NZ229524A

NZ229524A - Condensed diazepinones and pharmaceutical compositions

Info

Publication number: NZ229524A
Application number: NZ229524A
Authority: NZ
Inventors: Gerhard Mihm; Wolfgang Eberlein; Wolfhard Engel; Gunter Trummlitz; Norbert Mayer; Henri Doods; Jonge Adriaan De
Original assignee: Thomae Gmbh Dr K
Priority date: 1988-06-15
Filing date: 1989-06-13
Publication date: 1990-11-27
Also published as: ZA894459B; PT90847A; NO892469D0; DD284015A5; JPH0240371A; DK291089A; AU3644889A; EP0346744A1; NO168586B; HU201758B; NO892469L; DE3820345A1; NO168586C; AU612495B2; FI892896A0; KR900000364A; DK291089D0; IL90591A0; HUT50471A; FI892896A

Description

<div class="application article clearfix" id="description"> New Zealand Paient Spedficaiion for Paient Number £29524 22 9 5 2* NO DRAWINGS Complete Specification Filed: ^ Class: £cO /. t £ f JLSf.1 S9j&+\3/ \.4\i.\ /s o7? .OW71) J.Q ^.f. I Publication Date: ?.7.^.QY..®®. P.O. Journal. No: .... 13^:. Class Cont: i .V< Patents Fora No. 5 NEW ZEALAND PATENTS ACT 1953 COMPLETE SPECIFICATION CONDENSED DIA2EPIN0NES V WE. DR KARL TIIOHAE GMBH, a body corporate organised under the lavs of the Federal Republic of Geraany of D-7950 Biberach an dcr Riss, Federal Republic of Geraany, hereby declare the invention, for which X/We pray that a patent nay be granted to c$6/us, and the aethod by which it is to be perforaed. to be particularly described in and by the following stateaent: - 1 - (followed by Page 2) c 30 22 9 5 la 54-131.500 Condensed diazepinones 5 The present invention relates to certain condensed diazepinones, processes for their preparation and pharmaceutical compositions containing them. a Condensed diazepinones with anti-ulcerative 10 properties and an inhibitory effect on the secretion of gastric juices are disclosed 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. 15 EP-A—156191 (US-A-4550107) describes how valuable pharmacological properties completely different from those of the compounds of the publications mentioned above can be induced by the introduction of new 20 aminoacyl groups into condensed diazepinones. However we have now found that certain new condensed diazepinones are, compared with the compounds of EP-A-156191, distinguished by having a substantially greater activity and resorption after oral administration, 25 whilst having comparable or better selectivity. Thus, viewed from one aspect, the present invention provides a compound of formula I z O - A 35 I i N I. R' (I) (followed by Page 2) "V ' - ^ ' ,J' ' " ' ' — "*»• I . n 30 22 9 5 24 2 (wherein represents one of the divalent groups (S), (T), (U) and (V) FH3 o 'R5 O (s) <T> (v) w 10 I X represents a »CH- group, a «C-C1 group or a nitrogen atom; A1 and A* which nay be the sane or different, each 15 represents a straight-chained or branched Cx.4 alkylene group; Z represents an oxygen aton or a Cw alkylene chain; 20 R1 represents a branched or unbranched Cw alkyl group, a cycloalkyl or (cycloalkyl)alkyl group containing up to 8 carbon atoms or a hydrogen atom; ,r~v ' R2 represents a branched or unbranched C,.# alkyl group 25 or a cycloalkyl group containing up to 7 carbon atoms; R* and R4, which may be the sane or different, each represents a hydrogen, fluorine, chlorine or bromine w atom or a Ct.« alkyl group; Rs represents a hydrogen or chlorine atom or a methyl group; 35 R* and R7, which may be the sane or different, each represents a hydrogen atom or a C,.4 alkyl group and R7 nay also represent a halogen atom; 22 9 5 24 with the proviso that where^}(fi\ represents a group (V), X represents a =CH- or =C-C1 group). The compounds of formula I may, after reaction with 5 inorganic or organic acids, also exist in salt form. The physiologically acceptable salts are, of course, particularly preferred. Examples of suitable acids include hydrochloric, hydrobromic, sulphuric, methylsulphuric, phosphoric, tartaric, fumaric, citric, 10 maleic, succinic, gluconic, malic, p-toluenesulphonic, methanesulphonic and amidosulphonic acids. Particularly preferred compounds according to the invention include: 15 5,ll-dihydro-ll-[ ([2-(l-methyl-2-piperidinyl) ethyl]-methylamino]acetyl)-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one; 20 5,11-dihydro-ll-C C [ 2- (l-methyl-hexahydro-lH-2-azepinyl) -ethyl ] methyl ami no] acetyl ] -6H-pyrido (2,3-b][l,4 ]benzo-diazepin-6-one; 9-chloro-5,ll-dihydro-ll-C(t2-(l-mothyl-hexahydro-lH-2-25 azcpinyl) ethyl ] mothy lamino] acetyl] -6H-pyrido[ 2,3-b] -[1,4]benzodiazepin-6-one; 5,ll-dihydro-8-methy1-11-([ [ 2-(l-methyl-hexahydro-lH-2-azepinyl)ethylJmethylamino]acetyl]-6H-pyrido(2,3-b]-30 [l,4]bcnzodiazepin-6-one; and the isomers and salts, especially physiologically acceptable acid addition salts, thereof. 35 Viewed from a further aspect, the present invention also provides a process for the preparation of the compounds of the invention, said process comprising at t1'\, . t **;**■.« '4-7-1 ""-M? > 22 9 5 24 o 4 least one of the following steps: a) (to prepare compounds of formula la 10 (la) 15 (wherein X, Z, A1, A*, Rl and Rx are as hereinbefore defined and ) (bJ) represents one of the groups (S), (0) and (V) as hereinbefore defined or a group (T1) 20 p> 25 (T*) ..5' i » t\ wherein R5' represents a chlorine atoa or a aethyl group)) reacting a conpound of fornula II 229524 (ii) O = C - A - Hal 10 (wherein A1, X and are as hereinbefore defined and Hal represents a chlorine, bromine or iodine aton) with an amine of formula III 15 R* - NH - A4 o N (III) 20 (wherein A2, Z, R1 and R2 are as hereinbefore defined); b) (to prepare conpounds of formula la) acylating a diazepinone of formula IV 25 30 H 0 1 u N I K (IV) (wherein X and ^ (bJ) are as hereinbefore defined) with a carboxylic acid derivative of formula V 35 15 35 22 9 5! -,-..,0 o II Nu - C h !* <v> 1? (wherein Z, A1, A2, Rl and R2 are as hereinbefore defined and Nu represents a nucleofugic or leaving group); 10 c) (to prepare compounds of formula lb 20 u = c-A - N - A J (lb) 25 (wherein X, Z, A1, A2, R1 and R2 are as hereinbefore defined, and R5" represents a hydrogen atom)) hydrogenolysing a 30 compound of formula lb wherein R3" represents a chlorine atom; d) resolving a compound of formula I into its isomers; and e) converting a compound of formula I into an acid addition salt thereof or an acid addition salt of a 22 9 5 2 4 7 compound of formula I into the free base. The amination of step (a) is conveniently carried out in an inert solvent at temperatures of between -10*C 5 and the boiling temperature of the solvent, preferably either with at least 2 moles of the secondary amine of formula III per mole of the haloacyl compound of formula II or with 1 to 2 moles of the secondary amine of fs formula III and an auxiliary base. Examples of solvents w 10 include chlorinated hydrocarbons such as methylene chloride, chloroform or dichloroethane; open-chained or cyclic ethers such as diethyl ether, tetrahydrofuran or dioxan; aromatic hydrocarbons such as benzene, toluene, xylene, chlorobenzene or pyridine; alcohols such as 15 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 triethylamine, N-methyl-piperidine, diethylaniline, pyridine and 4-20 (dimethylamino) pyridine or inorganic bases such as alkali metal or alkaline earth metal carbonates or hydrogen carbonates, hydroxides or oxides. If ^ necessary, th'e reaction may be accelerated by the w addition of alkali nctal iodides. The reaction times 25 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 the compounds of formula IV with 30 the acid derivatives of formula V in step (b) may be carried out using conventional procedures. 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 35 carboxylic acid derivatives include acid halides, esters, anhydrides and mixed anhydrides, such as those formed from salts of the corresponding acids (where NU 22 9 5 24 8 represents OH) and acid chlorides such as phosphorus oxychloride, diphosphoric acid tetrachloride or chlorofornic acid esters or the N-alkyl-2-acyloxypyridinium salts formed when compounds of formula V (where Nu represents OH) are reacted with N-alkyl-2-halopyridinium salts. Preferably, the reaction of step (b) is carried out with nixed anhydrides of strong mineral acids, particularly dichlorophosphoric acid. The reaction may optionally be effected in the presence of an acid binding agent (a proton acceptor). Examples of suitable proton acceptors include alkali netal carbonates and hydrogen carbonates such as sodium carbonate and potassiun hydrogen carbonate; tertiary organic anines such as pyridine, triethylamine, ethyl diisopropylamine, 4-dinethylaninopyridine, and sodium hydride. The reaction is conveniently carried out at temperatures of between -25*C and 130*C in an inert solvent. Examples of inert solvents include chlorinated aliphatic hydrocarbons such as nethylene chloride, 1,2-dichloroethane; open-chained or cyclic ethers such as diethyl ether, tetrahydrofuran or 1,4-dioxan; aromatic hydrocarbons such as benzene, toluene, xylene or o-dichlorobenzene; polar aprotic solvents such as acetonitrile, dimethylfornamide, and hexamethylphosphoric acid trianide; and nixtures thereof. The reaction tines generally range from 15 ninutes to 80 hours depending on the nature and quantity of the acylating agent of formula V used. It nay be noted that it is not nocessary to produce the conpounds of fornula V in pure forn; instead, they can be prepared in situ in the reaction mixture, in a conventional nanner. The hydrogenolysis of step (c) is conveniently carried out in the presence of catalysts of netals of X 22 9 5 2 4 o the Vlllth sub-group of the periodic table, for example palladium on animal charcoal, palladium on barium sulphate, Raney nickel and Raney cobalt, under hydrogen pressures of from 1 to 300 bar, and at temperatures of 5 from 0*C to 130*C, in the presence of solvents, for example alcohols such as methanol and ethanol; ethers such as dioxan, tetrahydrofuran; carboxylic acids, e.g. acetic acid; and tertiary amines, for example triethylamine. If the operation is carried out in the 10 absence of additional hydrogen chloride acceptors, for example sodium carbonate, potassium hydrogen carbonate, triethylamine and sodium acetate, the hydrochlorides of the desired compounds may be formed directly and may be isolated after removal of the catalyst by evaporation of 15 the reaction solution. If in the hydrogenolysis reaction the hydrogen is replaced by formic acid, the reaction nay in principle be successful even under pressureless conditions. In this alternative embodiment, reaction with formic acid in the presence of 20 dimethylformamide as solvent and palladium on charcoal as catalyst at temperatures of between 70 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 25 as triphenylphosphine, tris-(o-tolyl)-phosphine, tris-(2,5-diisopropylphenyl)-phosphine, at temperatures of between 40 and 110*C, have proved particularly successful. 30 The condensed diazepinones of formula I contain up to two independent chiral elements, particularly if represents the group (U). In addition to the asymmetric carbon atom in the side chain, the acylated tricyclic group itself, which may occur in two mirror-image forms, 35 must be regarded as a further chiral element. It depends on the nature of the tricyclic group whether the energy barrier for inversion at this centre is so high 22 9 5 2 4 10 that the individual isomers are stable at ambient temperature and capable of isolation. It has been found that in compounds of formula I wherein X represents a nitrogen atom and the positions adjacent on the diazepinone ring are unsubstituted, the activating energy required is reduced so much that at ambient temperature diastereoisomers can no longer be detected, let alone preparatively separated. The aminoacylated condensed diazepinones of formula I according to the invention thus contain up to two chiral centres, one of which is not always configurationally stable at ambient temperature. These compounds may therefore occur in several diastereoisomeric forms or as enantiomeric (+) and (-) forms. The present invention includes within its scope all 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 raccnatcs of the compounds of 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. Using a conventional method of separating isomers, the racemate of a compound of formula I may be reacted with one of the optically active acids specified above in equimolar quantities in a solvent and the crystalline diastereoisomeric salts obtained may be separated, using their different solubilities. This reaction may be carried out in any type of solvent provided that the '<■ V 22 9 5 2 4 & $ li latter exhibits sufficiently different solubilities for the salts. Preferably, methanol, ethanol or mixtures thereof, e.g. in a ratio by volume of 50:50, are used. Each of the optically active salts is then dissolved in 5 water, 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 10 active diastereoisomeric compounds covered by formula I nay also be obtained by carrying out the syntheses described above with only one enantiomer of formula III or V. 15 The haloacyl compounds of formula II used as starting uaterials nay be prepared using conventional nethods (see, for exanple, US-A-4550107). Internedlate compounds of formula III nay easily be 20 synthesised by methods well known to those skilled in the art, e.g. by reduction of corresponding heterocyclic carboxylic acid alkylanides. The corresponding heterocyclic carboxylic acids are either connercially obtainable or nay be prepared by conventional nethods. 25 Thus, unsubstituted heterocycloalkanes nay be reacted, by conversion into the 1,2-dehydro derivatives (or the triners) thereof and reaction with nalonic esters, to obtain the corresponding a-heterocycloalkylacetic acid esters (see H. Fukawa, Y. Terao, K. Achiwa and M. 30 Sekiya, Chen. Phara. Bull. 11, 94 (1983)). Conpounds with longer alkylene chains nay be prepared from these by reduction with lithium aluminium hydride, reaction of the resulting alcohols with potassiun cyanide (see A. Nizuno, Y. Hanada, T. Shiori, Synthesis 1980. 1007) and 35 hydrolysis of the resulting nitriles. The carboxylic acids or carboxylic acid esters -r 22 95 24 12 produced in this way nay be converted into the corresponding carboxylic acid amides, after alkylation of the nitrogen, using methods conventional in the art. 5 Compounds of formula III, wherein R1 represents an alkyl group, may also be obtained by reacting corresponding primary amines to obtain the carboxamides and reducing them with lithium aluminium hydride or diborane. 10 The starting compounds of formula V, wherein Nu represents an alkoxy group, may be obtained by reacting diamines of formula III with halocarboxylic acid esters, optionally using additional auxiliary bases, e.g. 15 triethylamine, or catalysts such as Triton B. By saponification of the resulting esters, e.g. with barium hydroxide solution, the carboxylic acids covered by formula V are obtained, which say be used to prepare derivatives with other nucleofugic groups. 20 Viewed from a further aspect, the present invention provides a method of treatment of the human or non-human /-*• animal body to combat bradycardia and bradyarrhythmia, and spasm of the colon, bladder and bronchi, which 25 method comprises administering to said body a compound of formula I (as hereinbefore defined) or a physiologically acceptable acid addition salt thereof. Viewed from a yet further aspect, the present 30 invention provides the use of a compound of formula I (as hereinbefore defined) or a physiologically acceptable acid addition salt thereof for the manufacture of a therapeutic agent for use in a method of treatment of the human or non-human animal body for 35 the treatment of bradycardia and bradyarrhythmia and of spasm of the colon, bladder and bronchi. 3&S&1 13 22 9 5 24 Viewed from another aspect, the present invention provides a pharmaceutical composition comprising at least one compound of formula I, as herein defined, or a ^ physiologically acceptable acid addition salt thereof, 5 together with at least one pharmaceutical carrier or excipient. For pharmaceutical use, the compounds of the invention may be incorporated in a conventional manner ~ 10 into customary pharmaceutical preparation forms, such as solutions, suppositories, plain or coated tablets, capsules or infusions. The daily dosage is conveniently between 0.02 and 5 mg/kg, preferably between 0.02 and 2.5 mg/kg, more particularly between 0.05 and 1.0 mg/kg 15 of body weight, optionally administered in the form of several, preferably 1 to 3, individual doses, in order to achieve the desired results. The compounds of formula I and the physiologically 20 acceptable acid addition salts thereof have valuable properties; in particular, they have favourable effects on heart rate and in view of their lack of mydriatic ^ effects or inhibitory offects on the secretion of * w gastric acid and saliva, they crc suitable for use as 25 vagal pacemakers in the treatmont 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, ^ bladder and bronchi. 30 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 35 therapeutic agents having an anticholinergic component, is of particular importance in the therapeutic use of the substances. The following tests show that the 22 9524 14 compounds according to the invention exhibit surprisingly favourable correlations in this respect. A. Studies of binding to muscarinic receptors In vitro measurement of the ICM value The organs were donated by male Sprague-Dawley rats weighing 180-220 g. After the heart, submandibular gland and cerebral cortex had been removed, all other steps were carried out in ice cold Hepes HC1 buffer (pH 7.4; 100 millimolar NaCl, 10 millimolar MgCla). 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 Hepes buffer as follows: Whole heart 1: 400 (by volume) Cerebral cortex 1: 3000 (by volume) Submandibular gland 1: 400 (by volume) 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 *H-N-methylscopolamine (*H-NMS). Incubation was terminated by the addition of ice-cold buffer followed by vacuum filtration. The filters wore rinsed with cold buffer and their radioactivity was determined. This represents the sum of specific and non-specific binding of 5H-MMS. The proportion of non-specific binding was defined as that radioactivity which was bound in the presence of 1 micromolar quinuclidinylbenzylate. Determinations were carried out in quadruplicate. The ICjo values of the non-labelled test substances were determined 22 9 5 24 15 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%. The results are shown in Table I. - . " -rj- •vs 20 25 22 95 24 16 B. Investigation of functional selectivity of the antimuscarinic effect 5 Substances with antimuscarinic properties inhibit the effects of exogenous agonists 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 10 antimuscarinic agents. "In vivo" methods The objective of the methods was to confirm the 15 selectivity of the antimuscarinic effect. Those substances which had been selected on the basis of "in vitro" tests were tested for their 1. Mj/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. Mj/M2 selectivity in the rat The method used was described by Hammer and 30 Giachetti (Life Sciences 21, 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: 30s; voltage: supramaximal) 35 or 0.3 mg/kg of McN-A-343 were intravenously injected into male TH0M 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 - 4... n 22 9 5 24 17 which reduced either the vagal bradycardia (M2) or the rise in blood pressure (Mx) by 50% was determined graphically. The results are shown in Table II. 5 2. Salivation-inhibiting effect in the rat Using the method of Lavy and Hulder (Arch. Int. Pharnacodyn. 178. 437-445, (1969)) male THOM rats anaesthetised with 1.2 g/kg of urethane received 10 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 covered was measured every 5 minutes by planimetry. The 15 dosage of the substance which reduced the volume of saliva by 50% was determined graphically. The results are shown in Table II. 3. Inhibition of the effect of acetylcholine on the 20 bladder, bronchi and heart rate in guinea nias 5 minutes after the administration of the test substance, 10 microgram/kg of acetylcholine were simultaneously injected intravenously and intra-25 arterially into anaesthetised guinea pigs. The heart rate was recorded directly by extracorporeal derivation of the ECG, the expiration resistance according to Konzett-Ro01er and contraction of the exposed bladder. In order to determine the inhibition of the 30 acetylcholine activity on the organs under investigation, dosage/activity curves were recorded and from them -log EDM values were determined. The results are shown in Table III. 35 By way of example the following compounds were investigated according to the above procedures: wSigK ' ' *• c 22 9524 18 A 5,ll-dihydro-ll-[[[2-(l-methyl-2-piperidinyl)- ethyl]methylamino]acetyl]-6H-pyrido[2,3-b][l,4]-benzodiazepin-6-one 5 B 5,11-dihydro-ll-(t[2-(l-methyl-hexahydro-lH-2-azepinyl)-ethyl]methylamino]acetyl]-6H-pyrido-(2,3-b][l,4]benzodiazepin-6-one C 9-chloro-5,11-dihydro-ll-[ [[2-(1-methyl-hexahydro-10 lH-2-azepinyl)ethyl]methylamino]acetyl]-6H-pyrido- [2,3-b][1,4]benzodiazepin-6-one hydrochloride D 5#ll-dihydro-8-methyl-ll-[[[2-(1-methyl-hexahydro-lH-2-azepinyl)ethyl]methylamino]acetyl]-SKIS pyrido[2,3-b][l,4]benzodiazepin-6-one. Comparison substances E ll-[(2-((diethylamino)methyl]-l-piperidinyl]-20 acetyl]-5,ll-dihydro-6H-pyrido[2,3-b][1,4]- benzodiazepin-6-one (see US-A-4550107) F 5,11-dihydro-ll-((4-mothyl-l-piperazinyl)acetyl]-6H-pyrido[2,3-b](1,4]benzodiazepin-6-one 25 (pirenzepine, see US-A-3660380) and G atropine 30 were similarly investigated. The following tables show the results found: ~i*.. 22 9524 19 Table X: o Receptor Binding Assay ill vitro: Results: o Receptor Binding Assay ICM [nnol l*1] Cortex Heart Submandibular gland Substance 10 15 20 A 40 9 80 B 40 5 50 C 20 3 40 D 30 4 80 E 1200 140 5000 F 100 1500 200 G 2 4 4 25 30 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 XCM values when the test substances are investigated on preparations from the heart compared with those from the cerebral cortex and submandibular gland. # 22 9 5 24 20 /"N Mj/M2 selectivity and salivation-inhibiting activity on 5 the rat: BSSUUfefi: C 10 -log EDm (mol kg"1] Substance Heart Blood pressure Salivation A 7.48 6.34 5.91 15 B 7.41 6.46 5.47 c 7.5 5.52 D 7.67 6.21 E 6.42 5.63 5.00 F 5.60 6.94 6.22 G 7.94 7.34 7.60 5 15 20 25 22 9 5 24 21 Inhibition of acetylcholine activity on the bladder, bronchi and heart rate in the guinea pig: Results: Substance -log EDm Heart [mol kg*1] Bronchi Bladder A 7.75 7.34 6.92 B 7.60 7.19 6.57 C 7.26 6.72 6.63 D 7.28 6.87 6.46 E 5.84 5.58 4.73 F 5.85 6.57 5.36 C 7.70 7.96 7.03 The pharmacological data in Tables II and III above show - in total agreement with the receptor binding 30 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. 35 Moreover, the pharmacological data in Table III above indicate a surprisingly high power of distinction between the heart and smooth muscle. 22 9 5 22 The compounds of the invention 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 to be administered to the patient 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 in the pharmacological trials. 22 95 24 23 The following non-1 imiting Examples are provided to illustrate the invention further. All percentages, parts and ratios are by weight unless otherwise indicated. Satisfactory elemental analyses, IR, UV and *H-NMR spectra are available for all the compounds and mass spectra are available for many of them. Example I S.ll-Dihvdro-ll-r f f2-fl-aethvl-2-pjperidinvl^ethvll-methvlawinol acetyl l-6H-pvridof 2.3-blr1.41benzodiazepine SzffillS 3.1 g (0.02 mol) of l-methyl-2-(2-(methylamino)-ethyl]piperidine were added dropwise to a solution of 5.7 g (0.02 mol) of ll-(chloroacetyl)-5,ll-dihydro-6H-pyrido[2,3-b][l,4)benzodiazepin-6-one and 2.8 ml of triethylamine in 50 ml of dime thy lformamide and the mixture was stirred for 0.5 hours at ambient temperature. After the solvent had been distilled off, column chromatography was carried out using silica gel (mobile phase: methylene chloride/mothanol 9:1 v/v). The concentrated eluates were taken up in potassium carbonate solution and extracted with ethyl acetate. After the solvent had been distilled off, the crystals obtained were recrystallised from diisopropyl ether/ethyl acetate. Yield: 3.0 g (37% of theory). Hp.: 143-144*c (diisopropyl ether/ethyl acetate). Example 2 ll-tilhvflre-ll-r f f 2-<l-iM*hvl-2-pirarltiinvI) - ethvl 1 methvl am i no 1 acetyl 1 -6H-pvrido f 2.3-b 1 f 1.41 benzo-diazepin-6-one Prepared analogously to Example 1 from 9-chloro-ll- '• * Vi 22 95 24 24 (chloroacetyl)-5,ll-dihydro-6H-pyrido[2,3-b][l,4]benzo-diazepin-6-one and l-methyl-2-[2-(methylamino)ethyl]-piperidine. Yield: 12.5% of theory. 5 Hp.: 183-184*C (ethyl acetate). Example 3 5.11-Dihvdro-l1-f f r2-1l-methvl-2-piperidinvl)ethvl1-10 amino!acetyl1-6H-Pvrido f 2.3-blf 1.4lbenzodiazepin-6-one Prepared analogously to Example 1 from 11-(chloroacetyl ) -5,1l-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one and 2-(2-aminoethyl)-1-methylpiperidine. Yield: 28% of theory. 15 Hp.: 123-125*C (cyclohexane). EXflffPlg 4 S.ll-Dihvdro-ll-rr f2-fi-ethvl-2-piperidinvllethvl1-20 methvlamlnol acetyl 1 -6H-pvridof 2.3-bl f 1.41benzodiazepine 6Z2DSL A solution of 2.9 g (0.01 mol) of 11-(chloroacetyl)-5,ll-dihydro-6H-pyrido[2,3-b][1,4]-benzodiazepin-6-one, 1.75 g (0.01 mol) of l-ethyl-2-[2-25 (methylamino)ethyl]piperidine and 3 g of potassium carbonate in 100 nl of acetonitrile was stirred for 2 hours at 60"C, the solvent was distilled off in vacuo, the residue was stirred with water and extracted with methylene chloride. The crystals obtained after 30 purification by column chromatography on silica gel (mobile phase: ethyl acetate/methanol/ammonia 70/30/3 by volume) and evaporation of the eluates were recrystallised from diisopropyl ether/ethyl acetate. Yield: 1.26 g (30% of theory). 35 Hp.: 138-140*C (diisopropyl ether/ethyl acetate). A 22 9524 25 Example 5 5-ll-Dihvdro-8-methvl—11-rr r2-fl-methvl-2-pjperidinvl)-^ ethvllroethvlamino1acetyl1-6H-pvrido f 2.3-blf 1.4lbenzo- 5 diazepm-6-one Prepared analogously to Example 4 from 11-(chloroacetyl)-5,ll-dihydro-8-methyl-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one and l-methyl-2-[2-(methylamino)ethyl]piperidine as an amorphous solid. w 10 Yield: 46% of theory. RF « 0.25 (Merck ready-made silica gel plates F 254; eluant: ethyl acetate/methanol/ammonia 8:2:0.3 by volume). 15 Example $ 5.11-Dihvdro-l1-f 4-f f 2-(1-methvl-2-pjperid invl)ethvl1-methvlaminoTbutvrvl 1-6H-pvridof2.3-bl f l. 4 Ibenzodiazeoin- 6-one 20 Prepared analogously to Example 4 fron ll-(4- chloro-butyryl)-5,ll-dihydro-6H-pyrido[2,3-b][1,4]benzo-diazepin-6-one and l-methyl-2-[2-(methylamino)ethyl]-piperidine. Yield: 4.3% of theory. 25 Mp.: 118*C (diisopropyl ether/ethyl acetate). Example 7 9-Chloro-5.11-d ihvdro-11-r r r 2-(l-ethvl-2-pjperidinvl\-30 ethvl1wethvlami no1acctvl1-6H-ovrido f 2.3-b1f1.41benzo- tiiasepin-S-pne Prepared analogously to Example 4 from 9-chloro-ll-(chloroacetyl)-5,ll-dihydro-6H-pyrido[2,3-b)[1,4]benzo-diazepin-6-one and l-ethyl-2-[2-(methylamino)ethyl)-35 piperidine. Yield: 15% of theory. Mp.: 164*C (diisopropyl ether/acetone). 22 95 2 26 Example 9 5.11-Dihvdro-ll-r r f 3-(l-methvl-2-pjperidinvl\propyl1-methvlawinolacetvll-6H-pyridor2.3-blf1.4lbenzodiazepin-6-one Prepared analogously to Example 4 from 11-(chloroacetyl )-5,ll-dihydro-6H-pyrido(2 , 3-b][1,4]benzodiazepin-6-one and l-raethyl-2-(3-(methylamino)propylJpiperidine. Yield: 23% of theory. Mp.: 145-146*0 (diisopropyl ether/ethyl acetate). Example 9 6.11-Pihvdro-ll-rrr3-fl-methvl-2-piperidinvllpropvll-methvlamino!acetyl1-SH-pyridof 2.3-blr1.41 benzodiazepine 5-one Prepared analogously to Example 4 from 11-(chloroacetyl )-6,ll-dihydro-5H-pyrido[2,3-b)[1,4]benzodiazepin-5-one and l-methyl-2-(3-(methylamino)propyl]piperidine. Yield: 24% of theory. Mp.: 132-133*C (diisopropyl ether/ethyl acetate). Example 10 5.10-Dihvdro-S-f tf 3-(l-methvl-2-plperldinvl\propyl1-methylamino!acetyl1-1lH-dibenzo fb.e1r1.41d iazepin-11-one Prepared analogously to Example 4 from 5-(chloroacetyl)-5,10-dihydro-llH-dibenzo[b,e]-[l,4]diazepin-ll-one and l-methyl-2-[3-(methylamino)propyl]piperid ine. Yield: 43% of theory. Mp.: 124—126*C (diisopropyl ether/ethyl acetate). 22 95 24 27 Example 11 5.11-Dihvdro-l1-r Tf 2-f1-nethvl-hexahvdro-lH-2-azepinvl 1 -ethvl1nethvlamino!acetyl1-6H-pvridor2.3-blr1.41benzo-diazepin-6-one Prepared analogously to Example 4 from 11-(chloroacetyl)-5,ll-dihydro-6H-pyrido[2,3-b][1,4]benzo-diazepin-6-one and l-methyl-2-[2-(methylamino)-ethyl ]hexahydro-lH-azepine. Yield: 30% of theory. Hp.: 139-140*0 (ethyl acetate). EXttffPl? 12 9-Chloro-S.ll-dihvdro-ll-rff2-fl-methvl-hexahvdro-lH-2-azepinvl)ethvl1nethvlaninolacetyl1-6H-nvridof 2.3-bl - f l .4 Hrengodl«gpin-$-ong hydrochloride Prepared analogously to Example 4 from 9-chloro-ll-(chloroacetyl)-6H-pyrido[2,3-b)(1,4]benzodiazepin-6-one and l-nethyl-2-[2-(methylamino)ethyl]hexahydro-lH-azepine. The base was converted into the hydrochloride with concentrated hydrochloric acid. Yield: 4.5% of theory. Hp.: 258-259*C (ether/ethyl acetate). Example 13 5.11—Dlhvdro—8—methyl—11—f ff 2-(1-nethvl-hexahvdro-lH-2-azepinvl1ethvl1nethvlani no1acetyl1-6H-pvridof 2.3-bl- f1.4ltanzriliflZCPln-S-gnQ Prepared analogously to Example 4 from 1l-(chloroacetyl ) -8 -methy l-6H-pyrido[ 2 ,3-b](1,4]benzodiazepin-6-one and l-methyl-2-(2-(methylamino)ethyl)-hexahydro-lH-azepine. Yield: 17% of theory. Hp.: 132-134*C (ethyl acetate). 22 95 24 # " 22 g 5.10-Dihvdro-5-fTr2-fl-methvl-hexahvdro-lH-2-azepinvl)-ethvl1methvlamino1acetyl1-1IH-d ibenzo f b.elf1.41d iazepin-11-one Prepared analogously to Example 4 from 5-(chloroacetyl) -5,10-dihydro-llH-dibenzo(b,e](1,4]diazepin-ll-one and l-methyl-2-(2-(methylamino) ethyl ]-hexahydro-lH-azepine. Yield: 53% of theory. Hp.: 112-114"C (diethyl ether). Example 15 6.11-Dlhvdro-ll-rrr2-ri-methvl-hexahvdro-lH-2-azepinvll- sthvX 1 methyl amino! acetyl 1 -5H-pvridor2.3-bl f 1.4 Ibenzo-diasepin-S-one Prepared analogously to Example 4 from 11-(chloroacetyl) -6, ll-dihydro-5H-pyrido(2,3-b] (1,5]-benzodiazepin-5-ona and l-methyl-2-(2-(methylamino)ethyl]-hexahydro-lH-azepine. Yield: 27% of theory. Hp.: 120-122*C (diisopropyl ether/ethyl acetate). O 10 * 229524 29 The following Examples illustrate the preparation of some pharmaceutical administration forms: Example I 5 Tablets containing 5 Big of 5,11-dihydro-ll-[ I [2-(l-methyl-hexahydro-lH-2-azepinyl) ethyl J methylamino ]acetyl]-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one Composition: 1 tablet contains: Active substance 5.0 mg Lactose 148.0 mg 15 Potato starch 65.0 ng Magnesium stearate 2.0 mo 220.0 mg A 10% mucilage is prepared from potato starch by 20 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 25 co&prcsscd using a 9aa punch to fore tablets weighing 220 mg. Example IT 30 Coated tablets containing 5 mg of 5,11-dihydro-ll-[[(2-(l-methyl-hexahydro-lH-2-azepinyl)ethyl]methyl-amino]acetyl]-6tf-pyrido[2,3-b) [1,4]benzodiazopin-6-one 35 Tablets prepared according to Example I are coated, in a conventional manner, with a coating consisting essentially of sugar and talc. The finished coated tablets are polished with beeswax. The polished 22 9 5 2 4 30 coated tablets weigh 300 mg. Example III Ampoules containing 10 mg of 5,ll-dihydro-ll-[[[2-(l-methyl-hexahydro-lH-2-azepinyl)ethyl)methylamino] acetyl ]-6H-pyrido[ 2 ,3-b][1,4]benzodiazepin-6-one Composition: 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 filter sterilised and transferred into 1 ml ampoules. Sterilisation: 20 minutes at 120*C. Example XV Suppositories containing 20 mg of 5,ll-dihydro-ll-[[[2-(l-Bethyl-hexahydro-lH-2-azepinyl) ethyl ] methylamino] acetyl ]-6H-pyrido[2,3-b) [1,4]benzodiazepin-6-one Composition: 1 suppository contains: Active substance Suppository mass (e.g. Witepsol W 45) (Hitepsol W45 is a trade mark) </div>

Claims

<div class="application article clearfix printTableText" id="claims"> . ■ - .j ,. 22 95 24 !j 31 1 ij Finely powdered active substance is suspended in 3 the molten suppository mass which has been cooled to 1 40*C. The mass is poured at 37*C into slightly chilled * 1 o suppository moulds to produce suppositories weighing I * 5 1.7 g. Drops containing 5,ll-dihydro-ll-([(2-(l-methyl-10 hexahydro-lH-2-azepinyl)ethyl)methylamino]acetyl]-6H-pyrido-(2,3-b](1,4]benzodiazepin-6-one C 15 Composition: 100 ml of drops solution contain: Methyl p-hydroxybenzoate 0.035 g Propyl p-hydroxybenzoate 0.015 g Aniseed oil 0.05 g 20 Menthol 0.06 g Pure ethanol 10.0 g Active substance 0.5 g Sodium cyclamate 1.0 g Glycerol 15.0 g 25 Distilled water ad 100.0 cl 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 30 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. o c 5 20 22 9 5 24 32 WHAT l/WE CLAIM Be- mime.

1. A compound of formula I O "X I 1 2 f "1 10 O = C — A - N- A (I) 1 1 N" * 1 2 R 15 (wherein ^)(b) represents one of the divalent groups (S), (T), (U) and (V) f«3 R4 <X 3 XX R7 <S) (T) (0) (V) I 25 X represents a -CH- group, a -C-Cl group or a nitrogen atom; A1 and A1 which may be the same or different, each represents a straight-chained or branched Cw alkylene 30 group; Z represents an oxygen atom or a C10 alkylene chain; 35 R1 represents a branched or unbranched Cw alkyl group, a cycloalkyl or (cycloalkyl)alkyl group containing up to 8 carbon atoms or a hydrogen atom; 22 9 5 24 33 R2 represents a branched or unbranched C}.6 alkyl group or a cycloalkyl group containing up to 7 carbon atoms; /"n R3 and R*, which may be the sane or different, each . >iv ■ 5 represents a hydrogen, fluorine, chlorine or bromine atom or a Cx.4 alkyl group; R5 represents a hydrogen or chlorine aton or a methyl ^ group; ^ 10 R* and R7, which may be the sane or different, each represents a hydrogen aton or a C,.4 alkyl group and R7 may also represent a halogen atom; 15 with the proviso that where represents a group (V) X represents a -CH- or «C-C1 group) or an isomer or acid addition salt thereof. 20

2. K compound as claimed in claim I being 5,11-dihydro-ll-[ [ (2-(l-methyl-2-piperidinyl)ethyl)-methylamino) acetyl ]-6H-pyrido( 2,3-b] [1,4 ]benzodiazepin- C-one; 25 5,11-dihydro-ll- [ [(2-(l-methyl-hexahydro-lH-2-azepinyl)-ethy 1 ] methylamino ] acetyl ] -6H-pyr ido [2,3-b] [1,4] benzo-diazepin-6-one; 30 9-chloro-5,11-dihydro-ll-[[(2-(l-methyl-hexahydro-lH-2-azepinyl)ethylJmethylamino)acetyl]-6H-pyrido[2,3-b] -[1,4]benzodiazepin-6-one; 5,ll-dihydro-8-methyl-ll-[[(2-(l-methyl-hexahydro-lH-2-35 azepinyl) ethyl) methylamino) acetyl) -6H-pyrido [ 2,3-b) -[1,4]benzodiazepin-6-one; a®. 22 9 5 2 n 34 or an acid addition salt thereof.

3. A compound as claimed in either of claims 1 and 2 being a physiologically acceptable acid addition salt of 5 a compound of formula I.

4. A pharmaceutical composition comprising at least one compound of formula I as defined in either of claims 1 and 2, or a physiologically acceptable acid addition 10 salt thereof, together with at least one pharmaceutical carrier or excipient.

5. A process for the preparation of a conpound as claimed in any one of claims 1 to 3, said process 15 comprising at least one of the following steps: a) (to prepare compounds of formula la 20 25 cc> 0-C-A - N - A4 X'; N (la) (wherein 30 X, Z, A1, A*, R1 and R* are as defined in claia 1 and ^ (B*) represents a group (S), (U) or (V) as defined in claim 1 or a group (T') CH, I 35 N \ (T*) XI R5' 22 9 5 24 35 wherein R5' represents a chlorine atom or a methyl group)) 5 reacting a compound of formula II (wherein 20 A1, X and ^(b*) are as hereinbefore defined and Hal represents a chlorine, bromine or iodine atom) with a compound of formula III 25 o R - NH - A J ("I) N R2 30 (wherein A2, Z, R1 and R2 are as hereinbefore defined); b) (to prepare compounds of formula la as hereinbefore defined) 35 reacting a diazepinone of formula IV 100$-, ' 'r» 229524 36 (IV) 10 (wherein X and ^^B*) are as defined in claim 1) with a compound of formula V 15 O 11 1 Nu - C - A1 - N - A k> o N (V) 20 (wherein Z, A1, A2, Rl and R2 are as defined in claim 1 and Nu represents a nucleofugic or leaving group); 25 30 35 c) (to prepare compounds of formula lb N N 0 « C - A1 ~ K - A2 S h R N I (lb) (wherein X, Z, A1, A2, R1 and R2 are as defined in claim 1 and R9n represents a hydrogen atom)) c 15 20 22 9 5 2 37 hydrogenolysing a conpound of formula lb (wherein R5" represents a chlorine atom); d) resolving a compound of formula I into its isomers; 5 and e) converting a compound of formula I into an acid addition salt thereof, or an acid addition salt of a compound of formula I into the free base. 10

6. A process as claimed in claim 5 wherein the reaction of step (a) is carried out in a solvent at temperatures of between -10*C and the boiling point of the reaction mixture.

7. A process as claimed in either one of claims 5 and 6 wherein the reaction of step (a) is carried out in the presence of an auxiliary base or an excess of the amine of formula III.

8. A process as claimed in claim 5 wherein the reaction of step (b) is effected in an inert solvent at temperatures of between -25*C and 130*C. 25

9. A process as claimed in any one of claims 5 and 8 wherein in step (b) an acid halide, ester, anhydride or mixed anhydride is used as the reactive carboxylic acid derivative of formula V. 30

10. A process as claimed in claim 5 wherein the hydrogenolysis of step (c) is effected in the presence of a solvent at temperatures of between 0*C and 130'C, and in the presence of a catalyst comprising a metal of the Vlllth subgroup of the periodic table, and under a 35 hydrogen pressure of from 1 to 300 bar.

11. A process as claimed in claim 5 wherein the *»» . i » 229524 38 reaction of step (c) is effected with formic acid or triethylammonium formate in the presence of triethylamine under ambient pressure.

12. A process as claimed in any one of claims 5, 10 and 11 wherein the reaction of step (c) is effected a) with palladium on animal charcoal or on barium sulphate, with Raney nickel or Raney cobalt as catalysts and in the presence of alcohols, ethers, carboxylic acids or tertiary amines as solvents, or b) with formic acid, optionally in the presence of dimethylformamide as solvent and palladium on charcoal as catalyst at temperatures of between 70 and 110'C, or c) with triethylammonium formate in the presence of excess triethylamine and palladium on animal charcoal or palladium acetate and triarylphosphines at temperatures of between 40 and 110*C.

13. The use of a compound of formula I as claimed in either of claims 1 and 2, or a physiologically acceptable acid addition salt thereof for the manufacture of a therapeutic agent for use in the treatment of bradycardia and bradyarrhythmia and spasm in the colon, bladder and bronchi.

14. A method of treatment of the non-human animal body . _ .combat bradycardia and bradyarrhythmia and spasm in tnfcolon, bladder and bronchi, which method comprises administering to said body a compound of formula I (as . I defined in claim 1) or a physiologically acceptable acid 'OCT1990^addition salt thereof.

15. Compounds of formula I as defined in claim 1, and Its thereof, substantially as herein disclosed in any e of the Examples. DR. KARIi THOMAE GMBH By t! Attorneys </div>