CA1163630A - Imidazobenzothiadiazepines, process for their manufacture, pharmaceutical preparations containing these compounds and their therapeutic application - Google Patents

Abstract

4-12896/CGC 921/+

Imidazobenzothiadiazepines, process for their manufacture, pharmaceu-tical preparations containing these compounds and their therapeutic application Abstract of the disclosure The invention concerns the compounds of the Formula I

(I) wherein each of R1 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 selectet from lower alkyl, lower alkoxy, lower alkylthio, halogeno, trifluoromethyl, sulfamoyl, mono- or di-lower alkylsulfamoyl; each of CmH2m ant CnH2n is lower alkylene separating both nitrogen atoms by 2 or 3 carbon atoms, and R3 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, and lower alkyl quaternary derivatives thereof salts of all these compounds. The compounds exhibit neuroleptic activity. They are prepared by concensing a compound of the general Formula III or a salt thereof with a compound of the general Formula IV

Description

-~ 1163~30 4-12896/CGC 92 V+

Imidazobenzothiadiazepines, process for their manufacture, pharmaceutical preparations containing these compounds and their therapeutic application The present invention relates to 5-diazacycloalkyl-imidazo-[2,1-b]-11,3,5]-benzothiadiazepines of the general formula I

2 (I) C~ / mH2m~

\C
nH2n wherein each of Rl 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, trifluoromethyl, sulfamoyl, mono- or di-lower alkylsulfamoyl; each of CmH2m and CnH2n is lower alkylene separating both nitrogen atoms by 2 or 3 carbon atoms, and R3 i8 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 ~pplication.
.

,,, ,,:

1 163~30 A lower alkyl group Rl, R2, R3 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 Rl 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 Rl and/or R2, or present in a 1,2-phenylene group Ph, is preferably carbomethoxy, carbethoxy; mono-or dimethylcarbamoyl or no- 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; sulfa yl, mono- or dimethyl-sulfamoyl.

A lower alkylene group CmH2m and CnH2n is especially 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 R3 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 R3 is lower alkyl or hydroxyalkyl, and in which the oxygen is attached to the nitrogen carrying said R3 group. Said S-oxides represent sulfoxides (SO) or s~lfones (S02).

Similarly, said lower alkyl quaternary derivatives of the compounds of formuls I 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 those of said acid addition salts, are preferably those of pharmaceutically acceptable acids, e.g. those listed below. Those compounds of formula I with Rl and~or R2 being carboxy, also form salts with bases, preferably those of pharmaceuti-cally 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; 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 tho~e with one or two carbon atoms.

The compounds of the invention exhibit valuable pharmacological properties, primarily neuroleptic activity. It is de nstrable in animal tests using advanta~eously mammals, e.g. mice, rats or monkeys, as te t objects. Said compounds can be administered to them enterally or parenterally, advantageously orally, or subcutaneously, intra-venously or intraperitoneally, for example, within gelatin capsules, or in the form of starchy suspensions or aqueous solutions respec-tively. The applied dosage may range between about 0.01 and 100 mg~
k&/day, preferably between about 0.05 and lO mg~kg/day, advantageously between about 0.1 and 5 mg~kg/day.

Said neuroleptic properties can be demonstrated in adult rats or , 1 16363~

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 (rsts) 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 snimals. 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]~1,3,5]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 neuro-leptics, have been found to induce a characteristic motor syndrome in squirrel nkeys, which were previously exposed to repeated anti-psychotic 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. Ater approximately 2-4 months of this treatment regimen, dystonic posture and dyskinetic vements are evident during 1-6 hours after administration of haloperiodol.
~t no other time abnormal movements are evident in these monkeys.

1 1~3~30 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 ~, 4 and 6 hours after treatment and the experiments are performed in an enclosed cubicle, which is equipped with a remotely controlled video observa-tion 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 thir~
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) 7 "visual" (visual response but no ambulation) and "none"
(no response). Activity, p~sture, tremors, salivation and other neuro-logical signs are observed. Particular attention i8 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 ant 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 exæmination 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 a~ least 1 minute for dyskinesias. A given sign or rating, which differs from ; control, is only cQnsidered 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, over-all inter-observer correspondence is good.

For example, after administration of 10 mg/kg of the compound of Example 1, only one of fi~e monkeys showed any type of dyskinetic movement, and that was confined to one form (writhing) only, as ob-served during one of three time periods. In contrast, severe dyskin-esia, characterized by various types of dyskinetic ~ovements, is recognized in all monkey~ treated with haloperidol (1.25 mg~kg).
Dyskinesias were also absent after clozapine (lO mg~kg), but were apparent after a moderate dose of haloperidol (0.625 mg~kg) in five nkeys, 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 hyper-salivation 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 sr 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 pro-ducts, especially of pharmaco~ogically 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, carba yl, sulfamoyl, mono- or di-lower alkyl-(carbamoyl or sulfam~yl); Ph is 1,2-phenylene, (lower alkyl)-.
, '- ` ~ ' ~

1163B3~

lS2-phenylene, ~lower alkoxy)-1,2-phenylene, (lower alkylthio)-1,2-phenylene, (halogeno)-1,2-phenylene, (trifluoromethyl)-1,2-2henylene, (sulfamoyl)~1,2-phenylene,(mono- or di-lower alkylsulfamoyl~-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; 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
(O) 5 ~-/ \N ~ 2 (II) ~._.

.--.
wherein each of Rl and R2 is hydrogen or lower alkyl; R4 is hydrogen, lower alkyl or 2- or 3-hydroxy-lower alkyl, R5 is hydrogen, lower alkyl, lower alkoxy, halogeno or trifluoromethyl; and p is an integer from O to 2; the N-oxide thereof; or salts, especially pharma-ceutically acceptable acid addition salts of all these compounds.

Preferred are those compounds of the general formula II, wherein each of Rl and R2 is hydrogen or methyl; R4 is alkyl or 2- or 3-hydroxyalkyl, in which alkyl has at most 4 carbon atoms; R5 is hydro-gen, methyl, methoxy, fluoro, chloro or trifluoromethyl; and p is O;
the N-oxide thereof; or salts, especially pharmaceutically acceptable acid addition salts of all these compounds.

The compounds of the invention are prepared according to methods 1 ~63630 known per se, advantageously 1) by condensing a compound of the general Formula III or a salt thereof with a compound of the general formula IV
(O) S~

/ m 2m\
~ Y ~ ~ R3 (III) C H2 /

(IV) wherein X is halogeno, lower alkoxy, lower alkylthio, cyanato or thio-cyanato; Y is hydr~gen or an alkali metal; p is an inte~er from 0 to 2, ant the remaining symbols have the meaning given for formula I and, if desired, co~verting 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 thiocyanato9 advantageously at temperatures between about 0 and 150, and preferably in an appropriate solvent such as a lower alkanol, for example amyl alcohol, or d~methylformamide, hexamethylphosphor-amide or toluene.

Another process for preparing the compounds of the general formula I
consists in 2) ring-closing of a compound of the general formula V

.

-R
2 (V) ~C H2 \

C H ~ 3 n 2n wherein Z is oxygen, sulfur or NH, and the other symbols have the above-given meaning, under dehydrating or dehydrosulfurating condi-tions, and, if desired, converting sny resulting compound into another compound of the invention.

Said ring-closing is carried out with strong dehydrating or dehydro-sulfurating agents, such as phosphorous 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 potassiu~ 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-b][1,3,5]-benzothiadiazepines of formula III are prepared according to ring clasure methods known per se, advantageously by contensing compounds of formula VI

2 (VI) Ph wherein Ph, Rl and R2 ilave meaning given for compounds of formula III, with reactive carbonic acid derivatives such as phosgene, thio-: ~ _ 9 _ : , '~ ~ ''`J

phQsgene, l,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 star~ing materials of formula V can be obtained from that of the (tautomeric~ precursors o formula III, wherein ~ 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 0 and 150 advantageously between 10 and 50. The ring opening reaction is preferably carried out at low temperature to minimize side reactions when Rl and R2 represent reactive functional groups.

Alternately, starting materials of formula V, wherein R3 is lower alkanoyl, lower alkoxvcarbonyl or phenyl-lower alkoxy carbonyl, are prepared by condensing a compound of formula VI with a compound of formula VII
/CmE12ii~\

C H ~ (VII) n 2n wherein Y' represents halocarbonyl, halothiocarbonyl or cyano, and R3 represents lower alkanoyl, lower alkoxycarbonyl or phenyl-lower alkoxycarbonyl, preferably in an inert solvent, at temperatures between 0 and 150C.

The ccmpounds of the invention so obtained can be converted into other compounds of formula I according to known methods. Thus, for example, those with R3 being hydrogen or alkali metal, e.g., sodium . ..

1 163~30 or lithium salts thereof, can be reacted with substituted or unsubsti-tutcd 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 astrong 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 qua~ernaries respectively, depending on the molar amount of the alkylating agent employed. Intermediates of formula I 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 R3 being lower alkenyl or lower alkynyl, may be hydrogenated with catalytically activated hydrogen to obtain compounds wherein R3 is the corresponding lower alkyl. Conversely, resulting N-alkylated compounds can be converted into ~-unsubstituted compounds, e.g. by reaction with lower alkyl haloformates, e.g. ethyl chloroformate, to yield N-acyl dcrivatives which, in turn, may be hydrolyzed to said unsubstituted compounds, those with R3aH, for example with aqueous bases, such as alkali metal hydroxides, such as aqueous sodium hydroxide solution.

Compounds of formula I wherein R3 i9 hydroxyalkyl can also be prepared by first reacting corresponding compounds of formula I, wherein R3 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 or example with hydrohalic or aromatic sulfonic acids, 1,2-dibromoethane or 1,2-dibro propane, ~, .;

.

et~yl bromoacetate or ethyl bromopropionate, ethyl tosyloxyaceta~e;
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 I wherein R3 is hydroxy-alkyl.

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

N-~cylated derivatives can be obtainet from compounds of formula I
with R3 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 Rl and/or R2 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 al~ali 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 a~monia, mono- or di-lower alkylamines, and resulting carboxyamides may be dehydrated to the corresponding nitriles according to conventional methods.

Resulting tertiary nitrogen compounds with R3 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 or perbenzoic acids, e.g. peracetic or m-chloro-perbenzoic acid, advan-tageously at temperatures at or below room temperature with the latter,or up to 100 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 herein R3 is acyl, such as al~oxycarbonyl 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 (S0) or sulfones (S~2) depending on the quantity of peracid used. Resulting compounds with R3 being phenylalkoxy carbonyl or alkoxycarbonyl so obtained can be converted to other compounds of formula I according to methods ~nown per se and previously described above.

~inally, 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 prepara-tion, 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 -...

.

4-hydroxybenzoic, salicylic, 4-aminosalicylic, pamoic, nicotinic, methanesulfonic, ethanesulfonic, hydroxyethanesulfonic, benzenesul~on-ic, toluenesulfonic, naphthalenesulfonic, 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 saltq, 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 separa-tion of diastereomeric salts thereof, e.g. by the fractional crystalli-zation of d- or l-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 inter~ediate 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, in which the starting materials are formed under the reaction con-ditions, 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 admi~ture with excipients suitable for either enteral or parenteral application. Preferred are tablets and gelatin capsules comprising the active ingredient to-gether 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, enzymes of the binders or effervescent mixtures and~or adsorbents, colorants, fl~vors and weeteners, Injectable compositions sre preferably aqueous isotonic solutions or suspensions, and suppositories are atvantageously fatty emul~ions or suspensions. Said compositions may be sterilizet 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 b, preferably about l to 50 ~ of the active ingredient. Unit dosages for mammals of about 50-70 kg weight may contain between about 5-100 mg of the active ingretient.

1 1~3630 The following examples illustrating the invention are not to be con-strued 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 ~mHg.

.

Example 1: To the mixture of 501 g of l-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 ~he temperature reaches 131.
Thereupon another S01 g of l-methylpiperazine are added, followed by 618.5 g of 5-methylthio-imidazo[2,1-b][1,3,5]benzothiadiazepine. The mixeure is stirred under nitrogen at 132-140 for 48 hours and evap-orated at about 80-90. The residue is dissolved in 3,000 ml of meth-ylene chloride, the solution washed 3 times with 1,000 ml of 3 N
aqueous sotium 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.~ 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 con-centrate allowed to stand in the refrigerator for 2 days. The white precipitate is filtered off, washed 3 times with cold isopropanol and dried at 40q/5 mmHg, to yield the 5-(4-methylpiperazino)-imidazo~2,1-b][1,3,5]benzothiadiazepine of the formula /-~/S\
Y, ~!, ,~
N=C ~ --\._. ~ 3melting at 145-147.

~, ,:,;

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/O.S 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 nitro-gen, 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 60~5 mm~g, 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 potassiu~ 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 mix~ure of 2,210 8 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 nitro-gen. 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.

:
. :
. . . -~ -The mixture is refluxed for 2 hours longer and 400 ml of 6 N aqueous sodium hydroxide are added. The resuleing suspension is diluted with 2,000 ml of methanol, filtered and the residue is washed 3 times with 1,000 ml of methanol. The combined filtrates are diluted with 40,000 ml 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 6,375 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 11,000 ml of 1.3 N hydrochloric acid. The suspen~ion 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[2,1-b][1,3J5]benzothia-diazepin-5t6H)-thione melting at 156-159.

1,184 g thereof are added to the solution of 278 g of sodium me-thoxide in 22,500mlof i~opropanol 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 20Q. It i8 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[2,1-b][1,3,5]benzothiadiazepine melting at 116-118Q.
:

~ - 19 -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[2,1-b][1,3,5]benzothiadiazepine, melting at 147-149;
c~ 8-fluoro-5-methylthio-imidszo[2,1-b][1,3,5]benzothiadiazepine, melting at 174-176~;
d. 8-methyl-5-methylthio-imidazo[2,1-b][1,3,5]benzothiadiazepine.

Example 2: To the solution of 480 mg of 5-thiocyanatffimidazo[2,1-b]
[1,3,5]benzothiadiazepine in 1 ml of hexamethylphosphoramide, 500 mg of l-methylpiperazine are added during 5 minutes while stirring under nitrogen at -5. Stirring is continued for 5 minutes at said temper-ature. The mixture i8 diluted with 80 ml of ethyl acetate, washed twice with saturated aqueous sodium chloride, dried and evaporated.
The residue is dissolvet 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]benzothiadiazepine 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 ~romide 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 ~mall volume, washed with diethyl ' . ' , . . ....... .

1 163~30 ether and filtered, to yield the 5-thiocyanato-imidazo~2,1-b~[1,3,5]ben_ zothiadiazepine melting at 111-113.

Example 3: The mixture of 333 mg of 1-[2-(imidazo-2-ylthio)-phenyl-iminothiocarbonyl]-4-methylpiperazine, 3.3 ml of dimethylformamide, 276 m8 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 tiluted 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)-imid-azo[2,1-b][1,3,5]benzothiadiazepine monomaleate, melting at 198-199 with decomposition; it is identical with that of Exa~ple 1.

The starting material is prepared as follows:
The mixture of 2.3 g of imidazo~2,1-b]l1,3,5]benzothiadiazepin-5(6H)-thione, 23 ml of methylene chloride and 1.0 g of l-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)-phenyliminothiocarbonyl]-4-methylpiperazine melting at 209-212.

E~ample 4: To the su~pension of 3.1 g of 1-[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 evap-orated, the residue suspendet 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 mix-ture 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)-imidazol2,1-b][1,3,5]benzothiadiazepine mono-maleate, melting at 198-199 with decomposition; it is identical with that of Example 1.

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]11,3,5]benzothiadiazepin-5(6H)-one, m.p.
261-263;
c. 8-trifluoromethylimidazo[2,1-b3[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][1,3,5]benzothiadiazepin-5(6H)-one, 1.0 g of l-methylpiperazine and 20 ml of methylene chloride is stirred at room temperature for 24 hours. The crystalline product fonmed i8 filtered off and washed with methylene chloride, to yield the l-12-(imidazo-2-ylthio)-phenyliminocarbonyl]-4-methylpiperazine, melting at 197-200.

In similar manner the following additional starting materials are obtained and are illu~trative of the process:

a. l-[2-(4-methylimidazo-2-ylthio)-phenyliminocarbonyl]-4-methyl-piperazine,melting at 101-105 (decomposition);
b. l-[2-(imidazo-2-ylthio)-phenyliminocarbonyl~-4-methylhomopiper-azine, melting at 134-138;
c. l-[2-(imidazo-2-ylthio)-phenyliminocarbonyll-4-carboethoxypiper-azine, melting at 161-170;
d. l-[2-(imidazo-2-ylthio)-phenyliminocarbonyl]-4-carbobenzoxypiper-azine, mel~ing at 206-208;
e. l-12-~4-carboethoxyimidazo-2-ylthio)-phenyliminocarbonyl]-4-methylpiperazine, melting at 166-169;
f. 1-[2-(imidazo-2-ylthio)-4-trifluoromethylphenyliminocarbonyl]-4-methylpiperazine,melting at 212-214.

Example 5: A mixture of 10 g of 5-methylthio-imidazo[2,1-bJ[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, washet 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-~-hydroxyethylpiperazine~
and 175 ml of amyl alcohol is refluxed under nitrogen for 48 hours with stirring. ~he 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-~-hydroxyethyl-piperazino~-imidazo[2,1-~][1,3,5]benzothiadiazepine dihydrochloride, meltin~ at 210-212.

`` 1~63630 Example 7: By repla_ement of the N-~-hydroxyethylpiperazine in example

6 by an equivalent amount of N-methylhomopiperazine one obtains 5-(4-methylhomopiperazino)-imidazo[2,1-b][1,3,5]benzothiadiazepine, 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 materisls;
Ph~4-R5-l~2-phenylene; CmH2m-(CH2)2; n 2n 2 n _ ....
N~ _ Rl R2 3 n' ¦ R Saltm-p. C

1 H H _ _ _ 2 H 2HCl249 dec.*
2 H H CH3 2 H 2HCl 216-219 3 H H CH3 2OCH32HCl 155 dec.
4 H H CH3 2 F maleate202-204 H H CH3 2Cl 2HCl 203-206 6 H H CH3 2CF3 2HCl 180 dec.

8 H H (CH2)20H 2 H 2HCl 210-212 9 H H COOEt 2 H 137-139 H H CH3 3 Hfumarate216-218 11 H H 2 6 5 2 H __ NMR:5.2,3.5 12 CH3 H CH3 2 H maleate191-192.5 *(dec. = decomposition).

.. . .

Example 9: To the solution of 0~2 g of 5-(4-carboethoxypipera2ino)-imidazo~2,1-b][1,3,5]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][1,3,5]benzo-thiadiazepine, melting at 145-147. It is identical with the compound obtained in Example 1.

Example 10: To the solution of 98 mg of 5-(4-methylpiperazino)-imidazo[2,1-b][1,3,5]benzothiadiazepine in 1 ml of methylena chloride, 74 mg of m-chloroperbenzoic acid are added at 0. The mixture is stir-red at 0 overnight; this is diluted with 1 ml of ether, one equivalent of etheral hydrochloric acid solution is added and the resulting pre-cipitate 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][1,3,5]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 tried over magnesium sulfate and evaporated to dryness to give 5-(4-carbo-benzoxypiperazino)-imidazo[2,1-b][1,3,5]benzothiadiazepine l-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 l,l-dioxide is obtained. Mass spectrum:
m/e 451, 420, 406, 386.

1 163~30 Example 12: a) To the solution of 100 mg of 5-(4-carbobenzoxypiper-zzino)-imidazo[2,1-b][1,3,5]benzothiadiazepine l-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[2,1-b][1,3,5]benzothiadiazepine l-oxide hydrobromide is fil-tered and washed with ether; m.p. 75 with decomposition.

b) In a similar manner the 5-(4-carbobenzoxypiperazino)-imidazo[2,1-b]~l,3,~]benzothiadia~epine l,l-dioxide is converted to S-(piperazino)-imidazo[2,1-b][1,3,5]benzothiadiazepine l,l-dioxide hydrobromide.
Rf 3 0.353 (silica gel, ethyl acetate-methylene chloride, 1:1).

Example 13: A mixture of 285 mg of 5-(4H-piperazino)-imidazo~2,1-b]
[1,3,5]benzothiadiazepine, 0.5 g of potassium carbonate, 0.142 g of methyl iodide and 2 ml of acetone is stirred at room temperature over-night 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 Exa~ple 1.

Example 14: Preparation of 10,000 tabiets each containing 5 mg of the active ingredient:
Formula:
5-(4-methylpiperazino)-imidazo[2,1-b][1,3,5]benzo-thiadiazepine maleate 50 g Lactose 1,157 g Corn starch 75 g Polyethylene glycol 6,000 75 g Talcum powder 75 g Magnesium stearate 18 g Purified water q.s.

1 16363~

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 hal~ 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 neces-sary, with an additional amount of water. The granulate is dried over-night at 35, b oken on a screen with 1.2 mm openings and compressed into tablets using concave punches with 6.4 mm diameter, uppers bisected.

Exa~ple 15: Preparation of 10,000 capsules each containing 10 mg of the active ingredient:
~ormula:
5-[4-(2-hydroxyethyl~-piperazino]-imidazo[2,1-b]
[1,3,5]benzothiadiazepine dihydrochloride 100 g Lactose 1,800 g Talcum powder 100 g Procedure:
A11 the powdars are passed through a screen with openings of 0.6 mm.
Then the drug substance i8 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.

.' '

Claims (9)

Claims

1. Process for the manufacture of 5-diazacycloalkyl-imidazo[2,1-b]-[1,3,5]benzothiadiazepines of the general formula I

(I) wherein each of R1 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, trifluoromethyl, sulfamoyl, mono- or di-lower alkyl-sulfamoyl; each of CmH2m and CnH2n is lower alkylene separating both nitrogen atoms by 2 or 3 carbon atoms, and R3 is hydrogen, lower alkyl, lower alkanoyl, lower alkoxycarbonyl, phenyl-lower alkoxy-carbonyl or hydroxy-lower alkyl, wherein the hydroxy group is se-parated from the nitrogen atom by at least 2 carbon atoms; their N- and/or S-oxides, pharmaceutically acceptable lower alkylquaternary derivatives thereof and salts of all these compounds, which con-sists in 1) condensing a compound of the.general Formula III or a salt thereof with a compound of the general formula IV

(III) (IV) wherein X is halogeno, lower alkoxy, lower alkylthio, cyanato or thio-cyanato; Y is hydrogen or an alkali metal; p is an inteoer from 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 condi-tions, and, a) if a compound of the formula I is required in which R3 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 lower alkynyl group instead of a lower alkyl group, and, c) if a compound is requiret in which R3 is hydroxy-lower alkyl, reacting a compound in which R3 is hydrogen or an alkali metal atom with a corresponding oxirane or with a reactive ester of a mono-esterified lower alkanediol, and d) if a compound is required in which R3 is hydroxy-lower alkyl, reacting a compound in which R3 is hydrogen with a reactive deriva-tive 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 R3 is lower alkyl into the above named group, and, f) if a compound is required in which R3 is an aryl radical named above, acylating a product in which R3 is hydrogen, and, b) if a compound is required in which R3 represents hydrogen, hydro-lyzing 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 R1 and/or R2 is halogen, halo-genating a product in which R1 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 com-pound 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 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 R1 and/
or R2 is hydrogen with a halosulfonic acid and treating the compound obtained with ammonia, a mono- or di-lower alkylamine, and, l) if a compound is required in which R1 and /or R2 is cyano, de-hydrating a product in which R1 and/or R2 is carbamoyl, and, m) if a compound is required in which R1 and/or R2 is carboxy, hydro-lyzing a product in which R1 and/or R2 is cyano, lower alkoxycarbonyl or carbamoyl, 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-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 R3 is different from hydrogen or represents hydrogen, with a reactive esterified lower alkanol, and, r) if required, converting a resulting free compound into a pharma-ceutically acceptable salt or a resulting salt into the free compound or into another pharmaceutically acceptable salt, and is 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.

2. Process according to claim 1 for the manufacture of compounds of Formula I shown in claim 1, wherein each or R1 and R2 is hydrogen, lower alkyl, lower alkanoyl, halogeno, cyano, carboxy, lower car-balkoxy, carbamoyl, sufamoyl, mono- or di-lower alkyl-(carbamoyl or sulfamoyl); Ph is 1,2-phenylene, (lower alkyl)-1,2-phenylene, (lower alkoxy)-1,2-phenylene, (lower alkylthio)-1,2-phenylene, (halogeno)-1,2-phenylene, (trifluoromethyl)-1,2-phenylene, (sulfamoyl)-1,2-phenylene, (mono- or di-lower alkylsulfamoyl)-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; pharmaceutically acceptable lower alkylquaternary derivatives thereof and salts of all these compounds, which consist in 1) condensing a compound of the formula III shown in claim 1 or a salt thereof with a compound of the formula IV shown in claim 1, in which formulae X, Y and p have the meanings given in claim 1, and the other symbols have the above given meanings, or 2) ring-closing of a compound of the formula V shown in claim 1, in which formula Z and p have the meanings given in claim 1, and the other symbols have the above given meanings, and if required, carrying out the reactions named under a) to r) in claim 1.

3. Process according to claim 1 for the manufacture of compounds of Formula II

(II) wherein each of R1 and R2 is hydrogen or lower alkyl; R4 is hydrogen, lower alkyl or 2- or 3-hydroxy-lower alkyl, R5 is hydrogen, lower alkyl, lower alkoxy, halogeno or trifluoromethyl; and p is an integer from 0 to 2; the N-oxide thereof; or pharmaceutically acceptable salts of all these compounds, which consists in 1) condensing a compound of the formula IIIa or a salt thereof with a compound of formula IVa (IIIa) (IVa) in which formulae X and Y have the meanings given in claim 1, and the other symbols have the above given meanings, or 2) ring-closing of a compound of the formula Va (Va) in which formula Z has the meaning given in claim 1, and the other symbols have the above given meanings, and, o) if only an N-acide is required, converting a product in which R4 is different from hydrogen into its N-oxide by specific oxidation, and r) if required, converting a resulting free compound into a pharma-ceutically acceptable salt or a resulting salt into the free compound or into another pharmaceutically acceptable salt.

4. Process according to claim 1 for the manufacture of compounds of the Formula II shown in claim 3, wherein each of R1 and R2 is hydro-gen or methyl; R4 is alkyl or 2- or 3-hydroxyalkyl, in which alkyl has at most 4 carbon atoms; R5 is hydrogen, methyl, methoxy, fluoro, chloro or trifluoromethyl; and p is 0; the N-oxide thereof; or pharma-ceutically acceptable salts of all these compounds, which consists in 1) condensing a compound of the formula IIIa shown in claim 3 or a salt thereof with a compound of formula IVa shown in claim 3, in which formulae X and Y have the meanings given in claim 1, and the other symbols have the above given meanings, or 2) ring-closing of a compound of the formula Va, in which formula Z has to be the meaning given in claim 1, and the other symbols have the above given meanings, and, o) if only an N-oxide is required, converting a product in which R4 is different from hydrogen into its N-oxide by specific oxidation, and r) if required, converting a resulting free compound into a pharma-ceutically acceptable salt or a resulting salt into the free compound or into another pharmaceutically acceptable salt.

5. Process according to claim 1 for the manufacture of 5-(4-methyl-piperazino)-imidazol[2,1-b][1,3,5]benzothidiazepine or pharmaceuti-cally acceptable salt thereof which consists in 1) condensing a compound of the formula IIIb or a salt thereof with a compound of formula IVb (IIIb) (IVb) in which X and Y have the meanings given in claim 1, or 2) ring-closing of a compound of the formula Vb (Vb) in which formula Z has the meaning given in claim 1, and, if required, converting a resulting free compound into a pharmaceutically acceptable salt or a resulting salt into the free compound or into another pharmaceutically acceptable salt.

6. Process according to claim 1 for the manufacture of 5-(4-methyl-piperazino)-imidazo[2,1-b][1,3,5]benzothiadiazepine or a pharma-ceutically acceptable salt thereof, which consists in 1) condensing 5-methylthio-imidazol[2,1-b][1,3,5]benzothiadiazepine with 1-methylpiperazine, or 2) ring-closing 1-[2-(imidazo-2-ylthio)-phenyliminocarbonyl]-4-methyl-piperazine, and, if required, converting a resulting free compound into a pharmaceutically acceptable salt or a resulting salt into the free compound or into another pharmaceutically acceptable salt.

7. Process according to claim 1 for the manufacture of 5-(4-methyl-piperazino)-imidazo[2,1-b][1,3,5]benzothiadiazepine or a pharma-ceutically acceptable salt thereof, which consists in reducing in the 5-(4-carboethoxypiperazino)-imidazo[2,1-b][1,3,5]benzothiadiazepine the carboethoxy group with lithium aluminium hydride to the methyl group, and, if required, converting a resulting free compound into a pharmaceutically acceptable salt or a resulting salt into the free compound or into another pharmaceutically acceptable salt.

8. Process according to claim 1 for the manufacture of 5-(4-methyl-piperazino)-imidazo[2,1-b][1,3,5]benzothiadiazepine or a pharma-ceutically acceptable salt thereof, which consists in methylating 5-(4H-piperazino)-imidazo[2,1-b][1,3,5]benzothiadiazepine with methyl iodide, and if required, converting a resulting free compound into a pharmaceutically acceptable salt or a resulting salt into the free compound or into another pharmaceutically acceptable salt.

9. A compound of the general Formula I shown in claim 1, in which formula all the symbols have the meanings given in claim 1; their N- and/or S-oxides, pharmaceutically acceptable lower alkyl quater-nary derivatives thereof and salts of all these compounds, whenever prepared or produced by the process of manufacture claimed in claim 1 or by any process which is an obvious chemical equivalent thereof.