FI69310C - FRAME FORM OF THE PHARMACEUTICAL FORM OF THE PHARMACEUTICAL FORM 5-DIAZA-CYCLOALKYL-IMIDAZO (2,1-B) (1,3,5) BENZOTIADIAZEPINER - 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

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Process for the preparation of new pharmaceutically useful 5-diazacycloalkylimidazo (2,1-b) (1,3,5) benzothiadiazepines - Preparation of a pharmaceutically acceptable pharmaceutical compound diazacycloalkylimidazo (2,1- b) (1,3,5) “benzothiadiazepiner

The invention relates to general formula I.

5-diazacycloalkylimidazo (2,1b) (1,3,5) benzothiadiazepines according to the formula R 1, R 2, R 2, R 2, R 2, n, n, n, hydrogen, C 1 -C 4 alkoxycarbonyl or C 1 -C 4 lower alkyl, represents hydrogen, C 1 -C 4 lower alkoxy, halogen or trifluoromethyl and p represents the number 0-2, each of the symbols m and n represents the integer 2 or 3 and R 3 represents hydrogen, C 1 -C 4 lower alkyl, C 1 -C 4 lower alkoxycarbonyl, benzyloxycarbonyl or hydroxy-C1-C4 lower alkyl in which 2

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the hydroxy group is separated from the nitrogen atom by at least two carbon atoms; their N-oxides, in which R3 represents lower alkyl or hydroxy-lower alkyl, and the oxidizing oxygen is attached to the nitrogen atom to which the group R3 is attached and / or the S-oxides, their lower alkyl quaternary derivatives and salts, in particular the therapeutically useful acids and salts formed with and methods for their preparation, pharmaceutical preparations containing these compounds and their therapeutic use.

The lower alkyl group R 1 or R 3 and / or the lower alkyl groups in said alkoxy, alkylthio or other said alkylated groups are in particular methyl and also ethyl, n- or iso- (propyl, butyl, pentyl, hexyl or heptyl), e.g. 2-methylpropyl or 3-methylbutyl.

The halogen atom is preferably fluorine or chlorine, but also bromine.

The carboxy-lower alkoxy group is preferably carbomethoxy or carboethoxy.

The 1,2-phenylene residue is preferably unsubstituted or monosubstituted by said substituents. Such substituents are, for example, methoxy, ethoxy or isopropoxy, or fluorine, chlorine or bromine or trifluoromethyl.

As the lower alkylene group, CmH2m is especially ethylene, but also 1,2- or 1,3-propylene, 1,2-, 1,3- or 2,3-butylene, which together with the adjacent nitrogen atoms preferably form a piperazino or homopiperazino group.

As the carboxy-lower alkoxy or hydroxy-lower alkyl group, R 3 is preferably carbomethoxy or carbethoxy, 2-hydroxy- (ethyl or propyl), 3-hydroxy- (propyl or butyl) or the like. 4-hydroxybutyl.

Said N-oxides are preferably those in which R3 3

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denotes lower alkyl or hydroxy-lower alkyl, and in which the oxygen atom is bonded to the nitrogen atom supporting the group R3. Said S-oxides are sulfoxides (SO) or sulfones (SO2).

Likewise, said quaternary lower alkyl derivatives of the compounds of formula I are derived from those in which R3 represents lower alkyl or hydroxy-lower alkyl and in which only the terminal nitrogen atom of the piperazino or homopiperazine ring is quaternized. The anions of said quaternary derivatives, but also of said acid addition salts, are preferably those which produce therapeutically useful salts, e.g. salts of the aforementioned acids.

The term "lower" in the organic residues or compounds mentioned above and below means those which preferably have 4, and in particular 1 or 2, carbon atoms.

The compounds of the invention have valuable pharmacological effects, primarily neuroleptic effects. These can be demonstrated in animal experiments, preferably in mammals, e.g., mice, rats, or monkeys. Said compounds may be administered enterally or parenterally, preferably orally or subcutaneously, intravenously or intraperitoneally, e.g. in the form of injectable capsules or starch-containing suspensions or aqueous solutions. The dose used may be about 0.01-100 mg / kg / day, preferably about 0.95-10 mg / kg / day, especially 0.1-5 mg / kg / day.

Said neuroleptic properties can be demonstrated in adult rats or squirrel monkeys (squirrel __ - - ______ 4

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monkeys). Animals are trained to use a lever to dodge an electric shock to the foot. Each press of the lever transfers the shock by 30 seconds. If the animal forgets to press the lever once during said interval, then it will be given short (0.5 sec.) Electric shocks every 15 seconds until the animal uses the lever again. Under control conditions, experimental animals weigh the lever at a reasonably steady rate and rarely receive more than 6 shocks over a 25-minute (rats) to 4-hour experimental period. The compounds mentioned above, which are administered to the animals 30, 90 and 120 minutes before the experiment, block the learned conditioned mapping behavior. The result is a deterioration of the avoidance response and a substantial increase in the shocks suffered by the animals.

Both the number of avoidance reactions and the number of misbehaviors (shocks received) are recorded for interpretation in this Sidman avoidance test. The compounds of the invention, e.g. 3- (4-methylpiperazino) -imidazo- (2,1-b) (1,3,5] benzothiadiazepine or its therapeutically useful salts, reduce mapping reactions in rats or monkeys by up to 10 mg / kg: n total dose.

The extra-pyramidal side effects (ENWs) known from classical neuroleptics trigger characteristic motor syndromes in saimiri monkeys repeatedly pretreated repeatedly with antipsychotics. These movement disorders consist of dystonic body postures and dyskinetic movements that are more consistent with ENW effects in humans than catalepsy or tremor.

Thus, potential extrapyramidal side effects, but possibly other neurological sympto-30s, e.g. from ptosis, can be assessed by observing adult saimir monkeys (weighing 700-1200 g). Animals are treated once a week or once every two weeks with halo-peridol (1.25 mg / kg). After such treatment, which lasts for about 2 to 4 months, clear dystonic body positions and dyspnoea occur 1 to 6 hours after administration of haloperidol.

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5 kinetic movements. Otherwise, no abnormal movements of the monkeys can be observed at other times. Following the occurrence of haloperidol-induced dyskinesias, the above treatment is discontinued. After this 5, the animals receive exclusively every 4-8 days. week 1.25 mg / kg haloperidol and are used as control animals in the study of the compounds of the invention.

Monkeys are evaluated after 2, 4, and 6 hours of treatment. The experiments are performed in closed booths equipped with remote-controlled video surveillance equipment and an integrated buzzer generator. The evaluation of the animals is carried out by two independent observers who do not know the compounds administered or the purpose of the experiment. During neurological examinations, the api-15 witch is treated by a third person. First, the animals are observed through a video system. Observers then enter the test booths and record the monkeys ’reactions as“ motor ”(the animal travels around the booth),“ visual ”(clear reaction, but no passing around), or 20“ none ”(no reaction). Activity, body position, tremor, increased salivation, and other neurological symptoms are also considered. In particular, the presence or absence of the "strange" dystonic body positions and dyskinetic movements mentioned above is monitored. The person handling the animals then takes the monkey out of the booth. In this case, the reactions of the monkey are approached separately as it is approached with a gloved hand, when first touched, and when blocked. Voting during the capture is also estimated. The person handling the animal then assesses the tendency and pupil size of the body and determines if ptosis is present.

If a previous study has found that catalepsy has occurred, then this symptom is evaluated. The monkey is first placed head down, on the floor, then at the entrance to the booth and lo-35 bush in the observation booth. If the monkey remains substantially immobile for at least 5 seconds in all of these 6931 0 positions, then the occurrence of catalepsy is considered positive. After the monkey returns to the test booth or after being taken there, it is observed for one minute to detect dyskinesias. A specific symptom or evaluation result that differs from control results is not credited to a given substance until both observers have reported this in one of the three observation periods. When the first observer considers a given symptom to be weaker than the second, 10 such a less severe assessment is accepted. In general, however, there is good agreement between observers.

Thus, for example, administration of the compound of Example 1 at 10 mg / kg occurred in only one of the five monkeys. This case 15 was limited to only one form (bending) and occurred once in three experimental cycles. In contrast, severe dyskinesia was observed in all monkeys treated with haloperidol (1.25 mg / kg), manifested as different types of discrete movements. There were also no dyskinesias after 20 clozapine (10 mg / kg). However, they can be detected after a low dose of haloperidol (0.625 mg / kg) in five monkeys. No dyskinesias occurred after administration of pharmaceutical excipients (carriers). However, in this test, clozapine caused increased salivary secretion in each of the 25 monkeys studied.

This side effect could not be observed when treated with other compounds, including the product of Example 1. Ptosis, catalepsy, decreased body waste, and poor responses to observers were observed in some or all of the monkeys after administration of the three agents.

According to the mentioned and also other classical test methods, the compounds according to the invention are valuable neuroleptic (antipsychotic) substances which can be used, for example, for aggression, agitation or pain states. They are practically devoid of the extrapyramidal side effects that clozapine, for example, has in humans. In addition, the absence of increased salivation represents an additional advantage of the new compounds over clozapine. In addition, the compounds according to the invention can be used as intermediates for the preparation of other valuable preparations, in particular pharmaceutically active preparations.

Further preferred are the general formula II

. Λ

v (SU

Compounds of formula R 3 wherein hydrogen is C 1 -C 2 lower alkyl, R 3 is hydrogen, C 1 -C 2 lower alkyl or 2- or 3-hydroxy-C 1 -C 2 lower alkyl, R 5 is hydrogen, C 1 -C 2 lower alkyl -C 2 -C 6 lower alkyl, C 1 -C 2 lower alkoxy, halogen or trifluoromethyl and p represents a number from 0 to 2, their N-oxides in which R 3 represents lower alkyl and oxido oxygen attached to the nitrogen atom to which the group R 3 is attached, and salts thereof, in particular therapeutically useful salts of these compounds.

Particularly preferred are compounds of the general formula II in which R 1 represents hydrogen or methyl, R 3 represents alkyl or 2- or 3-hydroxyalkyl having in each case at most 4 carbon atoms, R 5 represents hydrogen, methyl, methoxy, fluorine, chlorine or trifluoromethyl and p is zero, their N-oxides and salts, especially the therapeutically useful salts of these compounds.

The compounds according to the invention are prepared according to methods known per se, e.g. by a) condensing the compounds of the general formula III or their salts with the compounds of the general formula IV

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• N J> .c H

* T- / ”Yr, R.-i 8 i_S \ H2n 3 v Vcf ^ ° 2n (UI) X <IV) · in which formulas X represents a lower alkylthio or thiosya-Nato, Y is hydrogen or an alkali metal atom, p represents the number 0- 2 and the other symbols have the meanings given in connection with formula I, or b) compounds of general formula V

(Q) A

. i_E- (f \ -R

S \ / 3—! 1 (V), R -i · β H-.

. vv -, - <;, >>, n 2n is cyclized under dehydrating or desulfurizing conditions, wherein Z represents an oxygen or sulfur atom and other symbols have the meanings given above, and / or c) a compound of formula I obtained wherein R 3 represents lower alkoxycarbonyl, converted by reduction to a compound of formula I in which R 3 represents lower alkyl, and / or d) the resulting compound of formula I in which R 3 represents hydrogen is converted by methylation to a compound of formula I in which R 3 represents methyl, and / or e) the compound of formula I wherein R3 is benzyloxycarbonyl or lower alkoxycarbonyl is converted by hydrolysis to the compound of formula I wherein R3 is hydrogen and / or the compound of formula I wherein R3 is other than hydrogen is converted by oxidation to N- or S-oxide, and / or g) converting the resulting free compound to a salt or obtained

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9 salt to a free compound of formula I or another salt.

Said condensation is preferably carried out using an excess of piperazine IV (Y = H) or equivalent amounts of said metal derivatives thereof, especially when X represents lower alkylthio or thiocyanato. Preferably, work is carried out at temperatures of about 0-150 ° C and in a suitable solvent such as a lower alkanol, e.g. amyl alcohol, or dimethylformamide, hexamethylphosphoramide or toluene.

Said ring closure is carried out with strong dehydrating or dehydrosulfurizing agents, e.g. phosphoryl halides and / or oxyhalides or cyanogen halides, with or without crown ether catalysts, e.g. in the presence or absence thereof, preferably in an inert solvent, e.g. dimethylformamide.

The starting materials are known or, if they are new, can be prepared according to methods known per se, e.g. as shown in the examples. The novel starting materials are also the subject of the invention.

The novel imidazo (2,1-b) (1,3,5} benzothiadiazepine starting materials of the formula III are prepared according to ring-closure methods known per se, preferably by condensation of the formula VI

Π (VI).

/ ν 'Y

Compounds of the formula I 11 p - · · 5 V '* 2 in which the symbols and R5 have the meanings given for the compounds of formula III, reactive carbonic acid derivatives such as phosgene, thiophosgene, 1,1'-6931 0 10 carbonyldiimidazole or with bromocyanine.

The starting materials of formula V can be prepared starting from the (tautomeric) precursors of the compounds of formula III wherein X represents hydroxy, thio or amino. These compounds are condensed with the compounds of the formula IV in the presence or absence of other bases, e.g. the abovementioned bases, preferably in inert solvents such as methylene chloride or toluene at temperatures of 0 to 150 ° C, more preferably 10 to 50 ° C. The ring opening is preferably carried out at low temperatures to prevent any side reactions of the reactive functional group R 1 which may occur.

Starting materials of formula V wherein R 3 represents Lower alkoxycarbonyl or benzyloxycarbonyl can also be prepared by condensing compounds of formula VI of formula VII

<C H, m 2®Vr * (VII), CH, with a compound according to n 2n, wherein Y 'represents halocarbonyl, halothiocarbonyl or cyano, preferably in an inert solvent at temperatures of 0-150 ° C.

The compounds according to the invention obtained can be converted into other compounds according to the invention in a manner known per se. Thus, for example, compounds in which R3 represents a hydrogen or an alkali metal atom, e.g.

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11 sodium or lithium salts with substituted or unsubstituted oxiranes, e.g. ethylene oxide, or with reactive esters of unsubstituted or correspondingly substituted aliphatic or araliphatic alcohols, e.g. methanol, ethanol, allyl alcohol or propyl -substituted compounds or quaternary derivatives depending on the molar amount of alkylating agent used. These esters are derived, for example, from strong inorganic or organic acids, in particular from hydrohalic acids, e.g. hydrochloric, hydrobromic or hydroiodic acid, sulfuric acid or an aromatic sulfonic acid, e.g. p-toluenesulfonic acid or m-bromobenzenesulfonic acid. Intermediates of formula I in which R 1 represents an alkali metal atom can be prepared by metallization of reactive organic metal compounds, e.g. lithium diisopropylamide, alkali metal alkoxides, e.g. sodium methoxide, or alkali metal hydrides, e.g. sodium or with potassium hydride.

Unsaturated compounds, e.g. those in which 20 represents lower alkenyl or lower alkynyl, can be converted with catalytically activated hydrogen into compounds in which R1 represents the corresponding alkyl residue. Conversely, the resulting N-alkylated compounds can be converted to N-unsubstituted compounds. They are reacted, for example, with lower alkyl esters of ha-halogenic formic acid, e.g. R (H).

Compounds of formula I in which R 1 represents hydroxyalkyl may also be prepared by first reacting the corresponding compounds of formula I in which R 1 represents hydrogen with reactive derivatives of the corresponding glycols, glycolic acids or dicarboxylic acids, e.g. their lower alkyl esters. , halides of anhydrides, or derivatives of said glycols or glycolic acid derivatives.

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reactive esters, e.g. esters of hydrohalic acids or aromatic sulfonic acids, 1,2-dibromoethane or -1,2-dibromopropane, bromoacetic acid ethyl ester or bromopropionic acid ethyl esters of ethyl esters, tosyl-5-hydroxyacetic acid or esters, with ester chloride. The intermediates obtained are either hydrolysed or reduced with simple or complex light metal hydrides, e.g. lithium aluminum hydride yk-10 per se or with diborane, to give compounds of formula I in which hydroxyalkyl is represented.

Compounds of formula I in which methyl represents hydrogen can be prepared as follows: First, compounds in which R 1 represents hydrogen are converted by reacting them with halogen formic acid lower alkyl esters or phenyl lower alkyl esters, e.g. chloroformic acid ethyl ester, to give compounds of formula I wherein R 1 represents lower alkoxycarbonyl or benzyloxycarbonyl. These acyl derivatives are then reduced with simple or complex light metal hydrides, e.g. lithium aluminum hydride, sodium tri-tert-butoxyaluminum hydride or sodium bis- (2-methoxyethoxy) aluminum hydride.

1 3 6931 0

The resulting tertiary nitrogen-free nitrogen compounds can be converted to N- and / or S-oxides. Work using, for example, hydrogen peroxide or organic peracids, e.g. lower peralkanoic acids or perbenzoic acids, such as peracetic acid or m-chloroperbenzoic acid, preferably at room temperature or, in the case of the latter acid, below or at most 100 ° C in the case of dilution with hydrogen. in the presence of lower alkanoic acids, e.g. acetic acid. If exclusively N-oxides are desired, care must be taken, especially with said peracids, to prevent S-oxidation during a long reaction time.

If only S-oxides are desired, then compounds comprising alkoxycarbonyl or butyloxycarbonyl are treated with hydrogen peroxide or organic peracids, preferably m-chloroperbenzoic acid.

Preferably, work is carried out at or below room temperature, depending on the amount of peracid used, in order to prepare sulfoxides (SO) or sulfones (SO2). The compounds thus obtained, which denote benzyloxycarbonyl or alkoxycarbonyl, can be converted into other compounds of the formula I according to the methods described above.

Finally, the compounds of the invention may be obtained in the form of free bases or salts. The resulting free base can be converted to the corresponding acid addition salt, preferably with acids that result in therapeutically useful acid addition salts, and with anion exchangers. The resulting salts can be converted to the corresponding free bases, e.g. by treatment with a basic salt of a stronger base such as a metal hydroxide or ammonium hydroxide.

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14 or with a cation exchanger, e.g. an alkali metal hydroxide or carbonate. Acids / which produce therapeutically useful acid addition salts are, for example, inorganic acids, such as hydrohalic acids, e.g. hydrochloric acid or hydrobromic acid, or sulfuric, phosphoric, nitric or perchloric acid, or, preferably, organic acids, such as aliphatic or aromatic. carboxylic or sulfonic acids, e.g. formic, acetic, propionic, succinic, glycolic, lactic, malic, tartaric, gluconic, lemon, maleic, fu-10, hydroxymalein, fir grape , phenylacetic, benzoic, 4-aminobenzoic, anthranilic, 4-hydroxybenzoic, salicylic, 4-aminosalicylic, pamoic, nicotine, methanesulfonic, ethanesulfonic, hydroxyethanesulfonic, ethylenesulfonic , benzenesulfonic, toluenesulfonic, naphthalene-sulfonic, sulfanilic or cyclohexylsulfamic acid, or ascorbic acid. These or other salts, e.g. picrate and can also be used in the purification of free bases. The bases are converted to their salts, the salts are separated and the bases are liberated from the salts.

Due to the close connection between the free compounds and the new compounds in their salt form, free compounds and salts are to be understood above and below as meaning, where appropriate, the corresponding salts or the corresponding free compounds.

The resulting mixtures of isomers of the compounds, e.g. of the compounds of the formulas I to VII, can be separated into the individual isomers according to methods known per se, e.g. by fractional distillation, crystallization and / or chromatography. Racemic products can be separated into optical antipodes, e.g., by separation of their diastereoisomeric salts, e.g., by crystallization of the d- or 1-tartrates of the fractions.

The above reactions are carried out according to methods known per se in the presence of diluents, preferably those which are inert to and soluble in the reactants, catalysts, condensation and

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In the presence or absence of the other substances mentioned above and / or in an inert atmosphere, by cooling, at room temperature or at elevated temperature, preferably at the boiling point of the solvent used, at normal or elevated pressure.

The invention also relates to variations of the present process according to which the intermediate obtained at one stage of the process is used as starting material and the remaining steps of the process are carried out, or according to which the starting material is formed under reaction conditions or using the starting material in the form of salt or optically pure antipodes.

The starting materials used in the process according to the invention are those which give the compounds described above, in particular the compounds of the formula II.

The pharmacologically acceptable compounds of the invention may be used in the preparation of pharmaceutical preparations containing an effective amount of the active substance together or in admixture with carriers suitable for enteral or parenteral administration. Preferably, tablets or gelatin capsules are used which contain the active ingredient in combination with diluents, e.g. lactose, dextrose, crude sugar, mannitol, sorbitol, cellulose and / or glycine, and lubricants, e.g. diatomaceous earth, talc, stearic acid or with its salts, such as magnesium or calcium stearate, and / or polyethylene glycol. Tablets also contain binders, e.g. magnesium aluminosilicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and / or polyvinylpyrrolidone, and, if desired, blowing agents such as sodium starch, agar or agar, algin, agar binder enzymes and / or effervescent mixtures, or adsorbents, colorants, flavors and sweeteners. Formulations for injection are preferably isotonic aqueous solutions or suspensions, and the suppositories are primarily fat emulsions or suspensions. The pharmaceutical preparations can be sterilized and / or contain auxiliaries, e.g. preservatives, stabilizers, wetting and / or emulsifiers, solubilizers, salts for regulating the osmotic pressure or buffers. The present pharmaceutical preparations, which may, if desired, contain other pharmacologically valuable substances, are prepared in a manner known per se, e.g. by means of conventional mixing, granulating or granulating methods, and contain from about 0.1 to about 75%, in particular from about 1 to about 50% active ingredient. Single doses for mammals weighing about 50-70 kg may contain about 5-100 mg of active ingredient.

The following examples illustrate the invention. Heat-15 temperatures are shown in degrees Celsius, and parts are by weight. Unless otherwise specified, the evaporation of the solvents is carried out under reduced pressure, e.g. about 15-100 mm / Hg. Example 1:

To a mixture of 501 g of 1-methylpiperazine and 6000 ml of amyl alcohol is added 538 ml of 9.3-normal methanolic hydrogen chloride, and the mixture is distilled with stirring for one hour. During this time, 1000 ml of distillate are collected and the temperature rises to 131 °. 501 g of 1-methylpiperazine and 618.5 g of 5-methylthio-imidazo (2,1-b) (1,3,5) benzothiadiazepine are then added. The mixture is stirred under a nitrogen atmosphere at 132-140 ° for 48 hours and evaporated at about 80-90 °. The residue is dissolved in 3000 ml of methylene chloride, the solution is washed 3 times with 1000 ml of 3N aqueous sodium hydroxide solution and 5 times with 1000 ml of water. Finally, 750 ml of 2-N hydrochloric acid are extracted 4 times in each case. The combined extracts are washed once with 1000 ml of methylene chloride, decolorized with 75 g of activated carbon, filtered and the filtrate is adjusted to pH 9-10 with 500 ml of 29.9% aqueous ammonia. The mixture is extracted twice with 2000 ml of methylene chloride, the combined extracts are dried, filtered and evaporated at about 60 °. Dissolve 2810 g of residual

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17 to 14000 ml of hot isopropanol, treat the solution with 563 g of activated carbon, filter it and wash the residue with 1000 ml of cold isopropanol. The combined filtrates are reheated and treated with 563 g of activated carbon 5 in the same manner. The resulting clear solution is concentrated to 8500 ml and the concentrate is allowed to stand in the refrigerator for 2 days. The white precipitate is filtered off, washed 3 times with cold isopropanol and dried at 40 ° / 5 mmHg. The formula is obtained

-OF

• S- (f \

V II

\ i JN! 5- (4-methylpiperazino) -imidazo {2,1-b) (1,3,5) -benzothiadiazepine according to the general formula, melting at 145-147 °.

1614 g of this product are dissolved at 50-60 ° in 5450 ml of anhydrous ethanol and the hot solution is filtered. The filtrate is washed with a further 1000 ml of anhydrous ethanol and the combined filtrates are acidified with 688 g of maleic acid in 1600 ml of anhydrous ethanol while stirring. The mixture is stirred with cooling to 25 °, the precipitate is separated, washed twice with 800 ml of anhydrous ethanol and dried at 75 ° / 0.5 mmHg. The corresponding monomaleate is obtained, melting with decomposition at 198-199 °.

The starting material is prepared as follows. Under a nitrogen atmosphere, 7500 g of aminoacetaldehyde dimethyl acetal are added over 45 minutes to 39230 ml of 2N hydrochloric acid and then 6932 g of potassium thiocyanate-25 at a time. The mixture is heated to 98 ° and stirred for 2 hours. It is allowed to cool overnight at room temperature. The resulting suspension is stirred and cooled to 5 °, filtered and the residue is dried at 60 ° / 5 mm Hg. Imidazole-2-thiol is obtained, melting at 224-226 °. 3068 g of the latter compound are first added

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18 to a solution of 1604 g of an 86.9% aqueous solution of potassium hydroxide in 24,700 ml of isopropanol under stirring under a nitrogen atmosphere at room temperature and then 4986 g of 2-bromonitrobenzene. The mixture is stirred at 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 is washed 6 times with 4000 ml of water and 5 times with 3700 ml of diethyl ether and dried at 60 ° / 5 mmHg. 2- (o-Nitrophenylthio) -imidates-10 sol are obtained, melting at 178-180 °.

A mixture of 2210 g of the latter compound, 2000 ml of water, 2000 ml of ethanol and 1700 g of iron powder is heated to 70 ° with stirring under a nitrogen atmosphere. After the addition of 10 ml of conc. hydrochloric acid, the mixture is refluxed for 1.5 hours and then 200 ml of conc. hydrochloric acid in 1000 ml of ethanol. The mixture is further refluxed for 2 hours and 400 ml of 6N aqueous sodium hydroxide-20 solution are stirred. The suspension obtained is diluted with 2000 ml of methanol, filtered and the residue is washed 3 times with 1000 ml of methanol. The combined filtrates are diluted with 40,000 ml of water and the resulting suspension is allowed to settle overnight. The precipitate is separated, washed twice with 2000 ml of water and dried at 60 ° / 5 mmHg. 2- (o-Aminophenylthio) imidazole is obtained, melting at 137-138 °.

To a mixture of 55,000 ml of methylene chloride and 6975 ml of triethylamine is added 4775 g of 2- (o-aminophenylthio) imidazole, cooled to 5 ° C and added over 2.5 hours with stirring under a nitrogen atmosphere at 15 ° 3301 g 85 % of thiophosgene in carbon tetrachloride. The mixture is further stirred at 10 ° for 4 hours and overnight at room temperature. The resulting suspension is filtered, the residue is washed twice with 4000 ml of methylene chloride and once with 20,000 ml of water and suspended in 11000 ml of 1,3-hydrochloric acid. The suspension is stirred for 2 hours, filtered, the residue is washed 3 times with 4000 ml

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19 water and dried at 60 ° / 5 mmHg. An imidazo (2,1-b) (1,3,5) benzothiadiazepine-5 (6H) -thione is obtained, melting at 156-159 °.

1184 g of the latter compound are added to a solution of 278 g of sodium methoxide in 22,500 ml of isopropanol, and the mixture is stirred for 1.5 hours under a nitrogen atmosphere. 791 g of methyl iodide are then added to the mixture over 30 minutes and the mixture is stirred for a further 3.5 hours at about 20 °. The reaction mixture is diluted with 45,000 ml of water and the resulting suspension of sus-10 is stirred overnight at room temperature. After filtration, the residue is washed 5 times with 4000 ml of water and dried at 60 ° / 5 mmHg. 5-Methylthioimidazo- (2,1-b} (1,3,5) benzothiadiazepine is obtained, melting at 116-118 [deg.] C. ) 8-methoxy-5-methylthioimidazo (2,1-b) (1,3,5) benzothiadiazepine, m.p. 143-146 °; b) 8-chloro-5-methylthioimidazo (2,1-b) (1,3,5) benzothia-20-diazepine, m.p. 147-149 °; c) 8-Fluoro-5-methylthioimidazo (2,1-b) (1,3,5) benzothiadiazepine. mp 174-176 °.

25 Example 2:

To a solution of 480 mg of 5-thiocyanatoimidazo- (2,1-b) (1,3,5} benzothiadiazepine in 1 ml of hexamethylphosphoramide) is stirred under a nitrogen atmosphere at -5 ° with 500 mg of 1-methylpiperazine Within 5 minutes.

Stirring is continued for 5 min. at said temperature and 15 min. at room temperature. The mixture is diluted with 80 ml of ethyl acetate, washed twice with saturated aqueous sodium chloride solution, dried and evaporated. The residue is dissolved in 2 ml of acetone, the solution is acidified with 300 mg of maleic acid and diluted with diethyl ether. 5- (4-Methylpiperazino) -imidazo [2,1-b] (1,3,5) benzothiadiazepine monomaleate is obtained, melting with decomposition at 198-199 °. The product is identical to the product of Example 1.

The starting material is prepared as follows:

To a suspension of 1.44 g of 50% sodium hydride in mineral oil and 150 ml of dry tetrahydrofuran is added portionwise 6.45 g of imidazo [2,1-b) (1,3,5) benzothiadiazepine-5 (6H) ion, and the mixture is stirred under a nitrogen atmosphere at room temperature for one hour. The resulting white suspension is cooled to 0 ° and 3.5 g of bromocyanide in 10 ml of tetrahydrofuran are added dropwise to the solution. The mixture is stirred at room temperature for 0.5 hours and evaporated. The residue is triturated with methylene chloride, the mixture is washed with water, dried, concentrated to a small volume, washed with diethyl ether and filtered.

5-Thiocyanatoimidazo (2,1-b) (1,3,5) benzothiadiazepine is obtained, melting at 111-113 °.

Example 3:

A mixture of 333 mg of 1- (2- (imidazo-2-ylthio) -phenyliminothiocarbonyl) -4-methylpiperazine, 3.3 ml of diraethylformamide, 276 mg of potassium carbonate, 116 mg of bromocyanide and 50 mg of 8-crown-6 ether, stirred under nitrogen at room temperature for 3 hours. The mixture is diluted with ethyl acetate, washed with saturated aqueous sodium chloride solution, dried and evaporated. The residue is dissolved in acetone, the solution is treated with 116 mg of maleic acid and diluted with diethyl ether. 5- (4-Methylpiperazino) imidazo (2,1-b) (1,3,5) -benzothiadiazepine monomaleate is obtained, melting with decomposition at 198-199 °. The product is identical to the product of Example 1.

The starting material is prepared as follows:

A mixture of 2.3 g of imidazo (2,1-b) (1,3,5) benzothiadiazepine-5 (6H) -thione, 23 ml of methylene chloride and 1.0 g of 1-methylpiperazine is stirred at room temperature. 35 hours. The resulting crystalline product is filtered and washed with methylene chloride. 1- (2- (imidazo-2-ylthio) -phenyliminothiocarbonyl) -4-methylpiperazine is obtained, melting at 21209-212 ° · 6931 0

Example 4:

To a suspension 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 in one portion and the mixture is stirred at room temperature for 4 hours. . It is evaporated, the residue is suspended in 50 ml of dry methylene chloride, the suspension is cooled to 0 [deg.] C. and 2.02 g of tri-ethylamine are added dropwise with stirring. It is further stirred for 15 min. At 0 °, the mixture is washed with water, dried and evaporated. The residue is dissolved in acetone and the solution is acidified with maleic acid. 5- (4-Methylpiperazino) imidazo (2,1-b) - (1,3,5] benzothiadiazepine monomaleate is obtained, melting at 198-199 DEG C. The product is identical to the product of Example 1.

The starting material is prepared as follows:

A 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 for 24 hours at room temperature. The resulting solid is filtered off and washed with methylene chloride. Imidazo (2,1-bj (1,3,5) benzothiadiazepin-5 (6H) -one is obtained, melting with decomposition at 250-252 °.

In a similar manner (or by exchanging 1,1'-carbonyl-diimidazole for an equivalent amount of phosgene) the following intermediates are obtained: 6H) -one, m.p. 225 ° (by decomposition); b) 8-chloroimidazo (2,1-b) (1,3,5) benzothiadiazepin-5 (6H) -30 one, m.p. 261-263 °; c) 8-Trifluoromethylimidazo (2,1-b) (1,3,5) benzothiadiazepin-5 (6H) -one, m.p. 257-260 °; d) 3-methylimidazo (2,1-b) (1,3,5) benzothiadiazepin-5 (6H) -one, m.p. 225-229 °.

A mixture of 2.17 g of imidazo (2,1-b) (1,3,5) benzothiadiazepin-5 (6H) -one, 1.0 g of 1-methylpiperazine and 20 ml of methylene chloride is stirred for 24 hours. room temperature

6931 O

22 spores. The resulting crystalline material is filtered off and washed with methylene chloride. 1- (2- (Imidazo-2-ylthio) -phenyliminocarbonyl] -4-methylpiperazine is obtained, melting at 197-200 °.

In a similar manner, the following starting materials are obtained which clarify the process: a) 1- (2- (4-methylimidazo-2-ylthio) -phenyliminocarbonyl] -4-methylpiperazine, mp 101-105 ° ( b) 1- (2- (imidazo-2-ylthio) -phenyliminocarbonyl) -4-10 methylhomopiperazine, m.p. 134-138 °; c) 1- (2- (imidazo-2-ylthio) -phenyliminocarbonyl) -4-carboethoxypiperazine, m.p. 161-170 °; d) 1- (2- (imidazo-2-ylthio) -phenyliminocarbonyl) -4-carbobenzoxypiperazine, m.p. 206-208 °; 15 e) 1- (2- (4-Carboethoxyimidazo-2-ylthio) -phenyliminocarbonyl) -4-methylpiperazine, m.p. 166-169 °; f) 1- (2- (imidazo-2-ylthio) -4-trifluoromethyl-phenyliminocarbonyl) -4-methylpiperazine, m.p. 212-214 °. Example 5: A mixture of 10 g of 5-methylthioimidazo (2,1-b) - (1.3.5) benzothiadiazepine hydrochloride, 3.62 g of piperazine and 350 ml of amyl alcohol is boiled under stirring for 20 hours under nitrogen. in the atmosphere at reflux. The solvent is evaporated off under reduced pressure, the residue is triturated with methylene chloride, washed with 2N aqueous sodium hydroxide solution, dried over magnesium sulphate and evaporated to dryness. The residue is dissolved in 10 ml of methanol and treated with 2N aqueous hydrochloric acid. 5- (4H-Piperazino) -30 imidazo (2,1-b) f, 3,5) benzothiadiazepine dihydrochloride is obtained, melting with decomposition at 249 °.

Example 6:

A mixture of 5 g of 5-methylthioimidazo (2,1-b) - (1.3.5) benzothiadiazepine hydrochloride, 2.86 g of Ν-β-hydroxy-35-hydroxyethylpiperazine and 175 ml of amyl alcohol is boiled for 48 hours under a nitrogen atmosphere with stirring. refluxing. The solvent is evaporated off under reduced pressure.

6931 0 23 The residue is triturated with methylene chloride, washed with 2N aqueous sodium hydroxide solution, dried over magnesium sulphate and evaporated to dryness. The residue is dissolved in 5 ml of methanol and treated with 2-5N of ethereal hydrochloric acid. 5- (4-β-Hydroxyethyl-piperazino) -imidazo [2,1-b] [1,3,5] benzothiadiazepine dihydrochloride is obtained, melting at 210-212 °. Example 7:

Replacing the Ν-β-hydroxyethylpiperazine in Example 10 with an equivalent amount of N-methylhomopiperazine gives 5- (4-methylhomopiperazino) -imidazo (2,1-b) [1,3,5] -benzothiadiazepine, which is isolated as a fumarate. Mp 216-218 °.

Example 8: According to the methods set forth in the above examples, the following compounds of formula I are also obtained starting from equivalent amounts of the corresponding starting materials: Ph = 4-Rc-1,2-phenylene; C = (CH 2) -; C H_ = 5 1 m 2m 2 2 n 2n (CH2) n. ·

20 No R2 R · ^ n 'R ^ salt m.p. ° C

1 H H H 2 H 2 HCl 249 dec. 1 2 H H CH 3 2 H 2 HCl 216-219 3 H H CH 3 2 OCH 3 2HCl 155 dec.

4 H H CH3 2 F maleate 202-204 25 5 H H CH3 2 Cl 2HCl 203-206 6 H H CH3 2 CF3 2HCl 180 dec.

7 CO 2 C 2 H 5 H CH 3 2 H - 138-141 8 HH (CH 2) 2 OH 2 H 2 HCl 210-212 9 HH COOEt 2 H - 137-139 30 10 HH CH3 3 H fumarate 216-218 11 HH COOCH2C6H5 2 H - NMR: 5.2 , 3.5 12 CH3 H CH3 2 H maleate 191-192.5

13 CH3 CH3 CH3 2 H

(decomposition = decomposition) 24

Example 9: 69 31 0

To a solution of 0.2 g of 5- (4-carboethoxypiperazino) imidazo (2,1-b) (1,3,5) benzothiadiazepine in 2 ml of dry tetrahydrofuran is stirred 100 mg of lithium aluminum 5 hydride and the mixture boiled under nitrogen for 48 hours at reflux. The reaction mixture is cooled to room temperature, 0.2 ml of 30% aqueous sodium hydroxide solution is added and filtered. The filtrate is evaporated to dryness and the product is purified. 5- (4-Methylpiperat-10-sino) -imidazo (2,1-b) [1,3,5] benzothiadiazepine is obtained, melting at 145-147 ° and identical to the product of Example 1.

Example 10;

To a solution of 88 mg of 5- (4-methylpiperazino) -15-imidazo (2,1-b) (1,3,5) benzothiadiazepine in 1 ml of methylene chloride is added at 0 ° 74 mg of m-chloroperbenzoic acid. acid. The mixture is stirred overnight at 0 °, then diluted with 1 ml of diethyl ether and treated with one equivalent of ethereal hydrochloric acid solution. The resulting sak-20 ka is separated and recrystallized from methanol-acetic acid ethyl ester. 5- (4-Methyl-4-oxidopiperazino) -imidazo (2,1-b) (1,3,5) benzothiadiazepine hydrochloride is obtained, melting with decomposition at 155 °.

Example 11; 25 a) A solution of 0.5 g of 5- (4-carbobenzoxypiperazino) imidazo (2,1-b) (1,3,5) benzothiadiazepine in 5 ml of methylene chloride is cooled to 0 ° and a solution of 0.26 g of m-chloroperbenzoic acid in 2 ml of methylene chloride is added dropwise. The mixture is stirred at 0 ° for 1.5 hours and the solid is filtered off.

The filtrate is washed with 10% aqueous potassium carbonate solution and water, then dried over magnesium sulphate and evaporated to dryness. 5- (4-Carbobenzoxypiperazino) -imidazo [2,1-b] (1,3,5) benzothiadia-35-sepine-1-oxide is obtained. Mass spectrum: m / e 435, 418, 387.

(b) In a similar manner, using 0,61 g (2 equivalents) of m-chloroperbenzoic acid gives 5- (4-carbobenzoic acid)

II

6931 O

25 soxypiperazino) imidazo [2,1-b] [3,5] benzothiadiazepine 1,1-dioxide. Mass spectrum: m / e 451, 420, 406, 386. Example 12: a) To a solution of 100 mg of 5- (4-carbobenzoxypiperazino) imidazo (2,1-b) (1,3,5) benzothiadiazepine-1-oxide in 0.3 ml of acetic acid, 0.35 ml of 2-normal hydrobromic acid in acetic acid are mixed. The mixture is kept at 100 ° for one hour and stirred overnight at room temperature. Diethyl ether is added, the 5- (4H-pipe-10-racino) -imidazo (2,1-b) (Ί, 3,5) benzothiadiazepine hydrobromide is filtered off and washed with diethyl ether. The product melts with decomposition at 75 °.

b) In a similar manner, 5- (4-carbobenzoxy-piperazino) -imidazo (2,1-b) (1,3,5) benzothiadiazepine-1,1-dioxide is converted to 5- (piperazino) -imidazo (2,1- b) (1,3,5) benzothiadiazepine-1,1,1-dioxide hydrobromide. Rf = 0.352 (silica gel, acetic acid ethyl ester-methylene chloride, 1: 1). Example 13:

A mixture of 285 mg of 5- (4H-piperazino) -imidazo-20 (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 overnight. over and then evaporated. Water is added to the residue, and the mixture is extracted with methylene chloride. The extract is dried over magnesium sulfate, evaporated and the residue is purified. 5- (4-Methylpiperazino) imidazo (2,1-b) -f,3,3,5) benzothiadiazepine is obtained, melting at 145-147 °. The product is identical to the product shown in Example 1.

Claims (2)

26 _,,. 6931 0 Claim; A process for the preparation of novel pharmaceutically acceptable 5-diazacycloalkylimidazo (2,1-b] (1,3,5) benzothiadiazepines of the general formula I (C 1 H 2) 2N in which R 1 represents hydrogen, C -C 4 -C 4 alkoxycarbonyl or C 1 -C 4 lower alkyl, R 8 represents hydrogen, C 1 -C 4 lower alkoxy, halogen or trifluoromethyl and p represents 0-2, each of m and n represents an integer of 2 or 3 and R 3 represents hydrogen, C 1 -C 4 lower alkyl, C 1 -C 4 lower alkoxycarbonyl, benzyloxycarbonyl or hydroxy-C 1 -C 4 lower alkyl in which the hydroxy group is separated from the nitrogen atom by at least two carbon atoms; , and the oxidic oxygen is attached to the nitrogen atom to which the group R3 is attached and / or for the preparation of S-oxides, their lower alkyl quaternary derivatives and salts, characterized in that a) the compounds of general formula III or their salts are dense with compounds of general formula IV (O) • P S A β H, V / v "V · 1 * y- <“ ”>«, v \ A PJ \ -2. “'S (III) <IV> - in which formulas X represents a lower alkylthio or thiocyano, 6931 O 27 NATO, Y is hydrogen or an alkali metal atom, p represents the number 0-2 and the other symbols have the meanings given in connection with formula I, or b) Compounds according to V (Q) A. ! _ £ _S \ -R {V S— * 1 (V), R .- »v · 'C H. v 3 V \, - r- <m2 "> - R, Z tl, 'n 2n are closed in a ring under dehydrating or dehydrosulfurizing conditions, in which formula Z represents an oxygen or sulfur atom and the other symbols have the meanings given above, and / or c) the resulting compound of formula I wherein R 3 is lower alkoxycarbonyl is converted by reduction to a compound of formula I wherein R 3 is lower alkyl, and / or d) the resulting compound of formula I wherein R 3 is hydrogen is converted by methylation to a compound of formula I wherein R 3 represents methyl, and / or e) the resulting compound of formula I wherein R 3 represents benzyloxycarbonyl or lower alkoxycarbonyl is converted by hydrolysis to a compound of formula I wherein R 3 represents hydrogen, and / or f) the resulting compound of formula I wherein R 3 is other than hydrogen, is converted by oxidation to the N- or S-oxide, and / or g) the resulting free compound is converted into a salt or the resulting salt into a free compound of formula I or another si salt. __ - V ~ 28 Patentkrav? 6 9 31 0 Fertilizers for the manufacture of pharmaceutical products 5-diazacycloalkylimidazo (2,1-b) (1,3,5) benzothiadiazepine with all of the formulas I. (iVx-A _ rii_ il ch / 3 n 2n color Rjl betecknar derivative, C1-4Calkoxycarbonyl or C1-4hydroalkyl, R5 betecknar derivative, C1-4C1alkoxy, halogen or trifluoromethyl and p is that 0-2, a symbol of the formula or an alkyl or 2 or 3 or R3 is attached, C1-C4-alkoxycarbonyl, C1-C4-alkoxycarbonyl, benzyloxycarbonyl or hydroxy-C1-C4-alkylalkyl, the hydroxyl groups are separated from the quaternary atom of the Stminstone 2 cholesterol derivative N-oxider, the R3 is a substituent on the alkyl or hydroxylalkyl, and the oxido-cyanogen is a compound with the group R3 the quaternary hydrogen or / or S-oxide, the quaternary alkyl kännetecknat därav, att a) föreningar med denemänna Formula III or derat salter condenser with fermen-fören Formula IV / JVv * 1 - Y- <m 2a, XR3 V% A.} ^ (UI) (IV) - color X betecknar lägalkyltio eller tiocyanato, Y är väte eller en alkalimetallatorn, p är ett tai 0-2 och de övriga symbolerna har de för formeln I angivna betydelserna, eller