GB2077727A - Imidazo-[2,1-b]-[1,3,5]-benzothiadiazepines - Google Patents

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

1 GB 2 077 727 A 1 c SPECIFICATION lmidazobenzothiadiazepines, process for

their manufacture, pharmaceutical preparations containing these compounds and their therapeutic application The present invention relates to 5-diazacycloalkyi-imidazo-[2,1 -bl-[1,3, 51-benzothiadiazepines of 5 the general formula 1 N S-C R1 ps/ NI k1R2 \Ntl N / CmH2m 1.1 N-R3 \Cn H2n--"' (1) wherein each of R1 and R2 is hydrogen, lower alky], lower alkanoyl, halogeno, cyano, carboxy, lower carbalkoxy, carbamoyl, sulfamoyl, mono- or di-lower alkyi-(carbamoyl or sulfamoyl); Ph is 1,2phenylene, unsubstituted or substituted by up to two identical or different members selected from lower alkyl, lower alkoxy, lower alkylthio, halogeno, trifluoromethyl, sulfamoyl, mono- or di-lower alkylsulfamoyl; each of C..,,1-12n, and CnH2, 'S lower alkylene separating both nitrogen atoms by 2 or 3 carbon atoms, and R3 is hydrogen, lower alkyl, lower alkanoy], lower alkoxycarbony], 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, especially derived from pharmaceutically acceptable acids or bases; process for their manufacture, pharmaceutical preparations containing these compounds and their therapeutic application.

A lower alkyl group R, R2, R, and/or such present in a substituted 1,2phenylene Phgroup, as well as in said aikoxy, 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- methyibutyi; and lower alkanoyl is 20 preferably acetyl or propiony].

A halogen atom R1 and/or R2, 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 R1 and/or R2, or present in a 1,2-phenylene group Ph, is preferably carbomethoxy, carbethoxy; mono- or dimethylcarbamoyl or mono- or dimethyisulfamoyl respectively.

A 1,2-phenylene radical Ph is preferably unsubstituted, or monosubstituted by said substituents, for example methyl or ethyl; methoxy, ethoxy or i-propoxy; methylthio or ethylthio; fluoro, chloro or bromo; trifluoromethyl; sulfamoyl, mono- or dimethyIsulfamoyL A lower alkylene group C H, and C H, is especially ethylene; but also 1,2- or 11,3-propylene, 1,2- m rn n n 1,3- or 2,3-butylene; thus forming with both adjacent nitrogen atoms preferably a piperazino or homo- 30 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 phenyl methoxycarbonyl or phenyl ethoxyca rbonyl.

Said N-oxides are preferably those in which R3 is lower alkyl or hydroxyalkyl, and in which the 35 oxygen is attached to the nitrogen carrying said F1,3 group. Said S- oxides represent sulfoxides (SO) or sulfones (S02).

Similarly, said lower alkyl quaternary derivatives of the compounds of formula 1 are preferably derived from those wherein R3 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 40 those of said acid addition salts, are preferably those of pharmaceutical ly acceptable acids, e.g. those listed below. Those compounds of formula 1 with R, and/or R, being carboxy, also form salts with bases, preferably those of pharmaceutically acceptable bases, e.g. ammonia, mono- , di- or tri-lower alkylamines; lower alkyleneamines; morpholine, piperazine, pyridine or lower alkyl-derivatives of said cyclic bases; alkali metal 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, 50 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 2 GB 2 077 727 A 2 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 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 behaviour, manifested by a decrease in avoidance responding and a 10 marked increase in shocks taken by the animals. Both, the avoidance responses and failures (shocks received), are recorded separately for evaulation according to this Sidman Avoidance test. The compounds of the invention, for example the 5-(4-methylpiperazino)imidazo-[2,1 - bl [1,3,51benzothiadiazepine 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 20 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 adminstration of haloperiodol. At no other time abnormal movements are evident in these monkeys. After haioperidol- elicited dyskinesias had 25 developed, this regimen ends, and 1.25 mg/kg haloperidoi is given once every 4-8 weeks as a control for comparison with test agents of this invention.

Said monkeys are individually observed at intervalE 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 third person handles the monkeys during neurological examination. After initial obervations 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 neuroligical 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 45 differs from control, is only considered an agent-induced effect, if both observers recorded it during any of the three observation periods. When one 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 50 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 55 (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 60 (antipsychotic) agents, for example, in the treatment of 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.

f J 3 GB 2 077 727 A Particularly useful are compounds of Formula 1, in which each of R, and R2 is hydrogen, lower alkyl, lower alkanoyl, halogeno, cyano, carboxy, lower carbalkoxy, carbamoyl, sulfamoyl, mono- or dilower alkyi-(carbamoyl or sulfamoyl); Ph is 1,2-phenylene, (lower alkyi)-1,2-phenylene, (lower alkoxy)1,2-phenylene, (lower alkyithio)1,2-phenylene, (halogeno)1,2- phenylene, (trifluoromethyi)-1,2phenylene, (sulfamoyi)-1,2-phenylene, (mono- or di-lower alkyisulfamoyi)1,2-phenylene; each of m and n is the integer 2 or 3; and R. is hydrogen, lower alkyl, lower alkanoyl, lower alkoxycarbonyl, phenyllower alkoxycarbonyl or hydroxy-lower alky], 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 11 (0) S p N R, C NC_1 R2 N N-R \- 4 (11) wherein each of R, and R, is hydrogen or lower alkyl; R4 is hydrogen, lower alkyl or 2- or 3-hydroxylower alkyl, R5 is hydrogen, lower alkyl, lower alkoxy, halogeno or trifl uoro methyl; and p is an integer from 0 to 2; the N-oxide thereof; or salts especially pharmaceutical ly acceptable acid addition salts of all these compounds.

Preferred are those compounds of the general formula 11, herein each of R1 and R2 is hydrogen or methyl; R 4 is aikyl or 2- or 3-hydroxyalkyl, in which alkyl has at most 4 carbon atoms; R, is hydrogen, methyl, methoxy, fluoro, chloro or trifl uoro m ethyl; and p is 0; the N- oxide thereof; or salts, espebially pharmaceutical(y acceptable acid addition salts of all these compounds.

The compounds of the invention are prepared according to methods known per se, advantageously 1) by condensing a compound of the general formula 111 or a salt thereof with a compound of the general formula W (0)p R1 _C \N-C R2 X + Y-N CM H2M,,, N-R3 CH n 2n 1 OV) wherein X is halogeno, lower alkoxy, lower alkylthio, cyanato or thiocyanato; Y is hydrogen or an alkali 25 metal; p is an integer from 0 to 2, and the remaining symbols have the meaning given for formula 1 and, if desired, converting any resulting compound into another compound of formul a 1.

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 60 and 1501, and preferably in an 30 appropriate solvent such as a lower alkanol, for example amy] alcohol, or dimethylformamide, hexa methyl phosphora m ide or toluene.

Another process for preparing the compounds of the general formula 1 consists in 2) ring-closing of a compound of the general formula V (0)p S_ R, lhI WI -R 2 NH-C--N N-R3 "-Cn H2h_"' (V) 35 4 GB 2 077 727 A 4 wherein Z is oxygen, sulfur or NH, and the other symbols have the above- given meaning, under dehydrating or dehydrosu Ifu rating conditions, and, if desired, converting any resulting -compound into another compound of the invention.

Said ring-closing is carried out with strong dehydrating or dehyd rosu Ifu rating agents, such as phosphorous halides andlor oxyhalides, or cyanogen halides, with or without crown ether catalysts, 5 such as 8-crown-6-ether, and with or without basic catalysts such as triethylamine or potassium carbonate, preferably in an inert solvent, such as dimethylformamide.

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-bl [1,3,5]-benzothiadiazepines of formula Ill are prepared according to ring closure methods known per se, advantageously by condensing compounds of formula VI Phl-l N R,.1 1 N 1 S H R WH2 (V1) wherein Ph, R1 and R2 have meaning given for compounds of formula Ill, with reactive carbonic acid derivatives such as phosgene, thiophosgene, 1,1'-carbonyidiimidazole or cyanogen bromide.

Compounds of formula Ill wherein X is hydroxy can in turn be converted to compounds wherein X is sulfhydryl by conventional sulfonating agents, such as phosphorus pentasulfide, and these can be further derivatized to compounds of formula Ill 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 Ill, 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 01 and 1500 advantageously between 100 and 500. The ring opening reaction is preferably carried out at low temperature to minimize side reactions when R1 and R2 represent reactive functional groups.

Alternately, starting materials of formula V, wherein R, is lower alkanoyl, lower alkoxycarbonyl or phenyl-lower alkoxy carbony], are prepared by condensing a compound of f6Irmula VI with a compound of formula VII K-N.,,CMH2M-'N-Rl _1 H 1-11 Cn 2n (VII) wherein Y' represents haiocarbonyi, halothiocarbonyl or cyano, and R' represents lower alkanoy], lower 30 3 alkoxycarbonyl or phenyl-lower alkoxycarbonyl, preferably in an inert solvent, at temperatures between 01 and 1501C, The compounds of the invention so obtained can be converted into other compounds of formula 1 according to known methods. Thus, for example, those with R3 being hydrogen or alkali metal, e.g., sodium or lithium salts thereof, can be reacted with substituted or unsubstituted oxiranes, such as ethylene oxide, or reactive esters of unsubstituted 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 hydroiodic 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 1 wherein R3 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 alkynyi, may be 45 hydrogenated with catalytically activated hydrogen to obtain compounds wherein R, is the corresponding lower aiky]. Conversely, resulting Walkylated 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 R3=1-1, for example with aqueous bases, such as alkali metal hydroxides, such as aqueous sodium 50 hydroxide solution.

Compounds of formula 1 wherein R3 is hydroxyalkyl can also be prepared by first reacting corresponding compounds of formula 1, wherein R3 represents hydrogen, with reactive derivatives of A GB 2 077 727 A 5 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-clibromopropane, 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 compound of formula 1 wherein R3 is hydroxyalky].

Compounds of formula 1 wherein R. is methyl can be prepared by reacting the corresponding compounds of formula 1 wherein R3 represents hydrogen, with lower alkyl- or phenyl lower alkyl- haloformates, such as ethyl chloroformate, to obtain compounds of formula 1 wherein R3'S lower alkoxycarbonyl or phenyl-lower alkoxycarbony], and reducing said acyl derivatives with simple or complex light metal hydrides such as lithium aluminium hydride, sodium trit-butoxy or bis- (2methoxyethoxy) aluminium hydride.

N-Acylated derivatives can be obtained from compounds of formula 1 with R. being hydrogen, and corresponding reactive acid derivatives, e.g., halides, simple or activated esters, such as alkyl esters or 15. cyanoalkyl esters, anhydrides or isocyanates. Resulting compounds of formula 1 with R1 and/or R2 being hydrogen, can be converted to the corresponding 3- and/or 4-(halo- or acyl)-derivatives, e.g. by halogenation, 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 20 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 hydrogen peroxide or organic peracids, such as lower peralkanoic 25 or perbenzoic acids, e.g. peracetic or rn-chloro-perbenzoic acid, advantageously at temperatures at or below room temperature with the latter, or up to 1001 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 R. 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 (SO,) depending on the quantity of peracid used. Resulting compounds with R. being phenylaikoxy carbonyl or alkoxycarbonyl so obtained can be converted to other compounds of formula 1 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 40 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, hydroxymaleic, pyruvic, phenylacetic, benzoic, 4-aminobenzoic, anthranilic, 4-hydroxybenzoic, salicylic, 45 4-aminosalicylic, pamoic, nicotinic, methanesulfonic, ethanesulfonic, hydroxyethanesulfonic, benzenesulfonic, toluenesulfonic, naphthalenesulfonic, sulfanilic or cyclohexyIsulfarnic 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. 1 to VII are obtained, these can be separated into the single isomers by methods in themselves known, e.g. by 55 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 dor 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, 60 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 65 6 GB 2 077 727 A 6 out, or the process is discontinued at any stage thereof, 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 5 those compounds indicated above as being especially valuable, e.g. those of formula 11.

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 10 calcium salt and/or polyethyleneglycol; for tablets also binders, e.g. magnesium aluminium silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium ca rboxymethyl cell u lose and/or polyvinylpyrrolidone, if desired, disintegrants, e.g. starches, agar, alginic acid or its sodium salt, enzymes of the binders or effervescent mixtures and/or adsorbents, colorants, flavors and sweeteners, 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%, preferably about 1 to 50% 20 of the active ingredient. Unit dosages for mammals of about 50-70 kg weight may contain between about 5-100 mg of the active ingredient.

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 25 between about 15 and 100 mmHg.

EXAMPLE 1

To the mixture of 501 g of 1 -methylpiperazine and 6,000 m[ of arnyl alcohol, 538 m] of 9.3 N methanolic hydrogen chloride are added and the mixture is stirred and distilled for 1 hour, during which time 1,000 m] of distillate is collected and the temperature reaches 1310. Thereupon another 501 9 of 30 1-methylpiperazine are added, followed by 618.5 g of 5-methyithio- imidazo[2,1 bl [1,3,51benzothiadiazepine. The mixture is stirred under nitrogen at 132-1401 for 48 hours and evaporated at about 80-901. The residue is dissolved in 3,000 mi of methylene chloride, the solution washed 3 times with 1,000 mi of 3 N aqueous sodium hydroxide and 5 times with 1,000 m[ of water. It is finally extracted 4 times with 750 mi of 2 N hydrochloric acid each, the combined extracts are washed once with 1,000 mi of methylene chloride, decolorized with 75 g of charcoal, filtered and the filtrate Is basified with 500 m[ of 29.9% aqueous ammonia to a pH of 9-10. The mixture is extracted twice with 2,000 mi of methylene chloride, the combined extracts dried, filtered and evaporated at about 601. 2,810 g of this residue are dissolved in 14,000 mi of hot isopropanol, the solution treated with 563 g of charcoal, filtered and the residue washed with 1,000 mi of cold isopropanol. The combined filtrates are reheated and again treated with 563 9 of charcoal in the same manner. The resulting clear solution is concentrated to 8,500 mI and the concentrate allowed to stand in the refrigerator for 2 days. The white precipitate is filtered off, washed 3 times with cold isopropanol anddried at 4011/5 mmHg, to yield the 5-(4-methylpiperazino)-imidazo[2,1 bl[1,3,5]benzothiadiazepine of the formula C,-CNI:l \1 /---\ N N-CH3 melting at 145-1470.

1,614 g thereof are dissolved in 5,450 m[ of anhydrous ethanol at 50-601, the solution filtered hot, the filter rinsed with 1,000 mi more anhydrous ethanol amd the combined filtrates are acidified with the soluition of 688 g of maleic acid in 1,600 mi of anhydrous ethanol while stirring. The mixture is 50 stirred while cooling to 251', the precipitate collected, washed twice with 800 mi of anhydrous ethanol and dried at 75'/0.5 mm Hg, to yield the corresponding monomaleate melting at 198-1991 with decomposition.

The starting material is prepared as follows:

To 39,230 m[ of 2 N hydrochloric acid, 7,500 g of aminoacetaidehyde dimethylacetal are added 55 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 z 2! z 7 GB 2 077 727 A 7 temperature overnight. The resulting suspension is stirred and cooled to 50, filtered and the residue dried at 600/5 mmHg, 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 mi of isopropanol while stirring under nitrogen at room temperature, followed by 4,986 of 2 bromo-nitrobenzene. The mixture is stirred and heated to 82-851 for 5 hours, cooled to 501 and diluted with 37,000 mi of water. The resulting suspension is stirred at room temperature for 2 day, filtered, the residue washed 6 times with 4,000 m] of water and 5 times with 3,700 mi of diethyl ether, and dried at 601/5 mmHg, to yield the 2-(o-nitrophenyithio)-imidazole melting at 178-1800.

The mixture of 2,210 g thereof, 2,000 mi of water, 2,000 mi of ethanol and 1,700 g of iron powder is heated to 701 while stirring under nitrogen. After addition of 10 mi of concentrated 10 hydrochloric acid the mixture is refluxed for 1.5 hours, whereupon 200 mi of concentrated hydrochloric acid in 1,000 mi of ethanol are added during 95 minutes.

The mixture is refluxed for 2 hours longer and 400 m[ of 6 N aqueous sodium hydroxide are added.

The resulting suspension is diluted with 2,000 m[ of methanol, filtered and the residue is washed 3 times with 1,000 m[ of methanol. The combined filtrates are diluted with 40,000 mi of water, the resulting suspension allowed to settle overnight, the precipitate is collected, washed twice with 2,000 mi of water and dried at 600/5 mmHg, to yield the 2-(o-aminophenyithio)- imidazole melting at 137-1380.

4,775 9 thereof are added to the mixture of 55,000 m] of methylene chloride and 6,975 mi of triethylamine, the mixture cooled to 31 and 3,301 9 of 85% thiophosgene in carbon tetrachloride are 20 added during 2.5 hours while stirring under nitrogen at 151. Stirring is continued at 101 for 4 hours and at room temperature overnight. The resulting suspensio is filtered, the residue washed twice with 4,000 mi of methylene chloride and once with 20,000 mi of water and suspended in 11,000 m] of 1.3 N hydrochloric acid. The suspension is stirred for 2 hours, filtered, the residue washed 3 times with 4,000 m] of water and dried at 60'/5 mmHg, to yield the imidazo[2,1-bl [1,3,5]benzothiadiazepin-5(6H)-thione melting at 156-1591.

1,184 g thereof are added to the solution of 278 g of sodium methoxide in 22,500 mi 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 201. It is diluted with 45,000 mi of water and the resulting suspension stirred at room temperature overnight. It is filtered, the 30 residue washed 5 times with 4,000 mi of water and dried at 601/5 mmHg, to yield the 5-methylthio imidazo[2,1 -b] [1,3,5]benzothiadiazepine melting at 116-1180.

Similarly the following starting materials are prepared from the correspondingly substituted 2 bromonitrobenzenes:

a. 8-methoxy-5-methy[thio-imidazo[2,1-b] [1,3,51benzothiadiazepine, melting at 143-1460; 35 b. 8-chloro-5-methyithio-imidazo[2,1-bl[1,3,5]benzothiadiazepine' melting at 147-149'; c. 841 uoro-5-m 6thyithio-i mid azo [2,1 --b] [1,3,51benzothiadiazepine, melting at 174-1761; d. 8-methy]-5-methyithio-imidazo[2,1-bl[1,3,5]benzothiadiazepine.

EXAMPLE 2 40 To the solution of 480 mg of 5-thiocyanato-imidazo[2,1 -b] [1,3,51benzothiadiazepine in 1 mi of 40 hexamethylphosphoramide, 500 mg of 1 -methyl pipe razi ne are added during 5 minutes while stirring under nitrogen at -50. Stirring is continued for 5 minutes at said temperature. The mixture is diluted with 80 mi of ethyl acetate, washed twice with saturated aqueous sodium chloride, dried and evaporated. The residue is dissolved in 2 m] of acetone, the solution acidified with 300 mg of maleic acid and diluted with diethyl ether, to yield the 5-(4methylpiperazino)-imidazo[2,1 b] [1,3,51benzothiadiazepine monomaleate, melting at 198-1990 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 mi of dry tetrahydrofuran, 6.45 g of imidazo[2,1 -b] [1,3,5]benzothiadiazepin-5(6H)thione are added in portions, 50 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 mi 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 ether and filtered, to yield the 5thiocyanato-imidazo[2,1 b] [1,3,51benzothiadiazepine melting at 111-1131.

EXAM P LE 3 The mixture of 333 mg of 1 -[2-(i mid azo-2-yl thi o)-phenyl i m i nothioca rbonyll -4-m ethyl piperazi ne, 3.3 mi 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 60 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 diethyi ether, to 8 GB 2 077 727 A 8 yield the 5-(4-methylpiperazino)-imidazo[2,1 -b] [1,3, 51benzothiadiazepine monomaleate, melting at 198-1991 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] [1,3,5]benzothiadiazepin-5(6H)thione, 23 mi 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 1-[2(imidazo-2-ylthio)phenyl i m inothiocarbonyll-4-m ethyl piperazi ne melting at 209-2121.

EXAM P LE 4 To the suspension of 3.1 g of 1-[2-(imidazo-2-yithio)phenyliminocarbonyll-4-methylpiperazine and 25 m] of phosphorus oxychloride, 2.04 g of phosphorus pentachloride are added at once, and the 10 mixture is stirred at room temperature for 4 hours. It is evaporated, the residue suspended in 50 m] of dry methylene chloride, the suspension cooled to 01 and 2.02 g of triethylamine are added dropwise while stirring. Stirring is continued for 15 minutes at 01, 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] [1,3,51benzothiadiazepine monomaleate, melting at 198-1991 15 with decomposition; it is identical with that of Example 1.

The starting material is prepared as follows:

The mixture of 15 9 of 2-(imidazo-2-yithio)-aniline, 13.9 g of 1,1'carbonyidiimidazole and 675 m[ 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-bl [1,3, 5]benzothiadiazepin-5(6H)-one, 20 melting at 250-252' with decomposition.

In the analogous manner (or by replacing the 1,1'-carbonyidiimidazole by the equivalent amount of phosgene), the following intermediates are obtained and are illustrative of the process:

a. 3,4-dimethylimidazo[2,1-bl[1,3,Slbenzothiadiazepin-5(6H)-one,m.p.2251 (decomposition; b. 8-chloroimidazo[2,1-bl[1,3,5]benzothiadiazepin-5(6H)-one,m.p.261-2631; c. 8-trifluoromethylimidazo[2,1bl[1,3,5]benzothiadiazepin-5(6H)-one,m.p. 257-26 00; d. 3-methylimidazo[2,1-bl[1,3,5]benzothiadiazepin-5(6H)-one,m.p.225-2291> The mixture of 2.17 g of imidazo[2,1-bl[1,3,5]benzothiadiazepin-5(6H)-one, 1.0 g of 1 methylpiperazine and 20 m,l 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)-phenyliminocarbonyll-4-methylpiperazine, melting at 197-2000.

process:

In similar manner the following additional starting materials are obtained and are illustrative of the a. 1-[2-(4-methylimidazo-2yithio)-phenyliminocarbonyll-4-methylpiperazine, melting at 101-1051 (decomposition); b. 1-[2-(imidazo-2-yithio)-phenyliminocarbonyll-4-methyihomopiperazine, melting at 134-1381; c. 1-[2-(imidazo-2-yithio)-phenyliminocarbonyll-4carboethoxypiperazine, melting at 161-1701; - d. 1-[2-(imidazo-2-ylthio)-phenyliminocarbonyll-4- carbobenzoxypiperazine, melting at 206-2081; e. 1-[2-(4-carboethoxyimidazo-2-yithio)-phenyliminocarbonyl]-4methylpiperazine, melting at 40 166-1691; 142-0 midazo-2-yIth io)-4-trifl uoromethyl phenyl im inoca rbonyll-4-m ethyl piperazi ne, melting at 2122140.

EXAMPLE 5

A mixture of 10 g of 5-methyithio-imidazo[2,1 -b] [1,3, 5]benzothiadiazepine hydrochloride, 3.62 9 of piperazine, and 350 mi of amy] alcohol is refluxed with stirring and unter nitrogen for 20 hours. The 45 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 m] of methanol and treated with 2N etheral hydrochloric acid solution to give 5-(4H-piperazino)-imidazo[2,1 -b] [1,3,51benzothiadiazepine dihydrochloride, melting at 2491 with decomposition.

EXAMPLE 6

A mixture of 5 g of 5-methyithio-imidazo[2,1 -b] [1,3, 51benzothiadiazepine hydrochloride, 2.86 9 of N-p-hyd roxyethyl pipe razine, and 175 m] of amy] 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 55 dryness. The residue is dissolved in 5 mI of methanol and treated with 2N etheral hydrochloric acid solution to give 5-(4-p-hyd roxyethyl pipe razino)-i m idazo [2,1 -b] [1, 3,51benzothiadiazepine dihydrochloride, melting at 210-2121.

9 GB 2 077 727 A 9 EXAMPLE 7

By replacement of the N-A-hyd roxyethyl pipe razi ne in example 6 by an equivalent amount of Nmethylhomopiperazine one obtains 5-(4-m ethyl ho m opiperazi no)-i m idazo [2,1 - bl [1,3,51benzothiadiazepine, isolated as the fumarate salt melting at 216-2180.

EXAM P LE 8 According to the methods illustrated by the previous examples, the following compounds of formula 1 are obtained from equivalent amounts of the corresponding starting materials; Ph=4-R 5-1,2phenylene; C.. H2. =(CH2)2; C.1---12n=(CHIL' No. R, R 2 R, n R, Salt M.P, C 1 H H H 2 H 2HCl 249 dec.

2 H H CH, 2 H 2HCl 216-219 3 H H CH, 2 OCH 21-IC1 155 dec.

4 H H CH, 2 F maleate 202-204 H H CH, 2 Cl 21-IC1 203-206 6 H H CH, 2 CF, 21-IC1 180 - dec.

7 Cop 2H, H CH, 2 H 138-141 8 H H (CH2)20H 2 H 2HCl 210-212 9 H H COOEt 2 H 137-139 H H CH, 3 H f umarate 216-218 11 H H CO0CHAH, 2 H NIVIR: 5.2, 3.5 12 CH3 H CH3 2 H maleate 191-192.5 13 CH, CH, CH3 2 H (dec. decomposition) EXAMPLE 9

To the solution of 0.2 g of 5-(4-carboethoxypiperazino)-imidazo[2,1 -bl [11,3,51benzothiadiazepine in 2 m] of dry tetra hydrofu ran, 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 mi of 30% aqueous sodium hydroxide, and filtered. The filtrate is evaporated to dryness and the product is purified to give 5(4-m ethyl piperazi nol-i m idazo [2,1-bl [1,3,51benzothiadiazepine, melting at 145-1471. It is identical with the compound obtained in Example 1.

EXAMPLE 10

To the solution of 88 mg of 5-(4-m ethyl pipe razino)-i mid azo [2,1 -bl [ 1,3,51benzothiadiazepine in 1 mi of methylene chloride, 74 mg of mchloroperbenzoic acid are added at 00. The mixture is stirred at 01 overnight; this is diluted with 1 mi of ether, one equivalent of etheral hydrochloric acid solution is 20 added and the resulting precipitate is collected. Recrystallization from methanol-ethyl acetate yields 5 (4-methyi-4-oxidopiperazino)-imidazo[2,1 -bl [1,3,51benzothiadiazepine hydrochloride, melting at 1551 with decomposition.

EXAMPLE 11 a) To the solution of 0.5 g of 5-(4-carbobenzoxypiperazino)-imidazo[2,1- bl [1,3,51benzothiadiazepine in 5 mi of methylene chloride, cooled at 0', is added dropwise a solution of 0.26 9 of m-chloroperbenzoic acid in 2 mi 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 carbobenzoxypiperazino)-imidazo[2,1 -bl [1,3,51benzothiadiazepine 1 oxide. Mass spectrum: m/e 435, 30 418,387.

GB 2 077 727 A 10 b) In a similar manner and by using 0.61 g (2 equivalents) of m- chloroperbenzoic acid, the 5-(4carbobenzoxypiperazino)-imidazo[2,1 -bl [1, 3,51benzothiadiazepine 1,1 -dioxide is obtained. Mass spectrum: m/e 451, 420,406,386.

EXAMPLE 12 a) To the solution of 100 mg of 5-(4-carbobenzoxypiperazino)-imidazo[2,1 bl [1,3,51benzothiadiazepine 1 -oxide in 0.3 mi of acetic acid are added 0.35 m[ of a 2N solution of hydrobromic acid in acetic acid. The mixture is heated at 1001 for 1 hour and stirred at room temperature overnight. Ether is added, and the 5-(4H-piperazino)-imidazo[2,1 bl [1,3, 51benzothiadiazepine 1 -oxide hydrobromide is filtered and washed with ether; m.p. 750 with 10 decomposition.

b) In a similar manner the 5-(4-carbobenzoxypiperazino)-imidazo[2,1 -bl [1,3,51benzothiadiazepine 1,1 -dioxide is converted to 5-(piperazino)imidazo[2,1 -bl [1,3,5]benzothladiazepine 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[2,1 -bl [1,3, 5]benzothiadiazepine, 0.5 9 of 15 potassium carbonate, 0.142 g of methyl iodide and 2 m[ 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-bj [1,3, 51benzothiadiazepine melting at 145-1471. 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 -bl [1,3,51 benzothiadiazepine maleate 50g 25 Lactose 1,157 g Corn starch 75g Polyethylene glycol 6,000 75g Talcum powder 759 Magnesium stearate 18 g 30 Purified water q.s.

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 mi of water and the suspension added to the boiling solution of the 35 polyethylene glycol in 150 mi 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 351, 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-hydroxyethyl)-piperazinol-imidazo- [2,1 -bl [ 1,3,51benzothiadiazepine dihydrochloride 100g Lactose 1,8009 45 Talcum powder 1009 11 GB 2 077 727 A 11 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. 5 Analogously tablets or capsules are prepared from the remaining compounds of the invention, e.g. 5 those illustrated by the other examples herein.

Claims (28)

1. Compounds of the general Formula 1 Mor, N_ S 1 R1 Phl NI - R2 \Ncl CmH2m \ N / N-R3 H --"" \Cn 2n (i) wherein each of R1 and R2 is hydrogen, lower alky], lower alkanoyl, halogeno, cyano, carboxy, lower 10 carbalkoxy, carbamoyl, sulfamoyl, mono- or di-lower alkyi-(carbamoyl or sulfamoyl); Ph is 1,2phenylene, unsubstituted or substituted by up to two identical or different members selected from lower alkyl, lower alkoxy, lower alkylthio, halogeno, trifluoromethyl, sulfamoyl, mono- or di-lower aikyisulfamoyi; each of CM1-1,n and CnH,,, is lower alkylene separating both nitrogen atoms by 2 or 3 carbon atoms, and R3 is hydrogen, lower alky], lower alkanoy], lower alkoxycarbonyl, phenyl-lower is alkoxycarbonyl or hydroxy-lower alkyl, wherein the hydroxy group is separated from the nitrogen atom by at least 2 carbon atoms; their Nand/or S-oxides, and lower alkyl quaternary derivatives thereof.
2. 2. Compounds of the Formula 1 shown in claim 1, wherein R3 represents hydrogen, lower alkyl, lower alkanoyi, lower alkoxycarbonyl or hydroxylower 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 20 claim 1; their N- and/or S-oxides, and lower alkyl quaternary derivatives thereof.
3. 3. Compounds of the Formula 1 shown in claim 1 or 2, in which each of R1 and R2 is hydrogen, lower alkyl, lower alkanoyl, halogeno, cyano, carboxy lower carbalkoxy, carbamoyl, sulfamoyl, mon- or di-lower alkyl(carbarnoyl or sulfamoyl); Ph is 1,2-phnylene, (lower alkyl)-1,2phenylene, (lower' alkoxy)-1,2-phenylene, (lower alkyfthio)-1,2-phenylene, (halogeno)-1,2- phenylene, (trifluoromethyl)- 25 1,2-phenylene, (sulfamoyi)-1,2-phenylene, (mono- or di-lower alkylsulfamoyi)-1,2-phenylene; each of m and n is the integer 2 or 3; and R3 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. 4. Compounds of the Formula 11 (9)p N R, c R5 N= c "\,(- R2 (11) N N-R \4 wherein each of R1 and R2 is hydrogen or lower alkyl; R4 is hydrogen, lower alkyl or 2- or 3-hydroxylower alkyl, R. is hydrogen, lower alkyl, lower alkoxy, halogeno or trifl uoro methyl; and p is an integer 35 from 0 to 2; and the N-oxide thereof.
5. 5. Compounds of the Formula 11 shown in claim 4, wherein each of R, and R, is hydrogen or methyl; R4 is alkyl or 2- or 3-hydroxyalkyl, in which aikyl has at most 4 carbon atoms; R. is hydrogen, methyl, methoxy, fluoro, chloro or trifluoromethyl; p is 0; and the N- oxide thereof.
6. 6. Compounds of the Formula 1 shown in claim 1, named in the Example 8, as compounds 1 to 8.
7. 7 Compounds of the Formula 1 shown in claim 1, named in the Example 8, as compounds 9 to 13. 40
8. 8. 5-(4-Methylpiperazino)-imidazo[2,1 -bl [1,3,51benzothiadiazepine.
9. 9. 5-(4H-Piperazino)-imidazo[2,1 -bl [1,3,51benzothiadiazepine.
10. 10. 5-(4-P-Hydroxyethylpiperazino)imidazo[2,1-bj [11,3, 51benzothiadiazepine.
11. 11. 5-(4-M ethyl homopipe razino)-i mid azo [2,1 -bl [1,3, 51benzothiadiazepine.
12. 12. 5-(4-Methyi-4-oxido-piperazino)-imidazo[2,1 -bl [1,3, 51benzothiadiazepine.
13. 13. 5-(4-Carbobenzoxypiperazino)-imidazo[2,1 -bl [1,3, 5]benzothiadiazepine-1 oxide.

    12 GB 2 077 727 A 12
14. 14. 5-(4-Carbobenzoxypiperazino)-imidazo[2,1 -bl [1,3, 51benzothiadiazepine-1,1 -dioxide.
15. 15. 5-(4H-Piperazino)-imidazo[2,1-bJ [1,3,5]benzothiadiazepine-1 -oxide.
16. 16. 5-(4H-Piperazino)-imidazo[2,1 -bl [1,3,5]benzothiadiazepine-1,1 dioxide.
17. 17. A salt of a compound having a salt forming group, as claimed in any one of claims 1, 3-5, 7, 5 9 and 11-16.
18. 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.

    10.
19. 19. A salt of a compound having a salt forming group, as claimed in any one of claims 2, 6, 8 and
20. 20. A pharmaceutically acceptable salt of a compound having a salt forming group, as claimed in 10 any one of claims 2, 6, 8 and 10.
21. 2 1. 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. 22. A pharmaceutical preparation comprising a compound claimed in any one of claims 2, 6, 8, 10 15 and 20 in admixture or conjunction with a pharmaceutically suitable carrier.
23. 23. Process for the manufacture of 5-diazacycloalkyi-imidazo[2,1 -b] [1,3, 51benzothiadiazepines of the general formula 1 Ph / S -C R, 1:1 N 1 R2 C \ /, m H2m I, N-R3 \Cn H2 n wherein each of R1 and R2 is hydrogen, lower alkyl, lower alkanoyl, halogeno, cyano, carboxy, lower carbalkoxy, carbamoyl, sulfamoy], 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 alky], lower alkoxy, lower alkylthio, halogeno, trifluoromethy], sulfamoyl, mono- or di-lower aikyisulfamoy]; each of C H2,,, and CnH2n 'S lower alkylene separating both nitrogen atoms by 2 or 3 carbon atoms, and R3 is hydrogen, lower alky], lower alkanoyl, lower alkoxycarbonyl, phenyl-lower alkoxycarbonyl or hydroxy-lower alkyl, wherein the hydroxy group is separated from the nitrogen atom 25 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 Ill or a salt thereof with a compound of the general formula IV (1) k 9P N R1 S---, Phl C \N- C v XR2 (111) C H2m X + Y-N N-R3 Pn H2n OV) wherein X is halogeno, lower alkoxy, lower 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 1, or 2) ring-closing of a compound of the general formula V (0)p // N / S -C 1 pti HN rR 2 .-cjrnH2M-,,, NH-C-N N-R3 "'-CnH2n (V) 13 GB 2 077 727 A 13 wherein Z is oxygen, sulfur or NH, and the other symbols have the abovegiven meaning, under dehydrating or dehydrosulfu rating conditions, and, a) if a compound of the formula i is required in which R. is lower alkyl, introducing such a radical into a compound in which R3 is hydrogen or an alkali metal atom, and, b) if a compound is required in which R3 is lower alkyl, reducing in a compound having a lower alkenyl or 5 lower alkynyl group instead of a lower alkyl group, and, c) if a compound is required in which R3 is hydroxy-lower alkyl, reacting a compound in which R 3 is hydrogen or an alkali metal atom with a corresponding oxirane or with a reactive ester of a monoesterified lower alkanediol, and d) if a compound is required in which R. is hydroxy-lower alkyl, reacting a compound in which R 3 is 10 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 R3 is hydroxy-lower alkyl, and, e) if a compound is required in which R3 is lower alkoxycarbonyl, converting in a product in which R, is lower alkyl into the above named group, and, f) if a compound is required in which R3 is is an acyl radical named above, acylating a product in which 15 R, is hydrogen, and, b) if a compound is required in which R3 represents hydrogen, hydrolyzing a compound in which R3 is an acyl radical, and, h) if a compound is required in which R3 represents methyl, reducing in a product in which R3 is lower alkoxycarbonyl or phenyl-lower alkoxycarbonyl to obtain a compound in which R3 is methyl, and, i) if a compound is required in which R, and/or R2 is halogen, halogenating a product in which R, and/or R2 is hydrogen, and, j) if a compound is required in which R1 and/or R2 is carboxy, lower alkoxycarbonyl or a carbamoyl residue named above, reacting a compound in which R1 and/or R2 is hydrogen, with a trihaloacetyl halide and treating the compound obtained with an alkali metal lower alkoxide, alkali metal hydroxide or 25 alkali metal amide, and, k) if a compound is required in which R1 and/or R2 is sulfamoyl, 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, a mono- or di-lower aikyibmine, and, 1) if a compound is required in which R1 and/or R2 is cyano, dehydrating a product in which R1 and/or 30 R2 is carbamoyl, and, m) if a compound is required in which R, and/or R2 is carboxy, hydrolyzing a product in which R, and/or R2 -is cyano, lower alkoxycarbonyl or carbamoy], and, n) if an N- and/or S-oxide is required, oxidizing a product in which R3 is different from hydrogen, and, o) if only an N-oxide is required, converting a product in which R3 is different from hydrogen into its N- 35 oxide by specific oxidation, and, p) if only an S-oxide is required, S-oxidizing a product in which R3 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 1 into another compound of the invention, and/or, 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. 24. The process for the preparation of compounds described in any one of examples 1 to 4 and of compounds 1 to 8 of example 8.
25. 25. The process for the preparation of compounds described in any one of examples 5 to 7, 9 to 13 and of compounds 9 to 13 of example 8.
26. 26. The compounds prepared according to either of claims 23 and 25.
27. 27. The compounds prepared according to claim 24.
28. 28. Starting materials of the general formula Ill shown in claim 23, in which formula X represents hydroxy or mercapto, and the other symbols have the meanings given in claim 23.

    Printed for Her Majesty's Stationery Office by the Courier Press, Leamington Spa, 1981. Published by the Patent Office, 25 Southampton Buildings, London, WC2A lAY, from which copies may be obtained.