6H- pyrido[2,3-b][1,4]benzodiazepin-6-one (see US-A- 4550107), E = 5,11-dihydro-ll-[(4-methyl-l-piperazinyl)acetyl] 6H-pyrido[2,3-b][l,4]benzodiazepin-6-one (see US 3660380) and 25 F = atropine. 20 23 22 9 4 0 9 Table I Receptor Binding Tests in vitro Results: Receptor Binding Tests IC50 [nmol l"1] Substance Cortex Heart Submandibular gland (C) (H) (SM) A 100 40 100 B 30 6 60 C 20 4 40 D 1200 140 5000 E 100 1500 200 F 2 4 4 The information shown in Table I above shows that the new compounds of formula I distinguish between muscarinic receptors in different tissues. This is clear from the substantially lower IC50 values when the test substances are investigated on preparations from the heart compared with those from the cerebral cortex. Table II 24 22 9 4 0 9 Ml/M2 selectivity and salivation-inhibiting activity on the rat Results: Substance , -log ED50 Heart [mol kg"1] Blood pressure Salivation inhibition A 7.29 6.26 5.96 B 7.21 6.30 5.95 C 7.33 6.66 5.78 D 6.42 5.63 •5.00 E 5. 60 6.94 6.22 F 7.94 7.34 7.60 22 9 4 0 9 Table III Inhibition of acetylcholine activity on the bladder, bronchi and heart rate in the guinea pig Results: Substance -log ED50 .Heart [mol kg"1] Bronchi Bladder A 7.55 7.15 6.00 B 7.15 6.82 6.12 C 7.56 7.29 6.50 D 5.84 5.58 4.73 E 5.85 6.57 5.36 F 7.70 7.96 7.03 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 distinction between the heart and smooth muscle. The above-mentioned substances show a substantially improved effectiveness compared with the known compound D. At the same time, their therapeutically useful selectivity is retained. This results in a reduction in the quantity of drug to be administered to the patient n m 26 229409 without increasing the risk of muscarinic side effects. Furthermore, the compounds prepared according to the invention are well tolerated; even in the highest doses administered, no toxic side effects were observed 5 in the pharmacological trials. For pharmaceutical use the compounds of formula I or physiologically acceptable salts thereof may be incorporated in a conventional manner in customary pharmaceutical preparation forms, e.g. solutions, /~n 10 suppositories, plain or coated tablets, capsules and v. infusions. The daily dosage is generally between 0.02 and 5 mg/kg, preferably between 0.02 and 2.5 mg/kg, in particular between 0.05 and 1.0 mg/kg of body weight, optionally administered in the form of several, 15 preferably 1 to 3, individual doses in order to achieve the desired results. Thus, viewed from another aspect, the invention provides a pharmaceutical composition comprising at least one 2 0 compound of formula I as defined hereinbefore or a physiologically acceptable acid addition salt thereof together with at least one pharmaceutical carrier or excipient. e 25 Viewed from a further aspect, the invention provides the use of a compound of formula I as defined hereinbefore or a physiologically acceptable acid addition salt thereof for the manufacture of a pharmaceutical composition for combatting bradycardia and brady- 3 0 arrhythmia and optionally spasm in the bladder and colon. Viewed from a yet further aspect, the invention provides a method of treatment of the human or non-human animal 35 body for combatting bradycardia, bradyarrhythmia or spasm of the bladder or colon said method comprising administering to said body a compound of formula I as hereinbefore defined or a physiologically acceptable acid addition salts thereof. 22 9 4 0 9 27 The following non-limiting Examples are intended to illustrate the invention, without restricting its scope in any way. Satisfactory elemental analyses, IR, UV and 1H—NMR spectra are available for the compounds and mass spectra are available for many of them. All parts, percentages and ratios hereinafter are by weight unless otherwise stated. Example 1 11-f 4-r 2-f CDiethvlamino)methyl 1-1-piperidinvl1-1-oxobutvl1-5.ll-dihvdro-6H-pvrido f 2.3-b1r1.41benzo-diazepin-6-one A mixture of 9.5 g (0.03 mol) of 11-(4-chloro-l-oxobutyl)-5,ll-dihydro-6H-pyrido[2,3-b][1,4]benzo-diazepin-6-one, 100 ml of anhydrous dimethylformamide, 5.6 g (0.033 mol) of 2-[(diethylamino)methyl]piperidine and 0.5 g of sodium iodide was stirred for 7 days at a reaction temperature of 50°C. The mixture was evaporated down in a water jet vacuum, the residue was made significantly alkaline with sodium hydroxide and extracted exhaustively with dichloromethane. The dichloromethane extracts-were combined, dried over sodium sulphate and evaporated down. The crude product thus obtained (14.0 g) was purified by column chromatography on silica gel as the stationary phase and using dichloromethane/ethyl acetate/cyclo-hexane/methanol/conc. ammonia 58.5/25.1/7.7/7.7/1.0 (by volume) as eluant. The concentrated eluates crystallised when triturated with t-butyl methyl ether. After recrystallisation from ethyl acetate using animal charcoal, 3.8 g (28% of theory) of colourless crystals were obtained, m.p. 143-144"C; RF 0.7 (Macherey-Nagel, Polygram(R) SIL G/UV254, pre-coated plastic sheets for TLC; eluant: dichloromethane/cyclohexane/methanol/conc. ammonia 67.6/15.2/15.2/2 (by volume)) or Rf 0.3 (eluant: 229409 28 dichloromethane/ethyl acetate/cyclohexane/methanol/conc. ammonia 58.5/25.1/7.7/7.7/1.0 (by volume). C26H35N502 (449.59) Calculated: C 69.46 H 7.85 N 15.58 Found: 69.69 7.80 15.60 Example 2 5.11-Dihvdro-ll-r 4— r 2 — f(dimethvlamino)methyl1-1-pjperidinvl1-1-oxobutvl1-6H-pyrido f 2.3-b1I" 1. 41benzo-diazepine-6-one Prepared analogously to Example 1 from 11-(4-chloro-l-oxobuty1)-5,11-dihydro-6H-pyrido[ 2,3 -b ][1,4]benzo-diazepin-6-one and 2-[(dimethylamino)methyl]piperidine in a yield of 33% of theory. Colourless crystals, m.p. 157-158°C (acetonitrile). Example 3 ll-T4-r 2-T2-(Diethylamino^ethvl1-1-pjperidinvl1-1-oxobutvl 1-5.ll-dihvdro-6H-pvrido r2,3-blf1,41benzodiazepin-6-one Prepared analogously to Example 1 from 11-(4-chloro-l-oxobutyl)-5,ll-dihydro-6H-pyrido[2,3-b][1,4]benzo-diazepin-6-one and 2-[2-(diethylamino)ethyl]piperidine in a yield of 31% of theory. Colourless crystals, m.p. 8 6-58 °C; RF 0.55 (Macherey-Nagel, PolygramCR) SIL G/UV254, pre-coated plastic sheets for TLC? eluant: dichloromethane/cyclohexane/methanol/conc. ammonia 67.6/15.2/15.2/2.0 (by volume)). C27H37N502 (4 63.62) Calculated: C 69.95 H 8.04 N 15.11 Found: 69.97 7.97 15.00 22 94 09 29 Example 4 5.11-Dihvdro-ll-T4-r2-r2-fdimethylamino)ethyl1-1-pjperidinvl1-1-oxobutvl1-6H-pvrido r2.3-blr1.4]benzo-diazepin-6-one Prepared analogously to Example 1 from 11-(4-chloro-l-oxobutyl)-5,11-dihydro—6H-pyrido[2,3-b][1,4]benzo-diazepin-6-one and 2-[2-(dimethylamino)ethyl]piperidine in a yield of 6% of theory. Colourless crystals, m.p. 94-96 (diisopropyl ether/cyclohexane 1:1 v/v), soluble in water. Example 5 11-T 4 — f 3—T(Diethylamino)methyl1-4-morpholinvl1-1-oxobutvl 1 -5.ll-dihvdro-6H-pvridor 2.3-blfl.41benzo-diazepin-6-one Prepared analogously to Example 1 from 11-(4-chloro-l-oxobutyl)-5,ll-dihydro-6H-pyrido[2,3-b][1,4]-benzodiazepin-6-one and 3-[(diethylamino)methyl]-morpholine in a yield of 8% of theory. Colourless crystals, m.p. 108-110°C (t-butyl methyl ether), readily soluble in water. C25H33N502 (451.57) Calculated: C 66.50 H 7.37 N 15.51 Found: 66.65 7.17 15.42 Example 6 11-r 4-f 2-r(Diethylamino)methvl1-1-piperidinvl1-1-oxobutvll-5.ll-dihvdro-9-methvl-6H-pvridor 2.3-bl-fl.41benzodiazepin-6—one Prepared analogously to Example 1 from 11-(4-chloro-l-oxobutyl)-5,ll-dihydro-9-methyl-6H-pyrido[2,3-b][1,4]-benzodiazepin—6-one (m.p. 178°C [acetonitrile]) and 2- 22 9 4 0 9 [(diethylamino)methyl]piperidine in a yield of 53% of theory. Colourless crystals, m.p. 154-156°c (acetonitrile). C27H37N502 (463.62) Calculated: C 69.95 H 8.04 N 15.11 Found: 70.00 8.14 15.14 Example 7 8-Bromo-ll-r 4— f 2 — r(diethylamino)methvl1-1-pjperidinvl1 - I-oxobutvl 1-5-. ll-dihvdro-6H-pvrido r2 , 3-bl r 1.41 benzodiazepine-one Prepared analogously to Example 1 from 8-bromo-ll-(4-chloro-l-oxobutyl]-5,ll-dihydro-6H-pyrido[2,3-b][l,4]-benzodiazepin-6-one and 2-[(diethylamino)methyl]-piperidine in a yield of 50% of theory. Colourless, brittle resin, sparingly soluble in water, capable of being triturated with isooctane to produce a sandy product; RF 0.3 (Macherey-Nagel, PolygramCR) SIL G/UV25A, pre-coated plastic sheets for TLC; eluant: dichloro-methane/ethyl acetate/cyclohexane/methanol/conc. ammonia 58/25/8/8/1 (by volume)). C26H34BrN'502 (528.49) Calculated: C 59.09 H 6.43 Br 15.12 N 13.25 Found: 58.99 6.42 15.30 13.13 Example 8 II-T4-r 4-f 3—(Diethylamino)propyl!-1-piperidinvll-1-oxobutvll-5 , ll-dihvdro-6H-pvridor2 , 3-bl f 1. 4 lbenzo-diazepin-6-one Prepared analogously to Example 1 from 11-(4-chloro-l-oxobutyl)-5,ll-dihydro-6H-pyrido[2,3-b][1,4]benzo-diazepin-6-one and 4-[3-(diethylamino)propyl]piperidine in a yield of 4.2% of theory. Colourless crystals m.p. 164—165 ° C (ethyl acetate); RF 0.4 (Merck, ready-made TLC 31 22 9 4 09 plates, silica gel 60F-254. Eluant: dichloromethane/methanol/cyclohexane/conc. ammonia 68/15/15/2 (by volume)). Example 9 11-T4-T3-T 3-(Diethylamino)propyl1-1-pjperidinvl1-1-oxobutvll-5.ll-dihvdro-6H-pvridor2,3-bln.41benzo-dia2epin-6-one Prepared analogously to Example 1 from 11-(4-bromo-l-oxobutyl)-5,ll-dihydro-6H-pyrido[2,3-b][1,4]benzo-diazepin-6-one (m.p. 175-180°C) and 3-[3-(diethylamino)-propyl]piperidine in a yield of 14% of theory. Colourless crystals, m.p. 103-105°C (acetonitrile). C28H3gN502 (477.65) Calculated: C 70.41 H 8.23 N 14.66 Found: 70.2 6 8.16 14.55 Example 10 5.11-Dihvdro-ll-f 4-r2-r(l-pvrrolidinvl)methyl1-1-pjperidinvll-1-oxobutvll-6H-pyridor2.3-bln,41benzo-diazepin-6-one Prepared analogously to Example 1 from 11-(4-chloro-l-oxobutyl)-5,ll-dihydro-6H-pyrido[2,3-b][1,4]benzo-diazepin-6-one and 2-[(1-pyrrolidinyl)methyl]piperidine in a yield of 4.7% of theory. Colourless crystals, m.p. 144-145°C (acetonitrile). C26H33N502 (447.60) Calculated: C 69.77 H 7.43 N 15.65 Found: 69.93 7.43 15.77 22 9 4 0 Example 11 5.11-Dihvdro-ll-f 4-T4-r4-f1-pyrrolidirivl)butvl1-1-pjperidinvl1-1-oxobutyl1-6H-pvrido f 2.3-blP1.41-benzodiazepin-6-one Prepared analogously to Example 1 from 11-(4-chloro-l-oxobutyl) -5, ll-dihydro-6H-pyrid'o [ 2, 3-b] [ 1,4 ] benzo-diazepin-6-one and 4-[4-(1-pyrrolidinyl)butyl]piperidine in a yield of 36% of theory. Colourless crystals, m.p. 152-154"C (from acetonitrile using activated charcoal). C2gH39N502 (489.66) Calculated: C 71.14 H 8.03 N 14.30 Found: 71.04 8.03 14.46 Example 12 Il-r4-r3-f4-(Diethylamino)butvl1-1-pjperidinvl1-1-oxobutvll-5,ll-dihydro-6H-pvridor 2,3-blr1,41benzodiazepine-one Prepared analogously to Example 1 from 11-(4-chloro-l-oxobutyl)-5,ll-dihydro-6H-pyrido[2,3-b][1,4]benzo-diazepin-6-one and 3-[4-(diethylamino)butyl]piperidine in a yield of 4.7% of theory. Colourless crystals, m.p. 106-108°C (acetonitrile). C29H4iN502 (491.68) Calculated: C 70.84 H 8.40 N 14.24 Found: 70.6 0 8.14 14.19 Example 13 5.11-Dihvdro-ll-r4-T3-f2-d-pvrrolidinvl)ethvll-1-pjperidinvl1-1-oxobutvl1-6H-pyridof2.3-blfl,41benzo-diazeoin-6-one Prepared analogously to Example 1 from 11-(4-chloro-l-oxobutyl)-5,ll-dihydro-6H-pyrido[2,3-b][1,4]benzo- 22 9 4 0 9 33 diazepin-6-one and 3-[2-(l-pyrrolidinyl)ethyl]piperidine (but using acetonitrile instead of dimethylformamide as solvent) in a yield of 8.5% of theory. Colourless crystals, m.p. 126-128°C (acetonitrile); RF 0.47 (Macherey-Nagel, PolygramtR) SIL G/UV25A, pre-coated plastic sheets for TLC; eluant: dichloro-methane/methanol/cyclohexane/conc. ammonia 68/15/15/2 (by volume)). C27H35N502 (461.61) Calculated: C 70.25 H 7.64 N 15.17 Found: 69.95 7.80 15.08 Example 14 5.11-Dihvdro-ll-f 4— T 3 — T4-f1-pvrrolidinvl)butvl1-1-piperidinvll-l-oxobutvll-6H-pvridor2.3-blfl.41benzo-diazepin-6-one Prepared analogously to Example 1 from 11-(4-chloro-l-oxobutyl)-5,ll-dihydro-6H-pyrido[2,3-b][l,4]benzo-diazepin-6-one and 3-[4-(1-pyrrolidinyl)butyl]piperidine in a yield of 15.5% of theory. Colourless crystals, m.p. 110-112 0 C (acetonitrile). C29H39N502 (489.66) Calculated: C 71.14 H 8.03 N 14.30 Found: 70.97 8.08 14.40 Example 15 ll-F4-r 3-T(Diethylamino)methyl!-4-morpholinvll-1-oxobutvll-5.ll-dihvdro-6H-pvridor2.3-blf1,4Ibenzo-diazepin-6-one A mixture of 16.33 g (0.0632 mol) of 3-[(diethylamino)-methyl]-4-morpholinebutanoic acid and 2.0 g of a 75% sodium hydride dispersion in paraffin oil was heated in 160 ml of anhydrous dimethylformamide at 50-80°C until the development of hydrogen had ceased. 13.20 g 22 9 4 09 34 (0.0625 mol) of 5/ll-dihydro-6H-pyrido[2,3-b][l/4]benzo-diazepin-6-one were added to the resulting sodium salt of the above acid and at -10'C 9.9 g (0.0646 mol) of phosphorus oxychloride were added dropwise within 10 minutes. The resulting mixture was stirred for 4 hours at -10°C, for 4 hours at 0°C and for 2 0 hours at ambient temperature. The mixture was stirred into 3 00 g of ice, adjusted to pH 9 with sodium hydroxide solution and extracted exhaustively with dichloromethane. The combined organic phases 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 diisopropyl ether, whereupon crystallisation occurred. The precipitate was suction-filtered and recrystallised from t-butyl methyl ether. 6.55 g (23% of theory) of colourless crystals were obtained, m.p. 108-110'C, which were found, according to thin layer chromatography, mixed melting point, IR, UV and ^-NMR spectra, to be totally identical to a sample obtained according to Example 5. 35 22 9 4 0 9 The following non-limiting Examples illustrate the preparation of some pharmaceutical administration forms: Example I Tablets containing 5 mg of ll-[4-[3- [(diethylamino)methyl]-4-morpholinyl]-1-oxobutyl]-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one 1 tablet contains: Active substance Lactose Potato starch Magnesium stearate 5.0 mg 148.0 mg 65.0 mg 2.0 mg Total: 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 9 mm diameter punch to form tablets each weighing 22 0 mg. Example II Coated tablets containing 5 mg of 11-[4-[3-[(diethylamino)methyl]-4-morpholinyl]-1-oxobutyl]-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one 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. The coated tablets each weigh 300 mg. 22 9 4 0 9 36 Example III Ampoules containing 10 mg of 11-[4-[3-[(diethylamino)-methyl]-4-morpholinyl]-1-oxobutyl]-5,ll-dihydro-6H-pyrido[2,3-b][l,4]benzodiazepin-6-one 1 ampoule contains: Active substance Sodium chloride Distilled water 10.0 mg 8.0 mg 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 ll-[4-[3-[(diethylamino)methyl]-4-morpholinyl]-1-oxobutyl]-5,11-dihydro-6H-pyrido[2,3-b][l,4]benzodiazepin-6-one •1 suppository contains: Active substance 20.0 mg Suppository mass (e.g. Witepsol W 45(R)) 1 680.0 mg Total: 1 700.0 mg Finely powdered active substance is suspended in molten suppository mass which has been cooled to 40°C. The mass is poured at 37"C into slightly chilled suppository moulds, to produce suppositories each weighing 1.7 g. </div>

Claims

<div class="application article clearfix printTableText" id="claims"> 37 22 9 4 0 9 Example V Drops containing 11-[4-[3-[(diethylamino)methyl]-4-morpholinyl]-1-oxobutyl]-5,ll-dihydro-6H-pyrido[2,3-b] -5 [l,4]benzodiazepin-6-one 100 ml of drops solution contain: 10 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 20 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 25 the aqueous solution. Finally, the solution is made up to 100 ml with water and filtered to remove any suspended particles. WHAT ^WE CLAIM IS:- ■OlaiinsH— 38 22 9 4 09

1. A compound of formula I *xl .4 ? 0 N —II N 1© (I) 10 / Nn Li- R1*. A - N \rV 15 20 (wherein represents a group (S) I J CH, I 3 -N (T) , (U) , (V) or (W) „8 CH., l J ■N ^ (S) (T) R" (0) N ^ (V) N \ 10 (W) X1 and X2 each represents a methine group or, where 25 represents a group (S), (U) or (W), either or both of X1 and X2 may alternatively represent a nitrogen atom; C 30 35 A represents a straight-chained saturated C^g alkylene group; R1 and R2, which may be the same or different, each represents a C1.6 alkyl group or R1 and R2 together with the intervening nitrogen atom represent a 4- to 7-membered, saturated, monocyclic, heteroaliphatic ring optionally interrupted by an oxygen atom or a\-CH3 group; 22 9 4 OS c 39 R3 represents a alkyl group or a chlorine or hydrogen atom; RA represents a hydrogen atom or a methyl group; 5 R3 and R6, which may be the same or different, each represents a hydrogen, fluorine, chlorine or bromine atom or a Cx_4 alkyl group; Gk, 10 R7 represents a hydrogen or chlorine atom or a methyl group; R8 represents a hydrogen atom or a alkyl group; 15 R9 represents a hydrogen or halogen atom or a alkyl group; R10 represents a hydrogen atom or a methyl group; and 2 0 Z represents a single bond, an oxygen or sulphur atom or a methylene or 1,2-ethylene group; with the proviso that where ^)(^) represents a group (T) and R7 represents a hydrogen atom, then R3 represents a 25 hydrogen atom or a alkyl group and Z represents other than a sulphur atom) or an isomer or acid addition salt thereof. 3 0

2. A compound of formula I as claimed in claim 1 wherein: X1 represents a methine group; 3 5 X2 represents a nitrogen atom, represents a group (S) , R3, RA and R5 represent hydrogen atoms and R6 represents a hydrogen atom or a chlorine or bromine atom or a methyl or ethyl group in the 8- or 9- position of - 40 - 229409 the tricyclic moiety, or X2 represents a methine group, (^B^represents a group (V) or (U) , R8 represents a hydrogen atom and R9 represents a methyl group; A represents an unbranched, saturated C^_5 alkylene group; R1 and R2, which may be the same or different, each represents a alkyl group or R1 and R2 together with the intervening nitrogen atom represent a 4- to 7-membered, saturated, monocyclic, heteroaliphatic ring optionally interrupted by an oxygen atom or a ^N-CH3 group; and Z represents a single bond, an oxygen atom or a methylene or 1,2-ethylene group; or a diastereomer or enantiomer or acid addition salt thereof.

3. A compound of formula I as claimed in claim 1 or claim 2 wherein: X1 represents a methine group; X2 represents a nitrogen atom (jT)represents a group (S) , R3 R4 and R5 represent hydrogen atoms and R6 represents a hydrogen atom or a chlorine or bromine atom or a methyl or ethyl group in the 8- or 9- position of the tricyclic moiety; A represents an unbranched, saturated C,,_5 alkylene group; R1 and R2, which may be the same or different, each represents a C.,_5 alkyl group or R1 and R2 together 'Un.. 41 22 9 4 09 the intervening nitrogen atom represent a 5- to 7- membered, saturated, monocyclic, heteroaliphatic ring \ optionally interrupted by an oxygen atom or a ^N-CH3 group; and Z represents a single bond, an oxygen atom or a methylene or 1,2-ethylene group; or a diastereomer or enantiomer or acid addition salt thereof.

4. A compound as claimed in claim 1 being: 11—[4-[3—[(diethylamino)methyl]-4-morpholinyl]-1-oxobutyl]-5,ll-dihydro-6H-pyrido[2,3-b][l,4]benzo-diazepin-6-one; ll-[4-[2-[(diethylamino)methyl]-1-piperidinyl]-1-oxobutyl]-5,ll-dihydro-9-methyl-6H-pyrido[2,3-b]-[1,4]benzoaiazepin-6-one; 5,11-dihydro-ll-[4-[2-[(1-pyrrolidinyl)methyl]-1-piperidinyl]-1-oxobutyl]-6H-pyrido[2,3-b][1,4]-benzodiazepin-6-one; or an acid addition salt thereof.

5. A compound as claimed in any one of claims 1 to 4 being a physiologically acceptable acid addition salt of a compound of formula I.

6. A pharmaceutical composition comprising at least one compound of formula I as claimed in any one of claims 1 to 4 or a physiologically acceptable acid addition salt thereof together with at least one pharmaceutical carrier or excipient. 22 9 4 09

7. A process for the preparation of compounds as claimed in claim 1, said process comprising at least one of the following steps: 5 (a) (to prepare compounds of formula la 10 ? 0 rJ _1 N —II H' ' 4 >>.2- Q N (la) 15 20 25 R1*. .r* - vRv (wherein R1, R2, R3, r\ X1, X2, A and Z are as defined in claim 1 and ^)(^) represents a group (S) , (U) , (V) or (W) as defined in claim 1 or a group (T') CH. N (T«) ,7 1 wherein R71 is a chlorine atom or a methyl group)) reacting a compound of formula II 30 1 H 0 R3 i I , X. N -J 35 (II) R r 0 Hal r\ 10 22 9 4 0 9 43 (wherein R\ )© , X1 and X2 are as defined in claim 1 and Hal represents a chlorine, bromine or iodine atom) with a compound of formula III H I N> A - N ■ R1. R?.*' (XII) (wherein R1, R2, A and Z are as defined in claim 1) ; (b) (to prepare compounds of formula la as hereinbefore 15 defined) reacting a compound of formula IV 20 25 k: /^X2' H 0 N—" N I H © (IV) (wherein R3, R4, X1 and X2 are as defined in claim l,^j^B^is as hereinbefore defined) with a carboxylic acid derivative of formula V O 30 ■ R (V) 35 (wherein R1, R2, A and Z are as defined in claim 1 and Nu represents a nucleofugic group or leaving group); &SKS&iV 22 94 OS 44 (c) (to prepare compounds of formula lb 10 15 20 (wherein R , R R\ ,4/ X (lb) X1, X2 and A are as defined in claim 1, Z represents a single bond, an. oxygen atom or a methylene or 1,2-ethylene group, R3' represents a C^- alkyl group or a hydrogen atom and R7 represents a hydrogen atom)) hydrogenolysing a compound of formula lb wherein R7 represents a chlorine atom; O 25 (d) converting a compound of formula I into an acid addition salt thereof, or converting an acid addition salt of a compound of formula I into the free base or into another acid addition salt; (e) separating a compound of formula I into the enantiomers and/or diastereomers thereof. 3 0

8. A process as claimed in claim 7 wherein the reaction of step (a) is carried out in an inert solvent.

9. A process as claimed in claim 8 wherein the reaction of step (a) is carried out in the presence of 35 an auxiliary base or an excess of the amine of formula III, at temperatures of between -10"C and the boiling temperature of the reaction mixture. 22 9 4 0 45

10. A process as claimed in claim 7 wherein the reaction of step (b) is carried out in an inert solvent at temperatures of between -25 and 130"C, optionally in the presence of a proton acceptor.

11. A process as claimed in either one of claims 7 and 10 wherein, in the reaction of step (b), the carboxylic acid derivative of formula V used is an acid halide, ester, anhydride or mixed acid anhydride.

12. A process as claimed in claim 7 wherein the hydrogenolysis of step (c) is carried out in a solvent in the presence of a catalyst comprising a metal of the Vlllth sub-group of the periodic table under hydrogen pressures of from 1 to 3 00 bar and at temperatures of from 0°C to 130"C.

13. A process as claimed in claim 7 wherein the hydrogenolysis of step (c) is carried out in a solvent with formic acid in the presence of palladium on charcoal as catalyst at temperatures of between 70 and 110'C.

14. A process as claimed in claim 7 wherein the hydrogenolysis of step (c) is carried out in a solvent with triethylammonium formate in the presence of excess triethylamine and palladium on animal charcoal or palladium acetate and triarylphosphines, at temperatures of between 4 0 and 110"C.

15. The use of a compound as claimed in any one of claims 1 to 4 or a physiologically acceptable acid addition salt thereof for the manufacture of a pharmaceutical composition for use in combatting bradycardia and bradyarrhythmia and optionally spasm in the bladder and colon. - 46 - 229409

16. A method of treatment of the non-human animal body to combat bradycardia, bradyarrhythmia or spasm of the bladder or colon, said method comprising administering to said body a compound of formula I as claimed in any one of claims 1 to 4 or a physiologically acceptable acid addition salt thereof.

17. Compounds of formula X as claimed in claim 1 substantially as described herein in any of one of the Examples. DR KARL THOMAE GMBH by their Attorneys BALDWIN, SON & CAREY </div>