NZ229523A - Condensed diazepinones and pharmaceutical compositions thereof - Google Patents

Description

New Zealand Paient Spedficaiion for Paient Number £29523 22 9 5 2 3 A*fi .>* NO DRAWINGS Priority Date(s): ...ISc.W^S.' :'■■"■'■ (s-"4" %■=)■ Complete Specification Filed: Case: Publication Date: P.O. Journal, No: .. • • Patents Form No. 5 >»*>» NEW ZEALAND PATENTS ACT 1953 COMPLETE SPECIFICATION CONDENSED DIAZEPINONES 13JUN1989 I V £/WE, DR KARL THOMAE GMBH, a body corporate organised 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 which S(/We pray that a patent may be granted to ii^/us, and the method by which it is to be performed, to be particularly described in and by the following statement: (followed by Page la) - la - 54128.02 Condensed Diazepinones The invention relates to certain new condensed diazepinones, processes for preparing them and pharmaceutical compositions containing these compounds.

Condensed diazepinones with anti-ulcerative properties and an inhibitory effect on the secretion of gastric juices have already been 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.

It is also known from EP-A-156191 that valuable pharmacological properties completely different from those of the compounds in the publications mentioned above can be induced by the introduction of new aminoacyl groups. We have now found that certain new condensed diazepinones, compared with the compounds of EP-A-156191, are distinguished by substantially greater activity and resorption after oral administration, whilst having comparable or better selectivity.

Thus, viewed from one aspect the invention provides a compound of formula I 0 II NH — C R' (I) (wherein ](jj) represents one of the groups (S) , (T) , (U), (V) and (W); 2 ?29 5 2 3 (S) CH-i 3 ,N (T) (V) CH, I 3 •N v.

N il (W) \ R X represents a methine group or a nitrogen atom; A1 and A2, which may be the same or different, each represents a straight-chained saturated CX_A alkylene group; R1 and R2, which may be the same or different, each represents a hydrogen atom, a branched or unbranched alkyl group or a Cw cycloalkyl group optionally substituted by a hydroxy group; R3 represents a alkyl group or a chlorine or hydrogen atom; R* represents a hydrogen atom or a methyl group; R5 and R6, which may be the same or different, each represents a fluorine, chlorine or bromine atom, a Cx.k alkyl group or a hydrogen atom, with the proviso that, if X represents a nitrogen atom, A2 represents a straight-chained saturated C2.4 alkylene group and R1 represents a hydrogen atom, then at least one of the groups R5 and R6 represents a fluorine, chlorine or bromine atom or a Cj.A alkyl group; R7 represents a hydrogen or chlorine atom or a methyl group; 229523 R8 represents a hydrogen atom or a alkyl group; R9 represents a hydrogen or halogen atom or a C1.4 alkyl group; and R10 represents a hydrogen atom or a methyl group; with the provisos that where ] (IT) represents a group (T) and R7 represents a hydrogen atom then R3 represents a hydrogen atom or a Cv4 alkyl group, that where ] (iT) represents a group (V) then X represents a methine group and that where X represents a nitrogen atom and either R1 represents a methyl group and A2 represents a methylene group or R1 represents a hydrogen atom and A2 represents a C^_2 alkylene group then at least one of R5 and R6 must be other than hydrogen); or an isomer or acid addition salt thereof.

The compounds of formula I, after reaction with inorganic or organic acids, may be converted into their physiologically acceptable salts thereof. Examples of suitable acids include hydrochloric, hydrobromic, y Hj sulphuric, methylsulphuric, phosphoric, tartaric, fumaric, citric, maleic, succinic, gluconic, malic, toluenesulphonic, methanesulphonic and amidosulphoni! acids.

To illustrate the invention, the following preferred compounds may be mentioned by way of example: ,11-dihydro-ll-[[[2-(l-methyl-2-pyrrolidinyl)ethyl]-methylamino]acetyl]-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one, 9-chloro-5,11-dihydro-ll-[[[2-(l-methyl-2-pyrrolidinyl)-ethyl]ethylamino]acetyl]-6H-pyrido[2,3-b][1,4]benzo-diazepin-6-one and 229523 ,10-dihydro-5-[[[2-(l-methyl-2-pyrrolidinyl)ethyl]-methylamino]acetyl]-llH-dibenzo[b,e][1,4]diazepin-ll-one and the physiologically acceptable salts thereof with inorganic or organic acids.

Viewed from another aspect, the invention provides a process for the preparation of compounds according to the invention, said process comprising at least one of the following steps: (a) (to prepare compounds of formula la ■* ' > .'-O 0 . c . A1 - N - A N y il (wherein X, A1, A2 and R1 to R^ are defined as hereinbefore J 0 represents a group (S), (U), (V) or (W) as hereinbefore defined or a group (T1) (T«) r wherein R7* represents a chlorine atom or a methyl group)) reacting a compound of formula II •*'»•■• --'• J' "■ 229523 (id O = C - A - Hal (wherein X, A1, R3, R4 and are defined as hereinbefore and Hal represents a chlorine, bromine or iodine atom) with a compound of formula III 1 2 R - NH - A - (III) N R' (wherein R1, R2 and A2 are defined as hereinbefore) ; (b) (to prepare compounds of formula la as defined hereinbefore) reacting a compound of formula IV >< x 0 li NH— C.

N' I H 0 (IV) (wherein X, R3, R4 and |(^Bare defined as hereinbefore) with a carboxylic acid derivative of formula V ii , 2 Nu-C-A - N- A - (V) R (wherein A1, A2, R1 and R2 are defined as hereinbefore and Nu represents a nucleofugic group or a leaving group); 6 ? 2 9 5 2 3 (c) (to prepare compounds of formula lb R- ^fy 0 «3 ii 1 R 4 ^ X- NH ~ C.

N- 1 I R' 0=C-A1-N-A2- (Ib) N R (wherein X, A1, A2, R1, R2, R3 and R4 are defined as hereinbefore and R7" represents a hydrogen atom)) hydrogenolysing a compound of formula lb wherein R7" represents a chlorine atom ; (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 pharmacologically acceptable acid addition salt; and (e) separating a compound of formula I into the enantiomers and/or diastereomers thereof.

The amination of step (a) is conveniently carried out in 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 II or with 1 to 2 moles of a secondary amine of formula 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 22 9 5 23 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 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 compounds of formula IV with the acid derivatives 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 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 ■jr? " ?***'!•. -• . 22 9 5 2 3 8 pyridine, triethylamine, ethyl diisopropylamine, 4-dimethylaminopyridine and sodium hydride. The reaction of step (b) may conveniently be 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 methylene chloride and 1,2-dichloroethane; open-chained or cyclic 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 and hexamethylphosphoric acid triamide; 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. It is not necessary to produce the compounds of formula V in pure form; instead, they can be prepared in situ in 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 Vlllth sub-group of the periodic table, for example palladium on animal charcoal, palladium on barium sulphate, Raney nickel or Raney cobalt, and under hydrogen pressures of from 1 to 300 bar, and at temperatures of from 0°C to 130°C, in the presence of solvents, for example alcohols such as methanol and ethanol; ethers such as dioxan and 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 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 in principle be 9 22 9 5 23 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 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 as triphenylphosphine, tris-(o-tolyl)-phosphine, tris-(2,5-diisopropylphenyl)-phosphine, at temperatures of between 4 0 and 110°C, have proved particularly successful.

The compounds of formula I according to the invention contain up to two independent chiral elements, particularly if represents the divalent 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, 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 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 is a nitrogen atom and the positions adjacent to the diazepinone ring are unsubstituted, the activation energy required is reduced so much that at ambient temperature diastereoisomers can no longer be detected, let alone preparatively separated.

The compounds 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 invention includes the individual isomers as well as the mixtures thereof. The diastereomers may be separated on the basis of their different physico-chemical properties, e.g. by fractional recrystallisation from suitable solvents, by 229523 high pressure liquid chromatography, column chromatography or gas chromatography.

The separation of any racemates of the compounds of formula I may be carried out by 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.

According to a conventional method of separating isomers, the racemate of a compound of formula I is reacted with one of the optically active acids specified above in equimolar quantities in a solvent and the crystalline diastereoisomeric salts obtained are separated using their different solubilities. This reaction may be carried out in any type of solvent provided that the latter exhibits sufficiently different solubilities for the diastereoisomeric salts.

Preferably, methanol, ethanol or mixtures thereof, e.g. in a 1:1 ratio by volume, are used. Each of the optically active salts is then dissolved in 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 active diastereoisomeric compounds covered by formula X may also be obtained by carrying out the syntheses described above with only one enantiomer of formula III or V.

The haloacyl compounds of formula II may be prepared by methods analogous to known methods (see, for example, US-A-4550107).

Intermediate compounds of formula III can easily be synthesised using methods apparent to those skilled in the art, e.g. by reduction of corresponding pyrrolidine carboxylic acid alkylamides with lithium aluminium hydride or diborane.

The starting compounds of formula V wherein Nu 22 9 5 2 3 n represents an alkoxy group may be obtained by reacting diamines of formula III with halocarboxylic acid esters, optionally using additional auxiliary bases, e.g. 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 may be used to prepare derivatives with other nucleofugic groups.

The base-substituted condensed diazepinones of formula I and the physiologically 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 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, bladder and bronchi.

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 5 12 A. Studies of binding to muscarinic receptors: In vitro measurement of the IC50 value The organs were donated by male Sprague-Dawley rats weighing 180-2 20 g. After the heart and submandibular gland and cerebral cortex had been removed, all other steps were carried out in ice cold Hepes HCl buffer (pH 7.4; 100 millimolar NaCl, 10 millimolar MgClz). 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: 3 000 Submandibular gland 1: 4 00 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%. The results are set forth in Table I. 22 9 5 2 3 13 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. M1/Mz 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 that described by Hammer and Giachetti (Life Sciences 31, 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) or 0.3 mg/kg of McN-A-343 were intravenously injected into male THOM rats. The bradycardia caused by vagus stimulation and the rise in blood pressure caused by McN-A-343 were determined. The dosage of the substances 229523 14 which reduced either the vagal bradycardia (M2) or the rise in blood pressure (Mj) by 50% was determined graphically. The results are set forth in Table II. 2. Salivation-inhibiting effect in the rat Using the method of Lavy and Mulder (Arch. Int. Pharmacodyn. 178. 437-445, (1969)) male THOM rats 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 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. 3. Inhibition of the effect of acetylcholine on the bladder, bronchi and heart rate in guinea pigs minutes after the administration of the test substance, 10 microgram/kg of acetylcholine were simultaneously injected intravenously and intra-arterially into anaesthetised guinea pigs. The heart rate was recorded directly by extracorporeal derivation of the ECG, the expiration resistance according to Konzett-R6/31er and contraction of the exposed bladder. In order to determine the inhibition of the acetylcholine activity on the organs under investigation, dosage/activity curves were recorded and from them -log EDS0 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 5 2 3 A = 5,11-dihydro-ll[[[2-(l-methyl-2-pyrrolidinyl)- ethyl]methylamino]acetyl]-6H-pyrido[2,3-b][l,4]-benzodiazepin-6-one hydrochloride; B = 9-chloro-5,11-dihydro-ll-[[[2-(l-methyl-2- pyrrolidinyl)ethyl]ethylamino]acetyl]-6H-pyrido-[2,3-b][l,4]benzodiazepin-6-one; and (***) C = 5,10-dihydro-5-[[[2-(l-methyl-2-pyrrolidinyl)- ethyl]methylamino]acetyl]-llH-dibenzo[b,e][1,4]-diazepin-ll-one hydrochloride; n and as comparison substances D = ll-[[2-[(diethylamino)methyl]-l-piperidinyl]-acetyl]-5,ll-dihydro-6H-pyrido[2,3-b][l,4]-benzodiazepin-6-one (see US-A-4550107); E = 5,11-dihydro-ll-[(4-methyl-l-piperazinyl)acetyl]-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one (pirenzepine, see US-A-3660380) G and F = atropine. 22 9 5 2 3 16 Table I Receptor Binding Tests in vitro Results: Receptor Binding Tests IC50 [nmol l"1] Substance Cortex Heart Submandibular gland A 50 9 80 B 70 100 C 8 3 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 the invention 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 and submandibular gland. 22 95 17 Table II; Mi/Ma selectivity and salivation-inhibiting activity on the rat Results: Substance -log ED50 Heart [mol kg"1] Blood pressure Salivation A 7.91 7. 06 6.8 D 6. 42 .63 . 00 E . 60 6.94 6.22 F 7.94 7.34 7.60 C n 229523 18 Table III Inhibition of acetylcholine activity on the bladder, f*) bronchi and heart rate in the guinea pig Vw; Results; o Substance -log ED50[mol kg"1] Heart Bronchi Bladder A 7.7 7.6 6. 85 B 7.0 6.72 6.08 C 7.54 7.53 6.63 D .84 .58 4.73 E .85 6.57 . 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 I ^ 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.

I 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 1 I > i •1 229523 19 the quantity of drug to be administered to the patient without increasing the risk of muscarinic side effects.

Furthermore, the compounds according to the invention are well tolerated; even in the highest doses administered, no toxic side effects were observed in the pharmacological trials.

For pharmaceutical use, the compounds of formula I or physiologically acceptable salts thereof can be incorporated in a conventional manner in customary pharmaceutical preparation forms such as solutions, suppositories, plain or coated tablets, capsules and infusions. The daily dosage is generally 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 of body weight, optionally administered in the form of several, preferably 1 to 3, individual doses, in order to achieve the desired results.

Thus, viewed from another aspect, the invention provides a pharmaceutical composition comprising at least one compound of formula I as defined hereinbefore or a physiologically acceptable acid addition salt thereof together with at least one pharmaceutical carrier or excipient.

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 bradyarrhythmia and spasm in the colon, bladder and bronchi.

Viewed from a still further aspect, the invention provides a method of treatment of the human or non-human animal, preferably mammalian, body for combatting bradycardia, bradyarrhythmia or spasm of the colon, bladder or bronchi, said method comprising administering to said body a compound of formula I as defined hereinbefore or a physiologically acceptable acid addition salt thereof. 22 95 2 3 The non-limiting Examples which follow are intended to illustrate the invention without restricting its scope in any way.

Satisfactory elemental analyses, IR, UV and XH-NMR spectra are available for all 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 .ll-Dihvdro-8-methvl-ll-r f\2-(l-methvl-2-pvrrolidinvl^-ethvl1 amino 1 acetyl1-6H-pvrido r 2.3-b1T1.41benzodiazepin-6-one 9.0 g (0.03 mol) of 11-(chloroacetyl)-5,11-dihydro- 8-methyl-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one, 3.2 g of sodium carbonate and 5.1 g (0.04 mol) of 2-(2-aminoethyl)-1-methylpyrrolidine were refluxed for 2 hours in 12 0 ml of absolute dioxan. The mixture was filtered while hot, the solvent was evaporated off and the residue was purified by column chromatography on silica gel (eluant: methylene chloride/methanol/cyclo-hexane/ammonia 68/15/15/2 by volume). The eluate was recrystallised from ethyl acetate.

Yield: 1.9 g (16% of theory) Mp.: 107-109 ° C (ethyl acetate).

Example 2 9-Chloro-5.11-dihvdro-ll-r f r2-(l-methvl-2-pvrrolidinvH-ethvl1 amino1 acetyl1-6H-pyrido f 2.3-blI" 1.41benzodiazepin-6-one Prepared analogously to Example 1 from 9-chloro-ll-(chloroacetyl)-5,ll-dihydro-6H-pyrido[2,3-b][1,4]benzo-diazepin-6-one and 2-(2-aminoethyl)-1-methylpyrrolidine in a yield of 17% of theory.

Mp.: 130—132 °C (ethyl acetate). 229523 21 Example 3 6,ll-Dihydro-ll-[[[2-(l-methyl-2-pyrrolidinyl)ethyl]-amino]acetyl]-5H-pyrido[2,3-b][1,5]benzodiazepin-5-one-dihydrochloride Prepared analogously to Example 1 from 11-(chloroacetyl)-6,ll-dihydro-5H-pyrido[2,3-b][1,4]-benzodiazepin-5-one and 2-(2-aminoethyl)-1-methylpyrrolidine. The base was converted into the dihydrochloride by the addition of aqueous hydrochloric acid.

Yield: 14% of theory.

Mp.: 206-207°C (isopropanol).

Example 4 ,10-Dihvdro-5-r r\2-(l-methvl-2-pyrrolidinvl)ethvl1-amino 1 acetyl 1 -HH-dibenzof b. el r 1,41 diazepin-ll-one dihydrochloride Prepared analogously to Example 1 from 5-(chloroacetyl)-5,10-dihydro-llH- dibenzo[b,e][1,4]diazepin-ll-one and 2-(2-aminoethyl)-1-methylpyrrolidine. The base was converted into the dihydrochloride by the addition of aqueous hydrochloric acid.

Yield: 13% of theory.

Mp.: 215-2178C (isopropanol).

Example 5 4.9-Dihvdro-4-r f r2-fl-methvl-2-pvrrolidinvl)- ethvl1amino!acetyll-10H-thienor3.4-blri.51benzodiazepin- -one dihydrochloride Prepared analogously to Example 1 from 4-(chloroacetyl) -4,9-dihydro-10H-thieno[3, 4-b][1,5]benzodiazepin-10-one and 2-(2-aminoethyl)-1-methylpyrrolidine. The base was converted into the dihydrochloride by the addition of aqueous hydrochloric acid. 22 9 22 Yield: 20% of theory.

Mp.: 223-225°C (isopropanol).

Example 6 1.3-Dimethvl-4-rr f 2-d-methvl-2-pyrrolidinvl)-ethvllamino1 acetyl1-1.4,9.10-tetrahvdropyrazolo-f4.3-elpyridor3.2-bldiazepin-10-one difumarate Prepared analogously to Example 1 from 4-(chloroacetyl)-1,3-dimethyl-l,4,9,10-tetrahydro-pyrazolo[4,3-e]pyrido[3 , 2-b]diazepin-10-one and 2-(2-(aminoethyl)-1-methylpyrrolidine. The base was converted into the fumarate with fumaric acid.

Yield: 30% of theory.

Mp.: 200-2 02°C (isopropanol).

Example 7 ,11-Dihvdro-ll-r f r2-('l-ethvl-2-pvrrolidinvl') ethvl 1-aminolacetyl1-6H-pyridor 2,3-blf1,41benzodiazepin-6-one Prepared analogously to Example 1 from 11-(chloroacetyl)-5,ll-dihydro-6H-pyrido[2,3-b][l,4]benzo diazepin-6-one and 2-(2-aminoethyl)-1-ethylpyrrolidine Yield: 9.5% of theory, Mp.: 109-1110C (ethyl acetate/cyclohexane 2/1 v/v). Example 8 .11-Dihvdro-ll-r 3-r r2-(l-methvl-2-pvrrolidinvl)-ethvl1aminolpropionvll-6H-pvridor2,3-blr1.41benzo-diazepin-6-one 3.85 g (0.03 mol) of 2-(2-aminoethyl)-1-methylpyrrolidine were added dropwise to a solution of 7.1 g (0.024 mol) of 11-(3-chloropropionyl)-5,ll-dihydro-6H-pyrido[2,3-b][l,4]benzodiazepin-6-one and 3 g of triethylamine in 70 ml of dimethylformamide at ambient temperature and the resulting mixture was stirred at this temperature for a further 2 hours. After the 23 22 9 5 2 3 solvent had been evaporated off, the residue was purified by column chromatography on silica gel (mobile phase: ethylene chloride/methanol/ammonia 100/20/2 by volume). An amorphous solid substance was obtained. Yield: 2.93 g (31% of theory) Rf=0.23 (Merck ready-made plates, silica gel F 254; eluant: ethyl acetate/methanol/conc. ammonia 70/30/5 by volume).

Example 9 .10-Dihvdro-5-r 3-r f 2-fl-methyl-2-pyrrolidinvl)- ethvl1 amino!propionvl1-HH-dibenzo rb. el r1,41diazepin-ll-one Prepared analogously to Example 8 from 5-(3-chloro-propionyl)-5,10-dihydro-llH-dibenzo[b,e][1,4]diazepin-ll-one and 2-(2-amino-ethyl)-1-methylpyrrolidine as an amorphous solid.

Yield: 13% of theory.

Rf=0.34 (Merck ready-made plates, silica gel F 254; eluant: ethyl acetate/methanol/conc. ammonia 70/30/5 by volume).

Example 10 .11-Dihvdro-ll-r r\2-(l-methvl-2-Pvrrolidinvllethvll-methvlaminolacetyl1-6H-pvrido r 2.3-blr1.4lbenzodiazeoin-6-one hydrochloride A solution of 28.7 g (0.1 mol) of 11-(chloroacetyl)-5,ll-dihydro-6H-pyrido[2,3-b][1,4]benzo-diazepin-6-one and 15.7 g (0.11 mol) of l-methyl-2-[2-(methylamino)ethyl pyrrolidine in 300 ml of absolute dimethylformamide was stirred for 8 hours at ambient temperature. After the solvent had been distilled off the residue was triturated with a little methanol. The crystals precipitated were suction-filtered and purified by recrystallisation from ethyl acetate/methanol using activated charcoal. 22 9 5 2 3 24 Yield: 19.8 g (46% of theory) Mp.: 223-224"C (ethyl acetate/methanol).

Example 11 .10-Dihvdro-5-r r r2-(l-methvl-2-pyrrolidinvl)ethvl 1 -methylamino 1 acetyl 1 -HH-dibenzo rb .el r 1. 41 diazeoin-11-one hydrochloride Prepared analogously to Example 10 from 5-(chloroacetyl)-5,10-dihydro-llH-dibenzo[b,e][1,4]-diazepin-ll-one and l-methyl-2-[2-(methylamino)ethyl]-pyrrolidine.

Yield: 42% of theory.

Mp.: 208-210°C (ethyl acetate/methanol).

Example 12 .11-Dihvdro-ll-r r f 2-(l-methvl-2-pvrrolidinvllethvll-ethvlaminolacetyll-6H-pvridor2.3-blr1.4lbenzodiazepin-6-one 3.1 g (0.022 mol) of l-methyl-2-[2-(ethylamino)-ethyl]pyrrolidine were added dropwise to a solution of 5.7 g (0.02 mol) of 11-(chloroacetyl)-5,ll-dihydro-6H-pyrido[2,3-b][l,4]benzodiazepin-6-one and 2.8 ml of triethylamine in 50 ml of dimethylformamide and the mixture was stirred for a further 0.5 hours at ambient temperature. After the solvent had been distilled off, the residue was chromatographed on silica gel (mobile phase: methylene chloride/methanol 9/1 v/v). The concentrated eluates were distributed between potassium carbonate solution and ethyl acetate. After the solvent had been distilled off, the crystals obtained were recrystallised from diisopropyl ether/ethyl acetate.

Yield: 0.98 g (12% of theory) Mp.: 159-160°C (diisopropyl ether/ethyl acetate). 22 9 5 2 3 Example 13 9-Chloro-5.11-dihvdro-ll-rf T2-fl-methvl-2-pyrrolidinvll-ethvl1ethylamino1 acetyl1-6H-pvrido r 2.3-b1r1.41benzo-diazepin-6-one A solution of 3.2 g (0.01 mol) of 9-chloro-ll-(chloroacetyl)-5,ll-dihydro-6H-pyrido[2,3-b][1,4]benzo-diazepin-6-one, 1.6 g (0.01 mol) of methyl-2-[2-(ethylamino) ethyl] pyrrolidine and 3 g of potassium carbonate in 100 ml of acetonitrile were stirred at 60°C for 2 hours, the solvent was distilled off in vacuo, the residue was stirred with water and extracted with methylene chloride. The crystals obtained after purification by column chromatography on silica gel (mobile phase: ethyl acetate/methanol/conc. ammonia 7 0/3 0/3 by volume) and evaporation of the eluates were recrystallised from diisopropyl ether/methanol.

Yield: 0.15 g (3.5% of theory) Mp.: 164-165°C (diisopropyl ether/methanol).

Example 14 ,lO-Dihvdro-5-r f r2-(l-methvl-2-pyrrolidinvl)ethvll-ethylamino 1 acetyl 1 -HH-dibenzo rb. e] [ 1,4 ] diazepin-ll-one Prepared analogously to Example 13 from 5-(chloroacetyl)-5,10-dihydro-llH-dibenzo[b,e][1,4]-diazepin-ll-one and l-methyl-2-[2-(ethylamino)ethyl]-pyrrolidine.

Yield: 3.5% of theory.

RF=0.65 (Merck ready-made plates, silica gel F 254; eluant: ethyl acetate/methanol/conc. ammonia 70/3 0/5 by volume). 22 9 5 2 3 26 Example 15 6.11-Dihvdro-ll-r r F2-(l-methvl-2-pyrrolidinvl)ethvll-ethvlamino1 acetyl]-5H-pyridof 2,3-blr1.51benzodiazepin-5-one Prepared analogously to Example 13 from 11-(chloroacetyl ) -6,ll-dihydro-5H-pyrido[2,3-b][1,5]benzodiazepin-5-one and l-methyl-2-[2-(ethylamino)ethyl]pyrrolidine.

Yield: 13% of theory.

Mp.: 139—140 °C (diisopropyl ether/ethyl acetate/acetone). 27 229523 The following non-limiting Examples illustrate the preparation of some pharmaceutical administration forms: Example I Tablets containing 5 mg of 5,11-dihydro-ll-[[[2-(1-methyl-2-pyrrolidinyl)ethyl]methylamino]acetyl]-6H-pyrido-[2,3-b][1,4]benzodiazepin-6-one 1 tablet contains: Active substance Lactose Potato starch Magnesium stearate . 0 mg 14 8.0 mg 65.0 mg 2.0 mg Total: 22 0.0 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 220 mg.

Example II Coated tablets containing 5 mg of 5,11-dihydro-ll-[[[2-(l-methyl-2-pyrrolidinyl)ethyl]methylamino]acetyl]-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 5 2 3 28 Example III Ampoules containing 10 mg of 5,11-dihydro-ll-[[[2-(1-iriethyl-2 -pyrrolidinyl)ethyl]methylamino]acetyl]-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one 1 ampoule contains: Active substance Sodium chloride Distilled water .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 5,il-dihydro-ll-[[[2-(l-methyl-2-pyrrolidinyl)ethyl]methylamino]acetyl]-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one 1 suppository contains: Active substance 20.0 mg Suppository mass (e.g. Witepsol W 45(R)) 1 680.0 mg Total: 1 700.0 mg The finely powdered active substance is suspended in the molten suppository mass which has been cooled to 40°C. The mass is poured at 37°C into slightly chilled suppository moulds, to produce suppositories each weighing 1.7 g. ,>K»l 22 9 5 29 Example V Drops containing 5,11-dihydro-ll-[[[2-(l-methyl-2-pyrrolidinyl)ethyl]methylamino]acetyl]-6H-pyrido-[2,3-b][l,4]benzodiazepin-6-one 100 ml of drops solution contain: Methyl p-hydroxybenzoate 0. 035 g Propyl p-hydroxybenzoate 0. 015 g Aniseed oil 0. 05 g Menthol 0. 06 g Pure ethanol . 0 g Active substance 0. g Sodium cyclamate 1. 0 g Glycerol . 0 g Distilled water ad 100. 0 ml The active substance and sodium cyclamate are dissolved in about 70 ml of water and glycerol is added. The p-hydroxybenzoates, aniseed oil and menthol are dissolved in ethanol and this solution is added with stirring to the aqueous solution. Finally, the solution is made up to 100 ml with water and filtered to remove any suspended particles. 229523

Claims (18)

WHAT WE CLAIM IS:

1. A compound of formula I R" NH — c \ B I 1 2 0 = C-A - N - A - Ll N (I) (wherein J QO represents a group (S), (T), (U), (V) or (W); (S) CH. < 3 N„ (T) (V) CH_ I 3 N 10 (W) X represents a methine group or a nitrogen atom; A1 and A2, which may be the same or different, each represents a straight-chained saturated alkylene group; R1 and R2, which may be the same or different, each represents a hydrogen atom, a branched or unbranched c7,A alkyl group or a cw cycloalkyl group optionally substituted by a hydroxy group; R3 represents a Cv4 alkyl group or a chlorine or hydrogen atom; ^.v 220523 R4 represents a hydrogen atom or a methyl group; R5 and R6, which may be the same or different, each represents a fluorine, chlorine or bromine atom, a C.,_4 alkyl group or a hydrogen atom, with the proviso that, if X represents a nitrogen atom, A2 represents a straight-chained saturated C2.4 alkylene group and R1 represents a hydrogen atom, then at least one of the groups R5 and R6 represents a fluorine, chlorine or bromine atom or a C.,_4 alkyl group; R7 represents a hydrogen or chlorine atom or a methyl group; R8 represents a hydrogen atom or a C1.4 alkyl group; R9 represents a hydrogen or halogen atom or a C.,.4 alkyl group; and R10 represents a hydrogen atom or a methyl group; with the provisos that where *^} represents a group (T) and R7 represents a hydrogen atom then R3 represents a hydrogen atom or a C.,.4 alkyl group, that where represents a group (V) then X represents a methine group and that where X represents a nitrogen atom and either R1 represents a methyl group and A2 represents a methylene group or R1 represents a hydrogen atom and A2 represents a alkylene group then at least one of R5 and R6 must be other than hydrogen); or an isomer or acid addition salt thereof.

2. A compound as claimed in claim 1, being: ; \ 5,11-dihydro-ll-[[[2-(l-methyl-2-pyrrolidinyl)ethyl]-methylamino]acetyl]-6H-pyrido[2,3-b][l,4]be 6-one; "i i ' ' ' 229523 - 32 - 9-chloro-5,11-dihydro-ll-[[[2-(l-methyl-2-pyrrolidinyl) ethyl ] ethyl amino ] acetyl ] - 6H-pyr ido [2,3-b][1,4]benz o-diazepin-6-one; or 5,10-dihydro-5-[ [ [2- (l-methyl-2-pyrrolidinyl) ethyl]-methylamino] acetyl ] -llH-dibenzo[b, e] [1,4]diazepin-ll-one ; or an acid addition salt thereof.

3. A compound as claimed in claim 1 or claim 2 being physiologically acceptable acid addition salt of a . compound of formula I. 1 /tSHOVW90

4. A pharmaceutical composition comprising at least ^ ^ one compound of formula I as claimed in claim 1 or claim 2 or a physiologically acceptable acid addition salt thereof together with at least one pharmaceutical carrier or excipient. a * >=41^

5. A process for the preparation of compounds as claimed in claim 1, said process comprising at least one of the following steps: (a) (to prepare compounds of formula la (la) (wherein X, A1, A2, R1, R2, R3 and R4 are defined as in claim 1 and J(&\) represents a group (S), (U), (V) or (W) as defined in claim 1 or a group (T1) '. „ <\ I. ,'. ,L 33 CH, I 3 N\ (T') I) 7. 22 9 5 R wherein R71 is a chlorine atom or a methyl group)) reacting a compound of formula II R" (ii) R 0 = C - A - Hal (wherein X, A1, R3 and R4 are as defined in claim 1 and is defined as hereinbefore and Hal represents a chlorine, bromine or iodine atom) with a compound of formula III R" NH A2 (III) (wherein R1, R2 and A* are defined as in claim 1) , (b) (to prepare compounds of formula la as defined hereinbefore) 22 95 2 3 34 reacting a compound of formula IV > NH- N I H B ' (IV) (wherein X, R3 and RA are as defined in claim 1 and is defined as hereinbefore) with a carboxylic acid derivative of formula V % 1 1 2 Nu - C - A - N- A R ^ N (V) R (wherein A1, A2, R1 and R2 are defined as in claim 1 and Nu represents a nucleofugic group or leaving group); (c) (to prepare compounds of formula lb 35 22 95 2 3 o R wv^NH-C. u x. f»3 N v N" 0 = C-A1-N-A2- (ib) \ n ^ R (wherein X, A1, A2 and R1 to R* are defined as in claim 1, and R7" represents a hydrogen atom)) hydrogenolysing a compound of formula lb wherein R7" represents a chlorine atom; (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 into another pharmacologically acceptable acid addition salt; and (e) separating a compound of formula I into the enantiomers and/or diastereomers thereof.

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 temperature of the reaction mixture.

7. A process as claimed in claim 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 carried out in an inert solvent at temperatures of between -25°C and +130°C. 22 9 5 2 3 36

9. A process as claimed in claim 8 wherein the reaction of step (b) is carried out in the presence of an acid-binding agent and the inert solvent used is a chlorinated aliphatic hydrocarbon, an open-chained or cylic ether, an aromatic hydrocarbon or a polar aprotic solvent or a mixture of these solvents.

10. A process as claimed in claim 5 wherein the hydrogenolysis of step (c) is carried out 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 group of the period table under hydrogen pressures of from 1 to 3 00 bar.

11. A process as claimed in claim 5 wherein the hydrogenolysis of step (c) is carried out in the presence of a solvent with formic acid.

12. A process as claimed in claim 5 wherein the hydrogenolysis of step (c) is carried out in the presence of a solvent with triethylammonium formate in the presence of triethylamine.

13. A process as claimed in claim 5 or claim 8, wherein, in the reaction of step (b), the reactive carboxylic acid derivative of formula V used is an acid halide, ester, anhydride or mixed anhydride thereof.

14. A process as claimed in claim 13 wherein, in the reaction of step (b), the carboxylic acid derivative used is a mixed anhydride with a strong mineral acid.

15. A process according to claim 5, wherein the hydrogenolysis of step (c) is carried out (a) with palladium on animal charcoal or on barium sulphate, with Raney nickel or Raney cobalt as catalyst - 37 - acid or tertiary amine as solvent, 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 triarylphosphine or triarylphosphines at temperatures'of between 40 and 110°C.

16. The use of a compound of formula I as claimed in claim 1 or a physiologically acceptable acid addition salt thereof for the manufacture of a pharmaceutical composition for combatting bradycardia and bradyarrhythmia and spasm in the colon, bladder and bronchi.

17. A method of treatment of the non-human animal body for combatting bradycardia, bradyarrhythmia or spasm of the colon, bladder or bronchi, said method comprising administering to said body a compound of formula I as claimed in claim 1 or a physiologically acceptable acid addition salt thereof.

18. A process for the preparation of a compound of formula I as claimed in claim 1 substantially as described herein in any one of the Examples Vt° 15• By their attorneys BALDWIN SON & CAREY