IE52043B1 - Imidazobenzothiadiazepines process for their manufacture pharmaceutical preparations containing these compounds and their therapeutic application - 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

The present invention relates to 5-diazacycloalkyl-imidaao [2,1-b][l,3,5]benzothiadiazepines of the general formula I wherein each of R^ and Rj i® hydrogen, lower.alkyl, lower alkanoyl, halogeno, cyano;, carboxy, lower caxbalkoxy, carbamoyl, sulfamoyl, mono- or di-lower elkyl-(cerbamoyl or aulfaaoyl); Rh is 1,2phenylene, unsubstituted or substituted by up to two identical'or different members selected from lower alkyl, lower alkoxy, lower alkylthio, halogeno, trifluoromethyi, sulfamoyl, mono- or di-lower elkylsulfaaoyl; each of end is lower alkylene separating both nitrogen atoms by 2 or 3 carbon atoms, and Rj is hydrogen, lower alkyl, lower elkenoyl, lower alkoxycarbonyl, phenyl-lower alkoxycarbonyl or hydroxy-lower alkyl, wherein the hydroxy group is separated from the nitrogen etom by et least 2 carbon atoms; their 15 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 Lheir manufacture, snd pharmaceutical preparations containing these compounds .

A lower alkyl group Rp Rp Rj and/or such present in e substituted 1,2-phenylene Ph-group, as well as in said alkoxy, alkylthio or said other alkylated groups, is above all nethyl, but also ethyl, n- or i-(propyl, butyl, pentyl, hexyl or heptyl), e.g. 2-methylpropyl or 3-methy lbutyl; and lower alkanoyl is preferably acetyl or propionyl.

A halogen atom R^ and/or Rj, or such present in Ph, is preferably fluoro or chloro, but also bromo.

A lower carbalkoxy, mono- or di-lower alkylcarbaaoyl or mono- or di-lower alkylsulfaaoyl group R^ and/or Rp or present in a 1,2phenylene group Pb, is preferably carbomethoxy, carbethoxy; monoor diaethylcarbamoyl or mono- or dimethylsulfsaoyl respectively.

A 1,2-phenylene radical Ph is preferably unsubstituted, or monosubstituted by said substituents, for example methyl or ethyl; aethoxy, ethoxy or i-propoxy; methylthio or ethylthio; fluoro, chloro or bromo; trifluoromethyl; sulfamoyl, mono- or dimethylsulfamoyl.

A lower alkylene group Cn^2n ** 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 homopiperazino moiety.

A lower alkoxycarbonyl or hydroxy-lower alkyl group R^ is preferably methoxycarbonyl or ethoxycarbonyl; 2-hydroxy-(etbyl or propyl), 3-hydroxy-(propyl or butyl) or 4-hydroxybutyl respectively. A phenyl-lower alkoxyearbonyl group is for example phenylmethoxycarbonyl or pbenylethoxyearbonyl.

Said N-oxides are preferably those in which R^ is lower alkyl or hydroxyalkyl, end in which the oxygen is attached to the nitrogen carrying said Rj group. Said S-oxides represent sulfoxides (SO) or sulfones (SO^)· Similarly, said lower alkyl quaternary derivatives of the compounds of formula I are preferably derived from those wherein R^ is lower alkyl or hydroxyalkyl, and wherein only the terminal piperazino or homopiparazino-nitrogen atom it quaternized. The anions of said quaternary derivatives, as well as those of said acid addition salts, are preferably those of pharmaceutically acceptable acids, e.g. those listed below. Those compounds of formula I with R^ and/or Rj being Τθ carboxy, also form salts with bases, preferably those of pharmaceutically acceptable bases, a.g. asnonia, mono-, di- or tri-lower alkylamines; lower alkylenaasdnas; 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 2o properties, primarily neuroleptic activity. It is demonstrable in mima, tests using advantageously mammals, e.g. mice, rats or monkeys, as test objects. Said compounds can be administered to them enterally or parenterally, advantageously orally, or subcutaneously, intravenously or intraperitoneally, for example, within gelatin capsules, or in the form of starchy suspensions or aqueous solutions respectively. The applied dosage may range between 0.01 and 100 mg/ kg/day, preferably between 0.05 and. 10 mg/kg/day, advantageously between 0.1 and 5 mg/kg/day.

Said neuroleptic properties can be demonstrated in adult rats or 58043 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 aniaal fails to press the lever once within said period, brief ¢0.5 aac.) shocks are delivered at 15 second intervals until the aniaal again presses the lever. Under control conditions the aniaals press the lever at a moderately steady rate and seldom receive acre than five or six shocks during a 25ainute (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 tha learned conditioned avoidance behavior, manifested hy a decrease in avoidance responding and a marked increase in shocks taken hy the aniaals. Both, the avoidance responses and failures (shocks received), art recorded separately for evaluation according to thia Sidman Avoidance test. The compounds of the invention, for exanple the 5-(4-machylpiperazino)-imidazo[2,1-b][l,3,5]benzothiadiaeepin· or ite pharmaceutically acceptable salts, dscraasa tha avoidance responding in rata and monkeys at an overall dost of 10 mg/kg or lover.

The cxtrapyramidal side-effects (EPS) known from classical neuroleptics, have bean found to induce a characteristic motor syndrome in squirrel monkeys, which ware previously exposed to repeated antipsychotic treatment. These movement disorders consist of dystonic postures and dyakinetic movements, and correlate much batter with the reported incidence of EPS in man, than docs catalepsy or tremor in this monkey. Thus, the potential cxtrapyramidal liability, aa wall as the relative incidence of ocher neurological signs, such as ptosis, can be assessed by observation of these adult mala 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 dyskinetie movements are evident during 1-6 hours after administration of haloperiodol.

At no other time abnormal movements are evident in these monkeys.

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 et intervals of 2, 4 and 6 hours after treatment and tha experiments ere 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 observations through the video system, the observers enter the cubicle, recording Che monkeys* responses as motor (ambulation inside cage), visual (visual response but no ambulation) and none (no response). Activity, posture, tremors, salivation and other neurological signs are obeerved. Particular attention is devoted to the presence or absence of bizarre, dyttonic postures and dyakinetic movements, as previoualy characterized. The handler then removes the monkey from che cage and Che monkey's reactions are separately scored to the approach of the gloved hand, to che initial touch during capture and co restraint after capture. Vocalization during capture is also rseorded. The handler than 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 racing, which differs from control, is only considered an agent-induced effect, if both observies recorded it during any of the three observation periods. When one observer considered a given sign co be of lesser magnitude than did tha other observer, the less severe score is accepted. However, overall intar-observer correspondence is good.

For example, aftar administration of 10 mg/kg of tha compound of Example 1, only one of five monkeys shoved 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, ia recognized in ell 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, end no dyskinesias were observed at any time after vehicle (excipient) treatment. However, clozapine produced hypersalivation in every monkey which vas 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, end other classical tests, the compounds of tbe invention are useful neuroleptic (antipsychotic) agents, for example, in the treatment or management oi aggression, agitation or anxiety, and ere virtually devoid of extrepyramidel side-effects, es has clozapine in man. Moreover the absence of hypersalivation represents a further advantage of said new compounds over clozapine. They ere also useful intermediates in the preparation of other valuable products, especially of pharmacologically active compositions.

Particularly useful are compounds of Formula I, in which each of and is hydrogen, lower alkyl, lower alkanoyl, halogeno, cyano, carboxy, lover carbalkoxy, carbamoyl, sulfamoyl, mono- or di-lower alkyl-(carbamoyl or sulfamoyl); Ph is 1,2-phenylene, (lower alkyl)52043 1,2-phenylene, (lover alkoxy)-l,2-phenylene, (lower alkylthio)-1,2phenylene, (halogeno)-l,2-phenylene, (trifluoromethyl)-l,2-phenylene, (sulfamoy1)-1,2-phenylene,(mono- or di-lover alkyIsulfamoyl)-1,2phenylene; each of b and s is the integer 2 or 3; and R^ is hydrogen, lover alkyl, lower alkanoyl, lover alkoxyearbonyl, phenyl-lover alkoxyearbonyl 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 alkylquatemary derivatives thereof, and salts of all these compounds, especially pharmaceutically acceptable salts thereof.

Outstanding coapounds of the invention are those of the general formula II wherein each of R^ and R^ is hydrogen or lower alkyl; R^ is hydrogen, 15 lower alkyl or 2- or 3-hydroxy-lower alkyl, Rj is hydrogen, lover alkyl, lower alkoxy, halogeno or trifluoromethyl; and p is an integer from 0 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 2q each of R1 and R^ is hydrogen or methyl; R^ is alkyl or 2- or 3hydroxyalkyl, in which alkyl has at most 4 carbon atoms; R$ is hydrogen, methyl, methoxy, fluoro, chloro or trifluoromethyl; and p is 0; the N-oxide thereof; or salts, especially pharmaceutically acceptable acid addition salts of all these compounds.

Ihe compounds of the invention are prepared according to methods known per »e, advantageously 1) by condensing a compound of the general Formula III or a salt thereof with a compound of the general formula IV (IV) wherein X is halogeno, lower alkoxy, lower alkylthio, cyanato or thiocyanate} T is hydrogen or an alkali metal; p is an integer from 0 to 2, and the remaining symbols have the meaning given for formula I and, if desired, converting any resulting compound into another compound of formula 1.

Said condensation is advantageously carried out with an excess of the piperazine IV (Τ·Β), or wich equivalent amounts of said metal derivatives thereof, preferably when X is halogeno, lover alkylthio or chiocyanato, advantageously at temperatures between about 0* and 150*, and preferably in an appropriate solvent such as a lover alkanol, for example amyl alcohol, or dimethylformamide, hexamethylphosphor15 amide or toluene.

Another process for preparing the compounds of the general formula 1 consists in 2) ring-elosing of a compound of the general formula V TO wherein Z is oxygen, sulfur or NH, and the other symbols have the above-given meaning, under dehydrating or dehydrosulfurating conditions, and, if desired, converting any resulting compound into another compound of the invention.

Said ring-closing is carried out with strong dehydrating or dehydrosulfurating agents, such as 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 triethyl10 amine 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 novel starting imidaM[2,l-b][l,3,5]benzothiadiazepiiies of formula III are prepared according to ring closure methods known per se, advantageously by condensing compounds of formula VI (VI) wherein Ph, R^ and R^ have meaning given for compounds of formula III, with reactive carbonic acid derivatives such as phosgene, thio- phosgene, 1,1'-carbonyldiimidazole or cyanogen bromide.

Compounds of formula XII wherein X is hydroxy can in turn bs converted to compounds vherein X ie sulfhydryl by conventional sulfurating agents, such as phosphorus pentasulfide, and thaaa can ba further derivatized to compounds of formula III wherein X is as defined above, analogous to the procedures illustrated by the examples herein.

The storting materials of formula V can be obtained from that of the (tautomeric) precursors of formula III, vherein 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 0* and 150’ advantageously between 10* and 50*. The ring opening reaction is preferably carried out at low temperature to minimize side reactions when R^ and represent reactive functional groups.

Alternately, starting materials of formula V, wherein R^ is lever alkanoyl, lower alkoxycarbonyl or phenyl-lower alkoxy carbonyl, are prepared by condensing a coapound of foraula VI with a compound of formula VII wherein Τ' represents haloccrbonyl, halothiocarbonyl or cyano, and R^ represents lower alkanoyl, lower alkoxyearbonyl or phenyl-lower allcoxycarbonyl, preferably ic an inert solvent, at temperatures between 0* and 150*C.

The compounds of tbe invention to obtained can be converted into other compounds of formula I according to known methods. Thus, for example, those with Rj being hydrogen or alkali metal, e.g., sodium or lithium salts thereof, can he reacted with substituted or unsubscituted 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 hydriodic acid; sulfuric or an aromatic sulfonic acid, e.g. p-toluene or m-bromobenzene sulfonic acid, in order to obtain the corresponding N-substituted compounds or quaternaries respectively, depending on the molar amount of the alkylating agent employed. Intermediates of formula I wherein Rj alkali metal are obtained hy metallation with reactive organo metallic agenta such as lithium diisopropylamide, with alkali metal alkoxides such as sodium methoxide, or alkali metal hydrides such as sodium or potassium hydride.

Unsaturated compounds, such as those with R^ being lower alkenyl or lower alkynyl, are hydrogenated, eg with catalytically activated hydrogen to obtain compounds wherein R^ is the corresponding lower alkyl; Conversely, resulting N-alkylated compounds can he converted into N-unsubstituted compounds, e.g. by reaction with lower alkyl 2o haloformates, e.g. ethyl chlorofozmate, to yield N-acyl derivatives which, in turn, may be hydrolyzed Co said unsubstituted compounds, those with R^H, for example with aqueous bases, such as alkali metal hydroxides, such as aqueous sodium hydroxide solution.

Compounds of formula I wherein R3 is hydroxyalkyl can also be prepared by first reacting corresponding compounds of formula I, wherein R^ represents hydrogen, with reactive derivatives of corresponding glycols, glycolic acids or dicarboxylic acids, such as lower alkyl esters, halides or anhydrides thereof, or reactive esters of said glycols or glycolic acids derivatives for exanple with hydrohalic or aromatic sulfonic acids, 1,2-dibromoethane or 1,2-dibromopropane, 58043 ethyl broooacetate or ethyl bromopropionate, ethyl tosyloxyacetata; diethyl oxalate, diethyl malonate or ethyl oxalyl chloride. The intermediate* to obtained are either hydrolyzed or reduced vith simple or complex light metal hydride* such a* lithium aluminium hydride, alone or vith diborane to compound of formula I wherein R^ ia hydroxyalkyl.

Compounds of formula I wherein R^ is methyl can he prepared hy reacting cbt corresponding compound* of formul* I wherein R^ represents hydrogen,with lower alkyl- or phenyl lower alkyl- haloformate*, such as ethyl ehloroformate, to obtain compound* of formula I wherein R^ is lower alkoxycarb onyl or phenyl-lower alkoxycarbonyl, and reducing said acyl derivatives with simple or complex light matal hydrides such a* lithium aluminium hydride, aodiian tri-t-butoxy or bi*-(2methoxyethoxy) aluminium hydride.

N-Acylated derivative* can he obtained from compound* of formula 1 with Sj-being hydrogen, end 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 vith R^ and/or R^ being hydrogen, can b* converted to the corresponding 3- and/or 4-(halo- or acyl)-derivatives, e.g. by halogenation, preferably with chlorine in acetic acid or under FriadalCrafta-conditiona, end/or by acylation with a trihaloacttyl halid* or a haloaulfonic acid, followed by treatment vith an alkali matal lower alkoxide, hydroxide or amide. Resulting carboxylic or aulfonic acid derivatives may be hydrolyzed in known fashion, preferably under alkaline condition* and/or amidized with aznonia, mono- or di-lower alkylamines, and resulting carboxyamides may be dehydrated to the corresponding nitriles according to conventional methods.

Resulting tertiary nitrogen compounds with Rj different from hydrogen, can be converted into the N- end/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, advantageously 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-oxidetion at overly long reaction times.

If only S-oxides are desired, compounds wherein R^ is acyl, such es alkoxycarbonyl or phenylalkoxycarbonyl, are treated with hydrogen peroxide or organic peracids, preferably m-ehloro-perbenzoic acid advantageously at temperatures at or below room temperature to obtain either sulfoxides (SO) or sulfones (SOj) depending on the quantity of peracid used. Resulting compounds with Rj being phenylalkoxy carbonyl or alkoxycarbonyl so obtained can be -converted to other compounds of P5 formula I according to methods known per se and previously described above.

Finally, the compounds of the invention are either obtained in the free basic form, or as a salt thereof. Any resulting base can be converted into a corresponding acid addition salt, preferably with 2o 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 e 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, hydroxymaleic, pyruvie, phenylacetic, benzoic, 4-aminobenzoic, anthranilic, 53043 4-hydroxybenzoic, salicylic, 4-aminosalicylic, pamoic, nicotinic, methanesulfonic, ethanesulfonic, hydroxyethanesulfonic, bensenesulfonic, toluenesulfonic, naphthalenesulfonic, sulfanilic or cyclohexylsulfamic acid; or ascorbic acid. These or other salts, for example, the picrates, can alao be used for purification of the bases obtained; the bases ere converted into salts, the salts ere separated and the bases ere 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 csss mixtures of geometrical or optical isomers of the above compounds, e.g. I to VII ere obtained, these can be separated into the single isomers by methods in themselves known, e.g. hy fractional distillation, crystallization and/or chromatography. Racemic products can likewise be resolved into the antipodes, for example, by separation of diastereomeric salts thereof, e.g. by the fractional crystallization of d- or 1-tertretes.

The above-mentioned reactions are carried out according to standard methods, in the presence of absence of diluents, preferably such as are inert to the reagents and are solvents thereof, of cetalysta, condensing or said other agents respectively and/or inert atmospheres, at low temperatures, room temperature or elevated temperatures, preferably et the boiling point of the solvents used, at atmospheric or superatmospheric pressure.

The invention further includes any variant of the present process 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.

Ihe 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, eucrosa, mannitol, sorbitol, cellulose, and/or glycine, and lubricants, e.g. silica, talcum, stearic acid, its magnesium or calcium salt and/or polyethyleneglycol; for tablets also binders, e.g. magnesium aluminium silicate, starch paste, gelatin^ tragacanth,· methylcellulose, sodium carboxymethylcellulose and/or poylvinylpyrrolidona, 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 I, preferably about 1 to 50 Z of the active ingredient. Unit dosages for mammal» of about 50-70 kg weight may contain between about 5-100 mg of the 3q 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 between about 15 and 100 saBg.

Example 1: To the mixture of 501 g of 1-methyIpiperazine and 6,000 el of amyl alcohol, 538 ml of 9.3 N methanolic hydrogen ehloride are added and the mixture ia stirred and distilled for 1 hour, during which time 1,000 ml of distillate is collected and the temperature reaches 131*. Thereupon another 501 g of 1-methyIpiperazine are added, followed hy 618.5 g of 5-aethylthio-iaidazo[2,l-b](l,3,5]benzothiadiazepine. The mixture ia stirred under nitrogen at 132-140* for 48 hours and evaporated ae ahout 80-90*. The residua is dissolved in 3,000 ml of methylene chloride, che solution washed 3 times with 1,000 ml of 3 N aqueous sodium hydroxide and 5 times with 1,000 ml of water. It is finally extracted 4 times with 750 ml of 2 H hydrochloric acid tach, the combined extracts era vaahad once with 1,000 ml of methylene chloride, decolorized with 75 g of charcoal, filtered and the filtrate is basified with 500 ml of 29.9Z aqueous sononia 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 ere dissolved in 14,000 ml of hot isopropanol, the solution created with 563 g of charcoal, filtered and tha 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. Tha resulting clear solution is concentrated to 8,500 ml and the concentrate allowed to stand in Cha refrigerator for 2 days. The white precipitate is'filtered off, washed 3 times with cold isopropanol and dried et 40*/5 oaBg, to yield the 5-(4«m melting et 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 vith 1,000 ml more anhydrous ethanol and the combined filtrates are acidified vith the solution of 688 g of maleic acid in 1,600 ml of anhydrous ethanol while 5 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.5 mn Hg, to yield the corresponding monomaleate melting at 198-199° with decomposition.

The starting material is prepared as follows: To 39,230 ml of 2 N hydrochloric acid, 7,500 g of aminoacetaldehyde dimethylacetal are added during 45 minutes while stirring under nitrogen, followed by 6,932 g of potassium thiocyanate, which are added ell at once. The mixture is heated to 98°, stirred for 2 hours and allowed to cool to room temperature overnight. The resulting suspension is ' stirred and cooled to 5*, filtered and the residue dried at 60°/5mmHg, to yield the im.dazole-2-thiol melting at 224-226*. 2,468 g thereof are added to the solution of 1,604 g of 86.9Z aqueous potassium hydroxide in 24,700 nd of isopropanol while stirring under nitrogen at room tenperature, followed by 4,986 of 2-bromo-nitroben2o zene. The mixture is stirred md 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 tenperature 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-nitrophenyl25 thio)-imidazole malting at 178-180*.

The mixture of 2,210 g thereof, 2,000 ml of water, 2,000 ml of ethanol and 1,700 g of iron powder is heated to 70* while stirring under nitrogen. After addition of 10 ml of concentrated hydrochloric acid the mixture is refluxed for 1.5 hours, whereupon 200 ml of concentrated 30 hydrochloric acid in 1,000 ml of ethanol are added during 95 minutes.

The mixture is refluxed for 2 hours longer end 400 ml of 6 N aqueous sodium hydroxide ere added. The resulting suspension is diluted with 2,000 ml of methanol, filtered and the residue is washed 3 times with I, 000 ml of methanol. The combined filtrates are diluted wich 40,000 ml of water, the resulting suspension allowed to settle overnight, the precipitate is collected, washed twice wich 2,000 ml of water and dried at 60*/5 anHg, to yield the 2-(o-aminophenylthio)-imidazole melting at 137-138*. 4,775 g thereof are added to the mixture of 55,000 ml of methylene chloride and 6,975 ml of triethylamine, the mixture cooled to 3* and 3,301 g of 85Z thiophosgene in carbon tetrachloride are added during 2.5 hours while stirring under nitrogen at 15*. Stirring is continued et 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 end once with 20,000 ml of water and suspended in II, 000 ml of 1.3 N hydrochloric acid. The suspension is stirred for 2 hours, filtered, the residue washed 3 times with 4,000 ml of water and dried et 60*/5 anHg, to yield the imidezo[2,l-b][l,3,5]benzothiadiazepin-5(6H)-tbione melting at 156-159*. 1,184 g thereof ere added to the solution of 278 g of sodium methoxide in 22,500ml of isopropanol and the mixture is stirred for 1.5 hours under nitrogen. Thereupon 791 g of methyl iodide ere added during 30 minutes and the mixture is stirred 3.5 hours longer at about 20*. It is diluted with 45,000 ml of water and the resulting suspension stirred et room temperature overnight. It is filtered, the residue washed 5 times with 4,000 ml of water and dried et 60*/5 mmHg, to yield the 5-methylthio-imidazo[2,l-bIfl,3,5Ibenzothiediezepine melting et 116-118*.

Similarly the following starting materials are prepared from the correspondingly substituted 2-bromonitrobenzenes; a. 8-methoxy-5-methylthio-imidazo[2,l-b][l,3,5]benzothiadiazepine, melting at 143-146*; b. 8-chloro-5-methylthio-imidazo[2,l-b][l,3,5]benzothiadiazepine, melting at 147-149°; c. 8-fluoro-5-methylthio-imidazo[2,l-b][l,3,5]benzothiadiazepine, melting at 174-176*; d. 8-methyl-5-nethylthio-imidazo[2,l-b] [l,3,5]benzothiadiazepine.

Iq Example 2: To the solution of 480 mg of 5-thiocyanato-imidazo[2,l-b] [l,3,5]benzothiadiaz»pine 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 temperature. The mixture is diluted with 80 ml of «thyl acetate, washed twice with saturated aqueous sodium chloride, dried and evaporated.

The residue is dissolved in 2 al of acetone, the solution acidified with 300 mg of maleic acid and diluted with diethyl ether, to yield the 5-(4-methylpiperazino)-imidazo[2,l-b][l,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,l-b][1,3,5]ben20thiadiezepin-5(6H)-thione are added in portions, and the mixture is stirred at room temperature under nitrogen for one hour. The resulting white suspension is cooled to 0* and the solution of 3.5 g of cyanogen bromide in 10 ml of tetrahydrofuran are added dropwise. The mixture is stirred at room temperature for 0.5 hour and evaporated. The residue is triturated with methylene chloride, the mixture washed with water, dried, concentrated to a small volume, washed with diethyl 53043 etber and filtered, to yield tbe 5-thiocyen*Co-imidezo[2,l-bJ[l,3,5]beniothiadiazepine melting at 111-113*.

Examle_3.· The "ixtur* of 333 ®8 of l[2-(imidazo-2-ylthio)-phenyliainothioetrhonylJ-4-methylpiperazine, 3.3 ml of dimethylformamide, 276 mg of potassium carbonate, 116 mg of cyanogen bromide and 50 mg of 8-crown-6 ether is stirred at room temperature under nitrogen for 3 hours. It is diluted with ethyl acetate, washed with saturated aqueous sodium chloride, dried and evaporated. The residue is dissolved in acetone, th* aolution treated with 116 mg of maleic acid and diluted with diethyl ether, to yield th* 5-(4-methylpip*rarino)-imidazo[2,l-b][l,3,5]benzochiadiazepine monomaleate, melting at 198-199* with decomposition; it is identical with that of Example 1.

The starting material is prepared as follows: The mixture of 2.3 g of iaidazo[2,l-b][l,3,5]benzothiadiazepin-5(6H)thione, 23 ml of methylene chlorida and 1.0 g of 1-methylpiperazine is stirred at roan temperature for 15 hours. The crystalline product formed is filtered off aad washed with methylene chloride, to yield the l-[2-(ieidazo-2-ylthio)-phenyliminothiocarbonyl]-4-methylpiperazine melting ae 209-212*.

Example 4: To the suspension of 3.1 g of l-[2-(imidazo-2-ylthio)phenyliminoearbonylJ-4-methylpiper -(4-methylpiperazino)-imidazo[2,1-b 1(1,3,5]henzothiediazepine monomaleate, melting ac 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,l-b][l,3,5]benzothiadiazepin-5(6H)-one, melting at 250-252° with decomposition.

In the analogous manner (or by replacing the 1,1’-carbonyldiimidazole hy the equivalent amount of phosgene), the following intermediates are obtained and are illustrative of tbe process: a. 3,4-dimethylimidezo[2,l-b][l,3,5]benzothiadiszepin-5(6B)-one, - m.p. 225* (decomposition); h. 8-chloroim£dazo[2,l-b][l,3,5]benzothiadiazep£n-5(6H)-one, m.p. 261-263°; c. 8-trifluoromethylim£dazo[2,l-b][1,3,5jbenzothiadiazepin-5(6H)-one, !5 m.p. 257-260*; d. 3-methylimidazo[2,l-fa][l,3,5]b«nzothiad£azepin-5(6H)-one, m.p. 225-229*.

The mixture of 2.17 g of imidazo[2,l-b][l,3,5]benzothiadiazepin-5(6H)one, 1.0 g of 1-methylpiperazine and 20 ml of methylene chloride is 2q stirred at room temperature for 24 hours. The crystalline product formed is filtered off and washed with methylene chloride, to yield the l-[2-(imidaso-2-ylthio)-phenylimihocarbonyl]-4-methylpiperazine, melting ac 197-200°.

In similar manner the following additional starting materials are obtained and are illustrative of the process: l-[2-(4-methylimidazo-2-ylthio)-phenyliminocarbonyl]-4-methylpiperazine, malting at 101-105* (decomposition); b. l-[2-(imidazo-2-ylthio)-phenyliminocarfeonyl3-4-aetbylbomopiperazine, melting at 134-138*; c. 1-(2-(imidazo-2-ylthio)-pheny liminocarbonyl]-4-carho d. l-[2-(imidazo-2-ylthie)-phanyliminocarbonyl]-4-carbobanzoxypiparazina, melting at 206-208*; e. l-[t-(4-carboethoxyimidazo-2-ylthio)-phenyliminocarbonyl]-4methylpiperazine, melting at 166-169*; f. 1-(2-(imidazo-2-y1thio)-4-trifluoromethylphanyliminocarbonyl]-4methylpiperazina, malting at 212-214*.

Example 5; A mixture of 10 g of 5-wethylthio-imidazo[2,l-bj[l,3,5Jbenzothiadiazapine hydrochloride, 3.62 g ot piperazine, and 350 ml of amyl alcohol ia rafluxad with stirring and unter nitrogen for 20 hours. The solvent ia evaporated under reduced preaaure, tbe residua ia triturated with methylene chloride, washed vith 2R sodium hydroxide solution, dried over magnesium sulfate and evaporated to dryness.

The residue i* dissolved in 10 ml of methanol and treated with 2N etheral hydrochloric acid solution to give 5-(4H-piperazino)-imidazo [2,l-b][l,3,5]henzothi*diazapine dihydrochloride, melting at 249* with decomposition.

Example 6; A mixture of 5 g of 5-methylthio-imidazo[2,l-b3(l,3,5]benzothiadiazepine hydrochloride, 2.86 g of Ν-β-hydroxyethylpiperazine, and 175 ml of amyl alcohol is refluxed under nitrogen for 48 hours with stirring. The solvent is removed under reduced pressure, the residue is triturated vith methylene chloride, washed vith 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-g-hydroxyethylpiperaziao)-imidezo[2,l-b'][l,3,5]henzothiadiazepine dihydrochloride, melting at 210-212*.

Example 7: By replacement of the Ν-β-hydroxyethylpiperazine in example 6 by an equivalent amount of N-methylhomopiperazine one obtains 5-(4-methylhomopiperazino)-imidazo[2,1-b)(1,3,5]benzothiadi azepine, isolated as the fumarate salt melting at 216-218*.

Example 8; According to the methods illustrated by tbe previous exaaples, the following conpounds of formula I are obtained from equivalent amounts of tbe corresponding starting materials; Ph-4-R.-l,2-phenylene; CB^-tCB^; CB^-CCB^,.

No. *1 »2 *3 n’ *5 Salt m.p. *C 1 B H a 2 H 2BC1 249 dec.* 2 H H 2 a 2HC1 216-219 3 H a «3 2 °ca. - 2HC1 155 dec. 4 H B <*3 2 r maleate 202-204 5 B a ®3 2 Cl 2BC1 203-206 6 H a ®3 2 · CF3 2aci 180 dec. 7C02C2H5 a ch3 2 a -- 138-141 B H a (ca^oa 2 a 2BC1 210-212 9 B' a COOEt 2 H — 137-139 10 B a «3 3 a .fumarate 216-218 11 H a COOCH, 2 a — NMR:5.2,3.5 12ffi3 a % 2 B maleate 191-192.5 13 ch3ra3 ®3 2 a *(dec. · decomposition).

Example 9: To the solution of 0.2 g of 5-(4-cerboethoxypiperazino)imidazo[2,l-b][l,3,5]ben2othiadiazepine in 2 ml of dry tetrahydrofuran, 100 mg of lithium aluminium hydride are added at once end the mixture is refluxed under nitrogen for 48 hours. The mixture is cooled to room temperature, stirred with 0.2 ml of 30Z aqueous sodium hydroxide, end filtered. Tha filtrate is evaporated to dryness and the product is purified to give 5-(4-eathylpiperazino]-imidazot2,l-b][l,3,5]benzothiadiazepine, melting at 145-147*. It is identical with the compound obtained m Example 1.

Example 10: To the solution of 88 mg of 5-(4-nethyIpiperazine),‘wi d «zn [2,1-b Η1 -3 -5 Ibenzothiadiazeoine in 1 ml of methylene chloride, 74 mg of m-ehloroperbenzoic acid are added at 0*. Tha mixture ia stirred at 0* overnight; thia ia diluted with 1 ml of ether, one equivalent of etheral hydrochloric aeid solution ia added and the resulting precipitets is collected. Kecryetallization from methanol-ethyl acetate yields 5-(4-aethyl-4-oxidopiperazino)-imidazo[2,l-b][l,3,5]benzothiediazepine hydrochloride, melting at 155* with decomposition.

Example 11: e) To the aolution of 0.5 g of 5-(4-carbobenzoxypiperazino)-imidazo[2,l-b][l,3,5]banzothiadiazepine in 5 ml of methylene chloride, cooled at 0*, is added dropvise a solution of 0.26 g of m-chloroperbenzoic ecid in 2 ml of methylene chloride. The mixture is stirred et 0* for 1.5 hours, the solids ere filtered, and the filtrates ere washed with 10Z aqueous potassium carbonate and water, then dried over magnesium sulfate and evaporated to dryness to give 5-(4-carbobenzoxypiperezino)-imidazo[2,1-b][1,3,5]benzothiadiazepine 1-oxid*.

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,lbKl,3,5]benzothiadiazepine 1,1-dioxide is obtained. Moss spectrum: m/e 451, 420, 406, 386.

Example 12: a) To Che solution of 100 mg of 5-(4-carhobenzoxypiperazino)-imidazo[2,1-b][l,3,5]benzothiadiazepine 1-oxide in 0.3 ml of acetic acid are added 0.35 ml of a 2N solution of hydrobromic acid in acetic acid. The mixture is heated at 100* for 1 hour and stirred at room temperature overnight. Ether is added, and the 5-(4H-piperazino)imidazo[2,l-b][l,3,5]benzothiadiazepine 1-oxide hydrobromide is filtered end washed with ether; m.p. 75* with decomposition. b) In a similar manner the 5-(4-carbobenzoxypiperazino)-imidazo[2,1b][l,3,5]benzothiadiazepine 1,1-dioxide is converted to S-(piperazino)· ί mid 113:0(2,1-1.)(1 1,1-dioxide hydrobromide.

Bf - 0.353 (silica gel, ethyl acetate-methylene chloride, 1:1).

Example 13; A mixture of 285 mg of 5-(4H-piperazino).-imidazo[2,l-b] (l,3,5]benzothiadiazepine, 0.5 g of potassium carbonate, 0.142 g of methyl iodide and 2 ml of acetone is stirred at room temperature over15 night and evaporated. Veter is added to the residue, and the mixture is extracted with methylene chloride. The extracts are dried over magnesium culfate, evaporated, and the residue is purified to give 5-(4-methylpiperazino)-imidazo[2,l-h][l,3,5]benzothiadiazepxne melting et 145-147*. The product is identical to compound obtained in Example 1.

Example 14: Ereparation of 10,000 tablets each containing 5 mg of the active ingredient: Formula: -(4-methylpiperazino)-imidazo[2,1-b] [1,3,5]benzothiadiazepine 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. procedure! All the powders ere passed through * screes with openings of 0.6 ns. Then the drug substance, lactose, talcum, magnesium stearate and half of the starch are mixed in a suitable mixer. The other half of the stareh 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 tbe powders which are granulated, if necessary, with an additional amount of water. The granulate is dried overnight at 35*, broken on a screes with 1.2 mm openings and compressed into tablets using concave punches with 6.4 mm diameter, uppers bisected.

E-nmole 15; Preparation of 10,000 capsules each containing 10 mg of the active ingredient: Formula: -[4-(2-hydroxyethyl>-piperazinoj-imidazo[2,1-b ] [l,3,5]benzotbiadiazepine dihydroehloride 100 g Lactose 1,800 g Talcum powder 100 g Procedure: All the powders are passed through a screen with openings of 0.6 mm. Then the drug substance ia placed in a suitable mixer and mixed first with the talcum, then with the lactose until homogenous. No. 3 capsules are filled vith 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 (21)

Claims

1. Compounds of the general Formula I vherein eaeh of R^ and R? rs Hydrogen, lover allcyl, lover alkanoyl, halogeno, cyano, carboxy, lover carbalkoxy, carbamoyl, sulfamoyl, mono- or di-lower alkyl-(carb

2. Compounds of the Formula I shown in claim 1, wherein R^ represents hydrogen, lower alkyl, lower alkanoyl, lover alkoxyearbonyl or hydroxy-lower alkyl, wherein tha hydroxy group is separated from the nitrogen atom by at least 2 carbon atoms, and the other symbols have the meanings given in claim 1; thair N- and/or S-oxides, and lower alkyl quaternary derivatives thereof.

3. Compounds of the Formula I shown in claim 1 or 2, in which each of R ( and E-j rs hydrogen, lover alkyl, lower alkanoyl, halogeno, cyano, carboxy, lover carbalkoxy, carbamoyl, sulfamoyl, mono- or di-lover alkyl-(carbamoyl or sulfamoyl); Ph is 1,2-phenylene, (lower alkyl)25 58043 1,2-phenylene, (lower alkoxy)-I,2-phenyiene, (lower alkyl thio)-1,2phenylene, (halogeno)-l,2-phenylene, (trifluoromethyl)-i,2-phenylane, ( 3 .jifmy 1)-1.2-phenylent, (mono- or di-lower alkylsulfamoyl)-1,2phenylene; each of m and n is the integer 2 or 3; and R^ is hydrogen, lower alkyl, lower alkanoyl, lower alkoxycarbonyl, phenyl-lower alkoxycarbonyl or hydroxy-lower alkyl, wherein the hydroxy group is separated fro· the nitrogen atom hy at least 2 earbon atoms; their N- and/or S-oxides; and lower alkylquaternary derivatives thereof.

4. Compounds of the Formula II (II) wherein each of B^ and Rj is hydrogen or lower alkyl; R^ is hydrogen, lower alkyl or 2- or 3-hydroxy-lower alkyl, R $ is hydrogen, lower alkyl, lower alkoxy, halogeno or trifluoromethyi; and p is an ingeter from 0 to 2; and the N-oxide thereof.

5. Compounds of the Formula II shown in claim 4, wherein each of R^ and Rj is hydrogen or methyl; B^ is alkyl or 2- or 3-hydroxyalkyl, in which alkyl bas at most 4 carbon atoms; R$ is hydrogen, methyl, methoxy, fluoro, chloro or trifluoromethyi; p is 0; and the N-oxide thereof.

6. Compounds of the Foraula I shown in claim 1, named in the Example 8, as compounds 1 to 13.

7. 5-(4-Methylpiperazino)-imidazo[2,l-b][l,3,5]benzot:hiadiazepine.

8. 5-(4H-Piperazino)-irnidazo[2,l-b] [l,3,S]benzothiadiazepine.

9. 5-(4-p-Hydroxyethylpip«razino)-imidazo[2,l-b][l,3,5]ben2othiadiazepine.

10.XO. 5-(4-Methylhomopiperazino)-imidazo[2,1-b][1,3,5Jbenzothiadiazepine.

11. 5-(4-Metbyl-4-oxido-piperazino)-imidazo[2,l-b][l,3,5]benzothiadiazepine.

12. 5-(4-Carbobenzoxypiperazino)-imidazo[2,l-b] [l,3,5]benzothiadiazepine-1-oxide.

13.Iq 13. 5-(4-Carbobeazoxypiperazino)-imidazo[2,l-b][l,3,5]benzothiadiazepine-1,1-dioxide.

14. 5-(4B-Piperazino)-iaidazo[2,l-b][l,3,5]benzothiadiazepine-l-oxide.

15.•15. 5-(4H-Piperazino)-imidazo[2,1-b][1,3,5]henzothiadiazepine-l, 1-dioxide.

16.16. A salt, of a compound having a salt forming group, as claimed iu any one . .of claims 1 to 15.

17. A pharmaceutically acceptable salt of a compound having a salt forming group, as claimed in any one of claime 1 to 1552043

18. A pharmaceutical preparation comprising a caipound claimed in any one of claims 1 to 15 and 17 in admixture or conjunction with a pharmaceutically suitable carrier.

19. process for the manufacture of 5-diazacycloalkyl-lmida2o[2,l-b][l f 3 f 5]tenzothladi.azepine s of the general fontula I as defined in claim 1; their N- and/cr S-coddes, lower alkyl quaternary derivatives thereof and salts of all these catpounds, which consists in 1) condensing a conpound of the general Farnula III or a salt thereof with a compound of the general formula IV •R. η2a (IV) wherein X ia halogeno, lower alkoxy, lower alkylthio, cyanato or thiocyanate; T ia hydrogen or aa alkali metal; p is an integer from 0 to 2, and tha remaining symbols have tha meaning given for formula I, or 2. ) ring-closing of a compound of tha general formula V a. wherein Z is oxygen, sulfur or NH, and the other symbols have tha above-given meaning, under dehydrating or dehydrosulfurating 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 R 3 is hydrogen or an alkali metal atom, and, b) if a compound ia required in which R^ is lower alkyl, reducing in 5 a compound having a lower alkenyl or lower alkynyl group instead of a lower alkyl group, and, c) if a compound is required in which Rj is hydroxy-lower alkyl, reacting a compound in which R^ is hydrogen or an alkali metal atom with a corresponding oxirane or with a reactive ester of a mono10 esterified lower alkanediol, and d) if a compound is required in which R^ is hydroxy-lower alkyl, reacting a compound in which R^ is hydrogen with a reactive derivative of a corresponding glycol, glycolic acid or a dicarboxylic acid and hydrolyzing or reducing the compound so obtained to a product in which Rj is hydroxy-lower alkyl, and, e) if a compound is required in which R^ 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 R^ is an acyl radical named 20 above, acylating a product in which R^ is hydrogen, and, b) if a compound is required in which R^ represents hydrogen, hydrolyzing a compound in which Rg is an acyl radical, and, h) if a compound is required in which Rg represents methyl, reducing in a produce in which Rg is lower alkoxycarbonyl or phenyl-lower 23 alkoxycarbonyl to obtain a compound in which Rg is methyl, and, i) if a compound is required in which R^ and/or R^ is halogen, halogenating a product in which R^ and/or R^ is hydrogen, and, j) if a compound is required in which R^ and/or Rg is carboxy, lower alkoxycarbonyl or a carbamoyl residue named above, reacting a com30 pound in vhich R^ and/or R 2 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, lc) if a compound ia required in which R and/or R 2 is sulfamoyl, mono- or di-lower alkylsulfaseyl, reacting a product in which R^ and/ or R is hydrogen with a halosulfonic acid and treating the compound obtained with amaonia, a mono- or di-lower alkylamine, and, l) if a compound is required in which R^ end /or Rj is cyano, dehydrating a product ia which Rj^ and/or R^ is carbamoyl, and, m) if * coopound is required in which R^ and/or R^ is carboxy, hydrolysing a product in which R^ and/or Rj is cyano, lower alkoxyearbonyl or carbamoyl, and, n) if an K- and/or S-oxide is required, oxidizing a product in which Rj is different from hydrogen, and, o) if only an N-oxide is required, converting a product in which R$ 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 Rj 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 vhich R^ is different from hydrogen or represents hydrogen, with a reactive esterified lower alkanol, and, r) . if required, converting a resulting conpound of formula I into another compound of tha 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 racamatas obtained into the single isomers or racemates, and, if required, resolving a racemate obtained into the optical antipodes.

20. ihe precess for the preparation of cacfunds of formula I as described in any one of exanples 1 to 7 and 9 to 13 and of ccnpounds 1 to 13 of exanple 8.

21. The ccnpounds prepared according to either of claims 19 and 20.