NZ197392A

NZ197392A - 5-diazacycloalkyl-imidazo(2,1-b) (1,3,5)- benzothiadiazepines

Info

Publication number: NZ197392A
Application number: NZ197392A
Authority: NZ
Inventors: I Vlattes
Original assignee: Ciba Geigy
Priority date: 1980-06-12
Filing date: 1981-06-11
Publication date: 1984-03-30
Also published as: CA1163630A; ES513638A0; EP0042354A2; AU538864B2; ZA813930B; JPS57118589A; HU185128B; GB2077727A; EP0042354B1; DE3173184D1; ATE16935T1; ES8300761A1; GB2077727B; DK255281A; FI811771L; IE811302L; FI69310C; ES502949A0; DD160535A5; PT73173B

Abstract

The invention concerns the compounds of the Formula I <IMAGE> wherein each of R1 and R2 is hydrogen, alkyl, alkanoyl, halogeno, cyano, carboxy, carbalkoxy, carbamoyl, sulfamoyl, mono- or di-alkyl-(carbamoyl or sulfamoyl); Ph is 1,2-phenylene, unsubstituted or substituted by up to two identical or different members selected from alkyl, alkoxy, alkylthio, halogeno, trifluoromethyl, sulfamoyl, mono- or di-alkylsulfamoyl; each of CmH2m and CnH2n is alkylene separating both nitrogen atoms by 2 or 3 carbon atoms, and R3 is hydrogen, alkyl, alkanoyl, alkoxycarbonyl, phenyl-alkoxycarbonyl or hydroxyalkyl, wherein the hydroxy group is separated from the nitrogen atom by at least 2 carbon atoms; their N- and/or S-oxides, and alkyl quaternary derivatives thereof salts of all these compounds. The compounds exhibit neuroleptic activity. They are prepared by condensing a compound of the general Formula III or a salt thereof with a compound of the general Formula IV <IMAGE> wherein X is halogeno, alkoxy, alkylthio, cyanato or thiocyanato; Y is hydrogen or an alkali metal; p is an integer from 0 to 2, and the remaining symbols have the meaning given for formula I.

Description

<div class="application article clearfix" id="description"> New Zealand Paient Spedficaiion for Paient Number 1 97392 « r v ' • ' 197392 -(o • Bo • i * i * • ■ ■■■•■■a Priority Date{s}: Compls-tG Spe oificetlon FiSed: H M. V. ■ Publication Dato: P.O. Journa?; Ko: J <if Ts-r ■ f * <■ » Wl y. Patents Form No. 5 NEW ZEALAND PATENTS ACT 1953 COMPLETE SPECIFICATION "Imidazobenzothiadiazepines, process for their manufacture, pharmaceutical preparations containing these compounds and their therapeutic application" -J-/WE CIBA-GEIGY AG of Klybeckstrasse 141, 4002 Basle, Switzerland, a Swiss Corporation hereby declare the invention, for which -t/we pray that a patent may £>e granted to me^us, and the method by which it is to be performed, to be particularly described in and by the following statement:- - 1 - (folioby ptge f A } 4-12896/XJGC 921/+ Imidazobenzothiadiazepines» process for their manufacture, pharmaceutical preparations containing these compounds and their therapeutic application The present invention relates to 5-diazacycloalkyl-imidazo-[2,l-b]-[l,3,5]-benzothiadiazepines of the general formula I halogeno, cyano, carboxy, lower carbalkoxy, carbamoyl, sulfamoyl, or mono- or di-lower alkyl-(carbamoyl or sulfamoyl); Ph is 1,2- phenylene, unsubstituted or substituted by up to two identical or different members selected from lower alkyl, lower alkoxy, lower alkylthio, halogeno, trifluoromethyl, sulfamoyl, or mono- or di-lov^r alkylsulfamoyl; each of C H_ and C H is lower alkylene separating m Im n Zn both nitrogen atoms by 2 or 3 carbon atoms, and R^ is hydrogen, lower alkyl, lower alkanoyl, lower alkoxycarbonyl, phenyl-lower alkoxy-carbonyl or hydroxy-lower alkyl, wherein the hydroxy group is separated from the nitrogen atom by at least 2 carbon atoms; their N- and/'or S-oxides, lower alkyl quaternary derivatives thereof and salts of all these compounds, especially derived from pharmaceuti-cally acceptable acids or bases; process for their manufacture, pharmaceutical preparations containing these compounds and their therapeutic Application. (I) wherein each of and R2 is hydrogen, lower alkyl, lower alkanoyl A lower alkyl group R^, R^» R^ and/or such present in a substituted 1,2-phenylene Ph-group, as well as in said alkoxy, alkylthio or said other alkylated groups, is above all methyl, but also ethyl, n- or i-(propyl, butyl, pentyl, hexyl or heptyl), e.g. 2-methylpropyl or 3-methylbutyl; and lower alkanoyl is preferably acetyl or propionyl. A halogen atom R^ and/or or such present in Ph, is preferably fluoro or chloro, but also bromo. A lower carbalkoxy, mono- or di-lower alkylcarbamoyl or mono- or di-lower alkylsulfamoyl group R^ and/or R^, or present in a 1,2-phenylene group Ph, is preferably carbomethoxy, carbethoxy; mono-or dimethylcarbamoyl or mono- or dimethylsulfamoyl respectively. A 1,2-phenylene radical Ph is preferably unsubstituted, or mono-substituted by said substituents, for example methyl or ethyl; methoxy, ethoxy or i-propoxy; methylthio or ethylthio; fluoro, chloro or bromo; trifluoromethyl; and sulfaitoyl, or mono- or dimethylsulf amoyl. A lower alkylene group anc* *"n^2n *"S esPec^a^^y ethylene; but also 1,2- or 1,3-propylene, 1,2-, 1,3- or 2,3-butylene; thus forming with both adjacent nitrogen atoms preferably a piperazino or homo-piperazino moiety. A lower alkoxycarbonyl or hydroxy-lower alkyl group R^ is preferably methoxycarbonyl or ethoxycarbonyl; 2-hydroxy-(ethyl or propyl), 3-hydroxy-(propyl or butyl) or 4-hydroxybutyl respectively. A phenyl-lower alkoxycarbonyl group is for example phenylmethoxycarbonyl or phenylethoxycarbonyl. Said N-oxides are preferably those in which R^ is lower alkyl or hydroxyalkyl, and in which the oxygen is attached to the nitrogen - 2 - 1077QO I / / _• , carrying said group. Said S-oxides represent sulfoxides (SO) or sulfones (SO2). Similarly, said lower alkyl quaternai^ derivatives of the compounds of formula I are preferably derived from those wherein R^ is lower alkyl or hydroxyalkyl, and wherein only the terminal piperazino or homopiperazino-nitrogen atom is quaternized. The anions of said quaternary derivatives, as well as those of said acid addition salts, are preferably those of pharmaceutically acceptable acids, e.g. those listed below. Those compounds of formula I with R^ and/or R2 being carboxy, also form salts with bases, preferably those of pharmaceutically acceptable bases, e.g. ammonia, mono-, di- or tri-lower alkyl-amines; lower alkyleneamines; morpholine, piperazine, pyridine or lower alkyl-derivatives of said cyclic bases; and alkali raetal or alkaline earth metal hydroxides. The term "lower", referred to above or hereinafter in connection with organic radicals or compounds respectively, defines such with up to 7, preferably up to 4, and advantageously those with one or two carbon atoms. The compounds of the invention exhibit valuable pharmacological properties, primarily neuroleptic activity. It is demonstrable in animal tests using advantageously mammals, e.g. mice, rats or monkeys, as test objects. Said compounds can be administered to them enterally or parenterally, advantageously orally, or subcutaneously, intravenously or intraperitoneally, for example, within gelatin capsules, or in the form of starchy suspensions or aqueous solutions respectively. The applied dosage may range between about 0.01 and 100 mg/ kg/day, preferably between about 0.05 and 10 mg/kg/day, advantageously between about 0.1 and 5 mg/kg/day. Said neuroleptic properties can be demonstrated in adult rats or - 3 - ! N.Z. PATEMT OFFICE r — — ' 17NOV $63 squirrel monkeys, which were trained to press a lever to avoid the onset of an electric foot shock. Each lever press postpones the shock for 30 seconds. Whenever the animal fails to press the lever once within said period, brief (0.5 sec.) shocks are delivered at 15 second intervals until the animal again presses the lever. Under control conditions the animals press the lever at a moderately steady rate and seldom receive more than five or six shocks during a 25-minute (rats) and up to 4-hour experimental session. Said compounds, which are administered to the animals 30, 90 and 210 minutes prior to the experimental session, block the learned conditioned avoidance behavior, manifested by a decrease in avoidance responding and a marked increase in shocks taken by the animals. Both, the avoidance responses and failures (shocks received), are recorded separately for evaluation according to this Sidman Avoidance test. The compounds of the invention, for example the 5-(4-methylpiperazino)-imidazo-[2,1-b][l,3,5]benzothiadiazepine or its pharmaceutically acceptable salts, decrease the avoidance responding in rats and monkeys at an overall dose of 10 mg/kg or lower. The extrapyramidal side-effects (EPS) known from classical neuroleptics, have been found to induce a characteristic motor syndrome in squirrel monkeys, which were previously exposed to repeated antipsychotic treatment. These movement disorders consist of dystonic postures and dyskinetic movements, and correlate much better with the reported incidence of EPS in man, than does catalepsy or tremor in this monkey. Thus, the potential extrapyramidal liability, as well as the relative incidence of other neurological signs, such as ptosis, can be assessed by observation of these adult male squirrel monkeys, weighing 700-1200 g. They are treated with haloperidol (1.25 mg/kg) once weekly or biweekly. After approximately 2-4 months of this treatment regimen, dystonic posture and dyskinetic movements are evident during 1-6 hours after administration of haloperidol'. At no other time are abnormal movements evident in these monkeys. ~-T OFFICE 17 NOV 1983 I) 1 97 3 92 After haloperidol-elicited dyskinesias had developed, this regimen ends, and 1.25 mg/kg haloperidol is given once every 4-8 weeks as a control for comparison with test agents of this invention. Said monkeys are individually observed at intervals of 2, 4 and 6 hours after treatment and the experiments are performed in an enclosed cubicle, which is equipped with a remotely controlled video observation system and a white noise generator. Observations are performed by two independent observers, neither of whom has prior knowledge of the agent administered, nor the purpose of the experiment. A third1 person handles the monkeys during neurological examination. After initial observations through the video system, the observers enter the cubicle, recording the monkeys' responses as "motor" (ambulation inside cage), "visual" (visual response but no ambulation) and "none" (no response). Activity, posture, tremors, salivation and other neurological signs are observed. Particular attention is devoted to the presence or absence of "bizarre", dystonic postures and dyskinetic movements, as previously characterized. The handler then removes the monkey from the cage and the monkey's reactions are separately scored to the approach of the gloved hand, to the initial touch during capture and to restraint after capture. Vocalization during capture is also recorded. The handler then evaluates body tone and pupil size, and scores the presence or absence of ptosis. Catalepsy is then assessed, if preliminary examination suggested that this sign might be present. The monkey is first positioned on the floor with his head down, then at the entrance to the observation cage, and finally inside the observation cage. If the monkey remains essentially immobile in any of these positions for at least 5 seconds, catalepsy is judged to be present. After the monkey re-enters, or is replaced inside its observation cage, it is again observed for at least 1 minute for dyskinesias. A given sign or rating, which differs from control, is only considered an agent-induced effect, if both observers recorded it during any of the three observation periods. When one - 5 - •j 077 no I / / ■ y L- observer considered a given sign to be of lesser magnitude than did the other observer, the less severe score is accepted. However, overall inter-observer correspondence is good. For example, after administration of 10 mg/kg of the compound of Example 1, only one of five monkeys showed any type of dyskinetic movement, and that was confined to one form (writhing) only, as observed during one of three time periods. In contrast, severe dyskinesia, characterized by various types of dyskinetic movements, is recognized in all monkeys treated with haloperidol (1.25 mg/kg). Dyskinesias were also absent after clozapine (10 mg/kg), but were apparent after a moderate dose of haloperidol (0.625 mg/kg) in five monkeys, and no dyskinesias were observed at any time after vehicle (excipient) treatment. However, clozapine produced hypersalivation in every monkey which was examined in this experiment, but no hypersalivation was apparent after any other treatment, including said Example 1 compound. Ptosis, catalepsy, reduction in body tone and reduced responses to the observers were noted in some or all monkeys after administration of said 3 illustrative agents. According to said, and other classical tests, the compounds of the invention are useful neuroleptic (antipsychotic) agents, for example, in the treatment or management of aggression, agitation or anxiety, and are virtually devoid of extrapyramidal side-effects, as has clozapine in man. Moreover the absence of hypersalivation represents a further advantage of said new compounds over clozapine. They are also useful intermediates in the preparation of other valuable products, especially of pharmacologically active compositions. Particularly useful are compounds of Formula I, in which each of R^ and R2 is hydrogen, lower alkyl, lower alkanoyl, halogeno, cyano, carboxy, lower carbalkoxy, carbamoyl, sulfamoyl, or mono- or di-lower alkyl-(carbamoyl or sulfamoyl); Ph is 1,2-phenylene, (lower alkyl)- ~ 6 - N.Z. PATENT OFFICE ^ 17 NOV 1983 1,2-phenylene, (lower alkoxy)-1,2-phenylene, (lower alkylthio)-l,2-phenylene, (halogeno)-1,2-phenylene, (trifluoromethy1)-1,2-phenylene, (sulfamoyl)-l,2-phenylene, or (mono- or di-lower alkylsulfamoyl)-1,2-phenylene; each of m and n is the integer 2 or 3; and is hydrogen, lower alkyl, lower alkanoyl, lower alkoxycarbonyl, phenyl-lower alkoxycarbonyl or hydroxy-lower alkyl, wherein the hydroxy group is separated from the nitrogen atom by at least 2 carbon atoms; their N- and/or S-oxides; lower alkylquaternary derivatives thereof, and salts of all these compounds, especially pharmaceutically acceptable salts thereof. Outstanding compounds of the invention are those of the general formula II (0) wherein each of R^ and R^ is hydrogen or lower alkyl; R^ is hydrogen, lower alkyl or 2- or 3-hydroxy-lower alkyl, R,. is hydrogen, lower alkyl, lower alkoxy, halogeno or trifluoromethyl; and p is an integer from 0 to 2; the N-^oxides thereof; or salts, especially pharmaceutically acceptable acid addition salts of all these compounds. Preferred are those compounds of the general formula II, wherein each of R^ and R£ is hydrogen or methyl; R^ is alkyl or 2- or 3-hydroxyalkyl, in which alkyl has at most 4 carbon atoms; R^ is hydrogen, methyl, methoxy, fluoro, chloro or trifluoromethyl; and p is 0; the N-oxides thereof; or salts, especially pharmaceutically acceptable acid addition salts of all these compounds. The compounds of the invention are prepared - 7 - according to methods N.Z. PATENT OFFICE 2 5 NOV 1983 RECEIVED 1 973?2 known per se, advantageously 1) by condensing a compound of the general Formula III or an acid addition salt thereof with a compound of the general formula TV wherein X is halogeno, lower alkoxy, lower alkylthio, cyanato or thio-cyanato; Y is hydrogen or an alkali metal; p is an integer from 0 to 2, and the remaining symbols have the meaning given for formula I and, if desired, converting any resulting compound into another compound of formula I. Said condensation is advantageously carried out with an excess of the piperazine IV (Y=H), or with equivalent amounts of said metal derivatives thereof, preferably when X is halogeno, lower alkylthio or thiocyanato, advantageously at temperatures between about 0°C 150OC, and preferably in an appropriate solvent such as a lower alkanol, for example amyl alcohol, or dimethylformamide, hexamethylphosphor-amide or toluene. Another process for preparing the compounds of the general fonnula I consists in 2) ring-closing of a compound of the general formula V (0) (IV) 8 - wherein Z is oxygen, sulfur or NH, and the other symbols have the above-given meaning, under dehydrating or dehydrosulfurating conditions, and, if desired, converting any resulting compound into another compound of the invention. Said ring-closing is carried out with strong dehydrating or dehydrosulfurating agents, such as phosphorus halides and/or oxyhalides, or cyanogen halides, with or without crown ether catalysts, such as 8-crown-6-ether, and with or without basic catalysts such as triethyl-amine or potassium carbonate, preferably in an inert solvent, such as dimethyIformamide. The starting materials are known or if new, they may be obtained according to methods known per se, for example analogously to the methods described in the examples herein. The new starting materials also constitute an object of the invention. The novel starting imidazo[2,1-b][l,3,5]-benzothiadiazepines of formula III are prepared according to ring closure methods known per se, advantageously by condensing compounds of formula VI A »—n • • X' Y V, (vi) pv ,/ B 2 wherein Ph, and R^ have meaning given for compounds of formula III, with reactive carbonic acid derivatives such as phosgene, thio- - 9 - .V ^ SAT, PA7EMT OFFICE 17 NOV 1983 n /3? phosgene, 1,l'-carbonyldiimidazole or cyanogen bromide. Compounds of formula III wherein X is hydroxy can in turn be converted to compounds wherein X is sulfhydryl by conventional sulfurating agents, such as phorphorus pentasulfide, and these can be further derivatized to compounds of formula wherein X is as defined above, analogous to the procedures illustrated by the examples herein. The starting materials of formula V can be obtained from that of the (tautomeric) precursors of formula III, wherein X is hydroxy, thio or amino, by condensing them with compounds of formula IV in the presence or absence of other bases, e.g. those listed above, preferably in an inert solvent * such as methylene chloride or toluene at temperatures between 6°C and 150°C advantageously between 10°C and 50°C. The ring opening reaction is preferably carried out at low temperature to minimize side reactions when and R^ represent reactive functional groups. Alternately, starting materials of formula V, wherein R^ is lower alkanoyl, lower alkoxycarbonyl or phenyl-lower alkoxy carbonyl, are prepared by condensing a compound of formula VI with a compound of formula VII JC H„ / m 2n£\ ""No H„ Y'-N; >-R3 (VII) n 2n wherein Y' represents halocarbonyl, halothiocarbonyl or cyano, and R^ represents lower alkanoyl, lower alkoxycarbonyl or phenyl-lower alkoxycarbonyl, preferably in an inert solvent, at temperatures between 0° and 150°C. The compounds of the invention so obtained can be converted into other compounds of formula I according to known methods. Thus, for example, those with R^ being hydrogen or alkali metal, e.g., sodium - 10 - n.z. r,nt:; \rr office 17 NOV 1983 RECEIVED or lithium salts thereof, can be reacted with substituted or unsubsti-tuted oxiranes, such as ethylene oxide, or reactive esters of un-substituted or correspondingly substituted aliphatic or araliphatic alcohols such as methanol, ethanol, allyl alcohol or propargyl alcohol, e.g. such esterified by a strong inorganic or organic acid, above all a hydrohalic acid, e.g. hydrochloric, hydrobromic or hydriodic acid; sulfuric or an aromatic sulfonic acid, e.g. p-toluene or m-bromobenzene sulfonic acid, in order to obtain the corresponding N-substituted compounds or quaternaries respectively, depending on the molar amount of the alkylating agent employed. Intermediates of formula I wherein is alkali metal are obtained by metallation with reactive organo metallic agents such as lithium diisopropylamide, with alkali metal alkoxides such as sodium methoxide, or alkali metal hydrides such as sodium or potassium hydride. Unsaturated compounds, such as those with R^ being lower alkenyl or lower alkynyl, may be hydrogenated with catalytically activated hydrogen to obtain compounds wherein R^ is the corresponding lower alkyl. Conversely, resulting N-alkylated compounds can be converted into N-unsubstituted compounds, e.g. by reaction with lower alkyl haloformates, e.g. ethyl chloroformate, to yield N-acyl derivatives which, in turn, may be hydrolyzed to said unsubstituted compounds, those with R^H, for example with aqueous bases, such as alkali metal hydroxides, such as aqueous sodium hydroxide solution. Compounds of formula I wherein R3 is hydroxyalkyl can also be prepared by first reacting corresponding compounds of formula I, wherein R^ represents hydrogen, with reactive derivatives of corresponding glycols, glycolic acids or dicarboxylic acids, such as lower alkyl esters, halides or anhydrides thereof, or reactive esters of said glycols or glycolic acids derivatives for example with hydrohalic or aromatic sulfonic acids, 1,2-dibromoethane or 1,2-dibromopropane, - 11 - ethyl bromoacetate or ethyl bromopropionate, ethyl tosyloxyacetate; diethyl oxalate, diethyl malonate or ethyl oxalyl chloride. The intermediates so obtained are either hydrolyzed or reduced with simple or complex light metal hydrides such as lithium aluminium hydride, alone or with diborane to a compound of formula I vfoereiri R3 is hydroxy-alkyl. Compounds of formula I wherein is methyl can be prepared by reacting the corresponding compounds of formula I wherein R^ represents hydrogen,with lower alkyl- or phenyl lower alkyl- haloformates, such as ethyl chloroformate, to obtain compounds of formula I wherein R^ is lower alkoxycarbonyl or phenyl-lower alkoxycarbonyl, and reducing said acyl derivatives with simple or complex light metal hydrides such as lithium aluminium hydride, sodium tri-t-butoxy or bis-(2-methoxyethoxy) aluminium hydride. N-Acylated derivatives can be obtained from compounds of formula I with R^ being hydrogen, and corresponding reactive acid derivatives, e.g., halides,simple or activated esters, such as alkyl esters or cyanoalkyl esters, anhydrides or isocyanates. Resulting compounds of formula I with R^ and/or R^ being hydrogen, can be converted to the corresponding 3- and/or 4-(halo- or acyl)-derivatives, e.g. by halo-genation, preferably with chlorine in acetic acid or under Friedel-Crafts-conditions, and/or by acylation with a trihaloacetyl halide or a halosulfonic acid, followed by treatment with an alkali metal lower alkoxide, hydroxide or amide. Resulting carboxylic or sulfonic acid derivatives may be hydrolyzed in known fashion, preferably under alkaline conditions and/or amidized with ammonia, mono- or di-lower alkylamines, and resulting carboxyamides may be dehydrated to the corresponding nitriles according to conventional methods. Resulting tertiary nitrogen compounds with R^ different from hydrogen, can be converted into the N- and/or S-oxides, for example with - 12 - T OFFICE 17 NOV 1983 £$G£1VED hydrogen peroxide or organic peracids, such as lower peralkanoic or perbenzoic acids, e.g. peracetic or m-chloro-perbenzoic acid, advantageously at temperatures at or below room temperature with the latter, or up to 100°C with diluted hydrogen peroxide in the presence of lower alkanoic acids, e.g. acetic acid. If only N-oxides are desired, care should be taken, especially with said peracids, in order to prevent S-oxidation at overly long reaction times. If only S-oxides are desired, compounds wherein is acyl, such as alkoxycarbonyl or phenylalkoxycarbonyl, are treated with hydrogen peroxide or organic peracids, preferably m-chloro-perbenzoic acid advantageously at temperatures at or below room temperature to obtain either sulfoxides (SO) or sulfones (SO2) depending on the quantity of peracid used. Resulting compounds with R^ being phenylalkoxy carbonyl or alkoxycarbonyl so obtained can be converted to other compounds of formula I according to methods known per se and previously described above. Finally, the compounds of the invention are either obtained in the free basic form, or as a salt thereof. Any resulting base can be converted into a corresponding acid addition salt, preferably with the use of a therapeutically useful acid or anion exchange preparation, or resulting salts can be converted into the corresponding free bases, for example, with the use of a stronger base, such as a metal or ammonium hydroxide or a basic salt, e.g. an alkali metal hydroxide or carbonate, or a cation exchange preparation. Said acid addition salts are such of pharmaceutically acceptable inorganic acids, for example hydrohalic, e.g. hydrochloric or hydrobromic acid; sulfuric, phosphoric, nitric or perchloric acid; but preferably of organic acids, such as of aliphatic or aromatic carboxylic or sulfonic acids, e.g. formic, acetic, propionic, succinic, glycollic, lactic, malic, tartaric, gluconic, citric, maleic, fumaric, hydroxy-maleic, pyruvic, phenylacetic, benzoic, 4-aminobenzoic, anthranilic, - 13 - 17 MOV 1983 ■t ^ -7 "7 n o 4-hydroxybenzoic, salicylic, 4-aminosalicylic, pamoic, nicotinic, metihanesulfanic., ethanesulfonic, a hydroxy-ethanesulfonic, benzenesulfonic, a toluenesulfonic, a naphthalensulfonic, sulfanilic or cyclohexyl-sulfamic acid; or ascorbic acid. These or other salts, for example, the picrates, can also be used for purification of the bases obtained; the bases are converted into salts, the salts are separated and the bases are liberated from the salts. In view of the close relationship between the free compounds and the compounds in the form of their salts, whenever a compound is referred to in this context, a corresponding salt is also intended, provided such is possible or appropriate under the circumstances. In case mixtures of geometrical or optical isomers of the above compounds, e.g. I to VII are obtained, these can be separated into the single isomers by methods in themselves known, e.g. by fractional distillation, crystallization and/or chromatography. Racemic products can likewise be resolved into the antipodes, for example, by separation of diastereomeric salts thereof, e.g. by the fractional crystallization of d- or 1-tartrates. The above-mentioned reactions are carried out according to standard methods, in the presence or absence of diluents, preferably such as are inert to the reagents and are solvents thereof, of catalysts, condensing or said other agents respectively and/or inert atmospheres, at low temperatures, room temperature or elevated temperatures, preferably at the boiling point of the solvents used, at atmospheric or superatmospheric pressure. The invention further includes any variant of the present process, in which an intermediate product obtainable at any stage of the process is used as starting material and the remaining steps are carried out, or the process is discontinued at any stage thereof, 14 - -'z- patent office 2 5 NOV 1983 in which the starting materials are formed under the reaction conditions, or in which the reaction components are used in the form of their salts or optically pure antipodes. Mainly those starting materials should be used in said reactions, that lead to the formation of those compounds indicated above as being especially valuable, e.g. those of formula II. The pharmacologically active compounds of the invention are useful in the manufacture of pharmaceutical compositions containing an effective amount thereof in conjunction or admixture with excipients suitable for either enteral or parenteral application. Preferred are tablets and gelatin capsules comprising the active ingredient together with diluents, e.g. lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, and/or glycine, and lubricants, e.g. silica, talcum, stearic acid, its magnesium or calcium salt and/or polyethyl-eneglycol; for tablets also binders, e.g. magnesium aluminium silicate, starch paste, gelatin,: tragacanth, methylcellulose, sodium carboxy-methylcellulose and/or poylvinylpyrrolidone, if desired, disintegrants, e.g. starches, agar, alginic acid or its sodium salt, 'Qnaynoo of the ■ -bandars. or effervescent mixtures and/or adsorbents, colorants, flavors and sweetners, Injectable compositions are preferably aqueous isotonic solutions or suspensions, and suppositories are advantageously fatty emulsions or suspensions. Said compositions may be sterilized and/or contain adjuvants, such as preserving, stabilizing, wetting or emulsifying agents, solution promoters, salts for regulating the osmotic pressure and/or buffers. They may also contain other therapeutically valuable substances. Said pharmaceutical compositions are prepared according to conventional mixing, granulating or coating methods respectively and contain about 0.1 to 75 % by vreight, preferably about 1 to-50% by weight of the active ingredient. : Unit dosages for mairmals of about 50,-70 kg weight may contain between about 5-100 mg of the active ingredient. 15 - 17 NOV 1983 The following examples illustrating the invention are not to be construed as being limitations thereon. Temperatures are given in degrees Centigrade, and all parts wherever given are parts of weight. If not mentioned otherwise, all evaporations are performed under reduced pressure, preferably between about 15 and 100 mmHg. - 16 - Example 1: To the mixture of 501 g of 1-methylpiperazine and 6,000 ml of amyl alcohol, 538 ml of 9.3 N methanolic hydrogen chloride are added and the mixture is stirred and distilled for 1 hour, during which time 1,000 ml of distillate is collected and the temperature reaches 131°. Thereupon another 501 g of 1-methylpiperazine are added, followed by 618.5 g of 5-methylthio-imidazo[2,l-b][1,3,5]benzothiadiazepine. The mixture is stirred under nitrogen at 132-140° for 48 hours and evaporated at about 80-90°. The residue is dissolved in 3,000 ml of methylene chloride, the solution washed 3 times with 1,000 ml of 3 N aqueous sodium hydroxide and 5 times with 1,000 ml of water. It is finally extracted 4 times with 750 ml of 2 N hydrochloric acid each, the combined extracts are washed once with 1,000 ml of methylene chloride, decolorized with 75 g of charcoal, filtered and the filtrate is basified with 500 ml of 29.9% aqueous ammonia to a pH of 9-10. The mixture is extracted twice with 2,000 ml of methylene chloride, the combined extracts dried, filtered and evaporated at about 60°. 2,810 g of this residue are dissolved in 14,000 ml of hot isopropanol, the solution treated with 563 g of charcoal, filtered and the residue washed with 1,000 ml of cold isopropanol. The combined filtrates are reheated and again treated with 563 g of charcoal in the same manner. The resulting clear solution is concentrated to 8,500 ml and the concentrate allowed to stand in the refrigerator for 2 days. The white precipitate is filtered off, washed 3 times with cold isopropanol and dried at 40°/5 mmHg, to yield the 5-(4-methylpiperazino)-imidazo[2,l-b][l,3,5]benzothiadiazepine of the formula /Vsv\ melting at 145-147°. - 17 - 1 /' 4) V 1,614 g thereof are dissolved in 5,450 ml of anhydrous ethanol at 50-60°, the solution filtered hot, the filter rinsed with 1,000 ml more anhydrous ethanol and the combined filtrates are acidified with the solution of 688 g of maleic acid in 1,600 ml of anhydrous ethanol while stirring. The mixture is stirred while cooling to 25°, the precipitate collected, washed twice with 800 ml of anhydrous ethanol and dried at 75°/0.5 mm Hg, to yield the corresponding monomaleate melting at 198-199° with decomposition. The starting material is prepared as follows: To 39,230 ml of 2 N hydrochloric acid, 7,500 g of aminoacetaldehyde dimethylacetal are added during 45 minutes while stirring under nitrogen, followed by 6,932 g of potassium thiocyanate, which are added all at once. The mixture is heated to 98°, stirred for 2 hours and allowed to cool to room temperature overnight. The resulting suspension is stirred and cooled to 5°, filtered and the residue dried at 60°/5mmHg, to yield the imidazole-2-thiol melting at 224-226°. 2,468 g thereof are added to the solution of 1,604 g of 86.9% aqueous potassium hydroxide in 24,700 ml of isopropanol while stirring under nitrogen at room temperature, followed by 4,986 of 2-bromo-nitroben-zene. The mixture is stirred and heated to 82-85° for 5 hours, cooled to 50° and diluted with 37,000 ml of water. The resulting suspension is stirred at room temperature for 2 days, filtered, the residue washed 6 times with 4,000 ml of water and 5 times with 3,700 ml of diethyl ether, and dried at 60°/5 mmHg, to yield the 2-(o-nitrophenyl-thio)-imidazole melting at 178-180°. The mixture of 2,210 g thereof, 2,000 ml of water, 2,000 ml of ethanol and 1,700 g of iron powder is heated to 70° while stirring under nitrogen. After addition of 10 ml of concentrated hydrochloric acid the mixture is refluxed for 1.5 hours, whereupon 200 ml of concentrated hydrochloric acid in 1,000 ml of ethanol are added during 95 minutes. - 18 - 197392 The mixture is refluxed for 2 hours longer and 400 ml of 6 N aqueous sodium hydroxide are added. The resulting suspension is diluted with 2,000 ml of methanol, filtered and the residue is washed 3 times with I,000 ml of methanol. The combined filtrates are diluted with 40,000ml of water, the resulting suspension allowed to settle overnight, the precipitate is collected, washed twice with 2,000 ml of water and dried at 60°/5 mmHg, to yield the 2-(o-aminophenylthio)-imidazole melting at 137-138°. 4,775 g thereof are added to the mixture of 55,000 ml of methylene chloride and 6,975 ml of triethylamine, the mixture cooled to 3° and 3,301 g of 85% thiophosgene in carbon tetrachloride are added during 2.5 hours while stirring under nitrogen at 15°. Stirring is continued at 10° for 4 hours and at room temperature overnight. The resulting suspension is filtered, the residue washed twice with 4,000 ml of methylene chloride and once with 20,000 ml of water and suspended in II,000 ml of 1.3 N hydrochloric acid. The suspension is stirred for 2 hours, filtered, the residue washed 3 times with 4,000 ml of water and dried at 60°/5 mmHg, to yield the imidazo[2,l-b][1,3,5Jbenzothia-diazepin-5(6H)-thione melting at 156-159°. 1,184 g thereof are added to the solution of 278 g of sodium me^ thoxide in 22,500 ml of isopropanol and the mixture is stirred for 1.5 hours under nitrogen. Thereupon 791 g of methyl iodide are added during 30 minutes and the mixture is stirred 3.5 hours longer at about 20°. It is diluted with 45,000 ml of water and the resulting suspension stirred at room temperature overnight. It is filtered, the residue washed 5 times with 4,000 ml of water and dried at 60°/5 mmHg, to yield the 5-methylthio-imidazo[2,l-b][l,3,5]benzothiadiazepine melting at 116-118°. - 19 - 19/3 92 Similarly the following starting materials are prepared from the correspondingly substituted 2-bromonitrobenzenes: a. 8-methoxy-5-methylthio-imidazo[2,1-b] [ 1,3,5]benzothiadiazepine, melting at 143-146°; b. 8-chloro-5-methylthio-imidazo[2,l-b][1,3,5]benzothiadiazepinej melting at 147-149°; c. 8-fluoro-5-methylthio-imidazo[2,1-b][1,3,5]benzothiadiazepine, melting at 174-176°; d. 8-methy1-5-methylthio-imidazo[2,1-b][l,3,5]benzothiadiazepine. Example 2: To the solution of 480 mg of 5-thiocyanato-imidazo[2,1-b] [l,3,5]benzothiadiazepine in 1 ml of hexamethylphosphoramide, 500 mg of 1-methylpiperazine are added during 5 minutes while stirring under nitrogen at -5°. Stirring is continued for 5 minutes at said temperature. The mixture is diluted with 80 ml of ethyl acetate, washed twice with saturated aqueous sodium chloride, dried and evaporated. The residue is dissolved in 2 ml of acetone, the solution acidified with 300 mg of maleic acid and diluted with diethyl ether, to yield the 5-(4-methylpiperazino)-imidazo[2,1-b] [ 1,3,5 ]benzothiadi azepine monomaleate, melting at 198-199° with decomposition; it is identical with that of Example 1. The starting material is prepared as follows: To the suspension of 1.44 g of 50% sodium hydride in mineral oil and 150 ml of dry tetrahydrofuran, 6.45 g of imidazo[2,1-b][1,3,5]benzo-thiadiazepin-5(6H)-thione are added in portions, and the mixture is stirred at room temperature under nitrogen for one hour. The resulting white suspension is cooled to 0° and the solution of 3.5 g of cyanogen bromide in 10 ml of tetrahydrofuran are added dropwise. The mixture is stirred at room temperature for 0.5 hour and evaporated. The residue is triturated with methylene chloride, the mixture washed with water, dried, concentrated to a small volume, washed with diethyl - 20 - 19739 ether and filtered, to yield the 5-thiocyanato-imidazo[2,1-bJ[l,3,5]ben-zothiadiazepine melting at 111-113°. Example 3: The mixture of 333 mg of l-[2-(imidazo-2-ylthio)-phenyl-iminothiocarbonyl]-4-methylpiperazine, 3.3 ml of dimethylformamide, 276 mg of potassium carbonate, 116 mg of cyanogen bromide and 50 mg of 8-crown-6 ether is stirred at room temperature under nitrogen for 3 hours. It is diluted with ethyl acetate, washed with saturated aqueous sodium chloride, dried and evaporated. The residue is dissolved in acetone, the solution treated with 116 mg of maleic acid and diluted with diethyl ether, to yield the 5-(4-methylpiperazino)-imidazo^, 1-b] [1,3,5]benzothiadiazepine monomaleate, melting at 198-199° with decomposition; it is identical with that of Example 1. The starting material is prepared as follows: The mixture of 2.3 g of imidazo[2,1-b][l,3,5]benzothiadiazepin-5(6H)~ thione, 23 ml of methylene chloride and 1.0 g of 1-methylpiperazine is stirred at room temperature for 15 hours. The crystalline product formed is filtered off and washed with methylene chloride, to yield the l-[2-(imidazo-2-ylthio)-phenyliminothiocarbonyl]-4-methylpiperazine melting at 209-212°. Example 4: To the suspension of 3.1 g of l-[2-(imidazo-2-ylthio)-phenyliminocarbonyl]-4-methylpiperazine and 25 ml of phosphorus oxychloride, 2,04 g of phosphorus pentachloride are added at once, and the mixture is stirred at room temperature for 4 hours. It is evaporated, the residue suspended in 50 ml of dry methylene chloride, the suspension cooled to 0° and 2.02 g of triethylamine are added dropwise while stirring. Stirring is continued for 15 minutes at 0°, the mixture washed with water, dried and evaporated. The residue is dissolved in acetone and the solution acidified with maleic acid, to yield the 5-(4-methylpiperazino)-imidazo[2,1-b][1,3,5]benzothiadiazepine mono-maleate, melting at 198-199° with decomposition; it is identical with that of Example 1. - 21 - s 97: The starting material is prepared as follows: The mixture of 15 g of 2-(imidazo-2-ylthio)-aniline, 13.9 g of 1,1*-carbonyldiimidazole and 675 ml of methylene chloride is stirred at room temperature for 24 hours. The solids formed are filtered off and washed with methylene chloride to yield the imidazo[2,1-b][1,3,5]benzo-thiadiazepin-5(6H)-one, melting at 250-252° with decomposition. In the analogous manner (or by replacing the l,l'-carbonyldiimidazole by the equivalent amount of phosgene), the following intermediates are obtained and are illustrative of the process: a. 3,4-dimethylimidazo[2,1-b][1,3,5]benzothiadiazepin-5(6H)-one, - m.p. 225° (decomposition); b. 8-chloroimidazo[2,1-b][l,3,5]benzothiadiazepin-5(6H)-one, m.p. 261-263°; c. 8-trifluoromethylimidazo[2,1-b][1,3,5]benzothiadiazepin-5(6H)-one, m.p. 257-260°; d. 3-methylimidazo[2,1-b][1,3,5]benzothiadiazepin-5(6H)-one, m.p. 225-229°. The mixture of 2,17 g of imidazo[2,1-b][l,3,5]benzothiadiazepin-5(6H)-one, 1.0 g of 1-methylpiperazine and 20 ml of methylene chloride is stirred at room temperature for 24 hours. The crystalline product formed is filtered off and washed with methylene chloride, to yield the 1-[2-(imidazo-2-ylthio)-phenyliminocarbonyl]-4-methylpiperazine, melting at 197-200°. In similar manner the following additional starting materials are obtained and are illustrative of the process: - 22 - 11 W 3 a. 1-[2-(4-methylimidazo-2-ylthio)-phenyliminocarbonyl]-4-methyl-piperazine,melting at 101-105° (decomposition); b. 1-[2-(imidazo-2-ylthio)-phenyliminocarbonyl]-4-methylhomopiper-azine, melting at 134-138°; c. l-[2-(imidazo-2-ylthio)-phenyliminocarbonyl]-4-carboethoxypiper-azine, melting at 161-170°; d. 1-[2-(imidazo-2-ylthio)-phenyliminocarbonyl]-4-carbobenzoxypiper-azine, melting at 206-208°; e. 1-[2-(4-carboethoxyimidazo-2-ylthio)-phenyliminocarbony1] -4-methylpiperazine, melting at 166-169°; f. 1-[2-(imidazo-2-ylthio)-4-trifluoromethylphenyliminocarbony1]-4-methylpiperazine, melting at 212-214°. Example 5; A mixture of 10 g of 5-methylthio-imidazo[2,1-b}[1,3,5]ben-zothiadiazepine hydrochloride, 3.62 g of piperazine, and 350 ml of amyl alcohol is refluxed with stirring and unter nitrogen for 20 hours. The solvent is evaporated under reduced pressure, the residue is triturated with methylene chloride, washed with 2N sodium hydroxide solution, dried over magnesium sulfate and evaporated to dryness. The residue is dissolved in 10 ml of methanol and treated with 2N etheral hydrochloric acid solution to give 5-(4H-piperazino)-imidazo [2,1-b][1,3,5]benzothiadiazepine dihydrochloride, melting at 249° with decomposition. Example 6: A mixture of 5 g of 5-methylthio-imidazo[2,1-b][1,3,5]ben-zothiadiazepine hydrochloride, 2.86 g of N-3-hydroxyethylpiperazine, and 175 ml of amyl alcohol is refluxed under nitrogen for 48 hours with stirring. The solvent is removed under reduced pressure, the residue is triturated with methylene chloride, washed with 2N sodium hydroxide solution, dried over magnesium sulfate and evaporated to dryness. The residue is dissolved in 5 ml of methanol and treated with 2N etheral hydrochloric acid solution to give 5-(4-|3-hydroxyethyl-piperazino)-imidazo[2,1-b"][1,3,5]benzothiadiazepine dihydrochloride, melting at 210-212°. - 23 - 1 97 3 Example 7: By replacement of the N-p-hydroxyethylpiperazine in example 6 by an equivalent amount of N-methylhomopiperazine one obtains 5-(4-methylhomopiperazino)-imidazo[2,1-b][1,3,5 Jbenzothiadiazepine, isolated as the fumarate salt melting at 216-218°. Example 8: According to the methods illustrated by the previous examples, the following compounds of formula I are obtained from equivalent amounts of the corresponding starting materials; Ph=4-R -1,2-phenylene; C H. =(CH_).; C H- =(CH„) ,. 5 m 2m 2 2 n 2n 2 n no. ri r2 r3 n' r5 Salt m.p. °c 1 h h h 2 h 2hc1 249 dec.* 2 h h cha 2 h 2hc1 216-219 3 h h ch3 2 och3 2hc1 155 dec. 4 h h ch3 2 f maleate 202-204 5 h h ch3 2 ci 2hc1 203-206 6 h h ch3 2 cf3 2hc1 180 dec. 7 c02c2h5 h 2 h — 138-141 8 h h (ch2)2oh 2 h 2hc1 210-212 9 h h COOEt 2 h — 137-139 10 h h ch3 3 h fumarate 216-218 11 h h cooch2c6h5 2 h — nmr:5.2,3.5 12 <*3 h <*3 2 h maleate 191-192.5 13 ch3 ^3 ch3 2 h *(dec. = decomposition). - 24 - i 97<oo Example 9; To the solution of 0.2 g of 5-(4-carboethoxypiperazino)-imidazo[2,l-b][l,3,5]benzothiadiazepine in 2 ml of dry tetrahydrofuran, 100 mg of lithium aluminium hydride are added at once and the mixture is refluxed under nitrogen for 48 hours. The mixture is cooled to room temperature, stirred with 0.2 ml of 30% aqueous sodium hydroxide, and filtered. The filtrate is evaporated to dryness and the product is purified to give 5-(4-methylpiperazino]-imidazo[2,1-b][l,3,5]benzo-thiadiazepine, melting at 145-147°. It is identical with the compound obtained in Example 1. Example 10; To the solution of 88 mg of 5-(4-methylpiperazino)-imidazo[2,l-b][l,3,5]benzothiadiazepine in 1 ml of methylene chloride, 74 mg of m-chloroperbenzoic acid are added at 0°. The mixture is stirred at 0° overnight; this is diluted with 1 ml of ether, one mol equivalent of etheral hydrochloric acid solution is added and the resulting precipitate is collected. Recrystallization from methanol-ethyl acetate yields 5-(4-methyl-4-oxidopiperazino)-imidazo[2,1-b] [ 1,3,5]benzothia-diazepine hydrochloride, melting at 155° with decomposition. Example 11: a) To the solution of 0.5 g of 5-(4-carbobenzoxypiper-azino)-imidazo[2,1-b] [l,3,5]benzothiadiazepine in 5 ml of methylene chloride, cooled at 0°, is added dropwise a solution of 0.26 g of m-chloroperbenzoic acid in 2 ml of methylene chloride. The mixture is stirred at 0° for 1.5 hours, the solids are filtered, and the filtrates are washed with 10% aqueous potassium carbonate and water, then dried over magnesium sulfate and evaporated to dryness to give 5-(4-carbo-benzoxypiperazino)-imidazo[2,1-b] [l,3,5]benzothiadiazepine 1-oxide. Mass spectrum: m/e 435, 418, 387. b) In a similar manner and by using 0.61 g (2 equivalents) of m-chloroperbenzoic acid, the 5-(4-carbobenzoxypiperazino)-imidazo[2,1-b][1,3,5]benzothiadiazepine 1,1-dioxide is obtained. Mass spectrum: m/e 451, 420, 406, 386. - 25 - f 7 AJOV J9g3 Example 12: a) To the solution of 100 mg of 5-(4-carbobenzoxypiper-azino)-imidazo[2,1-b][l,3,5]benzothiadiazepine 1-oxide in 0.3 ml of acetic acid are added 0.35 ml of a 2N solution of hydrobromic acid in acetic acid. The mixture is heated at 100° for 1 hour and stirred at room temperature overnight. Ether is added, and the 5-(4H-piperazino)-imidazo[2,l-b][l,3,5]benzothiadiazepine 1-oxide hydrobromide is filtered and washed with ether; m.p. 75° with decomposition. b) In a similar manner the 5-(4-carbobenzoxypiperazino)-imidazo[2,l-b][l,3,5]benzothiadiazepine 1,1-dioxide is converted to 5-( 4H-piperazino) imidazo[2,l-b][l,3,5]benzothiadiazepine 1,1-dioxide hydrobromide. Rf = 0.353 (silica gel, ethyl acetate-methylene chloride, 1:1). Example 13: A mixture of 285 mg of 5-(4H-piperazino)-imidazo[2,l-b] [l,3,5]benzothiadiazepine, 0.5 g of potassium carbonate, 0.142 g of methyl iodide and 2 ml of acetone is stirred at room temperature overnight and evaporated. Water is added to the residue, and the mixture is extracted with methylene chloride. The extracts are dried over magnesium sulfate, evaporated, and the residue is purified to give 5-(4-methylpiperazino)-imidazo[2,1-b][1,3,5]benzothiadiazepine melting at 145-147°. The product is identical to compound obtained in Example 1. Example 14: Preparation of 10,000 tablets each containing 5 mg of the active ingredient: Formula: 5-(4-methylpiperazino)-imidazo[2,1-b][1,3,5 Jbenzo- thiadiazepine maleate 50 g Lactose 1,157 g Cora starch 75 g Polyethylene glycol 6,000 75 g Talcum powder 75 g Magnesium stearate 18 g Purified water g-r- - 26 - </div>

Claims

<div class="application article clearfix printTableText" id="claims"> 1 973 Procedure: All the powders are passed through a screen with openings of 0.6 mm. Then the drug substance, lactose, talcum, magnesium stearate and half of the starch are mixed in a suitable mixer. The other half of the starch is suspended in 40 ml of water and the suspension added to the boiling solution of the polyethylene glycol in 150 ml of water. The paste formed is added to the powders which are granulated, if necessary, with an additional amount of water. The granulate is dried overnight at 35°, broken on a screen with 1.2 mm openings and compressed into tablets using concave punches with 6.4 mm diameter, uppers bisected. Example 15: Preparation of 10,000 capsules each containing 10 mg of the active ingredient: Formula: 5-[4-(2-hydroxyethy1)-piperazino]-imidazo[2,1-b] [l,3,5]benzothiadiazepine dihydrochloride 100 g Lactose 1,800 g Talcum powder 100 g Procedure: All the powders are passed through a screen with openings of 0.6 mm. Then the drug substance is placed in a suitable mixer and mixed first with the talcum, then with the lactose until homogenous. No. 3 capsules are filled with 200 mg, using a capsule filling machine. Analogously tablets or capsules are prepared from the remaining compounds of the invention, e.g. those illustrated by the other examples herein. - 27 - 197 WHAT -f/WE CLAIM IS:- Claims wherein each of and R2 is hydrogen, lower alkyl, lower alkanoyl, halogeno, cyano, carboxy, lower carbalkoxy, carbamoyl, sulfamoyl, mono- or di-lower alkyl-(carbamoyl or sulfamoyl); Ph is 1,2- phenylene, unsubstituted or substituted by up to two identical or different members selected from lower alkyl, lower alkoxy, lower alkylthio, halogeno, trif luoromethyl, sulfamoyl, or mono- or di-lower alkylsulfamoyl; each of C H. and C H. is lower alkylene separating m 2m n 2n both nitrogen atoms by 2 or 3 carbon atoms, and is hydrogen, lower alkyl, lower alkanoyl, lower alkoxycarbonyl, phenyl-lower alkoxycarbonyl or hydroxy-lower alkyl, wherein the hydroxy group is separated from the nitrogen atom by at least 2 carbon atoms; their N- and/or S-oxides, and lower alkyl quaternary derivatives thereof.
2. Compounds of the Formula I shown in claim 1, wherein R^ represents hydrogen, lower alkyl, lower alkanoyl, lower alkoxycarbonyl or hydroxy-lower alkyl, wherein the hydroxy group is separated from the nitrogen atom by at least 2 carbon atoms, and the other symbols have the meanings given in claim 1; their N- and/or S-oxides, and lower alkyl quaternary derivatives thereof.
3. Compounds of the Formula I shown in claim 1, in which each of R^ and R^ is hydrogen, lower alkyl, lower alkanoyl, halogeno, cyano, carboxy, lower carbalkoxy, carbamoyl, sulfamoyl, or mono- or di-lower alkyl-(carbamoyl or sulfamoyl); Ph is 1,2-phenylene, (lower alkyl)- - 28 - • V::WT office 17 NOV 1983 1,2-phenylene, (lower alkoxy)-l,2-phenylene, (lower alkylthio)-l,2-phenylene, (halogeno)-1,2-phenylene, (trifluoromethyl)-l,2-phenylene, (sulfamoyl)-l,2-phenylene, or (mono- or di-lover alkylsulfamoyl)-1,2-phenylene; each of m and n is the integer 2 or 3; and is hydrogen, lower alkyl, lower alkanoyl, lower alkoxycarbonyl, phenyl-lower alkoxycarbonyl or hydroxy-lower alkyl, wherein the hydroxy group is separated from the nitrogen atom by at least 2 carbon atoms; their N- and/or S-oxides; and lower alkylquaternary derivatives thereof.
4. Compounds of the Formula II (0) ^ \ / \ / *-!. 3 L-'i (II) s - A.A '5 x > 2 wherein each of R^ and R^ is hydrogen or lower alkyl; R^ is hydrogen, lower alkyl or 2- or 3-hydroxy-lower alkyl, R^ is hydrogen, lower alkyl, lower alkoxy, halogeno or trifluoromethyl; and p is an ingeter from 0 to 2; and the N-oxides thereof.
5. Compounds of the Formula II shown in claim 4, wherein each of R^ and R£ is hydrogen or methyl; R^ is alkyl or 2- or 3-hydroxyalkyl, in which alkyl has at most 4 carbon atoms; R,. is hydrogen, methyl, methoxy, fluoro, chloro or trifluoromethyl; p is 0; and the N-oxides thereof.
6. Compounds of the Formula I shown in claim 1, named in the Example 8, as compounds 1 to 8.
7. Compounds of the Formula I shown in claim 1, named in the Example
8. as compounds 9 to 13. - 29 - N.Z. PATENT OFFICE 25N0VI983 RECEfV:"-; 

8. 5-(4-Methylpiperazino)- imidazo[2,1-b][1,3,5]benzothiadiazepine.
9. 5-(4H-Piperazino) imidazo[2,1-b][1,3,5]benzothiadiazepine.
10. 5-(4-p-Hydroxyethylpiperazino)-imidazo[2,1-b][1,3,5]benzothiadiazepine.
11. 5-(4-Methylhomopiperazino)-imidazo[2,1-b][l,3,5]benzothiadiazepine.
12. 5-(4-Methyl-4-oxido-piperazino)-imidazo[2,1-b][1,3,5]benzothiadiazepine.
13. 5-(4-Carbobenzoxypiperazino)-imidazo[2,1-b][1,3,5Jbenzothiadi-azepine-l-oxide.
14. 5-(4-Carbobenzoxypiperazino)-imidazo[2,l-b] [1,3,5]benzothiadiazepine- 1,1-d ioxide.
15. 5-(4H-Piperazino)-imidazo[2,1-b][1,3,5]benzothiadiazepine-1-oxide.
16. 5-(4H-Piperazino)-imidazo[2,1-b][1,3,5]benzothiadiazepine-l,1-di-oxide.
17. A salt of a compound having a salt forming group, as claimed in any one of claims 1, 3-5, 7, 9 and 11-16.
18. A pharmaceutically acceptable salt of a compound having a salt forming group, as claimed in any one of claims 1, 3-5, 7, 9 and 11-16.
19. A salt of a compound having a salt forming group, as claimed in any one of claims 2, 6, 8 and 10.
20. A pharmaceutically acceptable salt of a compound having a salt - 30 - * <? .'Cy 3983 •; o -7 7 o 1 1 / : ^ . i_ forming group, as claimed in any one of -claims 2, 8 and 10.
21. A pharmaceutical preparation comprising a compound claimed in any one of claims 1, 3-5, 7, 9, 11-16 and 18 in admixture or conjunction with a pharmaceutically suitable carrier.
22. A pharmaceutical preparation comprising a compound claimed in any one of claims 2, 6, 8, 10 and 20 in admixture or conjunction with a pharmaceutically suitable carrier.
23. Process for the manufacture of 5-diazacycloalkyl-imidazo[2,l-b]-[l,3,5]benzothiadiazepines of the general formula I .A nKi (i) wherein each of R^ and R2 is hydrogen, lower alkyl, lower alkanoyl, halogeno, cyano, carboxy, lower carbalkoxy, carbamoyl, sulfamoyl, or mono- or di-lower alkyl-(carbamoyl or sulfamoyl); Ph is 1,2- phenylene, unsubstituted or substituted by up to two identical or different members selected from lower alkyl, lower alkoxy, lower alkylthio, halogeno, trifluoromethyl, sulfamoyl, or mono- or di-lovrer alkylsulfamoyl; each of C H0 and C H is lower alkylene separating m 2m n Zn both nitrogen atoms by 2 or 3 carbon atoms, and is hydrogen, lower alkyl, lower alkanoyl, lower alkoxycarbonyl, phenyl-lower alkoxycarbonyl or hydroxy-lower alkyl, wherein the hydroxy group is separated from the nitrogen atom by at least 2 carbon atoms; their N- and/or S-oxides, lower alkyl quaternary derivatives thereof and salts of all these compounds, which consists in 1) condensing a compound of the general Formula III or antacid addition salt thereof - 31 - N.Z. PATENT OFFICE 2 5 NOV 1983 r- r 0 r* 1 v ■ •• I O 7 7 Q n I y / . • , L. with a compound of the general formula IV (0) #,AA (III) (IV) wherein X is halogeno, lower alkoxy, lower alkylthio, cyanato or thio-cyanato; Y is hydrogen or an alkali metal; p is an integer froji 0 to 2, and the remaining symbols have the meaning given for formula I, or 2) ring-closing of a compound of the general formula V (V) wherein Z is oxygen, sulfur or NH, and the other symbols have the above-given meaning, under dehydrating or dehydrosulfurating conditions, and, a) if a compound of the formula I is required in which is lower alkyl, introducing such a radical into a compound in which R^ is hydrogen or an alkali metal atom, and, b) if a ccarpound is required in which R3 is lower alkyl, reducing the double or triple bond respectively in a carpound having a lower alkenyl or lower alkynyl group instead of a lower alkyl group, and, c) if a compound is required in which R^ is hydroxy-lower alkyl, reacting a compound in which R^ is hydrogen or an alkali metal atom - 32 - f 7 j"!GV 1983 •j Q7 7 o n with a corresponding oxirane or with a reactive ester of a mono* esterified lower alkanediol, and d) if a compound is required in which is hydroxy-lower alkyl, reacting a compound in which R^ is hydrogen with a reactive derivative of a corresponding glycol, glycolic acid or a dicarboxylic acid and hydrolyzing or reducing the compound so obtained to a product in which R^ is hydroxy-lower alkyl, and, e) if a compound is required in which R^ is lower alkoxycarbonyl, converting the lovrer alkyl group in a product in which R^ is lower alkyl into the above named group, and, f) if a compound is required in which R^ is an acyl radical named above, acylating a product in which R^ is hydrogen, and, g) if a compound is required in which R^ represents hydrogen, hydrolyzing a compound in which R^ is an acyl radical, and, h) if a carpound is required in which R3 represents methyl, reducing lower alkoxy carbonyl or phenyl-lower alkoxycarbonyl. in a product in which R3 is lower alkoxy- , , , methyl, and, carbonyl or phenyl-lower alkoxycarbonyl to obtain a comoound in which R3 is/ i) if a compound is required in which R^ and/or is halogen, halo-genating a product in which R^ and/or R^ is hydrogen, and, j) if a compound is required in which R^ and/or *-s carboxy, lower alkoxycarbonyl or a carbamoyl residue named above, reacting a compound in which R^ and/or R£ is hydrogen, with a trihaloacetyl halide and treating the compound obtained with an alkali metal lower alkoxide, alkali metal hydroxide or alkali metal amide, and, k) if a compound is required in which R^ and/or i-8 sulfamoyl, or mono- or di-lower alkylsulfamoyl, reacting a product in which R^ and/ or R2 is hydrogen with a halosulfonic acid and treating the compound obtained with ammonia, or a mono- or di-lovrer alkylamine, and, 1) if a compound is required in which R^ and /or R£ is cyano, dehydrating a product in which R^ and/or R^ is carbamoyl, and, m) if a compound is required in which R^ and/or is carboxy, hydrolyzing a product in which R^ and/or R^ is cyano, lower alkoxycarbonyl or carbamoyl, and, /"-"C-V 2983 97392 n) if an N- and/or S-oxide is required, oxidizing a product in which R^ is different from hydrogen, and, o) if only an N-oxide is required, converting a product in which is different from hydrogen into its N-oxide by specific oxidation, and, p) if only an S-oxide is required, S-oxidizing a product in which represents an acyl radical, and, if required splitting off the acyl radical, and, q) if a lower alkyl quaternary derivative is required, reacting a product in which R^ is different from hydrogen or represents hydrogen, with a reactive esterified lower alkanol, and, r) if required, converting a resulting compound of formula I into another compound of the invention, anchor, if required, converting a resulting free compound into a salt or a resulting salt into the free compound or into another salt, and, if required, resolving a mixture of isomers or racemates obtained into the single isomers or racemates, and, if required, resolving a racemate obtained into the optical antipodes.
24. The process for the preparation of compounds of the formula I diown in claim 1 and described in any cane of Examples 1 to 4 and of canpounds 1 to 8 of example 8.
25. The process for the preparation of compounds of the formula I shown in claim 1 and described in any one of examples 5 to 7, and 9 to 13 and of compounds 9 to 13 of example 8.
26. The compounds prepared according to either of claims 23 and 25.
27. The compounds prepared according to claim 24. iq m-Tr--'"i- -rrf f—"nl f"-"-1- TTT "1—~ -'i rln-'m in which formula X rrprrirntn hyrirmrii m Hn n i|iln, and the other mvo tho moaningc givon in olaim 23-r •" OFFICE 983 - 34 - A OWE* "tshsfestatpv-'icantc </div>