NO824090L - IMIDAZOBENZODIAZEPINES, PROCEDURES FOR THEIR PREPARATION, PHARMACEUTICAL PREPARATIONS CONTAINING THESE COMPOUNDS AND THEIR THERAPEUTIC APPLICATIONS - Google Patents

Description

The invention relates to new 5-diazacycloalkylimidazo[1,2-c]-[1,3]-benzodiazepines of the general formula I

wherein each of the symbols R-^ and 1^ means hydrogen, lower-

alkyl, lower alkanoyl, halogen, cyan, carboxy, lower alkoxycarbonyl, carbamoyl, sulfamoyl, mono- or di-lower alkyl-(carbamoyl or -sulfamoyl), CnH2nst^r ^or loweralkylene, which separate the two nitrogen atoms by 2 or 3 carbon atoms and represent hydrogen, lower-

alkyl, lower alkenyl, lower alkynyl, lower alkanoyl, aryl-lower alkyl, lower alkoxycarbonyl, phenyl lower aryl oxycarbo-

nyl or (hydroxy, lower alkanoyloxy, aryloxy or lower alkoxy)-lower alkyl, in which the lower alkyl radical contains

holds at least 2 carbon atoms, R^ and R^ independently of each other mean hydrogen, lower alkyl, lower alkoxy, lower alkylthio, halogen, trifluoromethyl, hydroxy, lower alkanoyloxy, sulfamoyl, mono- or dilower alkyl sulfamoyl and Rg and R-,

means hydrogen or lower alkyl, their N-oxides, their lower alkyl quaternary lower alkyl derivatives and salts,

especially therapeutically useful salts with acids or bases, of all these compounds, as well as methods for their preparation, pharmaceutical preparations containing these compounds as well as their therapeutic use.

The term "lower" defines in the above or subsequently mentioned organic residues or compounds, such as e.g.

alkyl, alkenyl and alkynyl, those with at most 7, preferably 4, especially 1 or 2 carbon atoms.

A halogen atom is preferably fluorine or chlorine, but is

also bromine or iodine.

A lower alkyl group or one such in the mentioned alkoxy-, alkylthio- or other mentioned alkylated groups is above all methyl and also ethyl, n- or iso-(propyl, butyl, pentyl, hexyl or heptyl), e.g. 2-methylpropyl or 3-methyl-butyl, lower alkenyl preferably means allyl and lower alkynyl preferably propargyl.

Aryl lower alkyl preferably means benzyl, 1-, 2- or 3-phenylpropyl, 1- or 2-phenylethyl. Such substituents may be substituted in the phenyl ring optionally with halogen, lower alkoxy or lower alkyl.

A lower alkoxy group preferably contains 1-4 carbon atoms and means, for example, ethoxy, propoxy,. isopropoxy or especially methoxy.

A lower alkylthio group preferably contains 1-4 carbon atoms and means, for example, ethylthio, propylthio or especially methylthio.

An acyl group means, for example, lower alkanoyl, lower alkoxycarbonyl, carbamoyl, sulfamoyl, mono- or di-lower alkyl (carbamoyl or sulfamoyl), halosulfonyl or phenyl lower oxycarbonyl and the like.

Lower alkanoyl preferably stands for acetyl or propionyl and lower alkanoyloxy preferably stands for acetyloxy or propionyloxy.

A lower alkoxycarbonyl, mono- or di-lower alkylcarbamoyl or mono- or di-lower alkylsulfamoyl group is preferably methoxycarbonyl, ethoxycarbonyl, mono- or dimethylcarbamoyl or mono- or dimethylsulfamoyl.

A phenyl lower oxycarbonyl group is e.g. phenylmethoxycarbonyl or phenylethoxycarbonyl.

A lower alkylene group CnH2 is particularly ethylene, but also 1,2- or 1,3-propylene, 1,2-, 1,3- or 2,3-butylene, which preferably with the neighboring nitrogen atoms form a piperazino or homopiperazino group.

A hydroxy lower alkyl group is preferably 2-hydroxy-(ethyl or propyl), 3-hydroxy-(propyl or butyl) or 4-hydroxybutyl, respectively.

A lower alkanoyloxy lower alkyl group preferably means lower alkanoyloxy-(ethyl, propyl or butyl), for example 2-acetyloxy- or 2-propionyloxy- (ethyl, propyl or butyl), 3-acetyloxy- or 3-propionyloxy-(propyl or butyl.), 4- acetyloxy- or 4-propionyloxybutyl and similar compound groups.

A lower alkoxy lower alkyl group preferably means lower alkoxy (ethyl, propyl or butyl), which e.g. 2- methoxy- or ethoxy (ethyl, propyl or butyl), 3- methoxy- or 3-ethoxy (propyl or butyl), 4- methoxy- or 4-ethoxybutyl and similar compound groups.

An aryloxylaverealkyl group preferably means phenyloxy-(ethyl, propyl or butyl), whereby such groups can optionally be substituted in the phenyl ring preferably with halogen, lower alkoxy or also lower alkyl.

Lower alkyl quaternary derivatives of compounds of formula I are preferably e.g. methyl, ethyl or propyl quaternary salts derived from reactive esters of lower alkanols with preferably 1-4 carbon atoms, such as e.g. methanol, ethanol or propanol. The anions of the mentioned derivatives, i.e. salts, are preferably those which correspond to the therapeutically usable acids, such as e.g. halides, for example bromides or iodides, sulphate or lower alkyl sulphonates such as methyl sulfonate.

Although the N-oxides or quaternary lower alkyl salts of compounds of formula I also include those in which one or more ring nitrogen atoms are functionalized,

the mentioned N-oxides, quaternary lower alkyl salts are preferably derived from compounds of formula I, in which R means lower alkyl, aryl-lower alkyl or (hydroxy-, lower alkanoyloxy-, aryloxy- or lower alkoxy-) lower alkyl with at least 2 carbon atoms in the lower alkyl residue and in in which the nitrogen atom carrying the substituents R^ is functionalized.

The mentioned compounds of formula I give acid addition salts preferably with therapeutically applicable inorganic or also organic acids, such as e.g. with strong mineral acids - such as halogenated hydrogen acids, e.g. Hydrochloric or hydrobromic acid, sulphurous, phosphoric or also nitric acid, or with organic acids, such as e.g. aliphatic or aromatic carboxylic acids or sulphonic acids, e.g. formic, acetic, propionic, amber, ■glycol, milk, apple, wine, lemon, maleic, fumaric, hydroxymaleic, pyruvic, phenylacetic, benzo-, 4-aminobenzo- , anthranyl-, 4-hydroxybenzo-, salicyl-, 4-aminosalicyl-, pamoe-, nicotine, methanesulfone-, ethanesulfone-, hydroxyethanesulfone-, ethylenesulfone-, halobenzenesulfone-, toluenesulfone-, naphthalenesulfone-, sulfanil- or cyclohexylsulfamic acid or ascorbic acid.

Compounds of formula I, in which R 1 and/or R 2 is carboxy, also form salts with bases, preferably those which give therapeutically useful salts, e.g. ammonia, mono-, di- or tri-lower alkylamines, lower alkylene amines, morpholine, piperazih, pyridine or with lower alkyl derivatives of the aforementioned cyclic bases, alkali metal or alkaline earth metal hydroxides.

The compounds according to the invention exhibit valuable pharmacological properties, particularly psychoactive, such as e.g. neuroleptic effects, but also antiallergic such as e.g. antihistaminic effects. These can be demonstrated by animal experiments, preferably on mammals, e.g. mice, rats, guinea pigs or monkeys as test subjects. The said compounds can be administered enterally or parenterally, preferably orally or subcutaneously, intravenously or intraperitoneally, e.g. in the form of capsules or in the form of starch containing suspensions or aqueous solutions. The dose used may range from about 0.1 to 100 mg/kg/day, preferably about 0.5 to 50 mg/kg/day, especially between 1 to 30 mg/kg/day.

The aforementioned neuroleptic properties can be demonstrated in adult rats or squirrel monkeys. The animals are trained to operate a lever so that they can avoid

to be subjected to an electric shock to the foot. Each push of the bar moves the shock by 30 seconds. If the animal forgets to press the barbell once during the mentioned period of time, short electric shocks (0.5 sec.) are delivered every 15 seconds until the animal presses the barbell again. Under control conditions, the test animal presses down on the barbell at a moderately leisurely rate and rarely receives more than 5 or 6 shocks during a 25-minute (rat) to 4-hour test period. The said compounds, which are administered to the animals 30, 90 and 210 minutes before testing, block the learned conditioned avoidance behavior. The consequence is a reduction in the avoidance reactions and a significant increase in shock to which the animals are exposed. Both the number of avoidance reactions and the number of misbehavior (shocks received) are recorded for the assessment.

Finally, the antihistaminic properties can be demonstrated in vitro according to Chasin et al., J. Neurochem. 22^, 1031 (1974). Homogenates of a cell-free preparation from the cerebrum cortex of guinea pigs are initially incubated with <3>H-adenine, whereby endogenous "^H-adenosine triphosphate is formed. The homogenates are then incubated with 50 umolar histamine to activate the synthesis of ^H-cyclic adenosine monophosphate. This work is carried out in the presence or absence of the test compound, using concentrations between 0.01 and 100 umol. If the tested substance is active, then the histamine activation of adenylate cyclase is inhibited. IC^Q- the value means the concentration at which histamine activation is inhibited by 50%.

The compounds according to the invention can therefore be used as neuroleptics and antihistamine preparations, e.g. in the treatment and control of psychotic phenomena such as e.g. aggression, agitation, schizophrenia phenomena and/or allergic conditions in mammals, including humans. They can also be used as intermediates for the production of other valuable products, especially pharmacologically active preparations.

Preferred compounds according to the invention are those of formula I, in which each of the symbols R, and R2 means hydrogen, lower alkyl, cyan, carboxy, lower alkoxycarbonyl or carbamoyl and n means the whole numbers 2-4, R^ stands for hydrogen, lower alkyl, lower alkoxycarbonyl or hydroxy-lower alkyl with 2-4 carbon atoms in the lower alkyl residue, R^ means hydrogen, lower alkyl, lower alkoxy, lower alkylthio, halogen- or trifluoromethyl and R<- stands for hydrogen and Rg and R^ have the meaning of hydrogen or lower alkyl, their N-oxides, quaternary alkyl derivatives and salts, especially therapeutically useful salts of all these compounds.

Compounds of formula I are also preferred, in which each of the symbols R^ and means hydrogen, methyl, ethyl, cyano, carboxy, lower alkoxycarbonyl with 1-3 carbon atoms in the lower alkyloxy acid ring or carbamoyl, n means an integer 2 or 3, R^ stands for hydrogen, lower alkyl with 1-3 carbon atoms, lower alkoxycarbonyl with 1-3 carbon atoms in the lower alkoxy residue, hydroxyethyl or hydroxypropyl,

R^ means hydrogen, methyl, methoxy, methylthio, chlorine or trifluoromethyl, R<- means hydrogen and Rg and R^ means hydrogen or methyl, their N-oxides, quaternary methyl derivatives

and salts, especially therapeutically useful salts, of all these compounds.

Particularly preferred are compounds of formula II

in which each of the symbols R, and R2 independently of each other means hydrogen or lower alkyl, R^ stands for hydrogen, lower alkyl or hydroxy-lower alkyl, in which hydroxy is separated from the nitrogen atom by at least 2 carbon atoms, R^ means hydrogen, lower alkyl, lower alkoxy, lower alkylthio, halogen or trifluoromethyl, cnH2n stands for ethylene or propylene, their N-oxides and salts, especially therapeutically useful salts thereof.

Of particular interest are such compounds of formula II, in which each of the symbols R^ and R2 independently of each other means hydrogen or methyl, R^ means hydrogen, methyl, ethyl, propyl, 2-hydroxyethyl or 3-hydroxypropyl and R^ stands for hydrogen, methyl, methoxy, fluorine, chlorine or trifluoromethyl, CnH2n^ether ethylene or propylene, their N-oxides and salts, especially therapeutically useful salts thereof.

Also of particular importance are compounds of formula II, in which R^ and R2 independently of each other mean hydrogen or methyl and R^ means hydrogen, methyl, ethyl, propyl, 2-hydroxyethyl and R^ stands for hydrogen, methyl, fluorine, chlorine or trifluoromethyl and cnH 2 n means ethylene and their salts, especially therapeutically useful salts.

As a special representative of the compounds according to the invention, the compound according to the below-mentioned example 1,5-(4-methyl-1-piperazinyl)-11H-imidazo-[1,2-c][1,3Jbenzodiazepine alludes to the antipsychotic properties. The compound decreases avoidance responses (increase in error behaviors) in rats and squirrel monkeys at an orally administered total dose of 30 mg/kg or less.

The antihistaminic effect is particularly illustrated by 5-(4-methyl-1-piperazinyl)-11H-imidazo[1,2-c][1,3]benzodiazepine (compound from example 1). This compound inhibits the histamine activation of adenylate cyclase with an IC^q of approximately 1 x 10^ mol.

Furthermore, it should be further mentioned that the connection according to

the example below 1, 5-(4-methyl-1-piperazinyl)-11H-imidazo[1,2-c][1,3]-benzodiazepine also distinguished itself in that it is essentially free of extrapyramidal side effects, like for example. dyskinesias and dystonias in squirrel monkeys (dyskinetic movements and dystonic postures) and has only minimal α-adrenergic blocking activity in vitro.

The compounds according to the invention are produced according to methods known per se, e.g. in that one

a) condenses a compound of formula III

wherein X means a together with hydrogen or an alkali metal

leaving group and the other symbols have the meanings indicated under the formula I, with a connection with the formula

IV

or an alkali metal derivative thereof, in which it has the meaning given under formula I, and, if desired, converts a formed compound of formula I into another compound according to the invention.

A group that can be split off together with hydrogen or an alkali metal atom is e.g. primarily a free or preferably etherified mercapto group, further an optionally functional converted reactive hydroxy group, cyanato or thiocyanato group or the nitroamino group. An etherified mercapto group is primarily an etherified mercapto group with an optionally substituted hydrocarbon residue, especially of an aliphatic character. It indicates primarily lower alkylthio, e.g. methylthio, ethylthio or butylthio or phenyllower alkylthio, e.g. phenylthio or benzylthio. An optionally functionally converted reactive hydroxy group is a free and, among other things, a corresponding esterified hydroxy group. One such is, among other things, halogen, e.g.

chlorine or bromine, or lower alkylsulfonyloxy, e.g. methanesulfonyloxy. An etherified hydroxy group is, for example, a lower alkoxy group such as e.g. methoxy or ethoxy.

This condensation takes place advantageously in an excess of the used compound of formula IV or with an equivalent amount of the in situ prepared alkali metal compound thereof, when X as a leaving group of a compound of formula III preferably means halogen, lower alkylthio or thiocyanato. Depending on the meaning of X, the reaction takes place at temperatures between 0° and 150°C, preferably in a suitable solvent such as e.g. lower alkanol, for example amyl alcohol, dimethylformamide, hexamethylphosphoramide or toluene. However, the aforementioned condensation of a compound of formula III with a compound of formula IV can also be carried out in the presence of an acid, for example a halogen-hydrogen acid, e.g. hydrochloric acid (hydrochloric acid).

The new 11H-imidazo[1,2-c][1,3]benzodiazepine starting materials of formula III are prepared according to ring-closing methods known per se. Compounds of formula V are preferably condensed

in which R^, R2, R^-R-, have the meanings given under formula I, with reactive carboxylic acid derivatives, e.g. phosgene, thiophosgene, 1,1<1->carbonyldiimidazole, cyanogen bromide or chloroformic acid phenyl ester.

Compounds of formula III, in which X is hydroxy,

can be converted into those, in which X stands for sulfhydryl, with conventional sulphurizing agents, e.g. with phosphorus pentasulfide. These can be transferred in compounds, in which X

has the meaning given above under formula III, analogous to the methods described in the examples.

Starting compounds of formula V are preferably prepared by reduction of corresponding differently substituted 2-(o-nitro-benzyl)-imdazoles by reduction which in turn are preferably prepared from the correspondingly substituted o-nitrobenzylnitriles and 2-aminoacetals (or ketals), for example aminoacetaldehyde dimethyl acetal , according to known, analogous to the methods described in the examples.

A further method for preparing compounds of the general formula I consists in that one

b) ring-closes a compound of formula VI

under hydrating, dehydrosulfurizing and deaminating conditions, in which Z means an oxygen atom or sulfur atom or NH, and the other symbols have the meanings given above, and if desired, converts a formed compound into another compound according to the invention. The aforementioned ring closure method is preferably carried out at a temperature between 0° and 120°, for example with phosphorus halides, which e.g. phosphorus pentachloride and/or -oxyhalides or cyanide halides, with or without crown ether catalyst, e.g. 8-crown-6-ether, in the presence or absence of basic catalysts, such as e.g. triethylamine or potassium carbonate, preferably in an inert solvent, e.g. acetonitrile or toluene.

The starting substances with formula VI can, if they are new, be prepared according to methods known per se. For example, the starting substances with formula VI can be prepared starting from the (tautomeric) starting compounds with formula III, in which X means hydroxy, thio or amino. These compounds are condensed with compounds of formula IV in the presence or absence of other bases, e.g. those mentioned above, preferably in inert solvents, such as methylene chloride or toluene, at temperatures between 0° and 150°C, preferably between 10 and 50°C. The ring opening is preferably carried out at lower temperatures in order to prevent the reactions of possibly present reactive functional

groups and R2.

In another way, starting substances of formula VI, in which R3 is lower alkanoyl, lower alkoxycarbonyl or phenyl-lower alkyloxycarbonyl, can be prepared by condensation of compounds of formula V with a compound of formula VII

in which Y' means halocarbonyl, halothiocarbonyl or cyan, preferably in an inert solvent as already indicated above, at temperatures between 0° and 150°C

in the presence or in the absence of a basic catalyst, such as triethylamine or potassium carbonate.

Starting compounds of formula VII are preferably obtained from compounds of formula IV, in which R^ has the meanings given under formula VII, or from the corresponding N-trimethylsilyl derivatives by reaction with phosgene, triophosgene or cyanogen bromide in an inert solvent, such as e.g. diethyl ether, methylene chloride or dimethoxyethane at temperatures between -40°C and +50°C. The reaction can be carried out in the presence or absence of a basic catalyst, for example triethylamine or potassium carbonate.

The formed compounds according to the invention can be transferred in a manner known per se into other compounds of formula I according to the invention. Thus, e.g. compounds,

in which R^ is hydrogen or an alkali metal atom,

e.g. their sodium or lithium salts, with substituted or unsubstituted oxiranes e.g. with ethylene oxide or with reactive esters of unsubstituted or correspondingly substituted, aliphatic or araliphatic alcohols, e.g. methanol, ethanol, methoxyethanol, phenoxyethanol, allyl or propargyl alcohol are transferred in the corresponding N-substi-

tuated compounds or quaternary derivatives, depending on the molar amounts of the alkylating agent used. These esters are, for example, derived from strong inorganic or organic acids, preferably from halogen hydrogen acids,

e.g. hydrochloric, hydrobromic or hydroiodic acid, sulfuric acid or an aromatic sulphonic acid, e.g. p-toluenesulfonic acid or m-bromobenzenesulfonic acid. Intermediates of formula I, in which R^ denotes an alkali metal atom or also alkali metal derivatives of compounds of formula IV

can be formed by metallization with reactive organic metal compounds, e.g. lithium diisopropylamide, with alkali metal alkoxides, e.g. sodium methoxide (sodium methylate) or with alkali metal hydrides, e.g. sodium or potassium hydride.

Unsaturated compounds, e.g. such, in which R^ means lower alkenyl or lower alkynyl, can be converted with catalytically activated hydrogen in the compounds, in which R^ means the corresponding lower alkyl radical. Conversely, N-alkylated compounds formed can be converted into N-unsubstituted compounds. The N-benzyl compounds are catalytically hydrogenolysed or they are converted, e.g. with haloformic acid lower alkyl esters, e.g. chloroformic acid ethyl ester, whereby the N-acyl derivative is obtained, by which e.g. can be transferred with aqueous bases, e.g. alkali metal hydroxides, such as an aqueous sodium hydroxide solution, in the aforementioned N-unsubstituted compounds (R^ = H).

Compounds of formula I, in which R^ means hydroxyl lower alkyl, can also be prepared by reacting corresponding compounds of formula I, in which R^ means hydrogen, first with reactive derivatives of corresponding glycols, glycolic acids or dicarboxylic acids, e.g. their lower alkyl esters, halides of the anhydrides, or react with reactive esters of the aforementioned glycols or glycolic acid derivatives, e.g. with esters of hydrohalogen acids or aromatic sulphonic acids, 1,2-dibromoethane or -1,2-dibromopropane, bromoacetic acid ethyl ester or bromopropionic acid ethyl ester, tosyloxyacetic acid ethyl ester, oxalic acid diethyl ester, malonic acid diethyl ester or oxalic acid monoethyl ester chloride. The intermediate products formed are either hydrolyzed or reduced with simple or complex light metal hydrides, e.g. lithium aluminum hydride, alone or with diborane, to compounds of formula I, in which R-. means hydroxy lower alkyl.

Compounds of formula I, in which R^ means lower alkyl, for example methyl, can be prepared as described below: First compounds, in which R^ stands for hydrogen,

by reaction with haloformic acid lower alkyl esters or -phenyl lower alkyl esters, e.g. chloroformic acid ethyl ester, transferred in the compounds of formula I, in which R 1 means lower alkoxycarbonyl or phenyl lower oxycarbonyl. These acyl derivatives are then reduced with simple or complex light metal hydrides, e.g. with lithium aluminum hydride, sodium tri-tert.butoxy aluminum hydride or sodium bis(2-methoxyethoxy)aluminum hydride.

N-acyl derivatives, in which R^ for example means a lower alkanoyl group, can be formed from compounds of formula I,

in which R^ denotes hydrogen and correspondingly reactive acid derivatives, e.g. acid halides, simple or activated esters, e.g. alkyl esters or cyanoalkyl esters, anhydrides or isocyanates. These formed compounds can further be reduced in compounds of formula I, in which R^ means lower alkyl, as indicated above, compounds of formula I,

in which R 2 is hydroxyl lower alkyl, can be acylated as indicated above to compounds in which R 2 is lower alkanoyloxy lower alkyl. Formed compounds with formula

I, in which R^ and/or R~ means hydrogen, can be converted

in the corresponding (halogen or acyl) derivatives, e.g.

by halogenation, preferably with chlorine in acetic acid or under conditions of the Friedel-Crafts reaction by acylation with a trihaloacetyl halide or a halosulfonic acid, and subsequent treatment with an alkali metal-lower alk-

oxide, hydroxide or amide. Formed carboxylic acid-

or sulfonic acid derivatives can then be hydrolyzed in a known manner, preferably under alkaline conditions and/or amidated with ammonia, mono- or di-lower alkyl amines. The carboxamides formed can be hydrated according to conventional methods to the corresponding nitriles. Compounds of formula I, in which R, and/or R^ means carboxy, can for example be formed by hydrolysing compounds, in which R-^ and/or R^ means cyan, carbalkoxy or carbamoyl.

Tertiary amines formed, in which R^ separates from hydrogen and for example means lower alkyl or aryl lower alkyl,

can be converted in a manner known per se into the N-oxides. One works e.g. with hydrogen peroxide or organic peracids, e.g. lower peralkanoic acids or perbenzoic acids such as peracetic acid or m-chloro-perbenzoic acid, preferably at room temperature or with the latter acid at a temperature lower or up to 100° with dilute hydrogen peroxide, in the presence of lower alkanoic acids, e.g. acetic acid. If mono-N-oxides are desired, then it must be ensured that further oxidations are prevented.

Finally, the compounds according to the invention can be obtained in the form of free bases or as salts. A formed free base can be transferred into the corresponding acid addition salt, preferably with acids that give therapeutically useful acid addition salts or with anion exchangers. Formed salts can be converted into the corresponding free bases, e.g. by treatment with a stronger base such as with a metal hydroxide or ammonium hydroxide, basic salt or a cation exchanger, e.g. with an alkali metal hydroxide or carbonate. Acids that give therapeutically useful acid addition salts are e.g. the inorganic acids or organic acids described above.

Compounds of formula I, in which R-^ and/or R^ denotes carboxy, can also be transferred in the corresponding metal or ammonium salts, e.g. by treatment with alkali or alkaline earth metal hydroxides or carbonates, ammonia or with the above-mentioned amines. These or other salts e.g. the picrates can also be used in the purification of the formed free bases. The bases are transferred in their salts, the salts are separated and the bases are released from the salts.

Because of the narrow relationship between the new connections

in free form and in the form of their salts, in the foregoing and the following, free compounds and salts also possibly mean the corresponding salts or free compounds.

Formed racemates of compounds, e.g. those with a formula

I to VII, can be divided according to per se known methods, e.g. by fractional distillation, crystallization and/or chromatography, in the individual isomers. Racemic products can thus be resolved into their optical antipodes, e.g. by separation of their diastereoisomeric salts, e.g. by fractional crystallization of d- or a-tar-trates.

The above-mentioned reactions are carried out according to methods known per se in the presence or absence of diluents, preferably in those that are inert to the reagents and dissolve them, catalysts, condensation or other above-mentioned agents and/or in an inert atmosphere under cooling at room temperature or elevated temperatures, preferably at the boiling point of the solvent used at normal or elevated pressure.

The invention also includes modifications of the method according to which an intermediate product formed at one or another step of the method is used as starting material,

and the remaining process steps are carried out or the process is interrupted at one step or another, or according to which a starting material is formed under the reaction conditions or in which a starting material is used in the form of a salt or optically pure antipodes.

In the process, starting materials are preferably used which lead to the compounds described above as particularly valuable, especially those with formula II.

Pharmacologically usable compounds according to the invention can be used for the production of pharmaceutical preparations containing an effective amount of the active substance together or in mixtures with carriers suitable for enteral or parenteral administration. Preferably, tablets or gelatin capsules are used which contain the active substance together with a diluent, e.g. lactose, dextrose, cane sugar, mannitol, sorbitol, cellulose and/or glycine, and lubricants, e.g. diatomaceous earth, talc, stearic acid or salts thereof, such as magnesium or calcium stearate and/or polyethylene glycol. Tablets also contain binders, e.g. magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and/or polyvinylpyrrolidone, and if desired explosives, e.g. starches, agar, alginic acid or its salt, as well as sodium alginate and/or fizzy mixes or adsorbents, colourants, flavorings and sweeteners. Injectable preparations are preferably isotonic aqueous solutions or suspensions and suppositories, primarily fat emulsions or suspensions. The pharmacological preparations may be sterilized and/or contain excipients, e.g. preservative, stabiliser, wetting and/or emulsifying agent, solubility mediators, salts for regulating the osmotic pressure and/or buffers. The pharmaceutical preparations which, if desired, can contain additional pharmacologically valuable substances, are produced in a manner known per se, e.g. using usual mixing, granulating or coating methods, and contains from approx. 0.1% to approx. 75%, especially from approx. 1% to approx. 50% of the active substance. A single dose for mammals weighing approximately 50-70 kg may contain between approximately 25-200 mg of the active ingredient.

The following examples a) to e) shall, for example, generally illustrate the production of some typical forms of application, however they in no way indicate the only forms of execution of such. Separate embodiments are described in the examples.

a) 100.0 g is mixed with 610.0 g lactose and 442.0 g potato starch, the mixture is moistened with an alcoholic solution

of 8 g of gelatin and granulate through a sieve. After drying, 60.0 g of talc, 10.0 g of magnesium stearate and 20.0 g of colloidal silicon dioxide are mixed and the mixture is pressed into 10,000 tablets each weighing 125 g and containing 10 mg of active ingredient, which can be supplied with a portion if desired - slits for more precise adjustment of the dosage.

b) From 100.0 g of active ingredient, 379.0 g of lactose and the alcoholic solution of 6.0 g of gelatin, a granulate is prepared which, after drying, is mixed with 10.0 g of colloidal silicon dioxide, 40.0 g of talc , 60.0 g potato starch and 5.0 g magnesium stearate and presses to 10,000 dragon kernels. These are then coated with a concentrated syrup

of 533.5 g of crystal, sucrose, 20.0 g of shellac, 75.0 g of gum arabic, 250.0 g of talc, 20.0 g of colloidal silicon dioxide and 1.5 g of dye and dried. The formed dragees each weigh 150 mg and each contain 10 mg of active ingredient. c) 10.0 g of active substance and 1990 g of finely grated suppository base mass (e.g. cocoa butter) are thoroughly mixed and then melted. From the homogeneous melt formed by stirring, 1000 suppositories of 2.0 g are cast. They each contain 25 mg of active ingredient. d) To make a syrup with 0.25% active ingredient content, dissolve in 3 liters of dist. water 1.5 liters glycerin, 42 g

p-Hydroxybenzoic acid methyl ester, 18 g of p-hydroxybenzoic acid n-propyl ester and, under slight heating, 25.0 g of active substance, add 4 liters of 70% sorbitol solution, 1000 g of crystals, sucrose, 350 g of glucose and a flavouring, e.g. 250 g

"Orange Peel Soluble Fluid" from Eli Lilly and Co., Indiana-polis, or 5 g of natural lemon flavor and 5 g of "Halb und Halb" essence, both from the firm of Haarmann und Reimer, Holzminden, Germany, filter the solution formed and fulfill the filtrate with dist. water to 10 litres.

e) To prepare a drip solution with 1.5% active substance content, dissolve 150.0 g of active substance and 30 g

sodium cyclamate in a mixture of 4 liters of ethanol (96%) and 1 liter of propylene glycol. On the other hand, 3.5 liters of 70% sorbitol solution are mixed with 1 liter of water and the mixture is added to the above-mentioned active substance solution. A flavoring substance is added to this, e.g. 5 g cough tablet aroma or 30 g grapefruit essence, both from the firm Haarmann und Reimer, Holzminden, Germany, all mixed well, filtered and filled with dist. water to 10 litres.

The following examples illustrate the preparation of the new compounds of formula I, but they should in no way limit the scope of the invention. Temperatures are given in degrees Celsius.

Example 1

A mixture of 5100 ml of amyl alcohol and 918.35 g (9.17 mol) of 1-methylpiperazine is filled into a 12 liter large three-necked flask

which is provided with a Dean-Stark essay. 989 ml of 10-normal ethanolic hydrogen chloride is quickly added to this solution mixture under nitrogen and stirring. The resulting reaction mixture is heated to reflux and the distillate

is captured in the Dean-Stark thesis. As soon as the temperature of the reaction mixture reaches 131°, the Dean-Stark apparatus is removed and an additional 918.35 g (917 mol) of 1-methylpiperazine and 1045.0 g (4.56 mol) of 5-methylthio-11H-imidazo[1,2 -c][1,3]-benzodiazepine is added. The mixture is heated under nitrogen for a further 20 hours at reflux. The amyl alcohol contained in the reaction mixture is removed in vacuo at a water bath temperature of 80°. They obtained viscous, oil-

active residues are dissolved in 10,000 ml of dichloromethane, the solution is washed 3 times with 4,000 ml of 4-normal aqueous sodium hydroxide solution and 6 times with 4,000 ml of water.

Finally, the dichloromethane solution is extracted 3 times with 2000 ml of aqueous 6-normal hydrochloric acid. The aqueous solution is then further washed out 2 times with 2000 ml of dichloromethane, decolorized with activated carbon, filtered and the clear filtrate is adjusted with 1500 ml of 29% aqueous ammonia to a pH value of 9-10. The oil which separates is extracted 3 times with 4000 ml of dichloromethane, the combined extracts are dried, filtered and evaporated at 60° water bath temperature.

An oil is obtained as a residue which quickly turns into a solid state and after further drying under vacuum (5 mm Hg/ 40°) a crude product is obtained which melts at 113-120°.

The crude product obtained is dissolved in 8000 ml of warm (60-70°) isopropanol, the solution is treated for decolorization with 200 g of activated charcoal and this is filtered.

A solution of 760.7 g (8.28 mol) of maleic acid in 2500 ml of warm (30°) isopropanol is added to this obtained filtrate, whereby the maleate is precipitated as a salt. The resulting suspension is stirred overnight at room temperature to complete crystallization. The crystalline precipitate obtained is filtered off and the product obtained is washed 3 times with 500 ml of cold isopropanol and dried under vacuum (0.5 mm/50°) and recrystallized from ethanol.

After washing with ethanol and ether, after drying, 5-(4-methyl-1-piperazinyl)-11H-imidazo[1,2-c][1,3]benzo-diazepine is obtained as monomaleate with a melting point of 204-205°

(fission).

A solution of 2246 g of the maleate salt prepared above in 9000 ml of water is treated with 100 g of activated carbon and then filtered. The aqueous solution is adjusted with 1000 ml of 29% aqueous ammonia to a pH value of

9 and the thereby obtained free base is separated as oil.

The oil formed is extracted 3 times with 2000 ml of dichloromethane, the combined extracts are dried over sodium sulfate, filtered and evaporated at approximately 40° water bath temperature.

The residue formed is recrystallized from 14,130 ml of heptane. The faint yellow residue is collected, washed twice with

500 ml of heptane and dried in vacuo (0.01 mm/50°). 5-(4-methyl-1-piperazinyl)-11H-imidazo[1,2-c][1,3]benzodiazepine is obtained as a free base which melts at a temperature of 123-124°.

The starting material is prepared as follows: 24,000 ml of absolute ethyl alcohol and 3240 g (60.0 mol) of sodium methylate are filled into a 70 liter reaction flask. This solution is stirred under nitrogen, a further solution of 8228.4 g (60.0 mol) of o-nitrotoluene and 8768.4 g (60.0 mol) of diethyl oxalate is added at once. The solution mixture formed is heated for 25 minutes at reflux, cooled to 60° using an ice bath and then carefully added with 18,000 ml of water. The reaction mixture is then heated at reflux for one hour, the largest part of the ethyl alcohol is removed, the solution is cooled to 50° and a solution of 4140 g (59.6 mol) of hydroxylamine hydrochloride in 6000 ml of water is added at once, whereby the temperature is continuously is kept at 50°. By adding 6000

ml of a 10-normal aqueous sodium hydroxide solution, the pH value of the reaction mixture is adjusted to 7. The reaction mixture is stirred overnight at room temperature. The resulting suspension is cooled to 10° and the pH is adjusted to 1 with 6000 ml of aqueous 12-N hydrochloric acid, whereby stirring of the reaction mixture is continued overnight at a temperature of 10° to continue the liberation of the free acid. The precipitate is separated, washed 6 times with 4000 ml of water, dried overnight in air and then suspended in 20,000

ml toluene. The resulting suspension is stirred for one hour under nitrogen, filtered and the residue washed 4 times with each time 2000 ml of toluene and 4x2000 ml of petroleum ether and dried at 60°/5 mm Hg. You get the oxime of 2-nitrophenylpyruvic acid

which melts at a temperature of 158-160<*> (during decomposition).

50,000 ml of water, 2940 ml of glacial acetic acid and 22.2 mol of the formed oxime of 2-nitrophenylpyruvic acid are filled into a 70 liter reaction vessel. The resulting suspension is heated and stirred under nitrogen for 2 hours at 90°. The reaction solution, which has assumed a dark color and is present as a suspension, is allowed to cool slowly, stirred overnight at room temperature, extracted 5 times with 4000 ml of methylene chloride each time, washed 3 times with 3000 ml of water each time, dried over magnesium sulfate and filtered. The resulting filtrate is treated with activated carbon, further filtered and the solvent is removed in vacuo. The fixed resi-

duum is recrystallized from 1000 ml of isopropanol. 2-nitrophenylacetonitrile with a melting point of 82-84° is obtained.

One fills 2250 ml abs. ethanol and 1500 g (9.25 mol) of 2-nitrophenylacetonitrile in a 22 liter flask. The suspension is cooled to 5-10° and hydrogen chloride is introduced into the mixture for 2.5 hours. The reaction mixture is stirred at 10° under nitrogen overnight, then diluted with 16,000 ml of ether and stirred for one hour. The precipitate is filtered off, washed with 4x1000 ml of ether and dried (5 mm Hg/40°). Ethyl 2-(2-nitrophenyl)acetimidate is obtained as hydrochloride. Melting point 122-123 °

(fission).

2200 ml of ethanol and 5156 g (8.81 mol) of ethyl 2-(2-nitrophenyl)-acetimidate as hydrochloride are filled into a 22 liter flask.

The resulting suspension is stirred under nitrogen at room temperature and 1022.9 g (9.73 mol) of aminoacetaldehyde-dimethylacetate is added. The reaction mixture is further stirred for one hour and then 1693 ml of aqueous 12-normal hydrochloric acid is added all at once, whereby the temperature of the reaction mixture due to the exothermic reaction increases to 40°.

When additional heat is added, the temperature is increased

to 70-80° and maintained for 30 minutes. The solution mixture is cooled using an ice bath to 20°, for

diluted with 2700 ml of aqueous 10-normal caustic soda, whereby the reaction product is precipitated. The resulting suspension is stirred for one hour at 10° under nitrogen, the precipitate is filtered off and washed 3 times with 2000 ml of water each time.

The 2-(2-nitrobenzyl)-imidazole produced melts at 155-157°.

5672 ml of a 50% aqueous ethanol and 2890 g (14.22 mol)

of the produced 2-(2-nitrobenzyl)-imidazole is filled into a 22 liter flask. The resulting suspension is stirred under nitrogen and added at once with 2400 g (42.97 mol) of iron powder (grain size = 100 mesh). The reaction mixture is then heated to 70° and added with a solution containing 1.7 ml of 12-normal hydrochloric acid in 8.3 ml of abs. alcohol. The rapidly progressing exothermic reaction that ensues heats the reaction mixture for 1.5 hours at reflux. After completion of the exothermic reaction, a mixture of 290 ml of a 12-normal hydrochloric acid and 1400 ml of absolute alcohol is added over a period of 30 minutes. The reaction mixture is heated for 2 hours at reflux, diluted with 6500 ml of absolute ethanol and adjusted with 700 ml of a 10 normal aqueous sodium hydroxide solution to a pH value of 8-9. The resulting suspension is stirred for one hour and then filtered. The formed precipitate (filter cake) is washed with 1000 ml of absolute ethanol, the filtrates are combined and the solvent is removed. The solid precipitate obtained from the filtrate is suspended in 10,000 ml of water, stirred under nitrogen for 2 hours, filtered off and washed with 2,000 ml of water and dried. The 2-(2-aminobenzyl)-imidazole is obtained with a melting point of 153-155°.

42,000 ml of dichloromethane and 5120 g (50.65 mol) of triethylamine are filled into a 70 liter flask. Under nitrogen and continuous stirring, 4370 g (25.23 mol) of 2-(2-aminobenzyl)-imidazole are added. The resulting suspension is cooled to a temperature of 0-5° and, over a period of more than 3 hours, 3421 g (29.75 mol) of an 85% thiophosgene containing

tetrachlorocarbon solution whereby the reaction temperature slowly increases to 15°. The suspension is further stirred for 4 hours at 10° and then overnight at room temperature. The precipitate is collected, washed 2 times with each time 3000 ml of dichloromethane and 5 times with each time 4000 ml of water, dried at 60° in vacuum (5 mm Hg). The 11H-imidazo[1,2-c][1,3]benzodiazepine-5(6H)-thione is obtained with a melting point of 182-183°.

to 20,000 ml of absolute ethanol is added under nitrogen and continuous stirring 517.62 g (9.58 mol) of sodium methylate.

(Charge in a 70 liter flask.) After stirring for half an hour, complete dissolution occurs so that 2063 g (9.58 mol) of 11H-imidazo[1,2-c][1,3]benzodiazepine-5(6H)- tion is added for further turnover. After a further hour of stirring at room temperature, complete dissolution occurs again. To the clear solution is added, while cooling at 1°, 1360 g (9.58 mol) of methylene iodide over a period of slightly more than 30 minutes. The resulting reaction mixture is stirred for 4 hours at a temperature of 5° and then overnight at room temperature. The cloudy solution formed is cooled to 5° and diluted with 50,000 ml of water. The resulting suspension is then further stirred for 4 hours at 5°, the precipitate is separated and dried at 60°

in vacuum (5 mm Hg). The 5-methylthio-11H-imidazo[1,2-c]-[1,3Jbenzodiazepine is obtained, which exhibits a melting point of 87.88°.

In an analogous way, starting from 4-chloro-2-nitrophenylacetonitrile, 8-chloro-11H-imidazo [1,2-c] [1,3]-benzodiazepine-5(6H)-thione is obtained with a melting point of 200-201° and The 8-chloro-5-methylthio-11H-imidazo [1,2-c] [1,3jbenzodiazepine hydrochloride which melts at a temperature of 255-257°.

The following starting compounds are prepared in the same way from the correspondingly substituted 2-nitrophenyl-acetonitrile: a) 8-methyl-5-methylthio-11H-imidazo[1,2-c][1,3]benzodiazepine, b) 8-fluoro -5-methylthio-11H-imidazo[1,2-c][1,3]benzodiazepine, c) 8-methoxy-5-methylthio-11H-imidazo[1,2-c][1,3]benzodiazepine.

Example 2

To a suspension of 2.46 g of 1-[2-(2-imidazolylmethyl)-phenyl-carbamoyl]-4-methylhomopiperazine in 19.4 ml of phosphorus oxychloride was added 1.66 g of phosphorus pentachloride and the resulting reaction mixture was further stirred for 4 hours at room temperature. The mixture is evaporated to dryness (in vacuo), the residue is suspended in 45.2 ml of methylene chloride, the resulting suspension is cooled to 0° and added dropwise over a period of 15 minutes while stirring with 21.4 ml of triethylamine. The mixture is allowed to warm to room temperature, stirred for a further 1 hour and the resulting liquid is poured

■reaction mixture in a 10% aqueous potassium carbonate solution (pot ash solution). The methylene chloride layer which thereby separates is separated, the aqueous layer is washed with methylene chloride and the combined methylene chloride extracts are dried over magnesium sulfate, decolorized with activated charcoal and evaporated to dryness. The residue formed is purified by column chromatography over 50 g of silica gel, whereby a solution mixture of methylene chloride/methanol/conc. ammonia solution (300:50:1) is used as eluent.

The 5-(4-methyl-1-homopiperazinyl)-11H-imidazole[1,2-c]-[1,3]benzodiazepine is obtained as an oil. The free base formed is dissolved in acetone and treated with maleic acid. The 5-(4-methyl-1-homopiperazinyl)-UH-imidazole[1,2-c][1,3jbenzo-diazepine monomaleate with a melting point of 160-163° is obtained. The 5-(4-methyl-1-piperazinyl)-11H-imidazo[1,2-c][1,3]-benzodiazepine monomaleate which has been described in Example 1 can be obtained analogously from 1-[2- (2-imidazolylmethyl)-phenylcarbamoyl]-4-methyl-piperazine.

The starting material is produced as follows:

A solution of 32.4 g of chloroformic acid phenyl ester in 100 ml of acetonitrile is added dropwise under nitrogen and with stirring to a mixture of 34.6 g of 2-(2-aminobenzyl)imidazole and 71 g of triethylamine in 600 ml of acetonitrile at room temperature. After complete addition, the reaction mixture is heated for 12 hours at reflux and after cooling to room temperature, 150 ml of water is added, the reaction mixture is stirred for a further h hour and cooled to 5°. The precipitate formed is filtered off, washed twice with each time 50 ml of water and then 3 times with each time 33 ml of cold acetone and dried. One obtains the 11H-imidazo[1,2-c][1,3]benzodiazepine-5(6H)-one which melts at 255-257°.

If desired, 0.75 g of 1,1'-carbonyldiimidazole can also be added all at once to a suspension of 0.79 g of 2-(2-amino-benzyl)-imidazole in 38 ml of methylene chloride and the mixture stirred overnight at room temperature. The precipitate formed is separated and recrystallized from methylene chloride. The crude 11H-imidazo[1,2-c][1,3]benzodiazepine-5(6H)-one is obtained with a melting point of 238-240°.

In an analogous way, using phosgene as a cyclization agent, the following intermediates can be prepared: a) 2,3-dimethyl-11H-imidazol[1,2-c][1,3]benzodiazepine-5(6H)-one,

b) 8-chloro-11H-imidazo[1,2-c][1,3]benzodiazepine-5(6H)-one,

c) 8-methyl-11H-imidazo[1,2-c][1,3]benzodiazepine-5(6H)-one,

d) 8-methoxy-11H-imidazo[1,2-c][1,3]benzodiazepine-5(6H)-one.

0.41

g of N-methyl-homopiperazine and stirs the mixture for a further 24 hours at room temperature. The reaction mixture is filtered and the resulting filtrate is evaporated in vacuo to dryness. After the recrystallization of the formed residue from a mixture of methylene chloride/diethyl ether, 1-[2-(2-imidazoyl-methyl)-phenylcarbamoyl]-4-methyl-homopiperazine is obtained which melts at a temperature of 139-143°.

In an analogous manner, 1-[2-(2-imidazolylmethyl)-phenylcarbamoyl]-4-methylpiperazine with a melting point of 172-174° is obtained from 1-methyl-piperazine.

The following compounds are prepared in an analogous manner, as described above: a) 1-[2-(4,5-dimethyl-2-imidazoylmethyl)-phenylcarbamoyl]-4-methyl-piperazine and b) 1-[2-(2 -imidazolylmethyl)-5-chlorophenylcarbamoyl]-4-methyl-piperazine .

Example 3

A solution of 2.4 g of 5-thiocyanato-11H-imidazo[1,2-c]-[1,3Jbenzodiazepine in 5 ml of hexamethylphosphosamide is cooled to -5° and added dropwise with active stirring and under nitrogen 2.1 g 1-methyl-piperazine over a period of 5 minutes. Stirring at -5° was further continued

10 minutes and then after the removal of the cooling bath is further stirred for 10 minutes. The reaction mixture is diluted with 100 ml of ethyl acetate, washed twice with sodium hydroxide solution, dried over magnesium sulfate and evaporated in vacuo to dryness. To the residue is added a solution of 1.2 g of maleic acid in 3 ml of acetone and diluted with diethyl ether, whereby the unpurified 5-(4-methyl-1-piperazinyl)-11H-imidazo[1,2-c ] -

[1,3]benzodiazepine monomaleate precipitates crystalline, melting point 183-186°. After recrystallization from ethanol, as described in example 1), the purified product with a melting point of 204-205° is obtained (decomposition). The starting material is prepared as follows: A suspension of 1.44 g of 50% sodium hydride in mineral oil and 100 ml of dry tetrahydrofuran is added portionwise with 6.45 g of 11H-imidazo[1,2-c][1,3]benzodiazepine- 5(6H)-thione. The addition takes place with stirring in a nitrogen atmosphere

during a time interval of 2 minutes. The reaction mixture is further stirred for 1% hour at room temperature. The white suspension formed is cooled to 0° and the solution is added dropwise with 3.5 g of cyanogen bromide in 10 ml of tetrahydrofuran. The reaction mixture is stirred for half an hour at room temperature and then evaporated in vacuo at 45°. The residue is dissolved in methylene chloride, the formed

solution is washed with water, dried over magnesium sulfate, decolorized with activated charcoal and evaporated in vacuo to a smaller volume. The 5-thiocyanato-11H-imidazo[1,2-c]-[1,3jbenzodiazepine is obtained, melting point 111-113°, crystalline by diluting the solution with diethyl ether.

Example 4

To a solution cooled at 0° of 8.9 g of 1-[2-(2-imidazolyl-methyl)-phenylthiocarbamoyl]-4-ethoxycarbonyl-piperazine in 70 ml of acetonitrile is added 2.4 g of solid potassium carbonate (pot ash) while stirring , followed by the dropwise addition of a solution of 2.5 g of cyanogen bromide in 10 ml of acetonitrile.

The reaction mixture is allowed to warm overnight to room temperature, the solid components are filtered off, these are washed out with ethyl acetate and the combined filtrates are evaporated in vacuo to dryness. The residue is dissolved in methylene chloride, the resulting solution is washed with water, dried over magnesium sulfate, decolorized with activated carbon and evaporated in vacuo. The resulting residue is purified chromatographically over 250 g of silica gel, whereby the solvent mixture ethyl acetate/methanol (9:1) is used as eluent.

The purified 5-(4-ethoxycarbonyl-1-piperazinyl)-11H-imidazole[1,2-c][1,3Jbenzodiazepine with a melting point of 137-139° is obtained.

The output connection is produced as follows:

A solution of 20 g of 1-ethoxycarbonylpiperazine in 400 ml of dry tetrahydrofuran is cooled to -65° and added dropwise with" 61.5 ml of a 2.1 molar solution of n-butyllithium in hexane over a period of 15 minutes. The reaction mixture becomes stirred for 15 minutes and added dropwise to a solution of 16.44 ml of chlorotrimethylsilane in 68 ml of tetrahydrofuran over 15 minutes. The mixture is allowed to warm overnight to room temperature and then evaporated in vacuo to dryness. Diethyl ether is added to the residue, which is filtered off the solid constituents and evaporate the filtrate in vacuo to dryness. The residue formed is distilled. The 1-ethoxycarbonyl-4-trimethylsilylpiperazine is obtained, boiling point 102-107°/0.1 mm Hg.

To a solution of 4.66 ml of an 85% thiophosgene in 200 ml of diethyl ether cooled at -76°, a solution of 7 g of 1-ethoxycarbonyl-4-trimethylsilylpiperazine in 37 ml of diethyl ether is added with stirring in a nitrogen atmosphere over a period of time of 20 minutes. The reaction mixture is allowed to warm overnight to room temperature. The suspension is filtered and the filtrate is evaporated to dryness. The residue is recrystallized from a solution mixture of methylene chloride/hexane. The 4-ethoxycarbonyl-1-piperazinyl-thiocarbonyl chloride with a melting point of 107-110° is obtained.

A solution of 5.5 g of 4-ethoxycarbonyl-1-piperazinyl-thiocarbonyl chloride is added dropwise to a suspension of 3.8 g of 2-(2-aminobenzyl)-imidazole in 38 ml of tetrahydrofuran and 3.23 ml of triethylamine in 10 ml of methylene chloride at room temperature. The reaction mixture is stirred for a week and the resulting suspension is filtered. The filtrate is first washed with a 10% aqueous potassium carbonate solution (pot ash), then with water, dried and then evaporated to dryness. The amorphous 1-[2-(2-imidazolyl-methyl)-phenylthiocarbamoyl]-4-ethoxycarbonylpiperazine is obtained, which is characterized on the basis of NMR spectra.

Example 5

According to the methods illustrated in the examples given above, the following compounds of formula I, especially of formula II, are also obtained starting from equivalent amounts of corresponding starting materials. R^ and R^ are hydrogen and the group ^nH2n^ is ethylene.

Example 6

A mixture of 315 mg of 1-[2-(2-imidazolylmethyl)-phenylthio-carbamoyl]-4-methylpiperazine, 3.3 ml of diethylformamide, 276 mg of potassium carbonate (pot ash), 116 mg of cyanogen bromide and 50 mg of 8-crown-6- ether is stirred for 3 hours under nitrogen at room temperature. 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-Methyl-1-piperazinyl)-11H-imidazo[1,2-c][1,3]benzodiazepine monomaleate is obtained. The product is identical to that produced in example 1.

The starting material is produced as follows:

A mixture of 2.1 g of 11H-imidazo[1,2-c][1,3jbenzodiazepine-5(6H)-thione, 23 ml of methylene chloride and 1.0 g of 1-methylpiperazine is stirred for 15 hours at room temperature. The crystalline product formed is filtered off and washed with methylene chloride. 1-[2-(2-imidazolylmethyl)-phenylthiocarbamoyl]-4-methyl-piperazine is obtained.

Example 7

A mixture of 9.5 g of 5-methylthio-11H-imidazo[1,2-c][1,3]-benzodiazepine hydrochloride, 3.62 g of piperazine and 350 ml of amyl alcohol is heated for 20 hours with stirring in a nitrogen atmosphere at backflow. The solvent is removed under vacuum, the residue formed is titrated with methylene chloride, washed with 2-normal aqueous sodium hydroxide solution, dried over magnesium sulfate and evaporated to dryness. The residue is dissolved in 10 ml of methanol and treated with 2-normal ethereal hydrochloric acid. 5-(4H-1-piperazinyl)-11H-imidazo[1,2-c][1,3]benzodiazepine dihydrochloride is obtained.

Example 8

To a solution of 0.2 g of 5-(4-carboethoxy-1-piperazinyl)-11H-imidazo[1,2-c][1,3jbenzodiazepine in 2 ml of dry tetrahydrofuran is added at once 100 mg of lithium aluminum hydride and under nitrogen the reaction mixture is heated to reflux. The mixture is allowed to cool to room temperature, stirred after adding 0.2 ml of a 30% aqueous sodium hydroxide solution and filtered. The filtrate is evaporated to dryness and the product formed is purified. 5-(4-methyl-1-piperazinyl)-11H-imidazo[1,2-c][1,3jbenzo-diazepine is obtained, which is identical to that prepared in example 1. Melting point 123-124°.

Example 9

To a solution of 82 mg of 5-(4-methyl-1-piperazinyl)-11H-imidazo[1,2-c][1,3]benzodiazepine in 1 ml of methylene chloride is added 74 mg of m-chloroperbenzoic acid at 0°. The mixture is stirred at 0° overnight, then diluted with 1 ml of diethyl ether, an equivalent of an ethereal hydrochloric acid solution (hydrochloric acid solution) is added and the precipitate formed is filtered off. After the recrystallization, 5-(4-methyl-4-oxido-1-piperazinyl)-11H-imidazo[1,2-c][1,3]benzo-diazepine-hydrochlorid is obtained.

Example 10

To a solution of 100 ml of 5-(4-benzyloxycarbonyl-1-piperazinyl)-11H-imidazo[1,2-c][1,3jbenzodiazepine in 0.3 ml of acetic acid is added 0.35 ml of 2-normal solution of hydrogen bromide in acetic acid. The mixture is heated for one hour at 100°

and then stirred overnight at room temperature. Diethyl ether is added, whereby the 5-(4H-1-piperazinyl)-11H-imidazo[1,2-c][1,3]benzodiazepine hydrobromide is precipitated.

The starting material is obtained in an analogous manner as described under example 4, replacing 1-ethoxycarbonylpiperazine with the equivalent amount of 1-benzyloxycarbonylpiperazine.

Example 11

A mixture of 265 mg of 5-(4H-1-piperazinyl)-11H-imidazo-[1,2-c][1,3jbenzodiazepine, 0.5 g of potassium carbonate, 0.142 g of methyl iodide and 2 ml of acetone is stirred overnight at room temperature. and then evaporated. Water is added to the residue and the mixture is extracted with methylene chloride. The combined extracts are dried over magnesium sulfate, evaporated and, after purification, 5-(4-methyl-1-piperazinyl)-11H-imidazo[1,2-c][1,3]benzodiazepine is obtained.

Example 12

According to the methods illustrated in the examples described above, the following compounds of formula I are also obtained, starting from equivalent amounts of corresponding starting substances. The substituents Rj- to R7 mean hydrogen:

Example 13

Production of 10,000 tablets each containing 25 mg of the active substance:

Ingredients:

Approach:

All powdered components are sieved with a sieve with a mesh size of 0.6 mm. The active ingredient is then mixed with milk sugar, talc, magnesium stearate and half of the starch in a suitable mixer. The other half of the starch is suspended in 40 ml of water and the suspension is added to the boiling solution of polyethylene glycol in 150 ml of water. The resulting paste is added to the powder and optionally granulated after adding a further amount of water. The granulate is dried overnight at 35°, passed through a sieve of 1.2 mm mesh and pressed into tablets of 6.4 mm diameter, which contain a fracture slit.

Example 14

Production of 10,000 capsules with a content of 50 each

mg of the active substance:

Ingredients:

Approach:

All powdered components are sieved with a sieve with a mesh size of 0.6 mm. The active ingredient is then first homogenized with talc and then with milk sugar in a suitable mixer. Capsule No. 34 is filled with each 200 mg of the mixture using a filling machine.

In an analogous way or as described above is produced

tablets or capsules of other compounds according to the invention, e.g. such as in the further examples illustrated here.

Example 15

A mixture of 10 g of 1-[2-(4-methyl-2-imidazolylmethyl)-phenyl-carbamoyl]-4-methylpiperazine, 86 ml of phosphorus oxychloride and 7.24 g of phosphorus pentachloride is stirred for 4 hours at room temperature and then evaporated to dryness. The residue is suspended in 186 ml of methylene chloride, the suspension is cooled to 0°. and 55.2 ml of triethylamine is added dropwise over a period of 15 minutes. The resulting mixture is stirred overnight at room temperature, poured into cold water that has been made basic with 10% aqueous sodium hydroxide solution and extracted with methylene chloride. The methylene chloride extracts are further extracted with 2-normal hydrochloric acid. The acidic extracts are made basic with 2-normal aqueous sodium hydroxide solution and extracted 3 times with methylene chloride. The organic extracts are dried over magnesium sulfate, decolorized with activated charcoal and evaporated to dryness. The residue is purified chromatographically over 180 g of silica gel using a solution mixture of methylene chloride/methanol/aqueous ammonia solution/(300:50:1) as eluent. You get a foam-like light product that is dissolved in acetone and added with the equivalent amount of maleic acid.

Dilution with diethyl ether gives the 2-methyl-5-(4-methyl-piperazinyl)-11H-imidazo[1,2-c][1,3]benzodiazepine monomaleate with a melting point of 195-197°.

The new starting materials are produced as follows:

A solution of ethanolic sodium alcoholate solution, prepared by dissolving 4.48 g of metallic sodium in 112 ml of absolute ethanol, is added dropwise to a suspension of 47.84 g of ethyl 2-(2-nitrophenyl)-acetamidate hydrochloride in 224 ml of ethanol and the mixture is stirred for one hour at room temperature. The sodium chloride that forms is filtered off, and 22.82 g of the ethylene ketal of 1-amino-2-propanone is added to the filtrate and the mixture is stirred overnight at room temperature. The insoluble precipitate is separated and the filtrate is evaporated in vacuo to dryness. The residue formed is dissolved in 470 ml conc. hydrochloric acid and the solution is heated for one hour at reflux. The mixture is washed once with diethyl ether, made basic with 2-N aqueous sodium hydroxide solution and then extracted 3 times with ethyl acetate. The extracts are dried over magnesium sulfate, decolorized with activated charcoal and evaporated. The residue formed is recrystallized from a mixture of methylene chloride/ether. 4-methyl-2-(2-nitrobenzyl)-imidazole is obtained with a melting point of 125-128°.

A mixture of 23.44 g of 4-methyl-2-(2-nitrobenzyl)-imidazole, 2.34 g of a 10% palladium-on-charcoal catalyst and 234 ml of ethanol is hydrated for 4 hours at room temperature and 3 atmospheres (42 psi). The catalyst is filtered off and the resulting filtrate is evaporated to dryness. The 4-methyl-2-(2-aminobenzyl)imidazole is obtained, which exhibits the following signals in the NMR spectrum: 62.09, 3.78 and 6.08.

A mixture of 18.61 g of 4-methyl-2-(2-aminobenzyl)-imidazole, 16.12 g of 1,1'-carbonyldiimidazole and 375 ml of methylene chloride is stirred at room temperature overnight. The methylene chloride of the reaction mixture is evaporated to a smaller volume and the remaining mixture is cooled to 0°. The precipitated solids remain. filtered off and washed with diethyl ether. 2-Methyl-11H-imidazol[1,2-c][1,3]benzo-diazepin-5(6H)-one is obtained with a melting point of 234.5-236.5°.

A mixture of 16 g of 2-methyl-11H-imidazo[1,2-c][1,3]benzo-diazepin-5(6H)-one, 9.68 g of N-methylpiperazine and 160 ml of methylene chloride is stirred overnight at room temperature. The reaction mixture is decolorized over activated carbon and evaporated in a vacuum. The residue is recrystallized from methanol/diethyl ether, whereby 1-[2-(4-methyl-2-imidazolyl-methyl)-phenylcarbamoyl]-4-methylpiperazine with a melting point of 177-179° is obtained.

Example 16

To a solution of 5-(4-methyl-1-piperazinyl)-11H-imidazo-[1,2-c][1,3Jbenzodiazepine in 50 ml of methylene chloride is added divided in portions 3.75 g of m-chloroperbenzoic acid while stirring at a temperature of 0°. The mixture is stirred overnight at room temperature and evaporated to dryness. The foamy residue formed is passed through an ion exchanger containing 100 g of "Amberlite-IRA-400" ion exchange resin, whereby water is used as eluent. After evaporation of the eluent (water), 5-(4-methyl-4-oxido-1-piperazinyl)-11H-imidazo[1,2-c][1,3jbenzodiazepine is obtained with a foam-like consistency which has an Rf value of 0.173 on plates coated with silica gel, whereby a mixture of methylene chloride/methanol/aqueous ammonia (150:50:1) is used as eluent. The manufactured product is identical to the product manufactured in example 9.

Example 17

A mixture of 8.67 g of 5-methylthio-11H-imidazo[1,2-c][1,3]-benzodiazepine, 3.38 g of piperazine and 326 ml of amyl alcohol is heated for 6 days at reflux under nitrogen and then evaporated in vacuum to dryness. The residue is dissolved in methylene chloride and the solution is successively washed with a 10% aqueous potassium carbonate solution and caustic soda, dried over magnesium sulfate, decolorized with activated charcoal and evaporated to dryness. The residue is purified chromatographically over 300 g of silica gel using methylene chloride/methanol/aqueous ammonia (150:50:1) as eluent, whereby 5-(4H-1-piperazinyl)-11H-imidazo[1,2-c][ 1,3]-benzodiazepine as an oil. The oil formed is treated with 2.74 g of maleic acid in acetone and 5-(4H-1-piperazinyl)-11H-imidazo[1,2-c][1,3]benzodiazepine bismaleate is obtained,

which melts at 171.5-173.5°.

Example 18

A mixture of 0.2 g of 5-(4-ethoxycarbonyl-1-piperazinyl)-11H-imidazo[1,2-c][1,3jbenzodiazepine, 10 ml of tetrahydrofuran and 50 mg of lithium aluminum hydride is heated overnight with stirring at reflux. The resulting reaction mixture is cooled to 0° and the excess of the lithium aluminum hydride is destroyed by the addition of ethyl acetate. The reaction mixture is then poured into cold water and extracted with ethyl acetate. The combined extracts are dried and evaporated to dryness, whereby after purification (see Example 1) 5-(4-methyl-1-piperazinyl)-11H-imidazo[1,2-c][1,3Jbenzodiazepine is obtained which is identical to the manufactured product in example 1.

Example 19

A mixture of 0.1 g of 5-(4H-piperazinyl)-11H-imidazo[1,2-c]-[1,3jbenzodiazepine, 0.058 g of methyl iodide, 0.16 g of potassium carbonate and 1 ml of dimethylformamide is stirred overnight at room temperature. . The reaction mixture is poured into cold water and then the solvent is extracted 3 times with ethyl acetate. The combined extracts are washed with soda ash, dried and evaporated in vacuo, whereby after purification (see example 1) 5-(4-methyl-1-piperazinyl)-11H-imidazo-, [1,2-c][1 ,3] the benzodiazepine which is identical to the manufactured product in example 1.

Avoidance reactions in rats

In the test procedure described above, a selection of the new compounds gives the following values.

The reduction of avoidance reactions shows the neuroleptic effect which indicates an increase in the number of wrong behaviours.

Claims (1)

1. Process for the preparation of new 5-diaza-cycloalkylimidazo[1,2-cJ[1,3]benzodiazepines of the general formula I wherein each of the symbols R, and R2 means hydrogen, lower alkyl, lower alkanoyl, halogen, cyan, carboxy, lower alkoxycarbonyl, carbamoyl, sulfamoyl, mono- or di-lower alkyl-(carbamoyl or -sulfamoyl), cn H2n st^r ^or lower_ alkylene which separates the two nitrogen atoms by 2 or '3 carbon atoms and R^ stands for hydrogen, lower alkyl, lower alkenyl, lower alkynyl, lower alkanoyl, aryl lower alkyl, lower alkoxycarbonyl, phenyl lower oxycarbonyl or (hydroxy, lower alkanoyloxy, aryloxy or lower alkoxy)-lower alkyl, in which the lower alkyl residue contains at least 2 carbon atoms , R^ and R,- independently mean hydrogen, lower alkyl, lower alkoxy, lower alkylthio, halogen, trifluoromethyl, hydroxy, lower alkanoyloxy, sulfamoyl, mono- or di-lower alkylsulfamoyl and R^ and R-, mean hydrogen or a lower alkyl, their N-oxides , their quaternary lower alkyl derivatives and salts of these compounds, characterized in that mana) condenses a compound of the formula (III) in which X means a group cleavable together with hydrogen or an alkali metal and the other symbols have the meanings indicated under the formula (I), with a compound of the form fiefdom (IV) or an alkali metal derivative thereof, in which R^ has the meaning given under formula (I), orb) a compound of formula (VI) rings under hydrating, dehydrosulfurizing and deaminating conditions, wherein Z represents an oxygen atom or sulfur atom or NH, and the other symbols have the meanings given above, and, if a compound of formula (I) is desired, wherein R^ represents lower alkyl, introducing into a compound of formula (I), in which R^ is hydrogen or an alkali metal atom, a mentioned residue, and/or if a compound of formula (I) is desired, in which R_. means lower alkyl, reduces a compound in which instead of lower alkyl there is a lower alkenyl or lower alkynyl, this to lower alkyl, and/or, if a compound is desired in which R^ means hydroxy-lower alkyl, reacts a compound in which R-j means hydrogen or an alkali metal atom, with corresponding oxiranes or with reactive esters of mono-esterified lower alkanediols, and/or if a compound is desired, in which R^ means hydroxy-lower alkyl, reacts a formed compound in which R^ stands for hydrogen, first with reactive derivatives of corresponding glycols, glycolic acids or dicarboxylic acids and hydrolyzes or reduces the compounds formed to those in which R^ means hydroxyalkyl, and/or if a compound is desired in which R^ means lower alkoxycarbonyl, in a final product in which R^ means lower alkyl, this transfers in a lower alkoxycarbonyl group, and/or, if a compound is desired in which R^ denotes an acyl residue defined in claim 1, acylates a compound formed in which R^ stands for hydrogen, and/or, if a compound is desired, in which R^ is hydrogen, hydrolyzes a compound formed in which R^ means an acyl residue, and/or if a compound is desired, in which R^ means methyl, in a product formed in which R^ means lower alkoxycarbonyl or phenyllower oxycarbonyl, reduces this residue to methyl, and/or, if a compound is desired, in which R^ and/or R 2 means halogen, halogenates a product formed, in which R^ and /or R 2 means hydrogen, and/or, if a compound is desired, in which R 1 and/or R 2 is carboxy, carbon lower alkyl or a carbamoyl residue mentioned in claim 1, reacts a formed compound in which R, and/or R 2 means hydrogen, with a trihaloacetyl halide and subsequently treated with an alkali metal lower alkoxide, hydroxide or amide, and/or if a compound is desired, in which R 1 and/or R 2 is sulphamoyl, mono- or di-lower alkyl sulphamoyl, reacts a product in which R3_ and/ or R 2 means hydrogen, with a halosulfonic acid and subsequent treatment with ammonia, a mono- or di-lower alkylamine, and/or, if a compound is desired, in which R-^ and/or R^ means cyan, dehydrates a product in which R- ^ and/or R^ stands for carbamoyl, and/or if a compound is desired, in which R-^ and/or R2 is carboxy, hydrolyzes a product in which R^ and/or R^ is cyano, carbalkoxy or carbamoyl, and/ or, if an N-oxide is desired, oxidizes a product in which R^ separates from hydrogen, and/or, if a quaternary lower alkyl derivative is desired, reacts a product in which R^ separates from hydrogen or R^ means hydrogen, with a reactive esterified lower alkanol, and/or, if desired, converts a formed compound of formula (I) into another compound according to the invention, and/or, if desired, transfers a formed free compound into a salt or a formed salt into the free compound or in another salt, and/or, if desired, sep resolves a formed mixture of isomers or racemates into the individual isomers or racemates, and/or, if desired, resolves the formed racemates into the optical antipodes.